FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Hursting, SD Kari, FW AF Hursting, SD Kari, FW TI The anti-carcinogenic effects of dietary restriction: mechanisms and future directions SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Review DE calorie restriction; carcinogenesis; cancer prevention; rodent; apoptosis; immunity; oxidative damage ID GROWTH-FACTOR-I; ALVEOLAR MACROPHAGE FUNCTION; RADIATION-INDUCED TUMORS; DNA EXCISION REPAIR; CALORIC RESTRICTION; FOOD RESTRICTION; SPONTANEOUS TUMORIGENESIS; CELL-PROLIFERATION; P53-DEFICIENT MICE; FISCHER-344 RATS C1 NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. Univ Texas, MD Anderson Canc Ctr, Dept Carcinogenesis, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. RP Kari, FW (reprint author), NIEHS, Lab Environm Carcinogenesis & Mutagenesis, POB 12233, Res Triangle Pk, NC 27709 USA. NR 121 TC 48 Z9 50 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD JUL 15 PY 1999 VL 443 IS 1-2 BP 235 EP 249 DI 10.1016/S1383-5742(99)00021-6 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 221XP UT WOS:000081753100015 PM 10415442 ER PT J AU Dickert, N Grady, C AF Dickert, N Grady, C TI What's the price of a research subject? Approaches to payment for research participation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Dickert, N (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 26 TC 194 Z9 195 U1 0 U2 2 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 JUL 15 PY 1999 VL 341 IS 3 BP 198 EP 203 DI 10.1056/NEJM199907153410312 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 215YV UT WOS:000081413800012 PM 10403861 ER PT J AU Read, JS AF Read, JS TI Mode of delivery and the risk of vertical transmission of HIV-1 - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NICHHD, Bethesda, MD 20892 USA. RP Read, JS (reprint author), NICHHD, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 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 JUL 15 PY 1999 VL 341 IS 3 BP 206 EP 207 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 215YV UT WOS:000081413800016 ER PT J AU Mironov, AA Koonin, EV Roytberg, MA Gelfand, MS AF Mironov, AA Koonin, EV Roytberg, MA Gelfand, MS TI Computer analysis of transcription regulatory patterns in completely sequenced bacterial genomes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ESCHERICHIA-COLI K-12; BINDING-SITES; GENE RECOGNITION; OUTER-MEMBRANE; DNA; EVOLUTION; PROTEINS; REPRESSOR; ALIGNMENT; PNEUMONIAE AB Recognition of transcription regulation sites (operators) is a hard problem in computational molecular biology. In mast cases, small sample site and low degree of sequence conservation preclude the construction of reliable recognition rules. We suggest an approach to this problem based on simultaneous analysis of several related genomes. It appears that as long as a gene coding for a transcription regulator is conserved in the compared bacterial genomes, the regulation of the respective group of genes (regulons) also tends to be maintained. Thus a gene can be confidently predicted to belong to a particular regulon in case not only itself, but also its orthologs in other genomes have candidate operators in the regulatory regions. This provides for a greater sensitivity of operator identification as even relatively weak signals are likely to be functionally relevant when conserved. We use this approach to analyze the purine (PurR), arginine (ArgR) and aromatic amino acid (TrpR and TyrR) regulons of Escherichia coli and Haemophilus influenzae. Candidate binding sites in regulatory regions of the respective H,influenzae genes are identified, a new family of purine transport proteins predicted to belong to the PurR regulon is described, and probable regulation of arginine transport by ArgR is demonstrated. Differences in the regulation of some orthologous genes in E,coli and H.influenzae, in particular the apparent lack of the autoregulation of the purine repressor gene in H.influenzae, are demonstrated. C1 NIIGenet, State Ctr Biotechnol, Moscow 113545, Russia. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Inst Math Problems Biol, Pushchino 142292, Russia. Russian Acad Sci, Inst Prot Res, Pushchino 142292, Russia. RP Gelfand, MS (reprint author), NIIGenet, State Ctr Biotechnol, Moscow 113545, Russia. RI Mironov, Andrey/C-8024-2012; Gelfand, Mikhail/F-3425-2012; Roytberg, Mikhail/O-1299-2013 OI Roytberg, Mikhail/0000-0002-5848-367X NR 49 TC 114 Z9 117 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 15 PY 1999 VL 27 IS 14 BP 2981 EP 2989 DI 10.1093/nar/27.14.2981 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 221WP UT WOS:000081750400022 PM 10390542 ER PT J AU Sheikh, MS Huang, Y Fernandez-Salas, EA El-Deiry, WS Friess, H Amundson, S Yin, J Meltzer, SJ Holbrook, NJ Fornace, AJ AF Sheikh, MS Huang, Y Fernandez-Salas, EA El-Deiry, WS Friess, H Amundson, S Yin, J Meltzer, SJ Holbrook, NJ Fornace, AJ TI The antiapoptotic decoy receptor TRID/TRAIL-R3 is a p53-regulated DNA damage-inducible gene that is overexpressed in primary tumors of the gastrointestinal tract SO ONCOGENE LA English DT Article DE p53; DNA damage; apoptosis ID INDUCED APOPTOSIS; DEATH DOMAIN; FACTOR-ALPHA; P53; TRAIL; IDENTIFICATION; EXPRESSION; KILLER/DR5; PROTEIN; FAMILY AB Both DR4 and DR5 have recently been identified as membrane death receptors that are activated by their ligand TRAIL to engage the intracellular apoptotic machinery. TRID (also named as TRAIL-R3) is an antagonist decoy receptor and lacks the cytoplasmic death domain, TRID protects from TRAIL-induced apoptosis by competing with DR4 and DR5 for binding to TRAIL, TRID has been shown to be overexpressed in normal human tissues but not in malignantly transformed cell lines. DR5 is a p53-regulated gene and me have recently reported that DR5 expression is induced in response to genotoxic stress in both a p53-dependent and independent manner (Sheikh et nl., 1998). In the current study, we demonstrate that TRID gene expression is also induced by the genotoxic agents ionizing radiation and methyl methanesulfonate (MR IS) in predominantly p53 mild-type cells, whereas UV-irradiation does not induce TRID gene expression, Consistent with these results, exogenous wild-type p53 also upregulates the expression of endogenous TRID in p53-null cells. Thus, TRID appears to be a p53 target gene that is regulated by genotoxic stress in a p53-dependent manner. Using primary gastrointestinal tract (GIT) tumors and their matching normal tissue, we also demonstrate for the first time that TRID expression is enhanced in primary tumors of the GIT, It is, therefore, possible that TRID overexpressing GIT tumors may gain a selective growth advantage by escaping from TRAIL-induced apoptosis. C1 NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NIA, Gene Express & Aging Sect, Biol Chem Lab, NIH, Baltimore, MD 21224 USA. NCI, Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Howard Hughes Med Inst, Oncol Mol Lab, Philadelphia, PA 19104 USA. Univ Bern, Inselspital, Dept Visceral & Transplantat Surg, CH-3010 Bern, Switzerland. Univ Maryland, Dept Med, GI Div, Baltimore, MD 21201 USA. Baltimore VA Hosp, Baltimore, MD 21201 USA. RP Sheikh, MS (reprint author), NCI, Div Basic Sci, NIH, Rm 5 C09,Bldg 37, Bethesda, MD 20892 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X FU NCI NIH HHS [CA77057, CA78843]; NIDDK NIH HHS [DK47717] NR 24 TC 114 Z9 116 U1 1 U2 3 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL 15 PY 1999 VL 18 IS 28 BP 4153 EP 4159 DI 10.1038/sj.onc.1202763 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 216FP UT WOS:000081431000013 PM 10435597 ER PT J AU Strausberg, RL Austin, MJF AF Strausberg, RL Austin, MJF TI Functional genomics: technological challenges and opportunities SO PHYSIOLOGICAL GENOMICS LA English DT News Item DE human genome; genomics databases; two-hybrid system; gene expression; DNA arrays; bioinformatics; proteomics; disease ID MASS-SPECTROMETRY; SACCHAROMYCES-CEREVISIAE; POLYACRYLAMIDE GELS; PROTEIN; YEAST; IDENTIFICATION; CANCER; MODEL AB In April, the Merck Genome Research Institute and the National Cancer Institute's Cancer Genome Anatomy Project, both supporters of functional genomics technology development and research, brought together a group of 27 scientists working at the forefront of this new field. Here we report on the presentations, discussions, and outcomes from this highly interactive and stimulating meeting held at the Banbury Center. C1 NCI, NIH, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Strausberg, RL (reprint author), Canc Genome Anat Project, Bldg 31,Rm 11A03,31 Ctr Dr,MSC 2590, Bethesda, MD 20892 USA. NR 22 TC 33 Z9 33 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD JUL 15 PY 1999 VL 1 IS 1 BP 25 EP 32 PG 8 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 316MN UT WOS:000087171300005 PM 11015558 ER PT J AU Albert, PS AF Albert, PS TI Longitudinal data analysis (repeated measures) in clinical trials SO STATISTICS IN MEDICINE LA English DT Review ID GENERALIZED ESTIMATING EQUATIONS; RANDOM-EFFECTS MODELS; MIXED-EFFECTS MODELS; CORRELATED BINARY REGRESSION; UNBALANCED REPEATED-MEASURES; RECURRENT EVENT RESPONSES; QUASI-LIKELIHOOD APPROACH; DIAGNOSTIC ERROR RATES; LINEAR-MODELS; MISSING DATA AB Longitudinal data is often collected in clinical trials to examine the effect of treatment on the disease process over time. This paper reviews and summarizes much of the methodological research on longitudinal data analysis from the perspective of clinical trials. We discuss methodology for analysing Gaussian and discrete longitudinal data and show how these methods can be applied to clinical trials data. We illustrate these methods with five examples of clinical trials with longitudinal outcomes. We also discuss issues of particular concern in clinical trials including sequential monitoring and adjustments for missing data. A review of current software for analysing longitudinal data is also provided. Published in 1999 by John Wiley & Sons, Ltd. This article is a US Government work;Ind is the public domain in the United States. C1 NCI, Biometr Res Branch, CTEP, Bethesda, MD 20892 USA. RP Albert, PS (reprint author), NCI, Biometr Res Branch, CTEP, DCTDC Execut Plaza N,6130 Execut Blvd,MSC 7434, Bethesda, MD 20892 USA. NR 130 TC 94 Z9 96 U1 2 U2 29 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 JUL 15 PY 1999 VL 18 IS 13 BP 1707 EP 1732 DI 10.1002/(SICI)1097-0258(19990715)18:13<1707::AID-SIM138>3.0.CO;2-H PG 26 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 214JU UT WOS:000081325500010 PM 10407239 ER PT J AU Hotchkiss, CE Hall, PD Cline, JM Willingham, MC Kreitman, RJ Gardin, J Latimer, A Ramage, J Feely, T DeLatte, S Tagge, EP Frankel, AE AF Hotchkiss, CE Hall, PD Cline, JM Willingham, MC Kreitman, RJ Gardin, J Latimer, A Ramage, J Feely, T DeLatte, S Tagge, EP Frankel, AE TI Toxicology and pharmacokinetics of DTGM, a fusion toxin consisting of a truncated diphtheria toxin (DT388) linked to human granulocyte-macrophage colony-stimulating factor, in cynomolgus monkeys SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE diphtheria toxin; fusion toxin; acute myeloid leukemia; GM-CSF ID ACUTE MYELOID-LEUKEMIA; A CHAIN IMMUNOTOXIN; FACTOR GM-CSF; CELL LYMPHOMAS; PHASE-I; THERAPY; PROTEIN; PROGENITORS; MODULATION; RECEPTORS AB We developed a fusion toxin consisting of the catalytic and translocation domains of diphtheria toxin linked to human granulocyte-macrophage colony-stimulating factor (GM-CSF) (DTGM) for the treatment of patients with acute myeloid leukemia (AML), Our goal in this study was to determine the toxicity and pharmacokinetics of DTGM in cynomolgus monkeys (Macacca fascicularis), which possess cross-reactive GM-CSF receptors. Four groups of young adult monkeys (6 males and 12 females) were treated with five daily bolus iv infusions of 1, 5, 7.5, and 10 mu g/kg DTGM. Monkeys (2 males and 2 females) treated at 1 mu g/kg/day showed no significant side effects. Monkeys (2 males and 2 females) treated at 5 mu g/kg/day showed Grade 1-2 thrombopenia (NCI common toxicity criteria) on day 9. In contrast, monkeys (6 females) treated at 7.5 mu g/kg/day developed Grade 3 neutropenia, Grade 1-2 thrombopenia, Grade 1-3 anemia, and Grade 1-3 hypoalbuminemia. The neutropenia developed by day 4 in the 7.5 mu g/kg/day monkeys and by day 3 or 5 in the 10 mu g/kg/day monkeys and resolved in both groups by day 9, but the thrombopenia, anemia, and hypoalbuminemia persisted until day 16. Monkeys (2 male and 2 female) treated with 10 mu g/kg/day showed Grade 4 neutropenia that resolved by day 8 and Grade 2-3 anemia, hypoalbuminemia, and thrombopenia. Three of the animals developed sepsis, DTGM plasma half-life was 30 min with a peak concentration of 0.1 mu g/mL or 2 nM (1000-fold higher than the IC50 in vitro for AML blasts). Immune responses were minimal in all animals tested at 14 and 28 days with anti-DTGM levels <1 mu g/mL. All four animals at 10 mu g/kg died or were euthanized, and necropsies were performed. Animals necropsied on days 4 and 6 showed marked apoptasis and hypoplasia in the marrow, which was completely resolved for animals necropsied on day 9. No injury to other organs, including kidney, heart, liver, central nervous system, or lung, was seen. The drug was selectively toxic to malignant or differentiated myeloid cells with little toxicity to myeloid progenitors or other organs. Minimal effects in nontarget tissues make DTGM a promising candidate chemotherapeutic agent. (C) 1999 Academic Press. C1 Wake Forest Univ, Sch Med, Dept Canc Biol, Winston Salem, NC 27157 USA. Wake Forest Univ, Sch Med, Dept Pathol, Winston Salem, NC 27157 USA. Med Univ S Carolina, Coll Pharm, Charleston, SC 29425 USA. NCI, Mol Biol Lab, NIH, Bethesda, MD USA. RP Frankel, AE (reprint author), Wake Forest Univ, Sch Med, Dept Canc Biol, Hanes 4046, Winston Salem, NC 27157 USA. FU PHS HHS [R0176738] NR 30 TC 21 Z9 22 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUL 15 PY 1999 VL 158 IS 2 BP 152 EP 160 DI 10.1006/taap.1999.8691 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 220JJ UT WOS:000081661600008 PM 10406930 ER PT J AU Yu, W Sipowicz, MA Haines, DC Birely, L Diwan, BA Riggs, CW Kasprzak, KS Anderson, LM AF Yu, W Sipowicz, MA Haines, DC Birely, L Diwan, BA Riggs, CW Kasprzak, KS Anderson, LM TI Preconception urethane or chromium(III) treatment of male mice: Multiple neoplastic and non-neoplastic changes in offspring SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article ID PATERNAL X-IRRADIATION; ATOMIC-BOMB SURVIVORS; LUNG-TUMOR INDUCTION; CHILDHOOD-CANCER; RAS PROTOONCOGENE; HARDERIAN-GLAND; TRANSGENIC MICE; INFANT LEUKEMIA; LIFE-SPAN; EXPOSURE AB Increase in neoplasia in offspring after preconception exposure of parents presents puzzling features such as high frequency of effects and lack of Mendelian inheritance. The present study examined the hypothesis that preconception carcinogenesis involves an increase in the rate of occurrence of neoplasms with a spontaneous incidence. Male NIH Swiss mice (12 per group) were exposed 2 weeks before mating (once, ip) to urethane (1.5 g/kg) or chromium(III) chloride (1 mmol/kg). Offspring (48-78/sex/group) were examined for all grossly apparent changes when moribund or at natural death, followed by histopathological diagnosis and statistical analysis. Significant exposure-related changes occurred in multiple organs. Ten to 20 percent of offspring showed changes related to paternal exposure, including at least one sired by most treated males. Pheochromocytomas occurred in both male: and female offspring after both treatments, with none in controls. These neoplasms are rare in mice and suggest endocrine dysfunction as a component of preconception carcinogenesis. This was supported by increases in thyroid follicular cell and Harderian gland tumors, ovarian cysts, and uterine abnormalities. Lung tumors were increased in female offspring only. Effects seen in offspring only after paternal urethane exposure were an increase in preneoplasia/neoplasia in the glandular stomach (males) and in females, increased lymphoma but decreased incidence of histiocytic sarcoma. Increases in incidence of male reproductive gland tumors and of renal non-neoplastic lesions occurred only after chromium exposure. Thus, preconception exposure of fathers to toxicants had a significant impact on both neoplastic and nonneoplastic changes in almost all tissues in which these lesions often occur naturally during the aging process. (C) 1999 Academic Press. C1 NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Data Management Serv Inc, Frederick, MD 21702 USA. RP Anderson, LM (reprint author), NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Comparat Carcinogenesis Lab, Bldg 538,Rm 205E, Frederick, MD 21702 USA. EM andersol@mail.ncifcrf.gov NR 73 TC 39 Z9 39 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUL 15 PY 1999 VL 158 IS 2 BP 161 EP 176 DI 10.1006/taap.1999.8692 PG 16 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 220JJ UT WOS:000081661600009 PM 10406931 ER PT J AU Fantin, VR Keller, SR Lienhard, GE Wang, LM AF Fantin, VR Keller, SR Lienhard, GE Wang, LM TI Insulin receptor substrate 4 supports insulin and interleukin 4-stimulated proliferation of hematopoietic cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID TYROSINE PHOSPHORYLATION; PHOSPHOTYROSINE PROTEIN; LIGAND-BINDING; IRS-1; ASSOCIATION; ADIPOCYTES; MEMBER; FAMILY; DOMAIN AB Signaling: from the activated insulin receptor is initiated by its tyrosine phosphorylation of the insulin receptor substrates (IRSs). The IRSs then act as docking/effector proteins for various signaling proteins containing src homology 2 domains. Four members of the IBS family, designated IRS-1 through IRS-4, have been identified. Although these IRSs show considerable structural homology, the extent to which they overlap in functions has not been explored in detail. The 32D hematopoietic cell line, which contains no detectable amounts of any IRS, provides a system in which to determine whether an IRS supports cell proliferation. Previous studies have shown that introduction of IRS-1 or -2 into 32D cells overexpressing the insulin and IL-4 receptors (32D-R cells) enables the cells to undergo mitogenesis in response do insulin and IL-4, In the present study, we have examined IRS-4, a member of the IRS family that we recently discovered, in this system. Expression of IRS-4 in 32D-R cells permitted the cells to undergo mitogenesis and continuous proliferation in response to insulin and IL-4. Immunoblotting of phosphotyrosine proteins showed that insulin and IL-4 elicited the tyrosine phosphorylation of IRS-4 in these cells. Thus, IRS-4,like IRS-1 and -2, can function in the signal transduction pathways linking insulin and IL-4 receptors to cell proliferation. (C) 1999 Academic Press. C1 Dartmouth Med Sch, Dept Biochem, Hanover, NH 03755 USA. NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. RP Lienhard, GE (reprint author), Dartmouth Med Sch, Dept Biochem, Hanover, NH 03755 USA. FU NIDDK NIH HHS [DK42816] NR 28 TC 17 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 14 PY 1999 VL 260 IS 3 BP 718 EP 723 DI 10.1006/bbrc.1999.0967 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 217MN UT WOS:000081503700025 PM 10403832 ER PT J AU Erzouki, HK Goldberg, SR Schindler, CW AF Erzouki, HK Goldberg, SR Schindler, CW TI Comparison of cocaine and Na+ channel blockers on cardio-respiratory function in the rabbit SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE cocaine; lidocaine; flecainide; heart rate; blood pressure; ECG ID SYMPATHETIC NEURAL ACTIVITY; CENTRAL-NERVOUS-SYSTEM; SODIUM-CHANNELS; ANESTHETIZED RATS; ABNORMALITIES; BICARBONATE; MECHANISMS; LIDOCAINE; HUMANS; DRUGS AB The cardio-respiratory effects of cocaine were compared to various Na+ channel blocking Class I antiarrhythmics. Anesthetized rabbits were treated with various doses of either cocaine, quinidine, procainamide, lidocaine or flecainide. Cocaine produced clear decreases in blood pressure and heart rate. None of the other sodium channel blockers produced any change in blood pressure, and heart rate was decreased only slightly by procainamide and lidocaine. Cocaine produced larger increases in QRS duration than were observed for the four sodium channel blockers. All five drugs produced comparable increases in respiratory rate. Separate rabbits were pretreated with either the alpha-adrenoceptor antagonist phentolamine or the beta-adrenoceptor antagonist propranolol prior to cocaine. Phentolamine attenuated the blood pressure decrease following cocaine and propranolol attenuated the heart rate decrease following cocaine. These results suggest that the sodium channel blocking properties contribute only minimally to the overall effects of cocaine on blood pressure and heart rate. Further, the large effect of cocaine on QRS duration suggests that cocaine may act at sodium channels in a manner different from the other drugs. This unique effect of cocaine may contribute to the sudden death associated with cocaine use in some individuals. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, NIH,Intramural Res Program, Baltimore, MD 21224 USA. RP Schindler, CW (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, NIH,Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 25 TC 0 Z9 0 U1 1 U2 2 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 JUL 14 PY 1999 VL 377 IS 1 BP 51 EP 56 DI 10.1016/S0014-2999(99)00411-2 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 219PB UT WOS:000081614700007 PM 10448925 ER PT J AU Clore, GM Starich, MR Bewley, CA Cai, ML Kuszewski, J AF Clore, GM Starich, MR Bewley, CA Cai, ML Kuszewski, J TI Impact of residual dipolar couplings on the accuracy of NMR structures determined from a minimal number of NOE restraints SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID IMMUNOGLOBULIN-BINDING DOMAIN; STREPTOCOCCAL PROTEIN-G; MULTIDIMENSIONAL NMR; REFINEMENT; DYNAMICS C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 21 TC 106 Z9 110 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUL 14 PY 1999 VL 121 IS 27 BP 6513 EP 6514 DI 10.1021/ja991143s PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 219QJ UT WOS:000081617900027 ER PT J AU Xu, ASL Macdonald, JM Labotka, RJ London, RE AF Xu, ASL Macdonald, JM Labotka, RJ London, RE TI NMR study of the sites of human hemoglobin acetylated by aspirin SO BIOCHIMICA ET BIOPHYSICA ACTA-PROTEIN STRUCTURE AND MOLECULAR ENZYMOLOGY LA English DT Article DE hemoglobin; aspirin; nuclear magnetic resonance; protein acetylation ID SICKLE-CELL HEMOGLOBIN; N-ACETYLIMIDAZOLE; GROWTH-HORMONE; SIDE-CHAINS; PHOSPHATE; BINDING; OXYGENATION; SUBUNITS; ALPHA; AGENT AB Acetylation of hemoglobin by aspirin and other acetylating agents has been used to generate hemoglobin analogs with altered structural and functional properties, and may prove useful in the treatment of sickle cell disease. We have studied the acetylation of human hemoglobin using [1'-C-13]acetylsalicylic acid in combination with two-dimensional HMQC and HSQC NMR analysis. The spectra of the acetylated hemoglobin exhibit a number of well resolved resonances. Several spectral assignment strategies were used: blocking the 2,3-DPG binding site non-covalently with inositol hexaphosphate or covalently with a cross-linking agent, selective carbamylation of the N-terminal valine amino groups with cyanate, spin-labeling the hemoglobin at beta Cys93, and analysis of a hemoglobin triple mutant: beta V1MH2 Delta K144R, in which beta Lys144 is replaced by an arginine residue. These studies support the conclusion that the most rapidly acetylated residue is beta Lys82 rather than beta Lys144, as previously reported. Further, it is apparent that acetyl beta Lys82 can give rise to several resonances due to additional acetylation of beta Lys82' or other nearby residues. An additional assignment strategy involving comparison of the chemical shifts of the acetyl resonances observed for adducts of diamagnetic carbonmonoxyhemoglobin with the shifts observed in paramagnetic cyanomethemoglobin provides information about the location of the acetyl derivatives relative to the heme irons. This approach is limited, however, by the lack of well defined structural information for the lysine residues on the protein surface. Additional tentative assignments have also been made, using the above approaches. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Univ Illinois, Dept Pediat, Chicago, IL 60612 USA. RP London, RE (reprint author), NIEHS, Struct Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. FU NHLBI NIH HHS [5RO1 HL57604] NR 40 TC 16 Z9 16 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4838 J9 BBA-PROTEIN STRUCT M JI Biochim. Biophys. Acta-Protein Struct. Molec. Enzym. PD JUL 13 PY 1999 VL 1432 IS 2 BP 333 EP 349 DI 10.1016/S0167-4838(99)00094-1 PG 17 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 218AN UT WOS:000081531300018 PM 10407155 ER PT J AU Blanchet, PJ Fang, J Hyland, K Arnold, LA Mouradian, MM Chase, TN AF Blanchet, PJ Fang, J Hyland, K Arnold, LA Mouradian, MM Chase, TN TI Short-term effects of high-dose 17 beta-estradiol in postmenopausal PD patients - A crossover study SO NEUROLOGY LA English DT Article ID ESTROGEN REPLACEMENT THERAPY; MPTP-TREATED MONKEYS; PARKINSONS-DISEASE; LIQUID-CHROMATOGRAPHY; INDUCED DYSKINESIAS; TREATMENT INCREASES; ALZHEIMERS-DISEASE; DOPAMINE-RECEPTORS; GABA(A) RECEPTORS; BRAIN DOPAMINE AB Objective: To examine the effect of 17 beta-estradiol on the severity of the cardinal signs of PD in postmenopausal women. Background: Although the impact of estrogens on the manifestations of PD has not been subjected to rigorous study, their use is generally thought to be associated with a detrimental antidopaminergic effect. Methods: A double-blind, placebo-controlled, two-arm crossover study of high-dose transdermal 17 beta-estradiol was conducted in eight postmenopausal women with mild to moderate PD, all but one of whom exhibited levodopa-induced dyskinesias. Patients were randomized initially to either hormonal treatment or placebo for 2 weeks, followed by a 2-week washout period, and then another 2-week crossover treatment period. Active treatment employed four skin patches each releasing 0.1 mg of estradiol daily, replaced every 2 to 3 days. Results: After 10 days of treatment a significant reduction was observed in the antiparkinsonian threshold dose of IV levodopa, Mean duration and magnitude of the antiparkinsonian response to threshold or high doses of levodopa were unchanged, and dyskinesia scores were unaltered during 17 beta-estradiol treatment compared with placebo. No worsening in "on" time or motor ratings with estrogen treatment was documented. Conclusions: 17 beta-estradiol appears to display a slight prodopaminergic (or antiparkinsonian) effect without consistently altering dyskinesias. Standard postmenopausal replacement therapy with transdermal 17 beta-estradiol is likely to be well tolerated by many female parkinsonian patients. C1 NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. Baylor Univ, Med Ctr, Kimberly H Courtwright & Joseph W Summers Inst Me, Dallas, TX USA. Univ Texas, SW Med Ctr, Dept Neurol, Dallas, TX 75235 USA. CHUM, Res Ctr, Montreal, PQ, Canada. Vanderbilt Univ, Med Ctr, Nashville, TN USA. RP Chase, TN (reprint author), NINDS, Expt Therapeut Branch, NIH, Bldg 10,Room 5C103,10 Ctr Dr MSC 1406, Bethesda, MD 20892 USA. OI Mouradian, M. Maral/0000-0002-9937-412X NR 33 TC 83 Z9 84 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 13 PY 1999 VL 53 IS 1 BP 91 EP 95 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 214XZ UT WOS:000081354000019 PM 10408542 ER PT J AU Ibanez, V Sadato, N Karp, B Deiber, MP Hallett, M AF Ibanez, V Sadato, N Karp, B Deiber, MP Hallett, M TI Deficient activation of the motor cortical network in patients with writer's cramp SO NEUROLOGY LA English DT Article ID CEREBRAL BLOOD-FLOW; PREMOTOR CORTEX; BASAL GANGLIA; SPASMODIC TORTICOLLIS; IDIOPATHIC DYSTONIA; PRIMATE MOTOR; MOVEMENT; PET; POTENTIALS; INHIBITION AB Objective: To study regional cerebral blood flow (rCBF) in patients with simple writer's cramp using PET to identify regions that malfunction. Background: Several lines of evidence indicate impaired cortical function in patients with focal dystonia, but the precise pathophysiology is still unknown, Methods: Seven patients with writer's cramp were compared with seven age- and sex-matched control subjects. Control subjects and patients were scanned during sustained contraction, tapping, and writing with the right hand. After realignment and stereotactic normalization of the scans, all tasks were compared with a rest condition. For each task, an intra- and intergroup comparison was performed using statistical parametric mapping. For each condition and within groups, rCBF correlation analysis was performed between some selected regions that were activated during movement. Results: In control subjects and patients, significant increases of rCBF were observed for each task in areas already known to be activated in motor paradigms. The intergroup comparison disclosed less activation in writer's cramp patients for several areas for all three tasks. This decrease reached significance for the sensorimotor cortex during the sustained contraction task and for the premotor cortex during writing. rCBF correlation analysis showed different patterns between control subjects and patients. At rest and during writing, the correlations between the putamen and premotor cortical regions and between the premotor cortical regions themselves mere stronger in control subjects. Conclusions: Deficient activation of premotor cortex and decreased correlation between premotor cortical regions and putamen suggest a dysfunction of the premotor cortical network in patients with writer's cramp possibly arising in the basal ganglia. The dysfunction is compatible with a loss of inhibition during the generation of motor commands, which in turn could be responsible for the dystonic movements. C1 NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Div Neuropsychiat, Geneva, Switzerland. CERMEP, INSERM, Lyon, France. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 5N226,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. RI Deiber, Marie-Pierre/M-5949-2014 NR 48 TC 145 Z9 151 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 13 PY 1999 VL 53 IS 1 BP 96 EP 105 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 214XZ UT WOS:000081354000020 PM 10408543 ER PT J AU Coffey, CE Saxton, JA Ratcliff, G Bryan, RN Lucke, JF AF Coffey, CE Saxton, JA Ratcliff, G Bryan, RN Lucke, JF TI Relation of education to brain size in normal aging - Implications for the reserve hypothesis SO NEUROLOGY LA English DT Article ID ALZHEIMERS-DISEASE; CARDIOVASCULAR HEALTH; RESONANCE; ABNORMALITIES; SEX; PREVALENCE; DEMENTIA; IMAGES; LIFE AB Objective: To examine the relations between Education and age-related changes in brain structure in a nonclinical sample of elderly adults. Background: education may protect against cognitive decline in late life-an observation that has led to the "reserve" hypothesis of brain aging. Little is known, however, about the effect of education on age-related changes in brain structure. Methods: Quantitative MRI of the brain was performed in 320 elderly volunteers (age range, 66 to 90 years) living independently in the community (Mini-Mental State Examination scores greater than or equal to 24), all of whom were participants in the Cardiovascular Health Study. Blinded measurements of global and regional brain size were made from T1-weighted axial images using computer-assisted edge detection and trace methodology. High measurement reliabilities were obtained. Results: Regression analyses (adjusting for the effects of intracranial size, sex, age, age-by-sex interactions, and potential confounders) revealed significant main effects of education on peripheral (sulcal) CSF volume-a marker of cortical atrophy. Each year of education was associated with an increase in peripheral CSF volume of 1.77 mt (p < 0.03). As reported previously, main effects of age (but not education) were observed for all of the remaining brain regions examined, including cerebral hemisphere volume, frontal region area, temporoparietal region area, parieto-occipital region area, lateral (Sylvian) fissure volume, lateral ventricular volume, and third ventricle volume. Conclusions: The authors' findings demonstrate a relation between education and age-related cortical atrophy in a nonclinical sample of elderly persons, and are consistent with the reserve hypothesis as well as with a small number of brain imaging studies in patients with dementia. The neurobiological basis and functional correlates of this education effect require additional investigation. C1 Henry Ford Hlth Syst, Dept Psychiat, Detroit, MI 48202 USA. Henry Ford Hlth Syst, Dept Neurol, Detroit, MI 48202 USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. HealthSouth Harmarville Rehabil Hosp, Pittsburgh, PA USA. NIH, Ctr Clin, Dept Radiol, Washington, DC USA. Univ Pittsburgh, Sch Nursing, Pittsburgh, PA 15261 USA. RP Coffey, CE (reprint author), Henry Ford Hlth Syst, Dept Psychiat, 1 Ford Pl, Detroit, MI 48202 USA. RI Bryan, R. Nick/P-1661-2014 FU NIMH NIH HHS [MH 46643] NR 32 TC 129 Z9 131 U1 3 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 13 PY 1999 VL 53 IS 1 BP 189 EP 196 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 214XZ UT WOS:000081354000035 PM 10408558 ER PT J AU Tohda, C Jacobowitz, DM AF Tohda, C Jacobowitz, DM TI The function and expression of sproutin, a novel neurite outgrowth factor SO NEUROREPORT LA English DT Article DE dendrite; microtuble associated proteins; neurite outgrowth; neurofilament-H; sproutin; SK-N-SH cells; transfection ID MICROTUBULE-ASSOCIATED PROTEIN-2; NEURONAL DIFFERENTIATION; GENE-EXPRESSION; TAU; RNA; ADULT; TA20 AB TA20 cDNA was previously cloned as a neurite outgrowth factor from a hybridoma of mouse and rat cells, NG108-15. To clarify the detailed function and tissue distribution of this gene, homologous sequences of rat and mouse were identified. The cloned sequences had no homology with known genes, and was designated as sproutin. A predicted open reading frame of rat sproutin was transfected into human SK-N-SH cells. The over-expressed protein was distributed in cytoplasm and neurites, and caused an increase in the levels of microtuble associated proteins, but not that of phosphorylated neurofilament-H. The percentage of cells with neurites, the length of neurites and the number of neurites per cell were increased by sproutin transfection. Sproutin mRNA was brain specific. These results suggest that an increase in sproutin promotes dendritic extension. NeuroReport 10:2089-2094 (C) 1999 Lippincott Williams & Wilkins. C1 Toyama Med & Pharmaceut Univ, Inst Nat Med, Res Ctr Ethnomed, Toyama 9300194, Japan. NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. RP Tohda, C (reprint author), Toyama Med & Pharmaceut Univ, Inst Nat Med, Res Ctr Ethnomed, 2630 Sugitani, Toyama 9300194, Japan. NR 15 TC 0 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUL 13 PY 1999 VL 10 IS 10 BP 2089 EP 2094 DI 10.1097/00001756-199907130-00018 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 214YB UT WOS:000081354200018 PM 10424680 ER PT J AU Murphy, EL Glynn, SA Fridey, J Smith, JW Sacher, RA Nass, CC Ownby, HE Wright, DJ Nemo, GJ AF Murphy, EL Glynn, SA Fridey, J Smith, JW Sacher, RA Nass, CC Ownby, HE Wright, DJ Nemo, GJ CA Retrovirus Epidemiology Donor Study TI Increased incidence of infectious diseases during prospective follow-up of human T-lymphotropic virus type II- and I-infected blood donors SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID INTRAVENOUS-DRUG-USERS; HEALTHY JAMAICAN CARRIERS; HTLV-I; CELL LEUKEMIA; STRONGYLOIDES-STERCORALIS; RISK; MYELOPATHY; PREVALENCE; ABUSERS; LYMPHADENOPATHY AB Background: To determine whether human T-lymphotropic virus type II (HTLV-II) infection is associated with an increased incidence of bacterial infections, we prospectively observed cohorts of HTLV-I- and HTLV-II-infected and seronegative subjects in 5 US cities. Methods: Of 1340 present and former blood donors examined at enrollment, 1213 (90.5%) were re-examined after approximately 2 years, including 136 HTLV-I- and 337 HTLV-II-seropositive subjects and 740 demographically stratified HTLV-seronegative subjects. All subjects were seronegative for human immunodeficiency virus. Odds ratios (ORs) for incident disease outcomes were adjusted for covariates, including age, sex, race or ethnicity, education, and, if significantly associated with the outcome, blood center, donation type, income, smoking, alcohol intake, and injected drug use. Results: Compared with seronegative status, HTLV-II infection was associated with an increased incidence of bronchitis (OR, 1.81; 95% confidence interval [CI], 1.20-2.75), bladder and/or kidney infection (OR, 1.94; 95% CI, 1.26-2.98), oral herpes infection (OR, 9.54; 95% CI, 3.33-27.32), and a borderline increased incidence of pneumonia (OR, 2.09; 95% CI, 0.92-4.76); HTLV-I infection was associated with an increased incidence of bladder and/or kidney infection (OR, 2.79; 95% CI, 1.63-4.79). One incident case of HTLV-I-positive adult T-cell leukemia was observed (incidence, 348 per 100 000 HTLV-I person-years), and 1 case of HTLV-II-positive tropical spastic paraparesis-HTLV-associated myelopathy was diagnosed (incidence, 140 per 100 000 HTLV-II person-years). Conclusions: These data support an increased incidence of infectious diseases among otherwise healthy HTLV-II- and HTLV-I-infected subjects. They are also consistent with the lymphoproliferative effects of HTLV-I, and with neuropathic effects of HTLV-I and HTLV-II. C1 Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. Westat Inc, Rockville, MD USA. Blood Bank San Bernardino Cty, San Bernardino, CA USA. Oklahoma Blood Inst, Oklahoma City, OK USA. Georgetown Univ Hosp, Dept Lab Med, Washington, DC 20007 USA. Amer Red Cross, Blood Serv Chesapeake Reg, Baltimore, MD USA. Amer Red Cross, Blood Serv SE Michigan, Detroit, MI USA. NHLBI, Bethesda, MD 20892 USA. RP Murphy, EL (reprint author), Univ Calif San Francisco, Dept Lab Med, Campus Box 0884, San Francisco, CA 94143 USA. FU NHLBI NIH HHS [N01-HB-97077]; PHS HHS [N01-97078, N01-47114] NR 42 TC 47 Z9 48 U1 0 U2 2 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 JUL 12 PY 1999 VL 159 IS 13 BP 1485 EP 1491 DI 10.1001/archinte.159.13.1485 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 212PA UT WOS:000081224400012 PM 10399901 ER PT J AU Anton, LC Schubert, U Bacik, I Princiotta, MF Wearsch, PA Gibbs, J Day, PM Realini, C Rechsteiner, MC Bennink, JR Yewdell, JW AF Anton, LC Schubert, U Bacik, I Princiotta, MF Wearsch, PA Gibbs, J Day, PM Realini, C Rechsteiner, MC Bennink, JR Yewdell, JW TI Intracellular localization of proteasomal degradation of a viral antigen SO JOURNAL OF CELL BIOLOGY LA English DT Article DE antigen presentation; molecular chaperone; nuclear proteins proteolysis; ubiquitin/immunology; proteasome ID MHC CLASS-I; ACUTE PROMYELOCYTIC LEUKEMIA; RETINOIC ACID; MONOCLONAL-ANTIBODIES; NUCLEAR-LOCALIZATION; CELLS; PROTEINS; ALPHA; INHIBITORS; EXPRESSION AB To better understand proteasomal degradation of nuclear proteins and viral antigens we studied mutated forms of influenza virus nucleoprotein (NP) that misfold and are rapidly degraded by proteasomes. In the presence of proteasome inhibitors, mutated NP (dNP) accumulates in highly insoluble ubiquitinated and nonubiquitinated species in nuclear substructures known as promyelocytic leukemia oncogenic domains (PODs) and the microtubule organizing center (MTOC). Immunofluorescence revealed that dNP recruits proteasomes and a selective assortment of molecular chaperones to both locales, and that a similar (though less dramatic) effect is induced by proteasome inhibitors in the absence of dNP expression. Biochemical evidence is consistent with the idea that dNP is delivered to PODs/MTOC in the absence of proteasome inhibitors. Restoring proteasome activity while blocking protein synthesis results in disappearance of dNP from PODs and the MTOC and the generation of a major histocompatibility complex class I-bound peptide derived from dNP but not NP. These findings demonstrate that PODs and the MTOC serve as sites of proteasomal degradation of misfolded dNP and probably cellular proteins as well, and imply that antigenic peptides are generated at one or both of these sites. C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. Univ Hamburg, Heinrich Pette Inst, Hamburg, Germany. NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. Univ Utah, Dept Biochem, Salt Lake City, UT 84112 USA. RP Yewdell, JW (reprint author), NIH, Room 213,Bldg 4,4 Ctr Dr, Bethesda, MD 20892 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012; Anton, Luis/C-4740-2013; OI Anton, Luis/0000-0001-9665-011X; Wearsch, Pamela/0000-0002-9569-3852 NR 38 TC 172 Z9 176 U1 0 U2 3 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 JUL 12 PY 1999 VL 146 IS 1 BP 113 EP 124 PG 12 WC Cell Biology SC Cell Biology GA 217QB UT WOS:000081509500009 PM 10402464 ER PT J AU Sunitha, I Shen, RL McKillop, IH Lee, JH Resau, J Avigan, M AF Sunitha, I Shen, RL McKillop, IH Lee, JH Resau, J Avigan, M TI A src-related kinase in the brush border membranes of gastrointestinal cells is regulated by c-met SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE hepatocyte growth factor; c-met; gtk; gastrointestinal cells; brush border membranes ID HEPATOCYTE-GROWTH-FACTOR; SCATTER FACTOR-RECEPTOR; EPITHELIAL-CELLS; IN-VIVO; PHOSPHATIDYLINOSITOL 3-KINASE; TYROSINE KINASE; AMNIOTIC-FLUID; PROTOONCOGENE; EXPRESSION; INDUCTION AB Hepatocyte growth factor (HGF) elicits pleiotropic cellular responses by binding to c-met, a PTK transmembrane receptor. The recent identification of HGF in fluids which enter the gut lumen suggests a mechanism by which c-met molecules are accessible to ligand that is present near the apical surfaces of polarized enterocytes. A subset of c-met molecules was detected, by confocal and immunoelectron microscopic analysis, which colocalizes with a recently identified src-related gastrointestinal tyrosine kinase (gtk) in the brush border membranes of enterocytes. Furthermore, treatment of c-met/gtk-transfected cells with a chemical cross-linking agent revealed that c-met forms a physical complex with gtk, in vivo. Not surprisingly, activation of the receptor molecules with HGF rapidly stimulated gtk enzymatic activity. Similarly, the stimulation of gtk activity occurred when nontransfected primary hepatocytes were exposed to ligand. These findings suggest a model in which HGF binding to luminally accessible c-met stimulates gtk activity. This brush border-associated c-met-linked pathway may be associated with a defined set of epithelial cell responses. (C) 1999 Academic Press. C1 Georgetown Univ, Sch Med, Dept Pathol, Washington, DC 20007 USA. Georgetown Univ, Sch Med, Dept Med, Washington, DC 20007 USA. Georgetown Univ, Sch Med, Dept Surg, Washington, DC 20007 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Analyt Cellular & Mol Microscopy Lab, Frederick, MD 21702 USA. RP Avigan, M (reprint author), Georgetown Univ, Sch Med, Dept Pathol, Basic Sci Bldg,3900 Reservoir Rd NW, Washington, DC 20007 USA. FU NCI NIH HHS [R01 CA75079] NR 47 TC 10 Z9 10 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 JUL 10 PY 1999 VL 250 IS 1 BP 86 EP 98 DI 10.1006/excr.1999.4550 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 217BV UT WOS:000081480400008 PM 10388523 ER PT J AU Malinda, KM Ponce, L Kleinman, HK Shackelton, LM Millis, AJT AF Malinda, KM Ponce, L Kleinman, HK Shackelton, LM Millis, AJT TI Gp38k, a protein synthesized by vascular smooth muscle cells, stimulates directional migration of human umbilical vein endothelial cells SO EXPERIMENTAL CELL RESEARCH LA English DT Article ID OVIDUCT-SPECIFIC GLYCOPROTEIN; HEPARIN-BINDING GLYCOPROTEIN; MOLECULAR-CLONING; SYNOVIAL-CELLS; IDENTIFICATION; EXPRESSION; MEMBER; FAMILY; CHITOTRIOSIDASE; ATHEROSCLEROSIS AB Gp38k is a 383-amino-acid secreted glycoprotein expressed by cultured vascular smooth muscle cells during the time of transition from a proliferating monolayer culture to a nonproliferating multilayered (differentiated) culture. Expression continues as the cell culture forms multicellular nodules, Because this transition period involves active cell migration, we evaluated the effects of exogenously added gp38k on vascular endothelial cell (HUVEC) migration and chemotaxis, Here we demonstrate that gp38k acts as a chemoattractant for HUVECs and stimulates cell migration in Boyden chambers at a level comparable to that achieved with the known endothelial cell chemoattractant bFGF. The migration effect is neutralized by the presence of a polyclonal anti-gp38k antibody. Because gp38k expression is also correlated with changes in culture morphology, we also assessed its ability to act as an agonist of HUVEC morphology using cultures growing on Matrigel. We report that gp38k stimulates endothelial cell tubulogenesis in this assay system. These results provide the first evidence that gp38k may function in angiogenesis by stimulating the migration and reorganization of vascular endothelial cells, (C) 1999 Academic Press. C1 SUNY Albany, Ctr Study Comparat Funct Gen, Dept Sci Biol, Albany, NY 12222 USA. NIDR, Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Millis, AJT (reprint author), SUNY Albany, Ctr Study Comparat Funct Gen, Dept Sci Biol, 1400 Washington Ave, Albany, NY 12222 USA. FU NHLBI NIH HHS [R01-HL40417] NR 32 TC 171 Z9 179 U1 1 U2 4 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 JUL 10 PY 1999 VL 250 IS 1 BP 168 EP 173 DI 10.1006/excr.1999.4511 PG 6 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 217BV UT WOS:000081480400015 PM 10388530 ER PT J AU Maisonneuve, P Agodoa, L Gellert, R Stewart, JH Buccianti, G Lowenfels, AB Wolfe, RA Jones, E Disney, APS Briggs, D McCredie, M Boyle, P AF Maisonneuve, P Agodoa, L Gellert, R Stewart, JH Buccianti, G Lowenfels, AB Wolfe, RA Jones, E Disney, APS Briggs, D McCredie, M Boyle, P TI Cancer in patients on dialysis for end-stage renal disease: an international collaborative study SO LANCET LA English DT Article ID CELL CARCINOMA; TRANSPLANT RECIPIENTS; HEMODIALYSIS-PATIENTS; KIDNEY-DISEASE; INFECTION; RISK; REGISTRY AB Background Previous studies have suggested that the frequency of cancer is higher in patients with end-stage renal disease (ESRD) than in the general population, but have not established whether this increase is confined to certain cancers or to certain categories of ESRD patients. The aim of this study was to examine the risk of cancer in a large cohort of patients treated by dialysis but not transplantation. Methods We assembled a cohort of 831 804 patients who received dialysis during the period 1980-94 for ESRD in the USA, Europe, Australia, or New Zealand. We compared the observed frequency ol: cancer among these patients during 2 045 035 person-years of follow-up with the frequency of cancer in the respective background populations. Findings During average follow-up of 2.5 years, 25 044 (3%) of 831 804 patients developed cancer compared with an expected number of 21 185 (standardised incidence ratio 1.18 [95% CI 1.17-1.20]). We observed a higher risk of cancer in patients younger than 35 years (3.68 [3.39-3.99]), and the risk gradually decreased with increasing age. High risks were observed for cancer of the kidney (3.60 [3.45-3.76]), bladder (1.50 [1.42-1.57]), and thyroid and other endocrine organs (2.28 [2.03-2.54]). Excess cancers appeared in several organs for which viruses have been suspected as causative agents, whereas cancers of the lung, colorectum, prostate. breast, and stomach were not consistently increased. Interpretation The overall risk of cancer is increased in patients with ESRD, and the distribution of tumour types resembles the pattern seen after transplantation (although we have no data to make the comparison with skin cancer). The excess risk can largely be ascribed to effects df underlying renal or urinary-tract disease, or of loss of renal function, on the kidney and bladder, and to increased susceptibility to viral carcinogenesis. The relative risk, which is especially high in younger patients, gradually diminishes with age. C1 European Inst Oncol, Div Epidemiol & Biostat, I-20141 Milan, Italy. NIDDKD, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. CSK AM Banacha, Dept Internal Med & Nephrol, Warsaw, Poland. Univ Otago, Dept Med, Dunedin, New Zealand. Hosp E Bassini San Gerardo, Dept Nephrol & Dialysis, Monza, Italy. New York Med Coll, Valhalla, NY 10595 USA. Univ Michigan, USRDS Coordinating Ctr, Ann Arbor, MI 48109 USA. ERA EDTA Registry, London, England. ANZDATA Registry, Adelaide, SA, Australia. Univ Otago, Dept Prevent & Social Med, Dunedin, New Zealand. NSW Canc Council, Canc Epidemiol Res Unit, Sydney, NSW, Australia. RP Maisonneuve, P (reprint author), European Inst Oncol, Div Epidemiol & Biostat, Via Ripamonti 435, I-20141 Milan, Italy. RI Gellert, Ryszard/F-4604-2010; Boyle, Peter/A-4380-2014; OI Boyle, Peter/0000-0001-6251-0610; Maisonneuve, Patrick/0000-0002-5309-4704 NR 32 TC 425 Z9 442 U1 1 U2 9 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUL 10 PY 1999 VL 354 IS 9173 BP 93 EP 99 DI 10.1016/S0140-6736(99)06154-1 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 215HW UT WOS:000081377100010 PM 10408483 ER PT J AU Patki, AH Purvis, SF Valdez, H Spritzler, J Connick, E Kuritzkes, DR Kessler, H Fox, L St Claire, M Landay, A Lederman, MM AF Patki, AH Purvis, SF Valdez, H Spritzler, J Connick, E Kuritzkes, DR Kessler, H Fox, L St Claire, M Landay, A Lederman, MM TI HIV infection perturbs DNA content of lymphoid cells: partial correction after 'suppression' of virus replication SO AIDS LA English DT Article DE HIV-1 infection; antiretroviral therapy; protease inhibitor; peripheral blood lymphocytes; apoptosis; cell cycle; DNA synthesis ID BLOOD MONONUCLEAR-CELLS; ANTIRETROVIRAL THERAPY; T-CELLS; SPONTANEOUS APOPTOSIS; CYCLE ARREST; IN-VITRO; CD4(+); LYMPHOCYTES; ACTIVATION; ZIDOVUDINE AB Objective: To examine the DNA content of circulating lymphocytes obtained from HIV-1-infected persons and to explore the effects of antiretroviral therapy on these indices. Design: Cross-sectional analysis and 48-week open label treatment trial (AIDS Clinical Trials Group Protocol 315) of zidovudine, lamivudine and ritonavir. Methods: Peripheral blood lymphocytes were obtained from HIV-1-infected patients and healthy controls and after 48 h of in vitro cultivation were stained with propidium iodide and analyzed for DNA content by flow cytometry. Results: HIV-1-infected patients had more hypodiploid cells (19%), fewer G(0)-G(1) phase cells (70%) and more S phase cells (10%) than did healthy controls (8%, 85% and 5% respectively; P = 0.002). Patients with sustained suppression of plasma HIV-1 RNA levels after antiretroviral therapy had only modest improvements in these indices. In contrast, patients who failed to suppress plasma HIV-1 RNA levels had decreases in G(0)-G(1) cells to 54% (P = 0.032) and increases in S phase cells to 24% (P = 0.055). Plasma HIV-1 RNA levels and the percentage of S phase cells were correlated (r, 0.23; P = 0.047). In patients failing antiretroviral therapy, there was an inverse correlation between the percentage of G(0)-G(1) cells and expression of the activation antigens CD38 and HLA-DR on CD4 cells (r, -0.409; P = 0.016) and CD8 cells (r, -0.363; P = 0.035). Conclusions: Lymphocytes obtained From HIV-1-infected patients display perturbations in DNA content after brief cultivation in vitro reflective of immune activation in vivo. The marginal improvement in these indices after 'successful' suppression of HIV-1 replication suggests that even low levels of HIV-1 replication are sufficient to induce immune activation and perturbations in DNA content. (C) 1999 Lippincott Williams & Wilkins. C1 Univ Hosp Cleveland, Div Infect Dis, AIDS Clin Trials Unit, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Cleveland, OH USA. Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. VA Med Ctr, Denver, CO USA. Rush Med Coll, Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. Glaxo Wellcome Inc, Res Triangle Pk, NC 27709 USA. RP Lederman, MM (reprint author), Univ Hosp Cleveland, Div Infect Dis, AIDS Clin Trials Unit, Foley Bldg,2106 Cornell Rd, Cleveland, OH 44106 USA. FU NIAID NIH HHS [AI-36219, AI-38858, AI-25879] NR 25 TC 14 Z9 14 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 9 PY 1999 VL 13 IS 10 BP 1177 EP 1185 DI 10.1097/00002030-199907090-00005 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 212NE UT WOS:000081222200005 PM 10416520 ER PT J AU Wang, J Zheng, LX Lobito, A Chan, FKM Dale, J Sneller, M Yao, X Puck, JM Straus, SE Lenardo, MJ AF Wang, J Zheng, LX Lobito, A Chan, FKM Dale, J Sneller, M Yao, X Puck, JM Straus, SE Lenardo, MJ TI Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II SO CELL LA English DT Article ID TUMOR-NECROSIS-FACTOR; FAS GENE-MUTATIONS; FADD-DEPENDENT APOPTOSIS; MATURE T-CELLS; NF-KAPPA-B; INTERLEUKIN-1-BETA-CONVERTING ENZYME; TNF RECEPTOR; LIGAND TRAIL; APO-2 LIGAND; IN-VIVO AB Caspases are cysteine proteases that mediate programmed cell death in phylogenetically diverse multicellular organisms. We report here two kindreds with autoimmune lymphoproliferative syndrome (ALPS) type II, characterized by abnormal lymphocyte and dendritic cell homeostasis and immune regulatory defects, that harbor independent missense mutations in Caspase 10. These encode amino acid substitutions that decrease caspase activity and interfere with death receptor-induced apoptosis, particularly that stimulated by Pas ligand and TRAIL. These results provide evidence that inherited nonlethal caspase abnormalities cause pleiotropic apoptosis defects underlying autoimmunity in ALPS type II. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Lenardo, MJ (reprint author), NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RI Chan, Francis/E-9647-2014; Chan, Francis K. L./F-4851-2010 OI Chan, Francis/0000-0002-4803-8353; Chan, Francis K. L./0000-0001-7388-2436 NR 65 TC 419 Z9 434 U1 1 U2 9 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JUL 9 PY 1999 VL 98 IS 1 BP 47 EP 58 DI 10.1016/S0092-8674(00)80605-4 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 216PL UT WOS:000081451000007 PM 10412980 ER PT J AU Haruki, M Oohashi, Y Mizuguchi, S Matsuo, Y Morikawa, M Kanaya, S AF Haruki, M Oohashi, Y Mizuguchi, S Matsuo, Y Morikawa, M Kanaya, S TI Identification of catalytically essential residues in Escherichia coli esterase by site-directed mutagenesis SO FEBS LETTERS LA English DT Article DE site-directed mutagenesis; active site; hormone-sensitive lipase; esterase; Escherichia coli ID HORMONE-SENSITIVE LIPASE; NUCLEOTIDE-SEQUENCE; BACILLUS-SUBTILIS; SERINE PROTEASE; ASPARTIC-ACID; ACETYLCHOLINESTERASE; PROTEINS; CLONING; GENE; SIMILARITY AB Escherichia coli esterase (EcE) is a member of the hormone-sensitive lipase family. We have analyzed the roles of the conserved residues in this enzyme (His(103), Glu(128), Gly(163), Asp(164), Ser(165), Gly(167), Asp(262), Asp(266) and His(292)) by site-directed mutagenesis. Among them, Gly(163), Asp(164), Ser(165), and Gly(167) are the components of a G-D/E-S-A-G motif. We showed that Ser(165), Asp(262), and His(292) are the active-site residues of the enzyme. We also showed that none of the other residues, except for Asp(164), is critical for the enzymatic activity. The mutation of Asp(164) to Ala dramatically reduced the catalytic efficiency of the enzyme by the factor of 10(4) without seriously affecting the substrate binding. This residue is probably structurally important to make the conformation of the active-site functional. (C) 1999 Federation of European Biochemical Societies. C1 Osaka Univ, Grad Sch Engn, Dept Mat & Life Sci, Suita, Osaka 5650871, Japan. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Kanaya, S (reprint author), Osaka Univ, Grad Sch Engn, Dept Mat & Life Sci, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. RI Morikawa, Masaaki/L-2823-2015 NR 32 TC 14 Z9 15 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUL 9 PY 1999 VL 454 IS 3 BP 262 EP 266 DI 10.1016/S0014-5793(99)00813-3 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 217AV UT WOS:000081477900019 PM 10431819 ER PT J AU Straface, E Natalini, B Monti, D Franceschi, C Schettini, G Bisaglia, M Fumelli, C Pincelli, C Pellicciari, R Malorni, W AF Straface, E Natalini, B Monti, D Franceschi, C Schettini, G Bisaglia, M Fumelli, C Pincelli, C Pellicciari, R Malorni, W TI C-3-Fullero-tris-methanodicarboxylic acid protects epithelial cells from radiation-induced anoikia by influencing cell adhesion ability SO FEBS LETTERS LA English DT Article DE epithelial cell; ultraviolet B; anoikia; fullerene; cytoskeleton ID EPIDERMOID CELLS; APOPTOSIS; PEROXIDE; OXYGEN; KINASE; DEATH AB Anoikia is a type of apoptotic cell death that occurs in cells that are substrate-restricted in their growth. Buckminster-fullerenes represent a new class of chemical compounds with wide potential pharmacological antioxidant activity. In this report me provide the first demonstration that a water-soluble fullerene derivative, C-3-fullero-tris-methanodicarboxylic acid, synthesized in our laboratories, is capable of inducing anoikia resistance in Epithelial cells by a mechanism involving a 'trophic' effect on cell spreading-associated cytoskeletal components, i.e. on actin microfilaments. (C) 1999 Federation of European Biochemical Societies. C1 Ist Super Sanita, Dept Ultrastruct, I-00161 Rome, Italy. Univ Modena, Dept Biomed Sci, Sect Gen Pathol, I-41100 Modena, Italy. Univ Genoa, Natl Canc Inst, Unit Pharmacol & Neurosci, Genoa, Italy. Univ Genoa, Adv Biotechnol Ctr, Dept Oncol, Genoa, Italy. Univ Perugia, Inst Chem & Technol Drugs, I-06100 Perugia, Italy. Univ Modena, Dept Dermatol, I-41100 Modena, Italy. RP Malorni, W (reprint author), Ist Super Sanita, Dept Ultrastruct, Viale Regina Elena 299, I-00161 Rome, Italy. RI Monti, Daniela/G-9556-2012; Malorni, Walter/G-5874-2016; Pincelli, Carlo/A-7288-2012 OI Monti, Daniela/0000-0001-8651-8123; Pincelli, Carlo/0000-0003-4416-2637 NR 17 TC 37 Z9 39 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUL 9 PY 1999 VL 454 IS 3 BP 335 EP 340 DI 10.1016/S0014-5793(99)00812-1 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 217AV UT WOS:000081477900034 PM 10431834 ER PT J AU Rivera-Nieves, J Thompson, WC Levine, RL Moss, J AF Rivera-Nieves, J Thompson, WC Levine, RL Moss, J TI Thiols mediate superoxide-dependent NADH modification of glyceraldehyde-3-phosphate dehydrogenase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CATALYZED ADP-RIBOSYLATION; NITRIC-OXIDE; S-NITROSYLATION; RELAXING FACTOR; ACID; RIBOSYLTRANSFERASE; PEROXYNITRITE; INVOLVEMENT; MECHANISM; OXIDATION AB Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is covalently modified by NAD in the presence of nitric oxide (NO) and dithiothreitol. Replacement of NAD with NADH in the presence of SIN-1 (3-morpholinosydnonimine) and dithiothreitol increased modification 25-fold. We now demonstrate that in contrast to NO-mediated attachment of NAD, covalent attachment of NADH to GAPDH proceeds in the presence of low molecular weight thiols, independent of NO. Removal of oxygen and transition metal ions inhibited modification, consistent with a role for reactive oxygen species; inhibition by superoxide dismutase, stimulation by xanthine oxidase/hypoxanthine, and the lack of an effect of catalase supported the hypothesis that superoxide, generated hom thiol oxidation, was involved. Electrospray mass spectrometry showed covalent Linkage of the NADH molecule to GAPDH Characterization of the product of phosphodiesterase cleavage demonstrated that linkage to GAPDH occurred through the nicotinamide of NADH. Lys-C digestion of GAPDH, followed by peptide isolation by high performance liquid chromatography, matrix-assisted laser desorption ionization time-of-flight analysis, and Ed-man sequencing, demonstrated that NADH attachment occurred at Cys-149, the active-site thiol. This thiol linkage was stable to HgCl(2). Thus, linkage of GAPDH to NADH, in contrast to NAD, occurs in the presence of thiol, is independent of NO, and is mediated by superoxide. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Moss, J (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10,Rm 5N-307,10 Ctr Dr,MSC 1434, Bethesda, MD 20892 USA. EM JR3u@virginia.edu RI Levine, Rodney/D-9885-2011 NR 38 TC 16 Z9 16 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 9 PY 1999 VL 274 IS 28 BP 19525 EP 19531 DI 10.1074/jbc.274.28.19525 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 215HY UT WOS:000081377300004 PM 10391884 ER PT J AU Powell, MD Beard, WA Bebenek, K Howard, KJ Le Grice, SFJ Darden, TA Kunkel, TA Wilson, SH Levin, JG AF Powell, MD Beard, WA Bebenek, K Howard, KJ Le Grice, SFJ Darden, TA Kunkel, TA Wilson, SH Levin, JG TI Residues in the alpha H and alpha I helices of the HIV-1 reverse transcriptase thumb subdomain required for the specificity of RNase H-catalyzed removal of the polypurine tract primer SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; PLUS-STRAND DNA; ALANINE-SCANNING MUTAGENESIS; ANGSTROM RESOLUTION; POLYMERASE DOMAIN; RIBONUCLEASE-H; CRYSTAL-STRUCTURE; TYPE-1; MUTATIONS; SEQUENCE AB During retrovirus replication, reverse transcriptase (RT) must specifically interact with the polypurine tract (PPT) to generate and subsequently remove the RNA primer for plus-strand DNA synthesis. We have investigated the role that human immunodeficiency virus-1 RT residues in the alpha H and alpha I helices in the thumb subdomain play in specific RNase H cleavage at the 3'-end of the PPT; an in vitro assay modeling the primer removal step was used. Analysis of alanine-scanning mutants revealed that a subgroup exhibits an unusual phenotype in which the PPT is cleaved up to seven bases from its 3'-end. Further analysis of alpha H mutants (G262A, K263A, N265A, and W266A) with changes in residues in or near a structural motif known as the minor groove binding track showed that the RNase H activity of these mutants is more dramatically affected with PPT substrates than with non-PPT substrates. Vertical scan mutants at position 266 were all defective in specific RNase H cleavage, consistent with conservation of tryptophan at this position among lentiviral RTs, Our results indicate that residues in the thumb subdomain and the minor groove binding track in particular, are crucial for unique interactions between RT and the PPT required for correct positioning and precise RNase H cleavage. C1 NICHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Genet Mol Lab, NIH, Res Triangle Pk, NC 27709 USA. Case Western Reserve Univ, Ctr AIDS Res, Cleveland, OH 44106 USA. RP Levin, JG (reprint author), NICHD, Genet Mol Lab, NIH, Bldg 6B,Room 216, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [GM 52263] NR 59 TC 42 Z9 42 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 9 PY 1999 VL 274 IS 28 BP 19885 EP 19893 DI 10.1074/jbc.274.28.19885 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 215HY UT WOS:000081377300054 PM 10391934 ER PT J AU Ilagan, JG Cvekl, A Kantorow, M Piatigorsky, J Sax, CM AF Ilagan, JG Cvekl, A Kantorow, M Piatigorsky, J Sax, CM TI Regulation of alpha A-crystallin gene expression - Lens specificity achieved through the differential placement of similar transcriptional control elements in mouse and chicken SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EPITHELIAL-CELLS; CHLORAMPHENICOL ACETYLTRANSFERASE; TRANSGENIC MICE; C-JUN; B-CRYSTALLIN; DNA-BINDING; PROMOTER; PROTEIN; AP-1; ACTIVATION AB The lens-preferred mouse alpha A-crystallin gene contains a conserved stretch (proximal element 2, +24/+43) in its 5'-noncoding region that we have previously shown binds nuclear proteins of lens and non-lens cells. The 5'-half of this sequence (PE2A, +25/+32) has consensus binding sites for AP-1 and other transcription factors. We show here by deletion experiments that PE2A is important for activity of the mouse alpha A-crystallin promoter and mediates phorbol ester and c-Jun responsiveness of this promoter in transfected lens cells. In vitro protein binding studies suggest that AP-1 complexes are capable of binding to PE2A. Our findings suggest that PE2A plays a role in mouse alpha A-crystallin gene expression through AP-1-mediated regulatory mechanisms. We propose that the mouse and chicken alpha A-crystallin genes are expressed with lens specificity using a similar assortment of transcription factors but with a different physical arrangement of their respective cis-elements within the promoter region. A fundamental role for AP-1 in lens-preferred expression of crystallin genes is consistent with the idea that a redox-sensitive mechanism is a selective force for recruiting lens crystallins. C1 NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Sax, CM (reprint author), Univ Maryland, Univ Coll, SFSC Bldg,Rm 4224B,Univ Blvd Adelphi Rd, College Pk, MD 20742 USA. RI Cvekl, Ales/B-2427-2013 NR 54 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 JUL 9 PY 1999 VL 274 IS 28 BP 19973 EP 19978 DI 10.1074/jbc.274.28.19973 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 215HY UT WOS:000081377300066 PM 10391946 ER PT J AU Saavedra, JE Booth, MN Hrabie, JA Davies, KM Keefer, LK AF Saavedra, JE Booth, MN Hrabie, JA Davies, KM Keefer, LK TI Piperazine as a linker for incorporating the nitric oxide-releasing diazeniumdiolate group into other biomedically relevant functional molecules SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID NO; GENERATION AB Synthetic procedures have been devised to exploit the bifunctional amine piperazine (pip) as a linker capable of attaching the nitric oxide (NO)-releasing diazeniumdiolate functional group [N(O)NO](-) to a diverse selection of biomedically useful molecules, One of the amino groups bears the diazeniumdiolate, which may be substituted on oxygen as necessary to control its dissociation to NO, while the other is used to provide a site suitable for covalent bonding to the molecule requiring NO donor capability. N,N'-Disubstituted piperazines of the structure R-pip-N(O)=NOE were prepared either by using the nucleophilic character of the amino group or by converting it into an electrophilic moiety for reaction with nucleophilic centers in the molecules to be derivatized. Examples are reported in which E = CH(3) and the R groups are bound to the N'-nitrogen: via amide linkages to the carboxyl groups of the drug ibuprofen and the amino acid derivative N-acetylmethionine; through a urea grouping to the E-amino group of a protected lysine; via a carbamate linkage to poly(ethylene glycol); and by replacing the NH(2) nitrogens of nicotinamide and adenosine. Synthesis of analogues in which E II vinyl has been facilitated by introduction of BrCH(2)CH(2)OSO(2)Cl as a novel, efficient bromoethylating agent. Spontaneous NO releasers in the diazeniumdiolated piperazine series include both a fluorescent anion of half-life 5.5 min in which E: = Na and R = dansyl and "MOM-PIPERAZINO" (E = CH(3)OCH(2), R = H), whose half-life for NO release was estimated as 17 days. The latter agent has made possible the conversion of poly( vinyl chloride)and phosphatidylethanolamine to NO-releasing derivatives. This chemistry should allow introduction of diazeniumdiolate groups into a wide variety of natural products, drugs, polymers, and other molecules whose activities could be beneficially combined with the ability to generate NO for biomedical applications. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Chem Synth & Anal Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Chem Sect, Frederick, MD 21702 USA. George Mason Univ, Dept Chem, Fairfax, VA 22030 USA. RP Saavedra, JE (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 NR 21 TC 49 Z9 49 U1 2 U2 12 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 JUL 9 PY 1999 VL 64 IS 14 BP 5124 EP 5131 DI 10.1021/jo9901539 PG 8 WC Chemistry, Organic SC Chemistry GA 216ZL UT WOS:000081474300019 ER PT J AU Lee, TH Yu, SL Kim, SU Kim, YM Choi, I Kang, SW Rhee, SG Yu, DY AF Lee, TH Yu, SL Kim, SU Kim, YM Choi, I Kang, SW Rhee, SG Yu, DY TI Characterization of the murine gene encoding 1-Cys peroxiredoxin and identification of highly homologous genes SO GENE LA English DT Article DE antioxidant enzyme; bacterial artificial chromosome; family gene; retrotransposition ID GLUTATHIONE-PEROXIDASE; RECEPTOR; DNA; ANTIOXIDANT; EXPRESSION; PROTEIN; FAMILY; MOUSE; OXIDATION; ELEMENT AB A new type of peroxiredoxin, named 1-Cys peroxiredoxin (1-Cys Prx), reduces hydrogen peroxide with the use of electrons from unidentified electron donor(s). We have isolated the mouse gene encoding 1-Cys Prx (CP-3) and shown that it is comprised of five exons and four introns. Analysis of 5' flanking regions revealed binding sequences of several putative transcription factors such as Sp1. Pit-la, c-Jun, c-Myc and YY1. It is noticeable that several potential Spl binding sites assigned the -60 through -96 bp from putative transcription initiation site, The gel shift assays showed that Spl and Pit-1a bind specifically to each binding site in I-Cys Prx promoter. We also isolated two highly related genes such as CP-2 and CP-5. These genes are encoded by single exons, and show 85% of nucleotide sequence homology with the CP-3. The structural features of these genes suggest that they might be intronless genes derived from the CP-3 by the mechanism involving retrotransposition. In addition, our data suggest that they are inserted to a specific site of the mouse L1 repetitive element. The 1-Cys Prx was actively transcribed in a variety of adult tissues as well as in the developing embryos. These results suggest that only the 1-Cys Prx gene might be relevant for studying the function of the 1-Cys Prx in the murine system. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Korea Res Inst Biosci & Biotechnol, Taejon 305600, South Korea. NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. RP Yu, DY (reprint author), Korea Res Inst Biosci & Biotechnol, POB 115, Taejon 305600, South Korea. NR 24 TC 29 Z9 30 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 JUL 8 PY 1999 VL 234 IS 2 BP 337 EP 344 DI 10.1016/S0378-1119(99)00190-0 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 217DA UT WOS:000081483500017 PM 10395907 ER PT J AU Bhattacharyya, N Banerjee, D AF Bhattacharyya, N Banerjee, D TI Transcriptional regulatory sequences within the first intron of the chicken apolipoproteinAI (apoAI) gene SO GENE LA English DT Article DE CAT assay; enhancer; footprint; promoter; tissue-specificity; trans-acting factor ID A-I-GENE; 1ST INTRON; CELL-LINE; B GENE; EXPRESSION; REGION; IDENTIFICATION; ENHANCER; ELEMENTS; EVOLUTION AB Previous studies demonstrated that the -82 to +87 nucleotides (nt) 5'-upstream region of the chicken apolipoprotein (apoAI) gene are necessary for maximum reporter chloramphenicol acetyl transferase (cat) gene activation in chicken hepatocarcinoma (LMH) cells [Bhattacharyya, N., Chattapadhyay, R., Oddoux, C., Banerjee, D,, 1993. Characterisation of the chicken apolipoprotein A-I gene 5'-flanking region. DNA Cell Biol. 12, 597-604]. The -82 to +87 nt contain the 5'-untranslated nt, part of the first intron, and the upstream regulatory sequences. In this study, we examined the role of the first intron in the transcriptional regulation of the chicken apoAI gene. Six different reporter cat gene constructs with or without part of the first intron were prepared and transfected into LMH, normal rat kidney (NRK) and human hepatocarcinoma (HepG2) cells. Cell extracts were prepared from each transfected cell line, and CAT activities were measured. All three cell-lines readily expressed CAT, indicating that transcriptional regulatory sequences are present within the first intron region of the chicken apoAI gene. Tn an enhancer assay, the first intron containing cat, construct exhibited a 5.4-fold increase of reporter activity in NRK cells when compared to a SV 40 promoter containing cat plasmid, suggesting the presence of a moderate enhancer element within +29 to +87 nt of the first intron. DNase I protection assays, electrophoretic mobility shift assays and binding experiments with nuclear proteins isolated from different chicken tissues and LMH cells showed interaction with +29 to +87 nt. Nuclear proteins isolated from tissues like liver and intestine, that actively express apoAI gene, failed to interact with +29 to +87 nt, whereas nuclear proteins isolated from tissues that are less active in apoAI gene expression readily interacted with this region. To show the binding of the LMH-specific tl ans-acting factors to the +50 to +68 nt intron region, DNA-affinity chromatography step was performed by using H-3-labeled nuclear proteins. These studies demonstrate that the first intron region of the apoAI gene interacts with transacting proteins and plays an important role in transcriptional regulation of the apoAI gene. (C) 1999 Elsevier Science B.V. All rights reserved. C1 New York Blood Ctr, Lindsley F Kimball Res Inst, Dept Membrane Biochem, New York, NY 10021 USA. RP Bhattacharyya, N (reprint author), NCI, Pathol Lab, Mol Pathol Sect, NIH, Bldg 10,Room 2A33,10 Ctr Dr,MSC 1500, Bethesda, MD 20892 USA. NR 27 TC 22 Z9 29 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JUL 8 PY 1999 VL 234 IS 2 BP 371 EP 380 DI 10.1016/S0378-1119(99)00183-3 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 217DA UT WOS:000081483500021 PM 10395911 ER PT J AU Dalgaard, LZ Klar, AJS AF Dalgaard, LZ Klar, AJS TI Orientation of DNA replication establishes mating-type switching pattern in S-pombe SO NATURE LA English DT Article ID YEAST SCHIZOSACCHAROMYCES-POMBE; FISSION YEAST; GENETIC-ANALYSIS; INITIATION; CELLS; TRANSPOSITION; ASYMMETRY; STRANDS; BREAKS AB The fission yeast Schizosaccharomyces pombe normally has haploid cells of two mating types, which differ at the chromosomal locus mat1. After two consecutive asymmetric cell divisions, only one in four 'grand-daughter' cells undergoes a 'mating-type switch', in which genetic information is transferred to mat1 from the mat2-P or mat3-M donor loci(1-4). This switching pattern probably results from an imprinting event at mat1 that marks one sister chromatid in a strand-specific manner(3-5), and is related to a site-specific, double-stranded DNA break at mat1(6,7). Here we show that the genetic imprint is a strand-specific, alkali-labile DNA modification at mat1. The DNA break is an artefact, created from the imprint during DNA purification. We also propose and test the model that mat1 is preferentially replicated by a centromere-distal origin(s), so that the strand-specific imprint occurs only during lagging-strand synthesis. Altering the origin of replication, by inverting mat1 or introducing an origin of replication, affects the imprinting and switching efficiencies in predicted ways. Two-dimensional gel analysis confirmed that mat1 is preferentially replicated by a centromere-distal origin(s). Thus, the DNA replication machinery may confer different developmental potential to sister cells. C1 NCI, Gene Regulat & Chromosome Biol Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. RP NCI, Gene Regulat & Chromosome Biol Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. EM klar@mail.ncifcrf.gov NR 24 TC 17 Z9 17 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUL 8 PY 1999 VL 400 IS 6740 BP 181 EP 184 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 214JM UT WOS:000081324900058 ER PT J AU Hallett, M AF Hallett, M TI One man's poison - Clinical applications of botulinum toxin SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID INJECTION C1 NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 16 TC 73 Z9 75 U1 1 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 JUL 8 PY 1999 VL 341 IS 2 BP 118 EP 120 DI 10.1056/NEJM199907083410209 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 214ET UT WOS:000081316200009 PM 10395637 ER PT J AU Carson, SA Guzick, DS Vogel, DL AF Carson, SA Guzick, DS Vogel, DL TI Efficacy of superovulation and intrauterine insemination in the treatment of infertility - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Baylor Coll Med, Houston, TX 77030 USA. Univ Rochester, Rochester, NY 14642 USA. NIH, Bethesda, MD 20892 USA. RP Carson, SA (reprint author), Baylor Coll Med, Houston, TX 77030 USA. NR 2 TC 0 Z9 0 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 JUL 8 PY 1999 VL 341 IS 2 BP 128 EP 129 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 214ET UT WOS:000081316200024 ER PT J AU Balint, E Bates, S Vousden, KH AF Balint, E Bates, S Vousden, KH TI Mdm2 binds p73 alpha without targeting degradation SO ONCOGENE LA English DT Article DE p73; p53; Mdm2; E6; protein degradation ID P53 TUMOR-SUPPRESSOR; IN-VIVO; P73; PROTEIN; GROWTH; GENE; E6; TRANSACTIVATION; ONCOPROTEINS; ACTIVATION AB The function of the p53 tumor suppressor protein is regulated by interaction with Mdm2, which targets p53 for ubiquitin dependent degradation. We show here that like p53, p73 alpha forms an interaction with Mdm2, both in vitro and in cells, but this does not result in the degradation of the p73 alpha protein. The human papillomavirus E6 protein also fails to degrade p73 alpha, suggesting that the mechanisms governing p73 alpha stability are distinct from those known to regulate p53 stability. However, the interaction of Mdm2 with 73 alpha is sufficient to impede p73 alpha transcriptional function, despite the lack of degradation. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 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. RI Balint, Eva/B-8695-2008 NR 28 TC 165 Z9 166 U1 0 U2 4 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL 8 PY 1999 VL 18 IS 27 BP 3923 EP 3929 DI 10.1038/sj.onc.1202781 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 214KU UT WOS:000081327800001 PM 10435614 ER PT J AU Katzman, GL Dagher, AP Patronas, NJ AF Katzman, GL Dagher, AP Patronas, NJ TI Incidental findings on brain magnetic resonance imaging from 1000 asymptomatic volunteers SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CARDIOVASCULAR HEALTH; SINUS ABNORMALITIES; PINEAL CYSTS; MRI AB Context Previous reports have discussed incidental disease found on brain magnetic resonance imaging (MRI) scans that had been requested for an unrelated clinical concern or symptom, resulting in a selection bias for disease. However, the prevalence of unexpected abnormalities has not been studied in a healthy population. Objective To evaluate the prevalence of incidental findings on brain MRI scans obtained for a healthy, asymptomatic population without selection bias. Design, Setting, and Participants Retrospective analysis of brain MRI scans obtained between May 17, 1996, and July 25, 1997, from 1000 volunteers who participated as control subjects for various research protocols at the National Institutes of Health. All participants (age range, 3-83 years; 54.6% male) were determined to be healthy and asymptomatic by physician examination and participant history. Main Outcome Measure Prevalence of abnormalities on brain MRI by category of finding (no referral necessary, routine referral, urgent referral [within 1 week of study], and immediate referral [within 1 to several days of study]), Results Eighty-two percent of the MRI results were normal, Of the 18% demonstrating incidental abnormal findings, 15.1% required no referral; 1.8%, routine referral; 1.1%, urgent referral; and 0%, immediate referral. In subjects grouped for urgent referral, 2 confirmed primary brain tumors (and a possible but unconfirmed third) were found, demonstrating a prevalence of at least 0.2%. Conclusion Asymptomatic subjects present with a variety of abnormalities, providing valuable information on disease prevalence in a presumed healthy population, A small percentage of these findings require urgent medical attention and/or additional studies. C1 NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Dagher, AP (reprint author), NIH, Dept Diagnost Radiol, Bldg 10,Room 1C660, Bethesda, MD 20892 USA. NR 16 TC 268 Z9 271 U1 0 U2 4 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 JUL 7 PY 1999 VL 282 IS 1 BP 36 EP 39 DI 10.1001/jama.282.1.36 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 212BE UT WOS:000081195800026 PM 10404909 ER PT J AU Haan, MN Shemanski, L Jagust, WJ Manolio, TA Kuller, L AF Haan, MN Shemanski, L Jagust, WJ Manolio, TA Kuller, L TI The role of APOE epsilon 4 in modulating effects of other risk factors for cognitive decline in elderly persons SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID APOLIPOPROTEIN-E EPSILON-4; DEPENDENT DIABETIC-PATIENTS; ALZHEIMERS-DISEASE; BLOOD-PRESSURE; CARDIOVASCULAR HEALTH; E GENOTYPE; POPULATION; DEMENTIA; OLDER; ASSOCIATION AB Context Cognitive decline in elderly persons is often an early predictor of dementia. Subclinical cardiovascular disease (CVD) and diabetes mellitus may contribute to substantial decline in cognitive function in the elderly. These risks may be modified by gene-environment interactions between apolipoprotein E (APOE) genotype and CVD risk factors or subclinical CVD. Objectives To examine the association between subclinical CVD and decline in cognitive functioning in the elderly and to examine effect modification by the APOE genotype of the association between subclinical disease and cognitive decline. Design The Cardiovascular Health Study, a population-based, prospective cohort study. Setting and Population A total of 5888 randomly selected Medicare-eligible participants from Sacramento County, California; Forsyth County, North Carolina; Washington County, Maryland; and Pittsburgh, Pa, aged 65 years or older, who were recruited in 1989-1990 (n = 5201) and in 1992-1993 (n = 687) and who were followed up for 7 and 5 years, respectively. Main Outcome Measures Change over time in scores on the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test as a function of APOE genotype, subclinical CVD, and diabetes mellitus. Results Seventy percent of participants had no significant decline on the Modified Mini-Mental State Examination. Systolic blood pressure, the ankle-arm brachial index, atherosclerosis of the internal carotid artery, diabetes mellitus, and several diagnoses of prevalent CVD were significantly associated with declines in scores on the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test. The rate of cognitive decline associated with peripheral vascular disease, atherosclerosis of the common and internal carotid arteries, or diabetes mellitus was increased by the presence of any APOE epsilon 4 allele. Conclusions Most healthy elderly people did not experience cognitive decline. Measures of subclinical CVD were modest predictors of cognitive decline. Those with any APOE epsilon 4 allele in combination with atherosclerosis, peripheral vascular disease, or diabetes mellitus were at substantially higher risk of cognitive decline than those without the APOE epsilon 4 allele or subclinical CVD. High levels of atherosclerosis increased cognitive decline independently of APOE genotype. C1 Univ Calif Davis, Sch Med, Dept Epidemiol & Prevent Med, Davis, CA 95616 USA. Univ Calif Davis, Sch Med, Dept Neurol, Davis, CA 95616 USA. Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. NHLBI, Dept Epidemiol, Bethesda, MD 20892 USA. NHLBI, Dept Biometry, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. RP Haan, MN (reprint author), Univ Calif Davis, Sch Med, Dept Epidemiol & Prevent Med, 1 Shields Ave, Davis, CA 95616 USA. FU NIA NIH HHS [R03 AG033751]; NIDDK NIH HHS [R01 DK060753] NR 59 TC 309 Z9 312 U1 1 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 7 PY 1999 VL 282 IS 1 BP 40 EP 46 DI 10.1001/jama.282.1.40 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 212BE UT WOS:000081195800027 PM 10404910 ER PT J AU Cornilescu, G Ramirez, BE Frank, MK Clore, GM Gronenborn, AM Bax, A AF Cornilescu, G Ramirez, BE Frank, MK Clore, GM Gronenborn, AM Bax, A TI Correlation between (3h)J(NC ') and hydrogen bond length in proteins SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID HUMAN UBIQUITIN; COUPLING-CONSTANTS; CHEMICAL-SHIFTS; BINDING DOMAIN; AB-INITIO; NMR; DISTANCES; SYSTEM; ANGLES; PHASE AB Establishing a quantitative relationship between backbone-backbone hydrogen-bond (H-bond) length observed in protein crystal structures and recently observed (3h)J(NC') couplings across such bonds is Limited:by the coordinate precision of the X-ray structure. For an immunoglobulin binding domain of streptococcal protein G, very high-resolution X-ray structures are available. It is demonstrated that over the small range of N-O H-bond lengths (2.8-3.3 Angstrom) for which (3h)J(NC') couplings are observable, the 32 measured (3h)J(NC') values can be fit to: (3h)J(NC') = -59000 exp(-4R(NO)) +/- 0.09 Hz, or R-NO = 2.75 - 0.25 In(-(3h)J(NC')) +/- 0.06 Angstrom. Backbone amide to side-chain carboxyl hydrogen bonds were also investigated, and the measured (3h)J(NC') values tend to be smaller than expected from their crystallographically determined H-bond lengths. The sign of (3h)J(NC'), determined from a zero-quantum/double-quantum experiment,is found to be the same as that of the (1)J(NH) coupling, i.e., negative. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008; Cornilescu, Gabriel/H-3113-2011 OI Clore, G. Marius/0000-0003-3809-1027; Cornilescu, Gabriel/0000-0002-1204-8904 NR 37 TC 162 Z9 163 U1 0 U2 6 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 JUL 7 PY 1999 VL 121 IS 26 BP 6275 EP 6279 DI 10.1021/ja9909024 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA 217RB UT WOS:000081511800023 ER PT J AU Caporaso, N AF Caporaso, N TI Genetics of smoking-related cancer and mutagen sensitivity SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID UPPER AERODIGESTIVE TRACT; GLUTATHIONE-S-TRANSFERASE; DIOL EPOXIDE; BLEOMYCIN; RISK; SUSCEPTIBILITY; POLYMORPHISM; CARCINOMA; CYP2D6; GSTM1 C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Caporaso, N (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Execut Plaza S,Rm 7116, Bethesda, MD 20892 USA. NR 19 TC 13 Z9 14 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 JUL 7 PY 1999 VL 91 IS 13 BP 1097 EP 1098 DI 10.1093/jnci/91.13.1097 PG 2 WC Oncology SC Oncology GA 215ZU UT WOS:000081416500001 PM 10393708 ER PT J AU Schoen, RE Tangen, CM Kuller, LH Burke, GL Cushman, M Tracy, RP Dobs, A Savage, PJ AF Schoen, RE Tangen, CM Kuller, LH Burke, GL Cushman, M Tracy, RP Dobs, A Savage, PJ TI Increased blood glucose and insulin, body size, and incident colorectal cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID VISCERAL ADIPOSE-TISSUE; COLON-CANCER; DIABETES-MELLITUS; FAT DISTRIBUTION; CARDIOVASCULAR-DISEASE; PHYSICAL-ACTIVITY; RISK-FACTORS; COMPUTED-TOMOGRAPHY; BINDING-PROTEIN; PREMENOPAUSAL WOMEN AB Background: Abdominal obesity-an elevated level of visceral adipose tissue-has been linked to colorectal cancer. Furthermore, elevated levels of visceral adipose tissue have been associated with hyperinsulinemia, and insulin is a growth factor in the colon. We assessed whether waist circumference, a surrogate measure of visceral adipose tissue, and metabolic parameters associated with visceral adipose tissue were related to colorectal cancer, Methods: In the Cardiovascular Health Study cohort, we examined the relationship of baseline measurements of body size, glucose, insulin, and lipoproteins to incident colorectal cancer. All P values are two-sided. Results: Among 5849 participants, 102 incident cases of colorectal cancer were identified. Individuals in the highest quartile of fasting glucose had a nearly twofold increased risk of colorectal cancer (relative risk [RR] = 1.8; 95% confidence interval [CI] = 1.0-3.1), and the linear trend RR (LT RR = 1.2; 95% CI = 1.0-1.5) for fasting glucose level was statistically significant (P =.02), Glucose and insulin levels 2 hours after oral glucose challenge also exhibited statistically significant associations with colorectal cancer (2-hour glucose levels: RR = 2.4 [95% CI = 1.2-4.7]/LT RR = 1.3 [95% CI = 1.0-1.6; P =.02]; 2-hour insulin levels: RR = 2.0 [95% CI = 1.0-3.8]/LT RR = 1.2 [95% CI = 1.0-1.5; P =.04]), Analysis of fasting insulin levels suggested a threshold effect, with values above the median associated with colorectal cancer (RR = 1.6; 95% CI = 1.1-2.4; P =.02). Higher levels of waist circumference were also statistically significantly associated with colorectal cancer (RR = 1.9; 95% CI = 1.1-3.3; P =.02). Conclusions: These data provide, to our knowledge, the first direct evidence of an association between elevated visceral adipose tissue level, its associated metabolic effects, and colorectal cancer. C1 Univ Pittsburgh, Dept Med & Epidemiol, Pittsburgh, PA USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Wake Forest Univ, Sch Med, Dept Publ Hlth & Sci, Winston Salem, NC 27109 USA. Univ Vermont, Dept Med, Burlington, VT USA. Univ Vermont, Dept Pathol, Burlington, VT USA. Univ Vermont, Dept Biochem, Burlington, VT USA. Johns Hopkins Univ, Dept Med, Baltimore, MD USA. NHLBI, Bethesda, MD 20892 USA. RP Schoen, RE (reprint author), PUH, Div Gastroenterol & Hepatol, Mezzanine Level,C Wing,200 Lothrop St, Pittsburgh, PA 15213 USA. FU NCI NIH HHS [K07CA72561]; NHLBI NIH HHS [N01HC85079] NR 70 TC 302 Z9 311 U1 1 U2 9 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 JUL 7 PY 1999 VL 91 IS 13 BP 1147 EP 1154 DI 10.1093/jnci/91.13.1147 PG 8 WC Oncology SC Oncology GA 215ZU UT WOS:000081416500014 PM 10393723 ER PT J AU Culleton, BF Larson, MG Kannel, WB Levy, D AF Culleton, BF Larson, MG Kannel, WB Levy, D TI Serum uric acid and risk for cardiovascular disease and death: The Framingham Heart Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article DE uric acid; cardiovascular diseases; outcome assessment (health care); diuretics; risk factors ID DIABETES-MELLITUS; FOLLOW-UP; HYPERTENSIVE PATIENTS; GLUCOSE-TOLERANCE; XANTHINE-OXIDASE; FREE-RADICALS; HYPERURICEMIA; WOMEN; POPULATION; INSULIN AB Background: Hyperuricemia is associated with risk for cardiovascular disease and death. However, the role of uric acid independent of established risk factors is uncertain. Objective: To examine the relation of serum uric acid level to incident coronary heart disease, death from cardiovascular disease, and death from all causes. Design: Community-based, prospective observational study. Setting: Framingham, Massachusetts. Patients: 6763 Framingham Heart Study participants (mean age, 47 years). Measurements: Serum uric acid level at baseline (1971 to 1976); event rates per 1000 person-years by sex-specific uric acid quintile. Results: During 117 376 person-years of follow-up, 617 coronary heart disease events, 429 cardiovascular disease deaths, and 1460 deaths from all causes occurred. In men, after adjustment for age, elevated serum uric acid level was not associated with increased risk for an adverse outcome. In women, after adjustment for age, uric acid level was predictive of coronary heart disease (P = 0.002), death from cardiovascular disease (P = 0.009), and death from all causes (P = 0.03). After additional adjustment for cardiovascular disease risk factors, uric acid level was no longer associated with coronary heart disease, death from cardiovascular disease, or death from ail causes. in a stepwise Cox model, diuretic use was identified as the covariate responsible for rendering serum uric acid a statistically nonsignificant predictor of outcomes. Conclusions: These findings indicate that uric acid does not have a causal role in the development of coronary heart disease, death from cardiovascular disease, or death from all causes. Any apparent association with these outcomes is probably due to the association of uric acid level with other risk factors. C1 Boston Univ, Sch Med, Boston, MA 02118 USA. NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 5 Thurber St, Framingham, MA 01702 USA. FU NHLBI NIH HHS [N01-HC-38038] NR 57 TC 610 Z9 676 U1 1 U2 16 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 6 PY 1999 VL 131 IS 1 BP 7 EP + PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 214UD UT WOS:000081345200002 PM 10391820 ER PT J AU Joshi, MK Bose, S Hendler, RW AF Joshi, MK Bose, S Hendler, RW TI Regulation of the bacteriorhodopsin photocycle and proton pumping in whole cells of Halobacterium salinarium SO BIOCHEMISTRY LA English DT Article ID PURPLE MEMBRANE; HALOBIUM; LIPOSOMES; KINETICS; LIPIDS; ENERGY; FORCE AB Single-turnover kinetics of the bacteriorhodopsin photocycle and proton-pumping capabilities of whole cells were studied. It was found that the Delta<(mu)over tilde>(+)(H) of the cell had a profound influence on the kinetics and components of the cycle. For example, comparing the photocycle in whole cells to that seen in PM preparations, we found that (1) the single-turnover time of the cycle was increased similar to 10-fold, (2) the mole fraction of M-fast (at high actinic light) decreased from 50 to 20%, and (3) the time constant for M-slow increased significantly, The level of Delta<(mu)over tilde>(+)(H) was dependent on respiration, ATP formation and breakdown, and the magnitude of a pre-existing K+ diffusion gradient. The size of the Delta<(mu)over tilde>(+)(H) could be manipulated by additions of HCN, nigericin, and DCCD (N,N'-dicyclohexylcarbodamide). At higher levels of Delta<(mu)over tilde>(+)(H), further changes in the photocycle were seen. (4) Two slower components of M-decay appeared as major components. (5) The apparent conversion of the M-fast to the O intermediate disappeared. (6) A partial reversal of an early photocycle step occurred. The photocycle of intact cells could be changed to that seen in purple membrane suspensions by the energy-uncoupler CCCP or by lysis of the cells. In fresh whole cells, light-induced proton pumping was nor seen until the K+ diffusion potential was dissipated and proton accumulation facilitated by use of a K+-H+ exchanger (nigericin), respiration was inhibited by HCN, and ATP synthesis and breakdown were inhibited by DCCD. In stored cells, the pre-existing K+ diffusion gradient was diminished through slow diffusion, and only DCCD and HCN were required to elicit proton extrusion. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hendler, RW (reprint author), Univ Calif San Diego, Dept Biol, La Jolla, CA 92093 USA. NR 28 TC 9 Z9 9 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 6 PY 1999 VL 38 IS 27 BP 8786 EP 8793 DI 10.1021/bi990104q PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 216KC UT WOS:000081440400021 PM 10393554 ER PT J AU Sievers, ML Bennett, PH Roumain, J Nelson, RG AF Sievers, ML Bennett, PH Roumain, J Nelson, RG TI Effect of hypertension on mortality in Pima Indians SO CIRCULATION LA English DT Article DE cardiovascular diseases; diabetes mellitus; epidemiology; hypertension; Indians, North American; mortality; proportional hazards models ID CORONARY HEART-DISEASE; STAGE RENAL-DISEASE; DEPENDENT DIABETES-MELLITUS; NATIVE-AMERICAN POPULATION; U-SHAPED ASSOCIATION; RISK-FACTORS; CARDIOVASCULAR-DISEASE; BLOOD-PRESSURE; INSULIN; PREVALENCE AB Background-The effect of hypertension on mortality was examined in 5284 Pima Indians, 1698 of whom had type 2 diabetes at baseline or developed it during follow-up. Methods and Results-During a median follow-up of 12.2 years (range, 0.01 to 24.8 years), 470 nondiabetic subjects and 488 diabetic subjects died. In the nondiabetic subjects, 45 of the deaths were due to cardiovascular disease, 208 to other natural causes, and 217 to external causes; in the diabetic subjects, 106 of the deaths were due to cardiovascular disease, 85 to diabetic nephropathy, 226 to other natural causes, and 71 to external causes. In the nondiabetic subjects, after adjusting for age, sex, body mass index, and serum cholesterol concentration in a proportional hazards model, hypertension predicted death from cardiovascular disease (death rate ratio [DRR]= 2.8; 95% CI, 1.4 to 5.6; P = 0.003). In the diabetic subjects, after additional adjustment for duration of diabetes, plasma glucose concentration, and proteinuria, hypertension strongly predicted deaths from diabetic nephropathy (DRR = 3.5; 95% CI, 1.7 to 7.2; P < 0.001), but it had little effect on deaths from cardiovascular disease (DRR = 1.4; 95% CI, 0.88 to 2.3; P = 0.15). Conclusions-We propose that the weak relationship between hypertension and cardiovascular disease in diabetic Pima Indians is not because of a diminished effect of hypertension on cardiovascular disease in diabetes, but because of a relatively greater effect of hypertension on the progression of diabetic nephropathy. Factors-that may account for this finding in Pima Indians include a younger age at onset of type 2 diabetes, a low frequency of heavy smoking, favorable lipoprotein profiles and, possibly, enhanced susceptibility to renal disease. C1 NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85014 USA. RP Nelson, RG (reprint author), NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. RI Nelson, Robert/B-1470-2012 NR 37 TC 20 Z9 20 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 6 PY 1999 VL 100 IS 1 BP 33 EP 40 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 213NC UT WOS:000081279300009 PM 10393678 ER PT J AU Uhl, GR Sora, I Wang, ZJ AF Uhl, GR Sora, I Wang, ZJ TI The mu opiate receptor as a candidate gene for pain: Polymorphisms, variations in expression, nociception, and opiate responses SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article; Proceedings Paper CT National-Academy-of-Sciences Colloguium on the Neurobiology of Pain CY DEC 11-13, 1998 CL IRVINE, CALIFORNIA ID POSITRON EMISSION TOMOGRAPHY; MORPHINE-INDUCED ANALGESIA; INBRED MOUSE STRAINS; OPIOID-RECEPTOR; MICE; MIGRAINE; BINDING; PREFERENCE; PROMOTERS; LINKAGE AB There are differences between human individuals and between mouse strains in levels of mu opiate receptor (mu OR) expression, responses to painful stimuli, and responses to opiate drugs. One of the best candidates for contributing to these differences is variation at the mu OR gene locus. Support for this idea comes from analyses of the human and murine mu OR genes. Assessments of individual differences in human mu OR expression add further support. Studies with mice, including knockout-transgenic, quantitative trait locus, and, strain-comparison studies, also strongly support the possibility that mu OR gene alleles would be strong candidates for contributing to individual differences in human nociception and opiate drug responses. This paper reviews current analyses of the murine and human mu OR genes, their important variants, and correlations between these variants and opiate influences on pain. C1 NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21224 USA. RP Uhl, GR (reprint author), NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NR 31 TC 148 Z9 149 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 JUL 6 PY 1999 VL 96 IS 14 BP 7752 EP 7755 DI 10.1073/pnas.96.14.7752 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 214RV UT WOS:000081342100030 PM 10393893 ER PT J AU Tien, M Berlett, BS Levine, RL Chock, PB Stadtman, ER AF Tien, M Berlett, BS Levine, RL Chock, PB Stadtman, ER TI Peroxynitrite-mediated modification of proteins at physiological carbon dioxide concentration: pH dependence of carbonyl formation, tyrosine nitration, and methionine oxidation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GLUTAMINE-SYNTHETASE; NITRIC-OXIDE; LIPID-PEROXIDATION; HYDROGEN-PEROXIDE; ONE-ELECTRON; MECHANISM; RESIDUES; ADENYLYLATION; SUPEROXIDE; KINETICS AB The ability of peroxynitrite to modify amino acid residues in glutamine synthetase (GS) and BSA is greatly influenced by pH and CO2. At physiological concentrations of CO2 (1.3 mM), the generation of carbonyl groups (0.2-0.4 equivalents/subunit) is little affected by pH over the range of 7.2-9.0, but, in the absence of CO2, carbonyl formation increases (from 0.1-1.2 equivalents/subunit) as the pH is raised from 7.2 to 10.5. This increase is attributable, in part but not entirely, to the increase in peroxynitrite (PN) stability with increasing pH, Of several amino acid polymers tested, only those containing lysine residues yielded carbonyl derivatives. In contrast, the nitration of tyrosine residues of both GS and BSA at pH 7.5 almost completely depends on the presence of CO2. However, the pH profiles of tyrosine nitration in GS and BSA are not the same. With both proteins, nitration decreases approximate to 65% with increasing pH over the range of 7.2-8.4, but, then in the case of GS only, there is a 3.1 fold increase in the level of nitration over the range pH 8.4-8.8. The oxidation of methionine residues in both proteins and in the tripeptide Ala-Met-Ala was inhibited by CO2 at both high and low pH values. These results emphasize the importance of controlling the pH and CO2 concentrations in studies involving PN and indicate that PN is not likely to contribute appreciably to carbonyl formation or oxidation of methionine residues of proteins at physiological pH and CO2 concentrations. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. RP Stadtman, ER (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3,Room 222,3 Ctr Dr,MSC-0342, Bethesda, MD 20892 USA. RI Levine, Rodney/D-9885-2011 NR 31 TC 123 Z9 124 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 JUL 6 PY 1999 VL 96 IS 14 BP 7809 EP 7814 DI 10.1073/pnas.96.14.7809 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 214RV UT WOS:000081342100040 PM 10393903 ER PT J AU Schrager, JA Marsh, JW AF Schrager, JA Marsh, JW TI HIV-1 Nef increases T cell activation in a stimulus-dependent manner SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; QUIESCENT CD4 LYMPHOCYTES; NF-KAPPA-B; DOWN-REGULATION; CYTOPLASMIC DOMAIN; SURFACE CD4; ANTIGEN RECEPTOR; PROTEIN; EXPRESSION; GENE AB Lentiviral Nef increases viral replication in vivo, plays a direct role in pathogenesis, and increases viral particle infectivity. We now find that HIV Nef also increases the activation of T cells, a cellular state required for optimal viral replication. This enhancement is stimulant-dependent. As defined by IL-2 generation, activation of T cells stimulated with classical mitogens [phorbol 12-myristate 13-acetate (PMA) + anti-CD3, PMA + phytohemagglutinin, and PMA + ionomycin] is unaffected by the expression of Nef. However, Nef increases IL-2 secretion when cells are stimulated through the T cell receptor and the costimulus receptor (CD28). This increase in activation, which depends on Nef myristylation, is caused by an increase in the number of cells reaching full activation and not by an increase in the amount of IL-2 secreted per cell. These findings demonstrate that Nef lowers the threshold of the dual-receptor T cell activation pathway. The capacity of Nef to increase T cell activity may be very important in vivo when Nef is the predominant or the only viral gene product expressed. C1 NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Marsh, JW (reprint author), NIMH, Mol Biol Lab, Bldg 36,Room 1B08,36 Convent Dr,MSC 4034, Bethesda, MD 20892 USA. NR 57 TC 147 Z9 147 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 JUL 6 PY 1999 VL 96 IS 14 BP 8167 EP 8172 DI 10.1073/pnas.96.14.8167 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 214RV UT WOS:000081342100103 PM 10393966 ER PT J AU Hegland, DD Sullivan, DM Rovira, II Li, A Kovesdi, I Bruder, JT Finkel, T AF Hegland, DD Sullivan, DM Rovira, II Li, A Kovesdi, I Bruder, JT Finkel, T TI Regulation of endothelial cell adherens junctions by a Ras-dependent signal transduction pathway SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID GTPASE-ACTIVATING PROTEIN; BETA-CATENIN; CADHERIN; ADHESION; ANGIOGENESIS; PLAKOGLOBIN; EXPRESSION; CONTACTS; WNT-1; GENE AB Adherens junctions, consisting of transmembrane cadherin molecules and their associated cytoplasmic alpha-, beta-, and gamma-catenin proteins, are thought to be critical for the development of stable cell adhesion and subsequent 3-dimensional tissue organization. In human endothelial cells there is a marked induction of gamma-catenin levels when cells reach confluence. We demonstrate that expression of a dominant negative ras gene product (N17ras) via adenoviral mediated gene transfer inhibits the confluent-dependent rise in gamma-catenin mRNA and protein levels. Consistent with its effects on overall gamma-catenin levels, expression of N17ras also reduces the amount of gamma-catenin associated with the adherens junction. Finally, although expression of N17ras under normal culture conditions produces no clear morphological phenotype, endothelial cells expressing a dominant negative ras gene product fail to form 3-dimensional, vascular-like structures when plated on reconstituted extracellular matrix, (C) 1999 Academic Press. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. GenVec Inc, Rockville, MD USA. RP Finkel, T (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10,Rm 7B15,10 Ctr Dr, Bethesda, MD 20892 USA. NR 26 TC 3 Z9 3 U1 0 U2 1 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 JUL 5 PY 1999 VL 260 IS 2 BP 371 EP 376 DI 10.1006/bbrc.1999.0919 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 216LH UT WOS:000081443800013 PM 10403777 ER PT J AU Ambalavanar, R Tanaka, Y Damirjian, M Ludlow, CL AF Ambalavanar, R Tanaka, Y Damirjian, M Ludlow, CL TI Laryngeal afferent stimulation enhances Fos immunoreactivity in periaqueductal gray in the cat SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE vocalization; adductor reflex; immunohistochemistry; superior laryngeal nerve; electrical stimulation ID ELECTRICALLY-INDUCED VOCALIZATION; NADPH-DIAPHORASE HISTOCHEMISTRY; CAUDAL VENTROLATERAL MEDULLA; FEMALE REPRODUCTIVE-BEHAVIOR; EXCITATORY AMINO-ACIDS; BRAIN-STEM INTEGRATION; FINAL COMMON PATHWAY; SQUIRREL-MONKEY; NITRIC-OXIDE; SOLITARY TRACT AB The main functions of the larynx are protection of the airways, respiration, and vocalization. Previous studies have suggested a link between the mechanisms controlling vocalization and afferent feedback from the larynx. We inquired whether stimulation of the laryngeal afferents that run in the internal branch of the superior laryngeal nerve (ISLN) activates neurons of the periaqueductal gray (PAG), a midbrain region implicated in vocalization. We counted the number of neurons expressing Fos, the protein product of the immediate early gene c-fos, in the PAG. The counts were done both in experimental cats after electrical stimulation of the ISLN and nonstimulated controls. We also investigated the possible presence of nitric oxide synthase, an enzyme that synthesizes nitric oxide, in PAG neurons that respond to laryngeal afferent stimulation by double labeling for reduced nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase and Fos. Fos expression was significantly greater (P less than or equal to 0.00714) in the lateral and dorsolateral regions of the PAG in the experimental group than in the controls. The Fos-immunoreactive neurons did not contain NADPH-diaphorase, a marker for nitric oxide synthase. Our study suggests that laryngeal afferent stimulation activates neurons in discrete longitudinal columns of the PAG including the regions that have previously been shown to be involved in vocalization, and that these neurons do not contain nitric oxide synthase. Published 1999 Wiley-Liss, Inc.(dagger). C1 NIDCD, VSS, NIH, Bethesda, MD 20892 USA. Kurume Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Kurume, Fukuoka 830, Japan. RP Ambalavanar, R (reprint author), NIDCD, VSS, NIH, 10 Ctr Dr MSC 1416, Bethesda, MD 20892 USA. EM ambalava@nided.nih.gov OI Ludlow, Christy/0000-0002-2015-6171 FU PHS HHS [653] NR 99 TC 11 Z9 11 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JUL 5 PY 1999 VL 409 IS 3 BP 411 EP 423 PG 13 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 200XA UT WOS:000080564400006 PM 10379827 ER PT J AU Miller, C Ragheb, JA Schwartz, RH AF Miller, C Ragheb, JA Schwartz, RH TI Anergy and cytokine-mediated suppression as distinct superantigen-induced tolerance mechanisms in vivo SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE CD4(+) T cell receptor transgenic cells; early response kinase activation; interleukin 2; interleukin 10; transforming growth factor beta ID T-CELL TOLERANCE; GROWTH-FACTOR-BETA; IN-VIVO; CLONAL ANERGY; MONOCLONAL-ANTIBODY; INTERLEUKIN-2 GENE; TRANSGENIC MICE; IL-10; PROLIFERATION; COMPLEX AB Recombinant-activating gene 2 (RAG-2(-/-)) T cell receptor-transgenic mice repeatedly injected with the superantigen staphylococcal enterotoxin;in A entered a tolerant state in which splenic CD4(+) T cells produced little interleukin (IL)-2, interferon gamma, or IL-4. This state resulted from a combination of both clonal anergy and cytokine-mediated immunosuppression. The anergy persisted for at least 3 wk and could be distinguished from the suppression by a decrease in IL-2 production per cell, a block in the activation of early response kinases, and a failure to be reversed with anti-transforming growth factor (TGF)-beta. Full suppression lasted for only 1 wk and involved both IL-10 and TGF-beta, but required additional unknown molecules for optimal effect. These experiments show that complex in vivo interactions of multiple peripheral tolerance mechanisms can now be dissected at both the cellular and molecular levels. C1 NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Schwartz, RH (reprint author), NIAID, Cellular & Mol Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 45 TC 81 Z9 83 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 JUL 5 PY 1999 VL 190 IS 1 BP 53 EP 64 DI 10.1084/jem.190.1.53 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 215RW UT WOS:000081397500006 PM 10429670 ER PT J AU Schust, DJ Tortorella, D Seebach, J Phan, C Bacik, I Bennink, JR Yewdell, JW Ploegh, HL AF Schust, DJ Tortorella, D Seebach, J Phan, C Bacik, I Bennink, JR Yewdell, JW Ploegh, HL TI Trophoblast class I major histocompatibility complex (MHC) products are resistant to rapid degradation imposed by the human cytomegalovirus (HCMV) gene products US2 and US11 (vol 188, pg 497, 1998) SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Correction C1 Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02119 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Schust, DJ (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012; OI Tortorella, Domenico/0000-0003-0961-3535 NR 1 TC 0 Z9 0 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 5 PY 1999 VL 190 IS 1 BP 151 EP 151 PG 1 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 215RW UT WOS:000081397500016 ER PT J AU Collins, PL Camargo, E Hill, MG AF Collins, PL Camargo, E Hill, MG TI Support plasmids and support proteins required for recovery of recombinant respiratory syncytial virus SO VIROLOGY LA English DT Article ID TRANSCRIPTION ELONGATION-FACTOR; MESSENGER-RNA; VACCINE CANDIDATE; GENE-EXPRESSION; MAMMALIAN-CELLS; SUBGROUP-A; M2 GENE; SEQUENCE; RSV; SUBSTITUTION AB Respiratory syncytial virus (RSV) can be recovered from plasmids that separately encode antigenomic RNA and the N, P, L, and M2-1 proteins of the nucleocapsid. However, in a recent study the inclusion of a separate M2-1 expression plasmid was found to be unnecessary (H. Jin, D. Clarke, H. Zhou, X. Cheng, K. Coelingh, M. Bryant, and S. Li, Virology 1998, 251, 206-214). This suggested that the M2-1 protein, which is a transcription antitermination factor, is not required to reconstitute the minimum unit of infectivity, namely a nucleocapsid fully functional for viral transcription and RNA replication. Here we show that the antigenomic plasmid is remarkably efficient as a substitute for an M2-1 expression plasmid in supporting processive transcription by an RSV minigenome. Thus, the simple expedient of omitting an expression plasmid is invalid for evaluating recovery requirements. The issue of the requirement of M2-1 for the recovery of infectious RSV is discussed. C1 NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Collins, PL (reprint author), NIAID, Infect Dis Lab, 7 Ctr Dr,MSC 0720, Bethesda, MD 20892 USA. NR 27 TC 17 Z9 19 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 JUL 5 PY 1999 VL 259 IS 2 BP 251 EP 255 DI 10.1006/viro.1999.9762 PG 5 WC Virology SC Virology GA 217KX UT WOS:000081499400001 PM 10388648 ER PT J AU Chang, MJ Kuzio, J Blissard, GW AF Chang, MJ Kuzio, J Blissard, GW TI Modulation of translational efficiency by contextual nucleotides flanking a Baculovirus initiator AUG codon SO VIROLOGY LA English DT Article ID NUCLEAR POLYHEDROSIS-VIRUS; SPODOPTERA-FRUGIPERDA CELLS; GP64 GENE-EXPRESSION; RNA-POLYMERASE; EARLY TRANSCRIPTION; PROTEIN GENE; SACCHAROMYCES-CEREVISIAE; EUKARYOTIC RIBOSOMES; MUTATIONAL ANALYSIS; SEQUENCES UPSTREAM AB In a previous study of translational regulation of a baculovirus gene, we observed that translation initiated at an unexpectedly high efficiency from an AUG codon found in what was believed to be a poor context (M.-J. Chang and G. W. Blissard, 1997, J. Virol 71, 7448-7460). In the current study, we examined the roles of nucleotides flanking a baculovirus AUG initiator codon in modulating translation initiation in lepidopteran insect cells. The roles of nucleotides flanking the AcMNPV gp64 initiator codon were examined by site-directed mutagenesis and functional assays in transfected Sf9 cells. To eliminate potential cis-acting sequences and effects, the gp64 initiator context was cloned in-frame with a chloramphenicol acetyl transferase reporter gene and under the control of a heterologous promoter. All possible single-nucleotide substitutions were generated in positions -6 to -1 and +4 to +6, relative to the A of the initiator AUG codon, which was designated +1. Constructs were transfected into lepidopteran cells and translation products were quantified by an enzyme-linked immunosorbent assay procedure. Substitutions of pyrimidines or other nucleotides at the -3 position resulted in little or no detectable effect on translation efficiency. In contrast, specific substitutions at the +4 and +5 positions resulted in approximately 2- to 3-fold increases in translation. Substitution of A in the +4 position resulted in an approximately 3-fold increase in translation, and substitution of any nucleotide for T in the +5 position resulted in approximately 1.9- to 2.8-fold increases. Substitutions at other positions (-6 to -1 and +6) resulted in no detectable increase or decrease in translation efficiency. These experimental results suggest an optimal initiator context of 5'-N N N N N N A U G A a/c/g N-3' for efficient translation initiation in lepidopteran cells. Consensus translation initiation contexts were generated from baculovirus genes and lepidopteran genes, then compared with the experimental results from the gp64 initiator context. (C) 1999 Academic Press. C1 Cornell Univ, Boyce Thompson Inst, Ithaca, NY 14853 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Blissard, GW (reprint author), Cornell Univ, Boyce Thompson Inst, Tower Rd, Ithaca, NY 14853 USA. RI Blissard, Gary/H-5544-2012; OI Blissard, Gary/0000-0001-9228-567X NR 59 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 JUL 5 PY 1999 VL 259 IS 2 BP 369 EP 383 DI 10.1006/viro.1999.9787 PG 15 WC Virology SC Virology GA 217KX UT WOS:000081499400014 PM 10388661 ER PT J AU Bellus, GA Bamshad, MJ Przylepa, KA Dorst, J Lee, RR Hurko, O Jabs, EW Curry, CJR Wilcox, WR Lachman, RS Rimoin, DL Francomano, CA AF Bellus, GA Bamshad, MJ Przylepa, KA Dorst, J Lee, RR Hurko, O Jabs, EW Curry, CJR Wilcox, WR Lachman, RS Rimoin, DL Francomano, CA TI Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): Phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3 SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE FGFR3; dwarfism; mental retardation; skin skeletal brain dysplasia ID THANATOPHORIC DYSPLASIA; NEURITE OUTGROWTH; CROUZON-SYNDROME; POINT MUTATION; ACTIVATION; GENE; FGFR3; HYPOCHONDROPLASIA; TRANSMEMBRANE; EXPRESSION AB We previously discovered a novel missense mutation (Lys650Met) in the tyrosine kinase domain of the fibroblast growth factor receptor 3 (FGFR3) gene in four unrelated individuals with a condition we called "severe achondroplasia with developmental delay and acanthosis nigricans" (SADDAN) [Tavormina et al,, 1999: Am. J. Hum. Grenet. 64:722-731], Here we present a more detailed clinical account of the SADDAN phenotype, The FGFR3 Lys650Met mutation results in severe disturbances in endochondral bone growth that approach and overlap those observed in thanatophoric dysplasia, type I. However, this mutation is most often compatible with survival into adulthood, Other unusual bone deformities, such as femoral bowing with reverse (i.e., posterior apex) tibial and fibular bowing and "ram's horn" bowing of the clavicle, are also seen in some patients, In addition to skeletal dysplasia, progressive acanthosis nigricans, and central nervous system structural anomalies, seizures and severe developmental delays are observed in surviving SADDAN patients. Despite its location within the same FGFR3 codon as the thanatophoric dysplasia type II mutation (Lys650Glu) and a similar effect on constitutive activation of the FGFR3 tyrosine kinase, the Lys650Met is not associated with cloverleaf skull or craniosynostosis. Am. J, Med, Genet. 85:53-65, 1999. (C) 1999 Wiley-Liss, Inc. C1 Natl Human Genome Res Inst, Med Genet Branch, NIH, Bethesda, MD USA. Univ Utah, Hlth Sci Ctr, Dept Pediat, Salt Lake City, UT USA. Johns Hopkins Univ, Sch Med, Ctr Med Genet, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Ctr Craniofacial Dev & Disorders, Baltimore, MD USA. Valley Childrens Hosp, Fresno, CA USA. Univ Calif Los Angeles, Sch Med,Burns & Allen Cedars Sinai Res Inst, Steven Spielberg Pediat Res Ctr, Ahmanson Dept Pediat, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Dept Pediat, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Dept Radiol, Los Angeles, CA 90024 USA. RP Bellus, GA (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Dermatol, B-153,4200 E 9th Ave, Denver, CO 80262 USA. OI Jabs, Ethylin/0000-0001-8983-5466 FU NIAMS NIH HHS [AR07411]; NIDCR NIH HHS [DE11441]; PHPPO CDC HHS [PHSM0100064] NR 45 TC 61 Z9 62 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD JUL 2 PY 1999 VL 85 IS 1 BP 53 EP 65 DI 10.1002/(SICI)1096-8628(19990702)85:1<53::AID-AJMG10>3.3.CO;2-6 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 202KG UT WOS:000080650900010 PM 10377013 ER PT J AU Xu, XM Zhou, X Carlson, BA Kim, LK Huh, TL Lee, BJ Hatfield, DL AF Xu, XM Zhou, X Carlson, BA Kim, LK Huh, TL Lee, BJ Hatfield, DL TI The zebrafish genome contains two distinct selenocysteine tRNA([Ser]Sec) genes SO FEBS LETTERS LA English DT Article DE zebrafish; selenocysteine; tRNA; gene; selenium ID EXPRESSION; EMBRYOGENESIS; EVOLUTION; PATTERNS; CELLS AB The zebrafish is widely used as a model system for studying mammalian developmental genetics and more recently, as a model system for carcinogenesis. Since there is mounting evidence that selenium can prevent cancer in mammals, including humans, we characterized the selenocysteine tRNA([Ser]Sec) gene and its product in zebrafish, Two genes for this tRNA were isolated and sequenced and were found to map at different loci within the zebrafish genome. The encoding sequences of both are identical and their flanking sequences are highly homologous for several hundred bases in both directions. The two genes likely arose from gene duplication which is a common phenomenon among many genes in this species, Tn addition, zebrafish tRNA([Ser]Sec) was isolated from the total tRNA population and shown to decode UGA in a ribosomal binding assay, (C) 1999 Federation of European Biochemical Societies. C1 NCI, Sect Mol Biol Selenium, Basic Res Lab, Div Basic Sci,NIH, Bethesda, MD 20892 USA. Seoul Natl Univ, Inst Mol Biol & Genet, Mol Genet Lab, Seoul 151742, South Korea. Kyungpook Natl Univ, Dept Genet Engn, Taegu 702702, South Korea. RP Hatfield, DL (reprint author), NCI, Sect Mol Biol Selenium, Basic Res Lab, Div Basic Sci,NIH, Bldg 37,Room 2D09, Bethesda, MD 20892 USA. NR 17 TC 12 Z9 12 U1 2 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUL 2 PY 1999 VL 454 IS 1-2 BP 16 EP 20 DI 10.1016/S0014-5793(99)00767-X PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 214ZX UT WOS:000081358400004 PM 10413087 ER PT J AU Schnier, JB Kaur, G Kaiser, A Stinson, SF Sausville, EA Gardner, J Nishi, K Bradbury, EM Senderowicz, AM AF Schnier, JB Kaur, G Kaiser, A Stinson, SF Sausville, EA Gardner, J Nishi, K Bradbury, EM Senderowicz, AM TI Identification of cytosolic aldehyde dehydrogenase 1 from non-small cell lung carcinomas as a flavopiridol-binding protein SO FEBS LETTERS LA English DT Article DE flavopiridol; CDK; aldehyde dehydrogenase class I; NSCLC; drug resistance ID DEPENDENT KINASE INHIBITOR; GROWTH-INHIBITION; P34(CDC2) KINASE; G(1) ARREST; APOPTOSIS; INDUCTION; L86-8275; PROGRESSION; MECHANISMS; EXPOSURE AB The synthetic flavone flavopiridol can be cytostatic or cytotoxic to mammalian cells, depending on the concentration of the drug and the duration of exposure. It has been shown to inhibit the cyclin-dependent kinase (CDK) family of cell cycle regulatory enzymes. However, the existence of additional potential targets for drug action remains a matter of interest to define, To identify cellular targets, flavopiridol was immobilized. CDKs, particularly CDK 4, bound weakly to immobilized flavopiridol when ATP was absent but not in its presence. Two proteins with molecular weights of 40 kDa and 120 kDa had high affinities to the immobilized flavopiridol independent of the presence of ATP, They were present in all cell lines analyzed: cervical (HeLa), prostate and non-small cell lung carcinoma (NSCLC) cell lines. A 60-kDa protein, which was present only in NSCLC cells and bound similarly well to immobilized flavopiridol, was identified as cytosolic aldehyde dehydrogenase class 1 (ALDH-1). The level of this protein correlated with the resistance of NSCLC cell lines to cytotoxicity caused by 500 nM flavopiridol but not higher flavopiridol concentrations, Despite binding to ALDN-1, there was no inhibition of dehydrogenase activity by flavopiridol concentrations as high as 20 mu M and flavopiridol was not metabolized by ALDH-1. The results suggest that high cellular levels of ALDH-1 may reduce cytotoxicity of flavopiridol and contribute to relative resistance to the drug. This is the first report that flavopiridol binds to proteins other than CDKs, (C) 1999 Federation of European Biochemical Societies. C1 Univ Calif Davis, Dept Biol Chem, Davis, CA 95616 USA. NCI, Lab Drug Discovery Res & Dev, Bethesda, MD 20892 USA. Univ Calif Davis, CEPRAP, Davis, CA 95616 USA. Los Alamos Natl Lab, Los Alamos, NM 87545 USA. NCI, Div Canc Treament & Diag, Med Branch, DTP Clin Trials Unit, Bethesda, MD 20892 USA. RP Univ Calif Davis, Dept Biol Chem, Tupper Hall,1 Shields Ave, Davis, CA 95616 USA. EM jbschnier@ucdavis.edu NR 26 TC 51 Z9 53 U1 2 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD JUL 2 PY 1999 VL 454 IS 1-2 BP 100 EP 104 DI 10.1016/S0014-5793(99)00773-5 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 214ZX UT WOS:000081358400021 PM 10413104 ER PT J AU Hall, HI Coates, RJ Uhler, RJ Brinton, LA Gammon, MD Brogan, D Potishcman, N Malone, KE Swanson, CA AF Hall, HI Coates, RJ Uhler, RJ Brinton, LA Gammon, MD Brogan, D Potishcman, N Malone, KE Swanson, CA TI Stage of breast cancer in relation to body mass index and bra cup size SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID WEIGHT; WOMEN; RISK; SURVIVAL; OBESITY; DISEASE; DIAGNOSIS; HEALTH; HEIGHT AB Most studies on women with breast cancer indicate that obesity is positively associated with late-stage disease. Some results have shown a similar relationship between breast size and stage. A recent study found that the association between body mass index (BMI) and stage was limited to cancers that were self-detected, suggesting that the BMI-stage relation may be due to delayed symptom recognition. We examined the relationships between stage and both BMI and breast (bra cup) size, stratified by method of detection, using data from a population-based case-control study of 1,361 women (ages 20-44 years) diagnosed with breast cancer during 1990-1992, Height and weight measurements and information on bra cup size, method of cancer detection and other factors predictive of stage at diagnosis were collected during in-person interviews. A case-case comparison was conducted using logistic regression to estimate odds of regional or distant stage rather than local stage in relation to BMI and bra size, Odds of late-stage disease were increased with higher BMI [adjusted odds ratio (OR) for highest to lowest tertile = 1.46, 95% confidence interval (CI) 1.10-1.93] and larger bra cup size (OR for cup D vs, cup A = 1.61, 95% CI 1.04-2.48), These relationships were not modified by the method of detection. Differences in etiologic effects, rather than differences in detection methods, may explain the relations observed between stage and both BMI and breast size. (C) 1999 Wiley-Liss, Inc. C1 CDC, NCCDPHP, DCPC, Atlanta, GA 30341 USA. NCI, Bethesda, MD 20892 USA. Columbia Univ, Sch Publ Hlth, New York, NY USA. Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Hall, HI (reprint author), CDC, NCCDPHP, DCPC, Mailstop K-53,4770 Buford Highway NE, Atlanta, GA 30341 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 21 TC 51 Z9 51 U1 2 U2 5 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 JUL 2 PY 1999 VL 82 IS 1 BP 23 EP 27 DI 10.1002/(SICI)1097-0215(19990702)82:1<23::AID-IJC5>3.0.CO;2-E PG 5 WC Oncology SC Oncology GA 201DF UT WOS:000080579100005 PM 10360815 ER PT J AU Chen, TP De Vries, EGE Hollema, H Yegen, HA Vellucci, VF Strickler, HD Hildesheim, A Reiss, M AF Chen, TP De Vries, EGE Hollema, H Yegen, HA Vellucci, VF Strickler, HD Hildesheim, A Reiss, M TI Structural alterations of transforming growth factor-beta receptor genes in human cervical carcinoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; TGF-BETA; DIFFERENTIAL RESPONSE; EPITHELIAL-CELLS; II RECEPTOR; CANCER; EXPRESSION; GROWTH-FACTOR-BETA-1; SENSITIVITY; PROTEIN AB The development and progression of invasive uterine cervical carcinomas appear to be associated with the progressive loss of sensitivity to transforming growth factor-beta (TGF beta)-mediated cell cycle arrest. In order to identify possible molecular mechanisms responsible for TGF beta resistance, we screened the 7 exons of the type II (T beta R-II) TGF beta receptor and the 9 exons of the type I (T beta R-I) TGF beta receptor genes for mutations in 16 paraffin-embedded primary invasive cervical carcinoma specimens. In one of these carcinomas, we found a novel G-->T transversion in exon 3 of T beta R-II that introduces a premature stop codon (E142Stop) and presumably results in the synthesis of a truncated soluble exoreceptor, In one tumor, a silent A-->C transversion mutation that may affect mRNA splicing was present in exon 6 of T beta R-I, In addition, 7 of 16 cases were heterozygous for a C-->A polymorphism in intron 7 of T beta R-I. Finally, we identified a 9 base pair in-frame germline deletion in exon I of T beta R-I resulting in loss of 3 of 9 sequential alanine residues at the hi-terminus in 6 of 16 cases. Analysis of specimens from case-control studies indicated that carriers of this del(GGC)(3) T beta R-I variant allele may be at a increased risk for the development of cervical carcinoma (p = 0.22), Furthermore, the response of cells expressing the variant receptor to TGF beta was diminished. Our results support the notion that diverse alterations in the TGF beta signaling pathway may play a role in the development of cervical cancer. (C) 1999 Wiley-Liss, Inc. C1 Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA. Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT 06520 USA. Univ Groningen, Dept Internal Med, Groningen, Netherlands. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Reiss, M (reprint author), Yale Univ, Sch Med, Dept Internal Med, 333 Cedar St,NS291, New Haven, CT 06520 USA. RI Reiss, Michael/A-8314-2009 FU NCI NIH HHS [CA41556] NR 25 TC 91 Z9 97 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 JUL 2 PY 1999 VL 82 IS 1 BP 43 EP 51 PG 9 WC Oncology SC Oncology GA 201DF UT WOS:000080579100009 PM 10360819 ER PT J AU Shiao, YH Bovo, D Guido, M Capella, C Cassaro, M Busatto, G Russo, V Sidoni, A Parenti, AR Rugge, M AF Shiao, YH Bovo, D Guido, M Capella, C Cassaro, M Busatto, G Russo, V Sidoni, A Parenti, AR Rugge, M TI Microsatellite instability and or loss of heterozygosity in young gastric cancer patients in Italy SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID ADENOCARCINOMA; CARCINOMA; STOMACH AB Gastric cancers are rarely diagnosed before the age of 40 years and the incidence reaches a peak during the 7th decade in the general population. A molecular mechanism of early tumor onset may be determined by comparing microsatellite instability (MSI), indicative of error-prone mismatch repair, and loss of heterozygosity (LOH) between gastric cancers in patients less than or equal to 40 years of age and those of older ages. Three to 5 chromosomal loci, where MSI and/or LOH are commonly found in gastric cancers in the general population, were examined in formalin-fixed, paraffin-embedded samples from 102 patients less than or equal to 40 years of age using a polymerase chain reaction-based non-radioactive screening method. MSI acid/or LOH at a minimum of I locus were detected in 11/102 patients, The frequency of MSI and/or LOH at the D11S904 locus was significantly higher than that at the D2S119, D2S123, D5S409 and IFNA regions. No preferential genetic changes at the D11S904 locus were observed in elderly patients, Among several clinicopathological variables, a statistically significant association with MSI and/or LOH was observed only for tumors located at the cardia, compared with tumors at the antrum and the corpus. Our findings suggest that a unique mechanism may be involved in increasing the susceptibility of the D11S904 locus for either MSI or LOH, especially for cardia tumors in young patients. Early onset of gastric cancers in patients less than or equal to 40 years of age is associated with genetic changes at preferential chromosomal loci, including D11S904. (C) 1999 Wiley-Liss, Inc. C1 NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, NIH, Frederick, MD USA. Univ Padua, Cattedra Anat Patol, Cattedra Istochim & Immunohistochim Patol, Dept Oncol & Surg Sci, Padua, Italy. Univ Pavia, Dept Clin & Biol Sci, I-27100 Pavia, Italy. Catania Univ, Dept Pathol, Catania, Italy. Univ Perugia, Dept Pathol, I-06100 Perugia, Italy. RP Rugge, M (reprint author), Univ Padua, Dept Oncol & Surg Sci, Via Aristide Gabelli 61, I-35121 Padua, Italy. RI Rugge, Massimo/K-7525-2016 NR 21 TC 16 Z9 18 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 JUL 2 PY 1999 VL 82 IS 1 BP 59 EP 62 DI 10.1002/(SICI)1097-0215(19990702)82:1<59::AID-IJC11>3.0.CO;2-2 PG 4 WC Oncology SC Oncology GA 201DF UT WOS:000080579100011 PM 10360821 ER PT J AU Yang, XN Rudolf, M Carew, RA Yoshida, M Nerreter, V Riley, AM Chung, SK Bruzik, KS Potter, BVL Schultz, C Shears, SB AF Yang, XN Rudolf, M Carew, RA Yoshida, M Nerreter, V Riley, AM Chung, SK Bruzik, KS Potter, BVL Schultz, C Shears, SB TI Inositol 1,3,4-trisphosphate acts in vivo as a specific regulator of cellular signaling by inositol 3,4,5,6-tetrakisphosphate SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHOLIPASE-C ACTIVITY; RAT PANCREATOMA CELLS; D-MYO-INOSITOL; MYOINOSITOL 1,3,4,5,6-PENTAKISPHOSPHATE; 1,4,5-TRISPHOSPHATE 3-KINASE; CHLORIDE SECRETION; AVIAN ERYTHROCYTES; POLYPHOSPHATE 4-PHOSPHATASE; MEMBRANE-PERMEANT; 1321N1 CELLS AB Ca2+-activated Cl- channels are inhibited by inositol 3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P-4) (Xie, W. Haetzel, M. A., Bruzik, K. S., Dedman, J. R., Shears, S. B., and Nelson, D. J. (1996) J. Biol. Chem. 271, 14092-14097), a novel second messenger that is formed after stimulus-dependent activation of phospholipase C (PLC). In this study, we show that inositol 1,3,4-trisphosphate (Ins(1,3,4)P-3) is the specific signal that ties increased cellular levels of Ins(3,4,5,6)P-4 to changes in PLC activity. We first demonstrated that Ins(1,3,4)P-3 inhibited Ins(3,4,5,6)P-4 1-kinase activity that was either (i) in lysates of AR4-2J pancreatoma cells or (ii) purified 22,500-fold (yield = 13%) from bovine aorta. Next, we incubated [H-3]inositol-labeled AR4-2J cells with cell permeant and non-radiolabeled 2,5,6-tri-O-butyryl-myo-inositol 1,3,4-trisphosphate-hexakis(acetoxymethyl) ester. This treatment increased cellular levels of Ins(1,3,4)P-3 2.7-fold, while [H-3]Ins(3,4,5,6)P-4 levels increased a-fold; there were no changes to levels of other H-3-labeled inositol phosphates. This experiment provides the first direct evidence that levels of Ins(3,4,5,6)P-4 are regulated by Ins(1,3,4)P-3 in vivo, independently of Ins(1,3,4)P-3 being metabolized to Ins(3,4,5,6)P-4. In addition, we found that the Ins(1,3,4)P-3 metabolites, namely Ins(1,3)P-2 and Ins(3,4)P-2, were >100-fold weaker inhibitors of the 1-kinase compared with Ins(1,3,4)P-3 itself (IC50 = 0.17 mu M). This result shows that dephosphorylation of Ins(1,3,4)P-3 in vivo is an efficient mechanism to "switch-off" the cellular regulation of Ins(3,4,5,6)P-4 levels that comes from Ins(1,3,4)P-3-mediated inhibition of the 1-kinase. We also found that Ins(1,3,6)P-3 and Ins(1,4,6)P-3 were poor inhibitors of the 1-kinase (IC50 = 17 and >30 mu M, respectively). The non-physiological trisphosphates, D/L-Ins(1,2,4)P-3, inhibited 1-kinase relatively potently (IC50 = 0.7 mu M), thereby suggesting a new strategy for the rational design of therapeutically useful kinase inhibitors. Overall, our data provide new information to support the idea that Ins(1,3,4)P-3 acts in an important signaling cascade. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. Univ Bremen, Inst Organ Chem, D-28359 Bremen, Germany. Univ Bath, Dept Pharm & Pharmacol, Wolfson Lab Med Chem, Bath BA2 7AY, Avon, England. Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA. Pohang Univ Sci & Technol, Dept Chem, Pohang 790784, South Korea. RP Yang, XN (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Potter, Barry/A-1845-2012; OI Schultz, Carsten/0000-0002-5824-2171 NR 48 TC 38 Z9 38 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 JUL 2 PY 1999 VL 274 IS 27 BP 18973 EP 18980 DI 10.1074/jbc.274.27.18973 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 212BK UT WOS:000081196300019 PM 10383396 ER PT J AU Hashimoto, T Fujita, T Usuda, N Cook, W Qi, C Peters, JM Gonzalez, FJ Yeldandi, AV Rao, MS Reddy, JK AF Hashimoto, T Fujita, T Usuda, N Cook, W Qi, C Peters, JM Gonzalez, FJ Yeldandi, AV Rao, MS Reddy, JK TI Peroxisomal and mitochondrial fatty acid beta-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor alpha and peroxisomal fatty Acyl-CoA oxidase - Genotype correlation with fatty liver phenotype SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RHIZOMELIC CHONDRODYSPLASIA PUNCTATA; RAT-LIVER; CARNITINE PALMITOYLTRANSFERASE; 3-KETOACYL-COA THIOLASE; MOLECULAR-CLONING; PTS2 RECEPTOR; HUMAN PEX7; GENE; PURIFICATION; EXPRESSION AB Fatty acid beta-oxidation occurs in both mitochondria and peroxisomes. Long chain fatty acids are also metabolized by the cytochrome P450 CYP4A omega-oxidation enzymes to toxic dicarboxylic acids (DCAs) that serve as substrates for peroxisomal beta-oxidation. Synthetic peroxisome proliferators interact with peroxisome proliferator activated receptor alpha (PPAR alpha) to transcriptionally activate genes that participate in peroxisomal, microsomal, and mitochondrial fatty acid oxidation. Mice lacking PPAR alpha (PPAR alpha(-/-)) fail to respond to the inductive effects of peroxisome proliferators, whereas those lacking fatty acyl-CoA oxidase (AOX(-/-)), the first enzyme of the peroxisomal beta-oxidation system, exhibit extensive microvesicular steatohepatitis, leading to hepatocellular regeneration and massive peroxisome proliferation, implying sustained activation of PPAR alpha by natural ligands. We now report that mice nullizygous for both PPAR alpha and AOX (PPAR alpha(-/-) AOX(-/-)) failed to exhibit spontaneous peroxisome proliferation and induction of PPAR alpha-regulated genes by biological ligands unmetabolized in the absence of AOX. In AOX-/- mice, the hyperactivity of PPAR alpha enhances the severity of steatosis by inducing CYP4A family proteins that generate DCAs and since they are not metabolized in the absence of peroxisomal beta-oxidation, they damage mitochondria leading to steatosis. Blunting of microvesicular steatosis, which is restricted to few liver cells in periportal regions in PPAR alpha(-/-) AOX(-/-) mice, suggests a role for PPAR alpha-induced genes, especially members of CYP4A family, in determining the severity of steatosis in livers with defective peroxisomal beta-oxidation. In age-matched PPAR alpha(-/-) mice, a decrease in constitutive mitochondrial beta-oxidation with intact constitutive peroxisomal beta-oxidation system contributes to large droplet fatty change that is restricted to centrilobular hepatocytes. These data define a critical role for both PPAR alpha and AOX in hepatic lipid metabolism and in the pathogenesis of specific fatty liver phenotype. C1 Northwestern Univ, Sch Med, Dept Pathol, Chicago, IL 60611 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Reddy, JK (reprint author), Northwestern Univ, Sch Med, Dept Pathol, 303 E Chicago Ave, Chicago, IL 60611 USA. RI Peters, Jeffrey/D-8847-2011 FU NIGMS NIH HHS [GM 23750] NR 49 TC 173 Z9 182 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 2 PY 1999 VL 274 IS 27 BP 19228 EP 19236 DI 10.1074/jbc.274.27.19228 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 212BK UT WOS:000081196300053 PM 10383430 ER PT J AU Pak, M Hoskins, JR Singh, SK Maurizi, MR Wickner, S AF Pak, M Hoskins, JR Singh, SK Maurizi, MR Wickner, S TI Concurrent chaperone and protease activities of ClpAP and the requirement for the N-terminal ClpA ATP binding site for chaperone activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAT-SHOCK PROTEIN; ESCHERICHIA-COLI; MOLECULAR CHAPERONE; SPECIFICITY COMPONENT; MUTATIONAL ANALYSIS; DEPENDENT PROTEASE; ACTIVATED ATPASE; MU-TRANSPOSASE; HSP104; PROTEOLYSIS AB ClpA, a member of the Clp/Hsp100 family of ATPases, is both an ATP-dependent molecular chaperone and the regulatory component of ClpAP protease. We demonstrate that chaperone and protease activities occur concurrently in ClpAP complexes during a single round of RepA binding to ClpAP and ATP-dependent release. This result was substantiated with a ClpA mutant, ClpA(K220V), carrying an amino acid substitution in the N-terminal ATP binding site. ClpA(K220V) is unable to activate RepA, but the presence of ClpP or chemically inactivated ClpP restores its ability to activate RepA. The presence of ClpP simultaneously facilitates degradation of RepA ClpP must remain bound to ClpA(K220V) for these effects, indicating that both chaperone and proteolytic activities of the mutant complex occur concurrently. ClpA(K220V) itself is able to form stable complexes with RepA in the presence of a poorly hydrolyzed ATP analog, adenosine 5'-O-(thiotriphosphate), and to release RepA upon exchange of adenosine 5'-O-(thiotriphosphate) with ATP. However, the released RepA is inactive in DNA binding, indicating that the N-terminal ATP binding site is essential for the chaperone activity of ClpA. Taken together, these results suggest that substrates bound to the complex of the proteolytic and ATPase components can be partitioned between release/reactivation and translocation/degradation. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wickner, S (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Rm 2D19,37 Convent Dr,MSC37-4255, Bethesda, MD 20892 USA. NR 40 TC 45 Z9 45 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 2 PY 1999 VL 274 IS 27 BP 19316 EP 19322 DI 10.1074/jbc.274.27.19316 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 212BK UT WOS:000081196300065 PM 10383442 ER PT J AU Pece, S Chiariello, M Murga, C Gutkind, JS AF Pece, S Chiariello, M Murga, C Gutkind, JS TI Activation of the protein kinase Akt PKB by the formation of E-cadherin-mediated cell-cell junctions - Evidence for the association of phosphatidylinositol 3-kinase with the E-cadherin adhesion complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETA-CATENIN; TYROSINE PHOSPHORYLATION; ALPHA-CATENIN; DIMERIZATION; EXPRESSION; TRANSITION; CARCINOMA; RECEPTORS; PHENOTYPE; SURVIVAL AB E-cadherins are surface adhesion molecules localized at the level of adherens junctions, which play a major role in cell adhesiveness by mediating calcium-dependent homophylic interactions at sites of cell-cell contacts. Recently, E-cadherins have been also implicated in a number of biological processes, including cell growth and differentiation, cell recognition, and sorting during developmental morphogenesis, as well as in aggregation-dependent cell survival. As phosphatidylinositol (PI) 3-kinase and Akt play a critical role in survival pathways in response to both growth factors and extracellular stimuli, these observations prompted us to explore whether E-cadherins could affect intracellular molecules regulating the activity of the PI 3-kinase/Akt signaling cascade. Using Madin-Darby canine kidney cells as a model system, we show here that engagement of E-cadherins in homophylic calcium-dependent cell cell interactions results in a rapid PI 3-kinase-dependent activation of Akt and the subsequent translocation of Akt to the nucleus. Moreover, we demonstrate that the activation of PI 3-kinase in response to cell-cell contact formation involves the phosphorylation of PI 3-kinase in tyrosine residues, and the concomitant recruitment of PI 3-kinase to E-cadherin-containing protein complexes. These findings indicate that E-cadherins can initiate outside-in signal transducing pathways that regulate the activity of PI 3-kinase and Akt, thus providing a novel molecular mechanism whereby the interaction among neighboring cells and their adhesion status may ultimately control the fate of epithelial cells. C1 NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), NIDCR, Oral & Pharyngeal Canc Branch, NIH, 9000 Rockville Pike,Bldg 30,Rm 211, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009; Pece, Salvatore/B-9609-2013; Murga, Cristina/E-1965-2014; Chiariello, Mario/O-3642-2014 OI Pece, Salvatore/0000-0003-1764-3929; Murga, Cristina/0000-0002-8964-4077; Chiariello, Mario/0000-0001-8434-5177 NR 32 TC 210 Z9 215 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 2 PY 1999 VL 274 IS 27 BP 19347 EP 19351 DI 10.1074/jbc.274.27.19347 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 212BK UT WOS:000081196300069 PM 10383446 ER PT J AU Racz, A Barsony, J AF Racz, A Barsony, J TI Hormone-dependent translocation of vitamin D receptors is linked to transactivation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GREEN FLUORESCENT PROTEIN; 1,25-DIHYDROXYVITAMIN D-3 RECEPTOR; TRANSCRIPTION FACTOR IIB; GLUCOCORTICOID RECEPTOR; LIVING CELLS; ACTIVATION FUNCTION-2; NUCLEAR-LOCALIZATION; BASAL TRANSCRIPTION; DNA-BINDING; DOMAIN AB Vitamin D receptor (VDR) acts as a transcription factor mediating genomic actions of calcitriol. Our earlier studies suggested that calcitriol induces translocation of cytoplasmic VDR, but the physiologic relevance of this finding remained uncertain. Previous studies demonstrated that the activation function 2 domain (AF-2) plays an essential role in VDR transactivation. To elucidate hormone-dependent VDR translocation and its role, we constructed green fluorescent protein (GFP) chimeras with full-length VDR (VDR-GFP), AF-2-truncated VDR (AF-2del-VDR-GFP), and ligand-binding domain LBD)-truncated VDR (LBDdel-VDR-GFP), COS-7 cells were transiently transfected with these constructs. Western blot analysis, fluorescent microscopy, and transactivation assays showed that the generated chimeras are expressed and fluoresce and that VDR-GFP is transcriptionally active. After hormone treatment, cytoplasmic VDR-GFP translocated to the nucleus in a concentration-, time-, temperature-, and analog-specific manner. Hormone dose-response relationships for translocation and for transactivation were similar. Truncation of LED and truncation of AF-2 each abolished hormone-dependent translocation and transactivation. Our data confirm a hormone-dependent VDR translocation, demonstrate that an intact AF-2 domain is required for this translocation, and indicate that translocation is part of the receptor activation process. C1 NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Barsony, J (reprint author), NIDDK, Lab Cell Biochem & Biol, NIH, Bldg 8,Rm 422,8 Ctr Dr, Bethesda, MD 20892 USA. NR 45 TC 76 Z9 78 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 JUL 2 PY 1999 VL 274 IS 27 BP 19352 EP 19360 DI 10.1074/jbc.274.27.19352 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 212BK UT WOS:000081196300070 PM 10383447 ER PT J AU Fedi, P Bafico, A Soria, AN Burgess, WH Miki, T Bottaro, DP Kraus, MH Aaronson, SA AF Fedi, P Bafico, A Soria, AN Burgess, WH Miki, T Bottaro, DP Kraus, MH Aaronson, SA TI Isolation and biochemical characterization of the human Dkk-1 homologue, a novel inhibitor of mammalian Wnt signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EXPRESSION CDNA CLONING; BETA-CATENIN; TYROSINE KINASE; HEAD INDUCTION; CELL-LINE; FAMILY; PROTEIN; GROWTH; TRANSFORMATION; ACTIVATION AB In an effort to isolate novel growth factors, we identified a human protein, designated Sk, that co-eluted with Neuregulin during chromatographic separation of conditioned medium from the SK-LMS-1 human leiomyosarcoma cell line. Degenerate oligonucleotides based on amino-terminal sequence analysis of the purified protein were used to isolate the corresponding cDNA from a library generated from this cell line. Sk is a novel 266-amino acid protein that contains a signal peptide sequence and two cysteine-rich domains with no similarity to other known growth factors. A single major 2-kilobase transcript was expressed in several embryonic tissues, Transfection of mammalian cells demonstrated that the protein was secreted and expressed as a doublet of approximately 35 kDa. In vitro translation and endoglycosylase analysis indicated that this doublet, which was also observed in cells expressing the endogenous protein, arises from posttranslational modification. A search of the GenBank(TM) data base revealed a match of Sk with Dkk-1, which is a novel secreted protein required for head induction in amphibian embryos and a potent Wnt inhibitor. When coexpressed with Wnt-2 in NIH3T3 cells, human Sk/Dkk-1 caused reversion of Wnt-2 induced morphological alterations and inhibited the Wnt-2 induced increase in uncomplexed beta-catenin levels. These results provide biochemical evidence that human Sk/Dkk-1 antagonizes Wnt signaling upstream of its effect on beta-catenin regulation. C1 CUNY Mt Sinai Sch Med, Derald H Ruttenberg Canc Ctr, New York, NY 10029 USA. Amer Red Cross, Jerome H Holland Lab, Rockville, MD 20855 USA. NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. European Inst Oncol, Dept Expt Oncol, I-20141 Milan, Italy. RP CUNY Mt Sinai Sch Med, Derald H Ruttenberg Canc Ctr, 1 Gustave L Levy Pl,Box 1130, New York, NY 10029 USA. EM pfedi@smtplink.mssm.edu RI Bottaro, Donald/F-8550-2010 OI Bottaro, Donald/0000-0002-5057-5334 FU NCI NIH HHS [CA71672, CA71997] NR 38 TC 171 Z9 188 U1 0 U2 9 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 JUL 2 PY 1999 VL 274 IS 27 BP 19465 EP 19472 DI 10.1074/jbc.274.27.19465 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 212BK UT WOS:000081196300086 PM 10383463 ER PT J AU Zeng, FY Wess, J AF Zeng, FY Wess, J TI Identification and molecular characterization of m3 muscarinic receptor dimers SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID 3RD CYTOPLASMIC LOOP; SITE-DIRECTED MUTAGENESIS; PROTEIN-COUPLED RECEPTOR; ACETYLCHOLINE-RECEPTOR; CHOLINERGIC RECEPTOR; ANTAGONIST BINDING; FUNCTIONAL RESCUE; DIMERIZATION; INTERNALIZATION; COEXPRESSION AB Several studies suggest, but do not prove directly, that muscarinic receptors may be able to form dimeric or oligomeric arrays. To address this issue in a more direct fashion, we designed a series of biochemical experiments using a modified version of the rat m3 muscarinic receptor (referred to as m3') as a model system. When membrane lysates prepared from m3' receptor-expressing COS-7 cells were subjected to Western blot analysis under non-reducing conditions, several immunoreactive species were observed corresponding in size to putative receptor monomers, dimers, and oligomers, However, under reducing conditions, the monomeric receptor species represented the only detectable immunoreactive protein, consistent with the presence of disulfide-linked m3 receptor complexes. Similar results were obtained when native m3 muscarinic receptors present in rat brain membranes were analyzed. Control experiments carried out in the presence of high concentrations of the SH group alkylating agent, N-ethylmaleimide, suggested that disulfide bond formation did not occur artifactually during the preparation of cell lysates, The formation of m3' receptor dimers/multimers was confirmed in coimmunoprecipitation studies using differentially epitope-tagged m3' receptor constructs. In addition, these studies showed that m3' receptors were also able to form non-covalently associated receptor dimers and that m3' receptor dimer formation was receptor subtype-specific, Immunological studies also demonstrated that m3' receptor dimers/multimers were abundantly expressed on the cell surface. Site-directed mutagenesis studies indicated that two conserved extracellular Cys residues (Cys-140 and Cys-220) play key roles in the formation of disulfide-linked m3' receptor dimers. These results provide the first direct evidence for the existence of muscarinic receptor dimers and highlight the specificity and molecular diversity of G protein-coupled receptor dimerization/oligomerization. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP NIDDKD, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-05, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov NR 42 TC 193 Z9 197 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 2 PY 1999 VL 274 IS 27 BP 19487 EP 19497 DI 10.1074/jbc.274.27.19487 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 212BK UT WOS:000081196300089 PM 10383466 ER PT J AU Janini, GM Metral, CJ Issaq, HJ Muschik, GM AF Janini, GM Metral, CJ Issaq, HJ Muschik, GM TI Peptide mobility and peptide mapping in capillary zone electrophoresis - Experimental determination and theoretical simulation SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE mathematical modelling; peptides ID FLIGHT MASS-SPECTROMETRY; PHYSICOCHEMICAL PROPERTIES; BUFFER PH; PROTEINS; CHROMATOGRAPHY; OPTIMIZATION; PREDICTION; SEPARATION; MOLECULES; SIZE AB The electrophoretic mobilities of 58 peptides that varied in size from 2 to 39 amino acids and varied in charge from 0.65 to 7.82 are presented. The measurements were conducted at 22 degrees C using a 10% linear polyacrylamide-coated column and a 50 mM phosphate buffer at pH 2.5. Excellent separation of peptides and highly reliable peptide maps of protein digests are routinely obtained using these experimental conditions. The electrophoretic data were used to test existing theoretical models that correlate electrophoretic mobility with physical parameters. The results indicate that the Offord model that correlates electrophoretic mobility with the charge-to-size parameter q/M-2/3 offers the best fit of our reliable experimental data. Furthermore, we also obtained the capillary zone electrophoretic profile of the endoproteinase Lys-C digests of a peptide sequencing standard, melittin, and horse myoglobin under the same experimental conditions as described above. The resulting peptide maps were compared with corresponding theoretical simulation. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NCI, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Janini, GM (reprint author), NCI, SAIC Frederick, Frederick Canc Res & Dev Ctr, POB B, Frederick, MD 21702 USA. FU NCI NIH HHS [N0-1-CO-56000] NR 33 TC 60 Z9 61 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD JUL 2 PY 1999 VL 848 IS 1-2 BP 417 EP 433 DI 10.1016/S0021-9673(99)00388-X PG 17 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 215YU UT WOS:000081413600037 PM 10427763 ER PT J AU Radko, SP Chrambach, A AF Radko, SP Chrambach, A TI Capillary zone electrophoresis of rigid submicron-sized particles in polyacrylamide solution - Selectivity, peak spreading and resolution SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE particles; submicron-sized; buffer composition; polyacrylamide; polystyrene ID POLYMER-SOLUTIONS; SPHERICAL-PARTICLES; DNA; SEPARATIONS; RETARDATION AB Submicron-sized rigid particles can be separated in a size-dependent fashion by electrophoresis in free solution. Yet it has remained unknown whether the presence of polymers in the solution confers an advantage in size-dependent separation of submicron particles and their resolution. The present study addresses that question, using capillary zone electrophoresis of carboxylate modified polystyrene latex microspheres of 55, 140 and 215 nm radius in solutions of linear polyacrylamide in the M-r range of 0.4.10(6) to 1.14.10(6). Selectivity of particle separation increases in direct relation to the polymer concentration in the concentration range of 0 to 1% (w/v). Selectivity was found to increase with M-r of the polymer for the particle sets of 55/140 (nm/nm), and 140/215 (nm/nm) but to decrease with polymer M-r for the 55/215 (nm/nm) set. Peak spreading is a complex and. in the case of the largest particle, non-monotonic function of polymer concentration, with a minimum at concentrations around the entanglement threshold, c*. Consequently, resolution of the 55/215 and 140/215 (nm/nm) sets also exhibits a maximum around the entanglement threshold while resolution for the 55/140 (nm/nm) set increases with a rise of polymer concentrations above c*. Within the range of optimally resolving polymer concentrations there also occurs a maximum of resolution for all particle sets at a field strength in the range of 150 to 250 V cm(-1) (C) 1999 Published by Elsevier Science B.V. All rights reserved. C1 NICHHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Chrambach, A (reprint author), NICHHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. NR 34 TC 9 Z9 9 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD JUL 2 PY 1999 VL 848 IS 1-2 BP 443 EP 455 DI 10.1016/S0021-9673(99)00456-2 PG 13 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 215YU UT WOS:000081413600039 PM 10427764 ER PT J AU Polikarpov, I Matilde, MS Marangoni, S Toyama, MH Teplyakov, A AF Polikarpov, I Matilde, MS Marangoni, S Toyama, MH Teplyakov, A TI Crystal structure of neurotoxin Ts1 from Tityus serrulatus provides insights into the specificity and toxicity of scorpion toxins SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE scorpion neurotoxin; Tityus serrulatus; crystal structure; sodium channel ID ANDROCTONUS-AUSTRALIS-HECTOR; NUCLEAR-MAGNETIC-RESONANCE; INSECT-SPECIFIC TOXIN; AMINO-ACID-SEQUENCE; SODIUM-CHANNEL; 3-DIMENSIONAL STRUCTURE; ANGSTROM RESOLUTION; CENTRUROIDES-NOXIUS; ANTIINSECT TOXIN; RECEPTOR-SITES AB The crystal structure of neurotoxin Ts1, a major component of the venom of the Brazilian scorpion Tityus serrulatus, has been determined at 1.7 Angstrom resolution. It is the first X-ray structure of a highly toxic anti-mammalian beta-toxin. The folding of the polypeptide chain of Ts1 is similar to that of other scorpion toxins. A cysteine-stabilised alpha-helix/beta-sheet motif forms the core of the flattened molecule All residues identified as functionally important by Chemical modification and site-directed mutagenesis are located on one side of the molecule, which is therefore considered as the Na+ channel recognition site. The distribution of charged and non-polar residues over this surface determines the specificity of the toxin-channel interaction. Comparison to other scorpion toxins shows that positively charged groups at positions 1 and 12 as well as a negative charge at position 2 are likely determinants of the specificity of beta-toxins. In contrast, the contribution of the conserved aromatic cluster to the interaction might be relatively small. Comparison of Ts1 to weak beta-toxins from Centruroides sculpturatus Ewing reveals that a number of basic amino acid residues located on the face of the molecule opposite to the binding surface may account for the high toxicity of Ts1. (C) 1999 Academic Press. C1 Lab Nacl Luz Sincrotron, BR-13083970 Campinas, SP, Brazil. UNICAMP, Inst Biol, Dept Bioquim, BR-13083970 Campinas, SP, Brazil. NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Polikarpov, I (reprint author), Lab Nacl Luz Sincrotron, CP 6192, BR-13083970 Campinas, SP, Brazil. RI Polikarpov, Igor/D-2575-2012 NR 58 TC 41 Z9 42 U1 1 U2 7 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 JUL 2 PY 1999 VL 290 IS 1 BP 175 EP 184 DI 10.1006/jmbi.1999.2868 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 214DA UT WOS:000081311300013 PM 10388565 ER PT J AU Koenekoop, R Pina, AL Loyer, M Davidson, J Robitaille, J Maumenee, I Tombran-Tink, J AF Koenekoop, R Pina, AL Loyer, M Davidson, J Robitaille, J Maumenee, I Tombran-Tink, J TI Four polymorphic variations in the PEDF gene identified during the mutation screening of patients with Leber congenital amaurosis SO MOLECULAR VISION LA English DT Article ID DOMINANT RETINITIS-PIGMENTOSA; EPITHELIUM-DERIVED FACTOR; CHROMOSOME 17P; SHORT ARM; LOCALIZATION; LOCUS; DYSTROPHY; FAMILY AB PURPOSE: Leber congenital amaurosis (LCA) has been mapped to chromosome 17p13.1. From the candidate genes mapped to this region, thus far, only Retinal Guanylate Cyclase (RetGC), has been found to have pathogenic LCA mutations, in families from North African origin. However, early reports, demonstrated eight LCA families linked to 17p13.1, but only four of them showed mutations in RetGC. Mapped in proximity to this locus is the candidate gene Pigment Epithelium Derived actor (PEDF), a factor implicated in photoreceptor differentiation and neuronal survival. Our purpose in this study was to identify mutations and polymorphisms in the PEDF gene in LCA patients of diverse ethnic origin. METHODS: Automated genotyping with four 17p13.1 markers flanking the PEDF gene was performed to assess homozygosity and PCR-SSCP combined with direct sequencing was used to detect mutations in the PEDF gene in 17 LCA patients. RESULTS: Homozygosity of markers D17S796 and D17S804 was found and four new intragenic basepair alterations were discovered: a Met72Thr polymorphism in exon 3 (T331C), a Thr130Thr polymorphism in exon 4 (T506C), a G to A transition in intron 5 (nine base pairs upstream from splice acceptor site), and a Tyr321Tyr polymorphism in exon 7 (C1079T) were detected. CONCLUSIONS: We report the discovery of four new polymorphic alterations in the PEDF gene in LCA patients and exclude by RFLP analysis the PEDF gene as a common cause of Leber congenital amaurosis. These single nucleotide polymorphisms will aid in future linkage analysis of complex multifactorial diseases involving retinal and RPE dysfunctions. C1 Montreal Childrens Hosp, Res Inst, Dept Ophthalmol, McGill Ocular Genet Lab, Montreal, PQ H3H 1P3, Canada. Johns Hopkins Ctr Hereditary Eye Dis, Baltimore, MD USA. NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Koenekoop, R (reprint author), Montreal Childrens Hosp, Res Inst, Dept Ophthalmol, McGill Ocular Genet Lab, 2300 Tupper, Montreal, PQ H3H 1P3, Canada. NR 31 TC 0 Z9 0 U1 0 U2 1 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUL 2 PY 1999 VL 5 IS 10 PG 4 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 240JX UT WOS:000082823800001 ER PT J AU Hayakawa, K Asano, M Shinton, SA Gui, M Allman, D Stewart, CL Silver, J Hardy, RR AF Hayakawa, K Asano, M Shinton, SA Gui, M Allman, D Stewart, CL Silver, J Hardy, RR TI Positive selection of natural autoreactive B cells SO SCIENCE LA English DT Article ID REGION GENE-EXPRESSION; TRANSGENIC MICE; AUTOIMMUNE-DISEASE; CLONAL SELECTION; NORMAL MOUSE; IMMUNOGLOBULIN; ANTIGEN; AUTOANTIBODIES; ANTIBODY; LINEAGE AB Lymphocyte development is critically influenced by self-antigens. T cells are subject to both positive and negative selection, depending on their degree of seif-reactivity. Although B cells are subject to negative selection, it has been difficult to test whether self-antigen plays any positive role in B cell development. A murine model system of naturally generated autoreactive B cells with a germ Line gene-encoded specificity for the Thy-1 (CD90) glycoprotein was developed, in which the presence of self-antigen promotes B cell accumulation and serum autoantibody secretion. Thus, B cells can be subject to positive selection, generated, and maintained on the basis of their autoreactivity. C1 Fox Chase Canc Ctr, Inst Canc Res, Philadelphia, PA 19111 USA. NCI, Lab Canc & Dev Biol, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Cornell Univ Med Coll, N Shore Univ Hosp, Div Mol Med, Manhasset, NY 11030 USA. RP Hayakawa, K (reprint author), Fox Chase Canc Ctr, Inst Canc Res, 7701 Burholme Ave, Philadelphia, PA 19111 USA. NR 33 TC 390 Z9 399 U1 0 U2 4 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 JUL 2 PY 1999 VL 285 IS 5424 BP 113 EP 116 DI 10.1126/science.285.5424.113 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 212CY UT WOS:000081199800043 PM 10390361 ER PT J AU Borbely, K Brooks, RA Wong, DF Burns, RS Cumming, P Gjedde, A Di Chiro, G AF Borbely, K Brooks, RA Wong, DF Burns, RS Cumming, P Gjedde, A Di Chiro, G TI NMSP binding to dopamine and serotonin receptors in MPTP-induced parkinsonism: relation to dopa therapy SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Article DE dopamine; L-dihydroxyphenylalanine (L-dopa); Hoehn-&-Yahr staging; N-methyl-phenyl-tetrahydio-pyridine (MPTP); N-methylspiperone (NMSP) binding; parkinsonism; positron emission tomography (PET) ID POSITRON EMISSION TOMOGRAPHY; LIVING HUMAN-BRAIN; C-11 RACLOPRIDE; RAT STRIATUM; DISEASE; PET; DENSITY; SCHIZOPHRENICS; QUANTIFICATION; NEURORECEPTORS AB We tested the hypothesis that N-methylspiperone binding to dopamine D-2 receptors must be reduced when L-dopa therapy of parkinsonism augments the binding of dopamine to the receptors and improves the clinical state expressed by the Hoehn & Yahr stage. A patient with MPTP-induced parkinsonism underwent two positron emission tomographic studies of the D-2-like dopamine receptors with N-[C-11]methylspiperone (NMSP), The first study took place 3 days after cessation of the L-dopa medication, the second 5 days after its resumption. Noticeable clinical deterioration occurred during both studies, consistent with significant dopamine receptor blockade by NMSP and elevated NMSP binding in both scans. The dopa treatment. did not reduce the NMSP binding. On the contrary, the rate of binding of NMSP (k(3)) was increased on-dopa, compared to off-dopa. The increase was consistent with the slightly greater dopamine receptor density estimated after resumption of the dopa therapy. The NMSP binding to serotonin receptors suggested lower synaptic serotonin on-dopa than off-dopa. The results are consistent with negative correlation between the Hoehn & Yahr stage and the amount of dopamine bound to dopamine D-2 receptors. Low synaptic serotonin may explain the depression seen in some patients on dopa for Parkinson's disease. C1 Aarhus Univ Hosp, PET Ctr, DK-8000 Aarhus C, Denmark. NINDS, Neuroimaging Branch, NIH, Bethesda, MD 20892 USA. NINDS, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Dept Radiol, Baltimore, MD 21287 USA. RP Gjedde, A (reprint author), Aarhus Univ Hosp, PET Ctr, 44 Norrebrogade, DK-8000 Aarhus C, Denmark. OI Gjedde, Albert/0000-0002-3756-7401 FU NIDA NIH HHS [DA09482]; NIMH NIH HHS [MH42821] NR 44 TC 6 Z9 6 U1 0 U2 2 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-6314 J9 ACTA NEUROL SCAND JI Acta Neurol. Scand. PD JUL PY 1999 VL 100 IS 1 BP 42 EP 52 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 209LZ UT WOS:000081050700007 PM 10416511 ER PT J AU Wada, K Greberman, SB Konuma, K Hirai, S AF Wada, K Greberman, SB Konuma, K Hirai, S TI HIV and HCV infection among drug users in Japan SO ADDICTION LA English DT Article ID UNITED-STATES; PREVALENCE; HBV; HDV AB Aims. To assess seroprevalence of human immunodeficiency virus (HIV), hepatitis C virus, injecting drug use, unsafe sexual behaviours, self-mutilation and tattoos in patients attending a drug and alcohol treatment centre in Japan. Design. Cross-sectional survey. Setting. The work was carried out at the National Sanitarium of Shimousa, Chiba, Japan, a 32-bed inpatient centre specializing in drug and alcohol treatment. Measurements. Laboratory analyses for HIV antibody, hepatitis C antibody, hepatitis B antigen and antibody; questionnaires for history of sexual activities, needle and syringe use; physical examination with assessment of self-amputated finger joints, tattoos, scars fi om lacerations and cigarette bums. Findings. No patients tested positive for anti-HIV. The seroprevalence of anti-HCV positives was 53.8% of methamphetamine-dependent patients, 18.4% of solvent-dependent patients and 5.6% of alcohol-dependent patients. Past needle sharing was reported by 82.1% of methamphetamine-dependent patients, 18.4% of solvent-dependent patients and 5.6% of alcohol-dependent patients. A history of syringe sharing was reported by 87.2% of methamphetamine-dependent patients. More than two-thirds of all patients reported contact with commercial sex workers. Casual sexual contacts were more common among solvent and methamphetamine-dependent patients than those dependent on alcohol. Tattoos and cigarette bums were more common among methamphetamine and solvent-dependent patients than among alcohol-dependent patients. Among the methamphetamine-dependent patients, 20.5% reported self-amputated finger joints compared with none in the other patient groups. Conclusions. HCV prevalence is a significant problem among methamphetamine users in Japan, probably because of a high rate of needle and/or syringe sharing. Although HIV infection is currently negligible, the very high rate of needle and syringe sharing could give rise to a significant increase in the HIV rate among drug users in the future. C1 NIMH, Div Drug Dependence & Psychotrop Drug Clin Res, Natl Ctr Neurol & Psychiat, Chiba 2720827, Japan. Natl Inst Drug Abuse, Div Intramural Res, NIH, Baltimore, MD USA. Natl Sanitarium Shimousa, Chiba, Japan. RP Wada, K (reprint author), NIMH, Div Drug Dependence & Psychotrop Drug Clin Res, Natl Ctr Neurol & Psychiat, 1-7-3 Kohnodai, Chiba 2720827, Japan. NR 16 TC 23 Z9 24 U1 0 U2 1 PU CARFAX PUBLISHING PI BASINGSTOKE PA RANKINE RD, BASINGSTOKE RG24 8PR, HANTS, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD JUL PY 1999 VL 94 IS 7 BP 1063 EP 1069 DI 10.1046/j.1360-0443.1999.947106311.x PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 215GL UT WOS:000081373500016 PM 10707444 ER PT J AU Lane, MA AF Lane, MA TI Nonhuman primate models in biogeront-ology. SO AGE LA English DT Meeting Abstract C1 NIA, Intramural Res Program, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER AGING ASSOC PI MEDIA PA SALLY BALIN MEDICAL CENTER, 110 CHESLEY DR, MEDIA, PA 19063 USA SN 0161-9152 J9 AGE JI Age PD JUL PY 1999 VL 22 IS 3 MA 10 BP 119 EP 119 PG 1 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 289RD UT WOS:000085635000014 ER PT J AU Liu, YS Holbrook, NJ AF Liu, YS Holbrook, NJ TI Age-related alterations in proliferation-associated and stress-activated signaling pathways. SO AGE LA English DT Meeting Abstract C1 NIA, Biol Chem Lab, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER AGING ASSOC PI MEDIA PA SALLY BALIN MEDICAL CENTER, 110 CHESLEY DR, MEDIA, PA 19063 USA SN 0161-9152 J9 AGE JI Age PD JUL PY 1999 VL 22 IS 3 MA 13 BP 119 EP 120 PG 2 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 289RD UT WOS:000085635000017 ER PT J AU Mattison, JA Wright, C Bronson, RT Roth, GS Ingram, D Bartke, A AF Mattison, JA Wright, C Bronson, RT Roth, GS Ingram, D Bartke, A TI Studies of aging in ames dwarf mice: Effects of caloric restriction. SO AGE LA English DT Meeting Abstract C1 So Illinois Univ, Dept Physiol, Carbondale, IL 62901 USA. Tufts Univ, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. NIA, NIH, Bethesda, MD 20892 USA. RI Bartke, Andzej/D-6640-2017 OI Bartke, Andzej/0000-0002-2569-557X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER AGING ASSOC PI MEDIA PA SALLY BALIN MEDICAL CENTER, 110 CHESLEY DR, MEDIA, PA 19063 USA SN 0161-9152 J9 AGE JI Age PD JUL PY 1999 VL 22 IS 3 MA 12 BP 119 EP 119 PG 1 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 289RD UT WOS:000085635000016 ER PT J AU Long, JM Hengemihle, JM Moon, EK Mouton, PR Ingram, DK AF Long, JM Hengemihle, JM Moon, EK Mouton, PR Ingram, DK TI Comparison of hippocampal glia number in C57BL/6J and 129/SvJ mice of different ages. SO AGE LA English DT Meeting Abstract C1 NIA, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER AGING ASSOC PI MEDIA PA SALLY BALIN MEDICAL CENTER, 110 CHESLEY DR, MEDIA, PA 19063 USA SN 0161-9152 J9 AGE JI Age PD JUL PY 1999 VL 22 IS 3 MA 39 BP 126 EP 126 PG 1 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 289RD UT WOS:000085635000042 ER PT J AU Black, A Tilmont, EM Handy, AM Ingram, DK Roth, GS Lane, MA AF Black, A Tilmont, EM Handy, AM Ingram, DK Roth, GS Lane, MA TI Body composition and bone mineral density during initiation of caloric restriction in young and aged rhesus macaques. SO AGE LA English DT Meeting Abstract C1 NIA, Ctr Gerontol Res, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER AGING ASSOC PI MEDIA PA SALLY BALIN MEDICAL CENTER, 110 CHESLEY DR, MEDIA, PA 19063 USA SN 0161-9152 J9 AGE JI Age PD JUL PY 1999 VL 22 IS 3 MA 51 BP 129 EP 129 PG 1 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 289RD UT WOS:000085635000052 ER PT J AU Handy, AM Black, A Ingram, DK Roth, GS Tilmont, EM Lane, MA AF Handy, AM Black, A Ingram, DK Roth, GS Tilmont, EM Lane, MA TI A nonhuman primate model of menopause: Evaluation of reproductive cycling and hormones. SO AGE LA English DT Meeting Abstract C1 ROW Sci Inc, Gaithersburg, MD 21224 USA. NIA, Gerontol Res Ctr, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER AGING ASSOC PI MEDIA PA SALLY BALIN MEDICAL CENTER, 110 CHESLEY DR, MEDIA, PA 19063 USA SN 0161-9152 J9 AGE JI Age PD JUL PY 1999 VL 22 IS 3 MA 52 BP 129 EP 129 PG 1 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 289RD UT WOS:000085635000053 ER PT J AU Moscrip, T Lane, M Roth, G Ingram, D AF Moscrip, T Lane, M Roth, G Ingram, D TI Age-related decline in food intake and motivation for food in rhesus monkeys. SO AGE LA English DT Meeting Abstract C1 ROW Sci, Gaithersburg, MD 20878 USA. NIA, Gerontol Res Ctr, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER AGING ASSOC PI MEDIA PA SALLY BALIN MEDICAL CENTER, 110 CHESLEY DR, MEDIA, PA 19063 USA SN 0161-9152 J9 AGE JI Age PD JUL PY 1999 VL 22 IS 3 MA 54 BP 129 EP 130 PG 2 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 289RD UT WOS:000085635000055 ER PT J AU Poydence, K Robinson, J Kemnitz, J Kohama, S Hayek, M Ingram, D Roth, G Lane, M AF Poydence, K Robinson, J Kemnitz, J Kohama, S Hayek, M Ingram, D Roth, G Lane, M TI Development and utility of a multicenter, longitudinal database of aging in nonhuman primates. SO AGE LA English DT Meeting Abstract C1 ROW Sci, Gaithersburg, MD 20878 USA. NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. Univ Wisconsin, Wisconsin Reg Primate Res Ctr, Madison, WI 53715 USA. Oregon Reg Primate Res Ctr, Beaverton, OR 97006 USA. Iams Co, Lewisburg, OH 45338 USA. NIA, Gerontol Res Ctr, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER AGING ASSOC PI MEDIA PA SALLY BALIN MEDICAL CENTER, 110 CHESLEY DR, MEDIA, PA 19063 USA SN 0161-9152 J9 AGE JI Age PD JUL PY 1999 VL 22 IS 3 MA 53 BP 129 EP 129 PG 1 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 289RD UT WOS:000085635000054 ER PT J AU Roth, GS Ingram, DK Lane, MA AF Roth, GS Ingram, DK Lane, MA TI Caloric restriction mimetics: Great taste, less filling, longer life. SO AGE LA English DT Meeting Abstract C1 NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER AGING ASSOC PI MEDIA PA SALLY BALIN MEDICAL CENTER, 110 CHESLEY DR, MEDIA, PA 19063 USA SN 0161-9152 J9 AGE JI Age PD JUL PY 1999 VL 22 IS 3 MA 67 BP 133 EP 133 PG 1 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 289RD UT WOS:000085635000067 ER PT J AU Hahn, T Matala, E Chappey, C Ahmad, N AF Hahn, T Matala, E Chappey, C Ahmad, N TI Characterization of mother-infant HIV type 1 gag p17 sequences associated with perinatal transmission SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MATRIX PROTEIN; VERTICAL TRANSMISSION; NUCLEAR-LOCALIZATION; NONDIVIDING CELLS; PRIMARY INFECTION; MEMBRANE-BINDING; ENVELOPE PROTEIN; TERMINAL REGION; VIRAL LOAD AB The gag p17 matrix sequences of human immunodeficiency virus type (HIV-1) from seven infected mother-infant pairs were analyzed after perinatal transmission. The p17 matrix open reading frame was maintained in 143 of the 166 clones analyzed (86.2% frequency of intact p17 open reading frames), The functional domains essential for p17 matrix function in HIV-1 replication, including targeting of Gag to the plasma membrane, virus assembly and release, envelope glycoprotein incorporation into virus particle, virus entry, and localization of the virus preintegration complex to the nucleus of nondividing cells, were highly conserved in most of the sequences. In addition, examination of the three-dimensional structure of the p17 matrix protein in mother-infant isolates showed a high degree of conservation of amino acids required for correct folding and biological activity, Several amino acid motifs common to most of the mother-infant pairs sequences, including pair-specific signature sequences, were observed, There was a low degree of heterogeneity of gag p17 sequences within mothers, within infants, and between mother-infant pairs, but the distances were greater between epidemiologically unlinked individuals. Phylogenetic analyses of 166 mother-infant pairs and 181 other p17 sequences available from HIV-1 databases revealed distinct clusters for each mother-infant pair and for other p17 sequences. In conclusion, these findings indicate that an intact and functional gag p17 matrix is maintained during maternal-fetal transmission and that several motifs in p17 may be associated with perinatal transmission. C1 Univ Arizona, Hlth Sci Ctr, Coll Med, Dept Microbiol & Immunol, Tucson, AZ 85724 USA. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Ahmad, N (reprint author), Univ Arizona, Hlth Sci Ctr, Coll Med, Dept Microbiol & Immunol, Tucson, AZ 85724 USA. FU NIAID NIH HHS [AI 40378] NR 73 TC 22 Z9 22 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUL 1 PY 1999 VL 15 IS 10 BP 875 EP 888 DI 10.1089/088922299310584 PG 14 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 212GC UT WOS:000081208100003 PM 10408724 ER PT J AU Harris, GJ Oscar-Berman, M Gansler, A Streeter, C Lewis, RF Ahmed, I Achong, D AF Harris, GJ Oscar-Berman, M Gansler, A Streeter, C Lewis, RF Ahmed, I Achong, D TI Hypoperfusion of the cerebellum and aging effects on cerebral cortex blood flow is abstinent alcoholics: A SPECT study SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE alcoholism; abstinence; SPECT; regional cerebral blood flow; cerebellum ID WHITE-MATTER; HUMAN BRAIN; ATROPHY; TOMOGRAPHY; GRAY; AGE; ASYMMETRIES; METABOLISM; DEFICITS; DISEASE AB Background: This study evaluated hypotheses concerning alcoholism, aging, and the relationship between cerebral hypoperfusion and residual deficits in the functioning of cerebellar and neocortical brain systems. Methods: The participants were 10 healthy abstinent alcoholics (9 men, 1 woman) and 12 nonalcoholic controls (10 men, 2 women) ranging in age from 35 to 67 years. Cerebral blood flow was observed through the use of regionally specific computer-derived quantitative analysis of single photon emission computed tomography (SPECT) perfusion images. Cerebellar perfusion was measured and compared with cerebral cortex perfusion in age-equivalent subgroups of alcoholics and controls (under 55 years; 55 years and over). Results: In abstinent alcoholics under age 55, cerebellar perfusion ratios were significantly reduced compared with the controls. In alcoholics asd nonalcoholic controls 55 years old and older, this relationship was reversed, probably as a result of diminished cortical perfusion with aging in the alcoholics and of cerebellar decline in the controls. Conclusions: The findings support hypotheses that the residual effects of alcoholism include cerebellar brain abnormalities and that aging combined with long-term alcoholism leads to cerebral cortical decline. C1 Massachusetts Gen Hosp, Radiol Comp Aided Diagnost Lab, Boston, MA 02114 USA. Tufts Univ, Sch Med, Dept Psychiat, New England Med Ctr, Boston, MA 02111 USA. Dept Vet Affairs Med Ctr, Psychol Serv, Boston, MA USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. NIDA, Boston Vet Adm, Med Dev Res Unit, Boston, MA USA. Dept Vet Affairs Med Ctr, Boston, MA USA. Tufts Univ, Sch Med, Dept Radiol, New England Med Ctr, Boston, MA 02111 USA. Univ Hawaii, John A Burns Sch Med, Honolulu, HI 96822 USA. RP Harris, GJ (reprint author), Massachusetts Gen Hosp, Radiol Comp Aided Diagnost Lab, Zero Emerson Pl,3C, Boston, MA 02114 USA. FU NIAAA NIH HHS [R37-AA07112, R37 AA007112, K05 AA000219]; NIDA NIH HHS [R03-DA09480]; NINDS NIH HHS [R29-NS31338] NR 61 TC 11 Z9 12 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 JUL PY 1999 VL 23 IS 7 BP 1219 EP 1227 PG 9 WC Substance Abuse SC Substance Abuse GA 219RB UT WOS:000081619600013 PM 10443989 ER PT J AU Prasad, A Husain, S Quyyumi, AA AF Prasad, A Husain, S Quyyumi, AA TI Effect of enalaprilat on nitric oxide activity in coronary artery disease SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CONVERTING-ENZYME-INHIBITORS; ENDOTHELIUM-DEPENDENT VASODILATION; CHRONIC HEART-FAILURE; HYPERTENSIVE PATIENTS; RESISTANCE ARTERIES; HUMAN FOREARM; ANGIOTENSIN; BRADYKININ; ATHEROSCLEROSIS; DYSFUNCTION AB Atherosclerosis is associated with vascular endothelial dysfunction and reduced nitric oxide (NO) activity. Enhancement of NO activity may have an antiatherogenic action. This study was performed to determine whether angiotensin-converting enzyme (ACE) inhibition improves peripheral vascular NO activity in patients with atherosclerosis. In the femoral circulation of 43 patients with atherosclerosis and 10 controls, we studied endothelium-dependent vasodilation with bradykinin and acetylcholine, and endothelium-independent vasodilation with sodium nitroprusside before and after enalaprilat, In 22 patients, we repeated these infusions in the presence of L-N-G monomethyl arginine (L-NMMA). Doppler-femoral artery flow velocity was measured. Before ACE inhibition, acetylcholine responses were depressed in patients with atherosclerosis compared with controls (p = 0.03). Enalaprilat did not alter femoral vascular tone at rest or vasodilation with sodium nitroprusside, but potentiated bradykinin-mediated vasodilation in patients (p <0.001) and controls (p = 0.02). Acetylcholine-mediated vasodilation was augmented only in patients (p <0.001), but not in control subjects. L-NMMA inhibited the potentiation by enalaprilat of acetylcholine and bradykinin responses. This study demonstrates that ACE inhibition selectively improves endothelial dysfunction in human atherosclerosis by enhancing NO activity. The antithrombotic and antiproliferative effects of NO may reduce adverse manifestations related to atherosclerosis during long-term therapy, (C) 1999 by Excerpta Medico, Inc. C1 NHLBI, NIH, Cardiol Branch, Bethesda, MD 20892 USA. RP Quyyumi, AA (reprint author), NHLBI, NIH, Cardiol Branch, Bldg 10,Rm 7B15,10 Ctr Dr MSC 1650, Bethesda, MD 20892 USA. NR 34 TC 31 Z9 31 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 JUL 1 PY 1999 VL 84 IS 1 BP 1 EP 6 DI 10.1016/S0002-9149(99)00182-4 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 211YD UT WOS:000081188700001 PM 10404842 ER PT J AU Psaty, BM Boineau, R Kuller, LH Luepker, RV AF Psaty, BM Boineau, R Kuller, LH Luepker, RV TI The potential costs for upcoding for heart failure in the United States SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article AB Miscoding of hospital discharge diagnoses for heart failure in older adults is common, and the direction favors high levels of reimbursement to hospitals. The potential costs to Medicare may be as high as $993 million per year. C1 Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. Univ Washington, Dept Med, Seattle, WA 98101 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98101 USA. NHLBI, Div Epidemiol & Clin Applicat, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. RP Psaty, BM (reprint author), Univ Washington, Cardiovasc Hlth Res Unit, Suite 1360,1730 Minor Ave, Seattle, WA 98101 USA. FU NHLBI NIH HHS [HL40628, HL43201]; NIA NIH HHS [AG09556] NR 6 TC 42 Z9 42 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 JUL 1 PY 1999 VL 84 IS 1 BP 108 EP + DI 10.1016/S0002-9149(99)00205-2 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 211YD UT WOS:000081188700024 PM 10404865 ER PT J AU Weyer, C Snitker, S Bogardus, C Ravussin, E AF Weyer, C Snitker, S Bogardus, C Ravussin, E TI Energy metabolism in African Americans: potential risk factors for obesity SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE ethnicity; metabolic rate; respiratory quotient; respiratory chamber; energy expenditure; blacks; whites; Caucasians; African Americans; fat oxidation; women; men ID WEIGHT-RELATED ATTITUDES; TIME PHYSICAL-ACTIVITY; BODY-COMPOSITION; BLACK-WOMEN; CAUCASIAN WOMEN; MENSTRUAL-CYCLE; WHITE FEMALES; UNITED-STATES; EXPENDITURE; MASS AB Background: Recent reports have identified a lower resting metabolic rate in African Americans than in whites, but most studies included only females and used short-term measurements with ventilated-hood systems. Objective: Our objective was to compare 24-h measurements of energy metabolism between African American and white women and men using a respiratory chamber. Design: Thirty-eight African American ((x) over bar +/- SD: 32 +/- 7 y of age, 24 +/- 10% body fat) and 288 white (31 +/- 7 y of age, 26 +/- 12% body fat) subjects spent 24 h in a respiratory chamber for measurement of 24-h energy expenditure (24EE), sleeping metabolic rate (SMR), 24-h respiratory quotient (24RQ), and substrate oxidation rates. Results: After adjustment for sex, age, and body composition (by hydrodensitometry), African Americans had lower SMR (-301 +/- 105 kJ/d; P < 0.01) and higher 24RQ (0.014 +/- 0.004; P < 0.001) than whites, whereas 24EE was similar. A sex-specific analysis, using a subset of 38 whites with an equal sex distribution and similar age and body weight, revealed that African American women had lower SMR (-442 +/- 182 kJ/d; P <0.05) and lower 24EE (-580 +/- 232 kJ/d; P < 0.05), but similar 24RQ values compared with white women. African American men tended to have lower SMRs than white men (-355 +/- 188 kJ/d; P = 0.07), but had higher 24RQ values, accounting for a 992 +/- 327-kJ/d lower 24-h fat oxidation rate (P < 0.005). Conclusions: These data not only confirm the findings of a lower metabolic rate in African American than in white women, but also suggest that fat oxidation is lower in African American men than in white men. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. RP Weyer, C (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16th St,Room 5-41, Phoenix, AZ 85016 USA. NR 46 TC 85 Z9 89 U1 1 U2 3 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 1999 VL 70 IS 1 BP 13 EP 20 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 212PF UT WOS:000081224900004 PM 10393133 ER PT J AU Wu, YY Rehak, NN Csako, G AF Wu, YY Rehak, NN Csako, G TI Falsely low uric acid, creatinine, cholesterol and triglyceride results due to dopamine, dobutamine, methyl-dopa and L-dopa with methods involving peroxidase-generated chromophores: A model for interference studies. SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Meeting Abstract C1 NIH, Ctr Clin, Dept Clin Pathol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLIN PATHOLOGISTS PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JUL PY 1999 VL 112 IS 1 MA 3 BP 130 EP 130 PG 1 WC Pathology SC Pathology GA 210CR UT WOS:000081088000023 ER PT J AU Issaragrisil, S Leaverton, PE Chansung, K Thamprasit, T Porapakham, Y Vannasaeng, S Piankijagum, A Kaufman, DW Anderson, TE Shapiro, S Young, NS AF Issaragrisil, S Leaverton, PE Chansung, K Thamprasit, T Porapakham, Y Vannasaeng, S Piankijagum, A Kaufman, DW Anderson, TE Shapiro, S Young, NS CA Aplastic Anemia Study Grp TI Regional patterns in the incidence of aplastic anemia in Thailand SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article DE aplastic anemia; incidence; epidemiology; Thailand ID NORTHERN REGION; ASSOCIATION AB The annual incidence of aplastic anemia has been determined in a rigorous and standardized epidemiologic study conducted in Thailand. A total of 374 cases were identified over a period of 3-6 years in three geographically defined and distinct regions of the country; Bangkok, Khonkaen in the northeast, and Songkla in the south. The incidence was 3.9 cases per million persons in Bangkok, 3.0 per million in Songkla, and 5.0 per million in Khonkaen, These rates are as high or higher than in any region of Europe or Israel as reported in the International Agranulocytosis and Aplastic Anemia Study, in which the methods and case definition were the same. Rates were stable over the course of the study. There were marked differences in incidence between northern and southern rural regions of Thailand, and among Bangkok suburbs. These differences, together with an unusual peak in the incidence among young people in Bangkok, suggest the possibility of occupational and environmental factors in the etiology of aplastic anemia. Am. J, Hematol, 61:164-168, 1999. (C) 1999 Wiley-Liss, Inc. C1 Mahidol Univ, Siriraj Hosp, Fac Med, Dept Med,Div Hematol, Bangkok 10700, Thailand. Univ S Florida, Coll Publ Hlth, Dept Epidemiol & Biostat, Tampa, FL USA. Khon Kaen Univ, Fac Med, Dept Med, Khon Kaen, Thailand. Prince Songkla Univ, Fac Med, Dept Med, Songkla, Thailand. Mahidol Univ, Asian Inst Hlth Dev, Bangkok, Thailand. Boston Univ, Sch Med, Slone Epidemiol Unit, Boston, MA 02118 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Issaragrisil, S (reprint author), Mahidol Univ, Siriraj Hosp, Fac Med, Dept Med,Div Hematol, Bangkok 10700, Thailand. OI Issaragrisil, Surapol/0000-0002-8924-0646 FU NHLBI NIH HHS [HL 35068] NR 28 TC 15 Z9 16 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 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD JUL PY 1999 VL 61 IS 3 BP 164 EP 168 DI 10.1002/(SICI)1096-8652(199907)61:3<164::AID-AJH2>3.0.CO;2-R PG 5 WC Hematology SC Hematology GA 211LA UT WOS:000081161500002 PM 10398308 ER PT J AU Gronberg, H Smith, J Emanuelsson, M Jonsson, BA Bergh, A Carpten, J Isaacs, W Xu, JF Meyers, D Trent, J Damber, JE AF Gronberg, H Smith, J Emanuelsson, M Jonsson, BA Bergh, A Carpten, J Isaacs, W Xu, JF Meyers, D Trent, J Damber, JE TI In Swedish families with hereditary prostate cancer, linkage to the HPC1 locus on chromosome 1q24-25 is restricted to families with early-onset prostate cancer SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID SUSCEPTIBILITY LOCUS; OVARIAN-CANCER; SWEDEN; GENE; RISK; 1Q; INHERITANCE; MUTATIONS; SUPPORT; HISTORY AB Prostate cancer clusters in some families, and an estimated 5%-10% of all cases are estimated to result from inheritance of prostate cancer-susceptibility genes. We previously reported evidence of linkage to the 1q24-25 region (HPC1) in 91 North American and Swedish families each with multiple cases of prostate cancer (Smith et al. 1996). In the present report we analyze 40 (12 original and 28 newly identified) Swedish families with hereditary prostate cancer (HPC) that, on the basis of 40 markers spanning a 25-cM interval within 1q24-25, have evidence of linkage. In the complete set of families, a maximum two-point LOD score of 1.10 was observed at D1S413 (at a recombination fraction [theta] of .1), with a maximum NPL (nonparametric linkage) Z score of 1.64 at D1S202 (P = .05). The evidence of linkage to this region originated almost exclusively from the subset of 12 early-onset (age <65 years) families, which yielded a maximum LOD score of 2.38 at D1S413 (theta = 0) and an NPL Z score of 1.95 at D1S422 (P = .03). Estimates from heterogeneity tests suggest that, within Sweden, as many as 50% of early-onset families had evidence of linkage to the HPC1 region. These results are consistent with the hypothesis of linkage to HPC1 in a subset of families with prostate cancer, particularly those with an early age at diagnosis. C1 Umea Univ, Dept Oncol, S-90185 Umea, Sweden. Umea Univ, Dept Pathol, S-90185 Umea, Sweden. Umea Univ, Dept Urol & Androl, S-90185 Umea, Sweden. Natl Human Genome Res Inst, Prostate Canc Invest Grp, NIH, Bethesda, MD USA. Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. Univ Maryland, Ctr Genet Asthma & Complex Dis, Baltimore, MD 21201 USA. RP Gronberg, H (reprint author), Umea Univ, Dept Oncol, S-90185 Umea, Sweden. RI Smith, Jeff/C-3484-2012 NR 20 TC 55 Z9 56 U1 0 U2 2 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 JUL PY 1999 VL 65 IS 1 BP 134 EP 140 DI 10.1086/302447 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 212NZ UT WOS:000081224300017 PM 10364525 ER PT J AU Weinberg, CR AF Weinberg, CR TI Methods for detection of parent-of-origin effects in genetic studies of case-parents triads SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID LINKAGE DISEQUILIBRIUM; RELATIVE RISKS; ASSOCIATION AB When affected probands and their biological parents are genotyped at a candidate gene or a marker, the resulting case-parents-triad data enable powerful tests for linkage in the presence of association. When linkage disequilibrium has been detected in such a study, the investigator may wish to look further for possible parent-of-origin effects. If, for example, the transmission/disequilibrium test restricted to fathers is statistically significant, whereas that restricted to mothers is not, the investigator might interpret this as evidence for nonexpression of the maternally derived disease gene-that is, imprinting. This report reviews existing methods for detection of parent-of-origin effects, showing that each can be invalid under certain scenarios. Two new methods are proposed, based on application of likelihood-based inference after stratification on both the parental mating type and the inherited number of copies of the allele under study. If there are no maternal genetic effects expressed prenatally during gestation, the parental-asymmetry test is powerful and provides valid estimation of a parent-of-origin parameter. For diseases for which there could be maternal effects on risk, the parent-of-origin likelihood-ratio test provides a robust alternative. Simulations based on an admired population demonstrate good operating characteristics for these procedures, under diverse scenarios. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Weinberg, CR (reprint author), NIEHS, Biostat Branch, POB 12233,MD A3-03, Res Triangle Pk, NC 27709 USA. NR 9 TC 160 Z9 162 U1 0 U2 1 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 JUL PY 1999 VL 65 IS 1 BP 229 EP 235 DI 10.1086/302466 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 212NZ UT WOS:000081224300028 PM 10364536 ER PT J AU Goldin, LR Sgambati, M Marti, GE Fontaine, L Ishibe, N Caporaso, N AF Goldin, LR Sgambati, M Marti, GE Fontaine, L Ishibe, N Caporaso, N TI Anticipation in familial chronic lymphocytic leukemia SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Letter ID RELATIVES; HISTORY C1 NCI, Dov Canc Epidemiol & Genet, Genet Epidemiol Branch, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. Westat Res Inc, Rockville, MD USA. RP Goldin, LR (reprint author), NCI, Dov Canc Epidemiol & Genet, Genet Epidemiol Branch, 6120 Execut Blvd,Room 7008,MSC 7236, Bethesda, MD 20892 USA. NR 19 TC 35 Z9 36 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL PY 1999 VL 65 IS 1 BP 265 EP 269 DI 10.1086/302458 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 212NZ UT WOS:000081224300036 PM 10364544 ER PT J AU Gunnarsdottir, HK Kjaerheim, K Boffetta, P Rafnsson, V Zahm, SH AF Gunnarsdottir, HK Kjaerheim, K Boffetta, P Rafnsson, V Zahm, SH TI Women's health: Occupation, cancer, and reproduction - a conference overview SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Editorial Material C1 Adm Occupat Safety & Hlth, Reykjavik, Iceland. Canc Registry Norway, Oslo, Norway. Int Agcy Res Canc, F-69372 Lyon, France. Univ Iceland, Reykjavik, Iceland. NCI, Rockville, MD USA. RP Gunnarsdottir, HK (reprint author), Adm Occupat Safety & Hlth, Reykjavik, Iceland. RI Zahm, Shelia/B-5025-2015; OI Kjaerheim, Kristina/0000-0003-0691-3735 NR 46 TC 4 Z9 5 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 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD JUL PY 1999 VL 36 IS 1 BP 1 EP 5 DI 10.1002/(SICI)1097-0274(199907)36:1<1::AID-AJIM1>3.0.CO;2-N PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 201YM UT WOS:000080624900001 PM 10361580 ER PT J AU Blair, A Zahm, SH Silverman, DT AF Blair, A Zahm, SH Silverman, DT TI Occupational cancer among women: Research status and methodologic consideration SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article; Proceedings Paper CT International Conference on Womens Health - Occupation, Cancer, and Reproduction CY MAY 14-15, 1998 CL REYKJAVIK, ICELAND DE cancer; women; occupation; epidemiologic methods ID FEMALE MANUAL WORKERS; DRY-CLEANING WORKERS; LUNG-CANCER; RISK-FACTORS; UNITED-STATES; BREAST-CANCER; BLADDER-CANCER; GENDER DIFFERENCES; ASBESTOS EXPOSURE; HISTOLOGIC TYPE AB Occupational causes of cancer have not been well-evaluated among women. An increase in the number of women in the workforce in jobs with potentially hazardous exposures during the past few decades raises the question as to whether there is a need to enhance our efforts in this area. The inability to evaluate occupational causes of female gynecologic tumors in studies of men, plus the potential for variation in outcome responses between men and women because of gender-based exposure and susceptibility differences, underscore the need for investigations specifically focused on women. Investigations of occupational exposures and cancer risk among women may require design considerations that differ somewhat from studies of men. Issues to consider include the impact of Studying outcomes with high survival (e.g., breast cancer), gender-specific exposure patterns and toxicokinetic processing of some chemicals, special limitations in the use of the general population as the referent, and the need to control for established risk factors for gynecologic tumors.. Am. J. Ind. Med. 36:6-17, 1999. Published 1999 Wiley-Liss, Inc.dagger. C1 NCI, Occupat Epidemiol Branch, Bethesda, MD 20892 USA. RP Blair, A (reprint author), NCI, Occupat Epidemiol Branch, Execut Plaza S,Room 8118, Bethesda, MD 20892 USA. RI Zahm, Shelia/B-5025-2015 NR 139 TC 27 Z9 29 U1 2 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD JUL PY 1999 VL 36 IS 1 BP 6 EP 17 DI 10.1002/(SICI)1097-0274(199907)36:1<6::AID-AJIM2>3.0.CO;2-F PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 201YM UT WOS:000080624900002 PM 10361581 ER PT J AU Dosemeci, M Cocco, P Chow, WH AF Dosemeci, M Cocco, P Chow, WH TI Gender differences in risk of renal cell carcinoma and occupational exposures to chlorinated aliphatic hydrocarbons SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article; Proceedings Paper CT International Conference on Womens Health - Occupation, Cancer, and Reproduction CY MAY 14-15, 1998 CL REYKJAVIK, ICELAND DE renal cancer; solvents; chlorinated hydrocarbons; trichloroethylene ID DRY-CLEANING WORKERS; LEAD SMELTER WORKERS; LUNG-CANCER; REFINERY WORKERS; HISTOLOGIC TYPE; P53 MUTATIONS; KIDNEY CANCER; UNITED-STATES; MORTALITY; FEMALE AB Background: Organic solvents have been associated with renal cell cancer; however; the risk by gender and type of solvents is unclear. Methods: We evaluated the risk of renal cell carcinoma among:men and women exposed to all organic solvents-combined, all chlorinated aliphatic hydrocarbons (CAHC)-combined, and nine individual CAHC using a priori job exposure matrices: developed by NCI in a population-based case-control study in Minnesota, U.S, We interviewed 438 renal cell cancer cases (273 men and 165 women) and 687 controls (462 men and 225 women); Results, Overall, 34% of male cases and 21% of female cases were exposed to organic solvents in general. The risk of renal cell Carcinoma:was significantly elevated among women exposed to all organic solvents combined (OR = 2.3; 95% CI = 1.3-4.2), to CAHC combined (OR = 2.1; 95% CI = 1.1-3.9), and to trichloroethylene (TCE) (OR = 2.0; 95% CI = 1.0-4.0). Among men, no-significant excess risk was observed among men exposed to any of these nine individual CAHCs, all CAHCs-combined, or all organic solvents-combined. Discussion: These observed gender: differences in risk of renal cell carcinoma in relation to exposure to organic solvents may be explained by chance based on small numbers, or by the differences in body fat content, metabolic activity, the rate of elimination of xenobiotics from the body, or by differences in. the level of exposure between men and women,even though they have the same job title. Am. J. Ind. Med. 36:54-59, 1999; Published 1999 Wiley-Liss, Inc.dagger. C1 NCI, Occupat Epidemiol Branch, Bethesda, MD 20892 USA. RP Dosemeci, M (reprint author), NCI, Occupat Epidemiol Branch, 6130 Execut Blvd,EPN Room 418, Bethesda, MD 20892 USA. NR 59 TC 50 Z9 50 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD JUL PY 1999 VL 36 IS 1 BP 54 EP 59 DI 10.1002/(SICI)1097-0274(199907)36:1<54::AID-AJIM8>3.0.CO;2-0 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 201YM UT WOS:000080624900008 PM 10361587 ER PT J AU Miligi, L Costantini, AS Crosignani, P Fontana, A Masala, G Nanni, O Ramazzotti, V Rodella, S Stagnaro, E Tumino, R Vigano, C Vindigni, C Vineis, P AF Miligi, L Costantini, AS Crosignani, P Fontana, A Masala, G Nanni, O Ramazzotti, V Rodella, S Stagnaro, E Tumino, R Vigano, C Vindigni, C Vineis, P TI Occupational, environmental, and life-style factors associated with the risk of hematolymphopoietic malignancies in women SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article; Proceedings Paper CT International Conference on Womens Health - Occupation, Cancer, and Reproduction CY MAY 14-15, 1998 CL REYKJAVIK, ICELAND DE lymphomas; leukemias; multiple myeloma; occupations; housewives; hair dyes ID NON-HODGKINS-LYMPHOMA; HAIR DYE USE; MULTIPLE-MYELOMA; CANCER; LEUKEMIA; SMOKING; DEATH; SWEDEN; EMPLOYMENT; EXPOSURES AB Background: The etiology of lymphomas, leukemias,, and multiple myeloma is still largely unknown, The known risk factors (ionizing radiation, solvent exposure, pesticide exposure, immunosuppression) explain only a small proportion of the cases that occur. Methods: We conducted a multicenter population-based case-control study on hematolympho-poietic malignancies in Italy and interviewed 2,011 women (1,183 cases and 828 controls). Results: There Was a suggestion of a positive association between smoking and the risk of non-Hodgkin's, lymphoma + chronic lymphocytic leukemia. A slight: increased: risk of leukemias was observed among women using permanent hair dye. Housewives were at increased risk for leukemia and multiple myeloma, The risk of non-Hodgkin's lymphomas + chronic lymphocytic leukemia leukemias, multiple myeloma, and Hodgkin's disease increased among women employed as hairdressers and textile workers. Teachers were at increased risk for non-Hodgkin's lymphomas + chronic lymphocytic leukemia, leukemias, and Hodgkin's disease. Conclusions: These results confirm previous associations and may provide additional clues to some determinants of hematolymphopoietic malignancies in women. Am.. Ind. Med. 36:60-69; 1999. (C) 1999 Wiley-Liss, Inc. C1 Az Osped Careggi, Ctr Study & Prevent Canc, Epidemiol Unit, I-50135 Florence, Italy. Natl Canc Inst, Epidemiol Unit, I-20133 Milan, Italy. Local Hlth Unit, Novara, Italy. Natl Canc Inst, Genoa, Italy. Ctr Study & Prevent Canc, Satellite Unit, Florence, Italy. Ist Oncol Romagnolo, Forli, Italy. Ist Regina Elena, Natl Canc Inst, I-00161 Rome, Italy. Az Osped, UO Miglioramento Qual, Verona, Italy. Canc Registry, Ragusa, Italy. Univ Siena, Inst Pathol, I-53100 Siena, Italy. Az Osped S Giovanni Battista, Canc Epidemiol Unit, Turin, Italy. Univ Turin, Turin, Italy. RP Miligi, L (reprint author), Az Osped Careggi, Ctr Study & Prevent Canc, Epidemiol Unit, Via S Salvi 12, I-50135 Florence, Italy. OI NANNI, ORIANA/0000-0001-7338-2896; Masala, Giovanna/0000-0002-5758-9069 FU NCI NIH HHS [CA51089] NR 37 TC 68 Z9 70 U1 3 U2 6 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 JUL PY 1999 VL 36 IS 1 BP 60 EP 69 DI 10.1002/(SICI)1097-0274(199907)36:1<60::AID-AJIM9>3.0.CO;2-Z PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 201YM UT WOS:000080624900009 PM 10361588 ER PT J AU Cocco, P Heineman, EF Dosemeci, M AF Cocco, P Heineman, EF Dosemeci, M TI Occupational risk factors for cancer of the central nervous system (CNS) among US women SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article; Proceedings Paper CT International Conference on Womens Health - Occupation, Cancer, and Reproduction CY MAY 14-15, 1998 CL REYKJAVIK, ICELAND DE neoplasms; central nervous system; electromagnetic fields; solvents; pesticides; epidemiology; job-exposure matrices; women AB Background: In a recent report, we found an elevated risk of cancer of the central nervous system (CNS) in several occupations and industries, and-a modest association with exposure to solvents and to contact with the public. Methods: To further explore the occupational risk of CNS cancer among women we extended the analysis of the previous death certificate-based case-control study, including 12,980 female cases (ICD-9 codes 191 and 192) in 24 US states in 1984-1992 and 51,920 female controls who died from diseases other than malignancies and neurological disorders. We applied newly designed job-exposure matrices for 11 occupational hazards,previously reported as brain cancer risk factors, to the occupation and industry codes in the death certificates We also conducted a separate analysis of 161 meningioma cases (ICD-9 Codes 192.1 and 192.3), a tremor more frequent among women, particularly in the postmenopausal age group. Results: Overall, CNS cancer risk showed a 20-30% increase among women exposed to electromagnetic fields (EMF), methylene chloride, insecticides and fungicides, and contact with the public. Risk for meningioma was elevated among women exposed to lead (OR = 1.9; 95% CI 1.0,3.9). CNS cancer did not show a clear pattern of risk increase by probability and intensity of exposure to any of the explored risk factors, Cross-classification by probability and intensity of exposure did not reveal any significant trend Cases were too few to explore trends of meningioma by probability and intensity of exposure to lead. Conclusions: We did not find evidence of a strong contribution of 11 occupational hazards to the etiology of CNS cancer. However; limitations of the occupational information might have reduced our ability to detect clear patterns of risk. Am. J. Ind. Med. 36:70-74, 1999. (C) 1999 Wiley-Liss, Inc. C1 Univ Cagliari, Inst Occupat Med, Cagliari, Italy. NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Cocco, P (reprint author), Univ Cagliari, Ist Med Lavoro, Via S Giorgio 12, I-09124 Cagliari, Italy. NR 11 TC 39 Z9 41 U1 1 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD JUL PY 1999 VL 36 IS 1 BP 70 EP 74 DI 10.1002/(SICI)1097-0274(199907)36:1<70::AID-AJIM10>3.0.CO;2-5 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 201YM UT WOS:000080624900010 PM 10361589 ER PT J AU t'Mannetje, A Kogevinas, M Luce, D Demers, PA Begin, D Bolm-Audorff, U Comba, P Gerin, M Hardell, L Hayes, RB Leclerc, A Magnani, C Merler, E Tobias, A Boffetta, P AF t'Mannetje, A Kogevinas, M Luce, D Demers, PA Begin, D Bolm-Audorff, U Comba, P Gerin, M Hardell, L Hayes, RB Leclerc, A Magnani, C Merler, E Tobias, A Boffetta, P TI Sinonasal cancer, occupation, and tobacco smoking in European women and men SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article; Proceedings Paper CT International Conference on Womens Health - Occupation, Cancer, and Reproduction CY MAY 14-15, 1998 CL REYKJAVIK, ICELAND DE sinonasal cancer; occupational diseases; case-control; wood dust; tobacco; gender ID WOOD DUST EXPOSURE; PARANASAL SINUSES; RISK-FACTORS; ATTRIBUTABLE RISK; NOSE; REANALYSIS; INDUSTRY; NASAL AB Background: In this analysis of European case-control studies on sinonasal cancer; we examined the risk for occupation and smoking, by gender and histological type. Methods: The pooled data included 104 female and 451 male cases, and 241 female and 1,464 male controls. Lifetime smoking and occupational history were recoded following uniform criteria, and job-exposure matrices were applied for wood and leather dust. Results: Wood dust exposure was associated with an excess risk in men (OR = 2.36, 95% CI 1.75-3.2) but not in women (OR = 1.17, 95% CI 0.31-4.47). Exposure to leather dust was associated with an excess risk in both genders. Both wood and leather dust were associated with adenocarcinomas rather than squamous cell carcinomas. Excess risks for smoking were higher for squamous cell carcinomas and higher in men than in women. Conclusions: In these European populations, occupation was associated with about 11% of all sinonasal cancers in women and 39% in men. This difference can, in part, be attributed to variation in exposure patterns between genders. Am. J. Ind. Med. 36:101-107, 1999. (C) 1999 Wiley-Liss, Inc. C1 Inst Municipal Invest Med, Resp & Environm Hlth Res Unit, E-08003 Barcelona, Spain. INSERM, Paris, France. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. Univ Montreal, Montreal, PQ, Canada. Hess Minist Frauen Arbeit & Sozialordnung, Wiesbaden, Germany. Inst Super Sanita, Rome, Italy. Orebro Med Ctr, Orebro, Sweden. NCI, Bethesda, MD 20892 USA. Univ Turin, Turin, Italy. Ctr Study & Prevent Canc, Florence, Italy. Int Agcy Res Canc, F-69372 Lyon, France. RP Kogevinas, M (reprint author), Inst Municipal Invest Med, Resp & Environm Hlth Res Unit, 80 Doctor Aiguader Rd, E-08003 Barcelona, Spain. RI LUCE, Daniele/J-9125-2015; Kogevinas, Manolis/C-3918-2017; OI Luce, Daniele/0000-0002-1708-4584 NR 24 TC 26 Z9 27 U1 1 U2 7 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 JUL PY 1999 VL 36 IS 1 BP 101 EP 107 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 201YM UT WOS:000080624900014 PM 10361593 ER PT J AU Fillmore, CM Petralia, SA Dosemeci, M AF Fillmore, CM Petralia, SA Dosemeci, M TI Cancer mortality in women with probable exposure to silica: A death certificate study in 24 states of the US SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article; Proceedings Paper CT International Conference on Womens Health - Occupation, Cancer, and Reproduction CY MAY 14-15, 1998 CL REYKJAVIK, ICELAND DE women; silica; occupational exposure; cancer; PMRs; pneumoconiosis ID LUNG-CANCER; ESOPHAGEAL CANCER; MULTIPLE-MYELOMA; WORKERS; RISK; DUST; OCCUPATION; SMOKING; FINLAND; PLANTS AB Background: Silica exposure is known to cause: an increased risk of neumoconiosis and some types of cancers. Exposure to silica is becoming an increasingly common occupational hazard for women. Studies contradict each other-on whether dr not women suffer more occupational pneumoconiosis than men, but no studies-have evaluated cancer risks among women exposed to silica. Methods: Death certificate data on occupation and industry from 24 states in the U.S. between 1984 and 1993 were used to calculate proportional mortality ratios (PMRs) for workers exposed to silica. Results: Over 20,000 deaths (4% of all deaths in persons with possible work-related silica-exposure) occurred among,women. The PMR for pneumoconiosis among women working in occupations or industries with possible silica exposure was 13.6 (95% CI: 7.2-23.2), for men 3.8 (CI: 3.7-4.0). Both men and women had higher than expected PMRs far respiratory diseases, lung and esophageal cancers, and external causes of death. In the group with probable silica exposure (both occupation and industry; associated with silica), women had elevated PMRs for thyroid cancer (PMR = 5.5),multiple myeloma (PMR = 1.3), digestive organ cancers (PMR = 1.2), whereas men-had-no increased PMRs for these cancers. Both genders had significantly decreased PMRs for breast cancel; cerebrovascular diseases, nervous system diseases, and brain and other central nervous system cancers. Conclusions: An in depth look at the types of silica exposures (specific work, duties) and adjustment for confounders is wart-anted to determine the importance of these gender-specific excess mortalities associated with possible silica exposure. Am. J. Ind. Med. 36:122-128, 1999. Published 1999 Wiley-Liss, Inc.dagger C1 NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Fillmore, CM (reprint author), NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, Rm EPS-8111,6130 Execut Blvd,Mailstop 7240, Bethesda, MD 20892 USA. NR 38 TC 11 Z9 11 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD JUL PY 1999 VL 36 IS 1 BP 122 EP 128 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 201YM UT WOS:000080624900017 PM 10361596 ER PT J AU Petralia, SA Dosemeci, M Adams, EE Zahm, SH AF Petralia, SA Dosemeci, M Adams, EE Zahm, SH TI Cancer mortality among women employed in health care occupations in 24 US States, 1984-1993 SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article; Proceedings Paper CT International Conference on Womens Health - Occupation, Cancer, and Reproduction CY MAY 14-15, 1998 CL REYKJAVIK, ICELAND DE cancer; mortality; health care; women; occupation ID HANDLING ANTINEOPLASTIC DRUGS; SISTER-CHROMATID EXCHANGES; BREAST-CANCER; RADIOLOGIC TECHNOLOGISTS; CHEMOTHERAPEUTIC-AGENTS; REGISTERED NURSES; RISK; WORKERS; CHINA; DEATH AB Background Health care workers are potentially exposed to a number of carcinogens. Studies among women in this field have focused on white nurses; however; workers in many health care occupations share exposures experienced by nurses. Methods Cancer mortality was examined among female health care workers using death certificate data collected in 24 U.S. states from 1984 through 1993. Cancer mortality odds ratios (MORs) were calculated by race (white, black) and age group. Results White nurses had a 30% elevation of mortality due to liver cancer and myeloid leukemia. White registered nurses (RNs) had a small excess and white licensed practical nurses (LPNs) had a small deficit of mortality due to breast cancel: Ovarian cancer was in excess among RNs, but decreased among LPNs. Among black nurses, excesses of death due to kidney cancer (MOR = 1.7) and multiple myeloma (MOR = 1.3), and a significant 50% deficit in mortality due to cancer of the esophagus were found. Black RNs, but not LPNs, had an excess of breast cancer (MOR = 1.3; 95% CI = 1.0-1.5). Ovarian cancer was elevated by 30% in both RNs and LPNs. Excess deaths due to cancers of the breast, ovary, and uterus occurred among white physicians. Among black physicians, lung cancer was significantly elevated (MOR = 2.8). White pharmacists had significant excesses of breast (MOR = 1.5) and ovarian (MOR = 2.4) cancers, and myeloid leukemia (MOR = 2.0). White clinical laboratory technicians had excess deaths from several cancers. The greatest excess was for myeloid leukemia (MOR = 2.3; 95% CI = 1.5-3.4). Excesses among radiologic technologists included cancers of the lung, pancreas, breast, uterus, and ovary. Conclusion Several findings reported here warrant further investigation. In particular excesses of myeloid leukemia among nurses, pharmacists, and clinical laboratory technicians and liver cancer among nurses should be investigated in studies with data on occupational and other exposures. Patterns of mortality from breast and ovarian cancers found in this study must be evaluated further in studies with data on reproductive history Am. J. Ind. Med. 36:159-165, 1999. Published 1999 Wiley-Liss, Inc.dagger C1 NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Petralia, SA (reprint author), NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8110, Bethesda, MD 20892 USA. RI Zahm, Shelia/B-5025-2015 NR 32 TC 24 Z9 25 U1 1 U2 5 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 JUL PY 1999 VL 36 IS 1 BP 159 EP 165 DI 10.1002/(SICI)1097-0274(199907)36:1<159::AID-AJIM23>3.0.CO;2-K PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 201YM UT WOS:000080624900023 PM 10361602 ER PT J AU Bulbulyan, MA Ilychova, SA Zahm, SH Astashevsky, SV Zaridze, DG AF Bulbulyan, MA Ilychova, SA Zahm, SH Astashevsky, SV Zaridze, DG TI Cancer mortality among women in the Russian printing industry SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article; Proceedings Paper CT International Conference on Womens Health - Occupation, Cancer, and Reproduction CY MAY 14-15, 1998 CL REYKJAVIK, ICELAND DE printing; women; cancer; occupation; bladder; melanoma; ovary; esophagus ID MALIGNANT-MELANOMA; ESOPHAGEAL CANCER; WORKERS; RISK; ASBESTOS; EXPOSURE; SYSTEM; FEMALE AB Background This study evaluates cancer mortality among women employed in two large printing plants in Moscow Methods A total of 3,473 women who were,actively employed as of December 31, 1978, with a minimum of 2 years employment were followed from 1 January 1979 to 31 December 1993. There were 47,791 person-years observed, with only 51 women lost to follow-up (1.5%). Standardized mortality ratios (SMRs) were Calculated using the population of Moscow to generate expected numbers. Analyses by job (compositors, press operators, and bookbinders), age hired, latency, and duration of employment were conducted. Results Among,women employed in the two printing plants, there was a significant excess of esophageal cancer, based on seven deaths (expected = 2.7, SMR 2.7 95% CI = 1.1-5.4). Four of the seven esophageal cancer deaths occurred among bookbinders (expected = 1.0, SMR = 4.1, 95% CI = 1.1-10.4), all among workers hired before 1957 (expected = 0.6, SMR = 7.1, 95% CI = 1.9-18.3), the last year benzene was used in bookbinding. Ovarian cancer was also significantly elevated among bookbinders (12 observed, 4.2 expected, SMR = 2.9, 95% CI = 1.5-5.0), which, along with one death from mesothelioma of the abdomen, might be related to the use of asbestos-contaminated talc fillers in paper Press operators had significantly elevated mortality from stomach, cancer (observed = 9, expected = 4.1, SMR = 2.2 95% CI = 1.0-4.2) and, based on two deaths each, melanoma and bladder cancer. Conclusions Women in this printing industry cohort experienced excess mortality of cancer of the esophagus and stomach, with suggested increases of melanoma and bladder cancer Further follow-up of this cohort, which would allow more in-depth analysis of rare cancer sites, latency, and duration of employment, is warranted. Gender comparisons within the cohort should also be conducted to clarify the role of occupational and lifestyle factors in the etiology of cancer among workers in the printing industry. Am. J. Ind. Med. 36:166-171 1999. Published 1999 Wiley-Liss, Inc.dagger C1 Russian Acad Med Sci, Canc Res Ctr, Moscow 115478, Russia. NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Bulbulyan, MA (reprint author), Russian Acad Med Sci, Canc Res Ctr, Kashirkoye Shaussee 24, Moscow 115478, Russia. RI Zahm, Shelia/B-5025-2015 NR 33 TC 29 Z9 30 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 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD JUL PY 1999 VL 36 IS 1 BP 166 EP 171 DI 10.1002/(SICI)1097-0274(199907)36:1<166::AID-AJIM24>3.0.CO;2-P PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 201YM UT WOS:000080624900024 PM 10361603 ER PT J AU Gridley, G Nyren, O Dosemeci, S Moradi, T Adami, HO Carroll, L Zahm, SH AF Gridley, G Nyren, O Dosemeci, S Moradi, T Adami, HO Carroll, L Zahm, SH TI Is there a healthy worker effect for cancer incidence among women in Sweden? SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article; Proceedings Paper CT International Conference on Womens Health - Occupation, Cancer, and Reproduction CY MAY 14-15, 1998 CL REYKJAVIK, ICELAND DE occupation; healthy worker effect; epidemiology; cancer; risk factors ID MORTALITY; EMPLOYMENT; OCCUPATION; INDUSTRY; COHORT; DEATH AB Background Our aim was to evaluate whether there is a healthy worker effect (HWE) for cancer incidence among women. HWE is a bias found in occupational studies that compare rates of disease among employed people to disease rates for the general population, which includes unemployed people (who may be less healthy than those who are employed). Methods Data from the 1960 and 1970 Swedish censuses were used to identify all 1,659, 940 Swedish women who were employed in either year: They were followed during 1971-1989 through linkages to the national cancer and death registers. Standardized incidence ratios (SIRs) were computed comparing employed women to the 1,627,873 women who were not employed in either 1960 or 1970. Results For the 545,857 women employed in both 1960 and 1970, the SIR for all cancers combined was 1.05 (1.04-1.06). When specific cancer sites were analyzed separately, the highest cancer risks were for cancers of the lung and bladder (SIR = 1.2) and reproductive organs (breast, ovary, endometrium, and cervix SIR = 1.1). Overall cancer risks were highest among full-time workers, younger workers, urban workers, and workers with the highest socioeconomic status (based on the woman's job Title). Conclusions These results show no general HWE for cancer incidence among employed Swedish women. Am. J. Ind. Med. 36:193-199, 1999. Published 1999 Wiley-Liss, Inc.dagger C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Karolinska Inst, Dept Med Epidemiol, Stockholm, Sweden. Informat Management Serv, Silver Spring, MD USA. RP Gridley, G (reprint author), NCI, Div Canc Epidemiol & Genet, EPS 8034-7244, Bethesda, MD 20892 USA. RI Zahm, Shelia/B-5025-2015 NR 28 TC 15 Z9 16 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD JUL PY 1999 VL 36 IS 1 BP 193 EP 199 DI 10.1002/(SICI)1097-0274(199907)36:1<193::AID-AJIM27>3.0.CO;2-M PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 201YM UT WOS:000080624900027 PM 10361606 ER PT J AU Kopp, JB AF Kopp, JB TI Glomerulosclerosis, tubulointerstitial fibrosis, and obstructive uropathy in PEPCK-TGF-beta 1 transgenic mice SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material ID EXPRESSION C1 NIH, Bethesda, MD 20892 USA. RP Kopp, JB (reprint author), NIH, Bdg 10,Rm 3N116, Bethesda, MD 20892 USA. OI Kopp, Jeffrey/0000-0001-9052-186X NR 8 TC 3 Z9 5 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUL PY 1999 VL 34 IS 1 BP 177 EP 180 DI 10.1016/S0272-6386(99)70128-9 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 213HT UT WOS:000081267200029 PM 10401036 ER PT J AU Molnar, M Rigo, J Romero, R Hertelendy, F AF Molnar, M Rigo, J Romero, R Hertelendy, F TI Oxytocin activates mitogen-activated protein kinase and up-regulates cyclooxygenase-2 and prostaglandin production in human myometrial cells SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 44th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 18-22, 1997 CL SAN DIEGO, CA SP Soc Gynecol Invest DE cyclooxygenase-2; oxytocin; prostaglandins; mitogen-activated protein kinase; signal transduction; human myometrial cells ID INTRACELLULAR FREE CALCIUM; SMOOTH-MUSCLE; EXPRESSION; INVOLVEMENT; INCREASES AB OBJECTIVE: The objective of our study was to test the hypothesis that oxytocin promotes prostaglandin production by up-regulating cyclooxygenase-2 via activation of mitogen-activated protein kinase cascade in human myometrial cells. STUDY DESIGN: Confluent cultures of human myometrial cells obtained from uterine specimens of premenopausal women undergoing hysterectomy were serum starved for 48 hours before oxytocin stimulation. Prostacyclin levels, as 6-keto-prostaglandin F(1 alpha), were measured by radioimmunoassay, and the cellular cyclooxygenase-2 protein content was determined by Western blot. Mitogen-activated protein kinase activity was assessed by measuring the phosphorylation of myelin basic protein. RESULTS: In a time- and dose-dependent manner oxytocin promoted prostacyclin production in human myometrial cells. Maximal responses were observed after 8 hours of stimulation at a dose of 100 nmol/L. This effect was mainly due to the expression of cyclooxygenase-2 protein. Within 5 minutes oxytocin significantly stimulated mitogen-activated protein kinase, as compared with the expression in untreated controls. The maximal increase in enzyme activity (2.5-fold) was obtained at 45 minutes. A selective inhibitor of mitogen-activated protein kinase activation (PD98059), as well as herbimycin, a tyrosine kinase inhibitor, and the transcriptional blocker actinomycin D, suppressed oxytocin-induced cyclooxygenase-2 expression and prostacyclin production. The stimulatory action of oxytocin was also sensitive to inhibition by pertussis toxin but appeared to be independent of protein kinase C activation. CONCLUSION: Our data indicate a largely unrecognized signal transduction mechanism for oxytocin, involving G-protein-coupled activation of mitogen-activated protein kinase and cyclooxygenase-2 gene expression, leading to increased prostaglandin production in human myometrial cells. This signaling pathway complements the rapid activation of the phosphoinositide cycle and may be responsible for sustained release of prostaglandins in uterine tissues, promoting labor and parturition. C1 Semmelweis Univ Med, Inst Pathophysiol, H-1085 Budapest, Hungary. Semmelweis Univ Med, Dept Obstet & Gynecol 1, H-1085 Budapest, Hungary. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. NICHHD, Perinatol Res Branch, NIH, Bethesda, MD 20892 USA. St Louis Univ, Sch Med, Dept Obstet & Gynecol, St Louis, MO 63117 USA. St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63117 USA. St Marys Hlth Ctr, St Louis, MO USA. RP Hertelendy, F (reprint author), St Louis Univ, Sch Med, Dept Obstet & Gynecol, St Marys W Pavil,1027 Bellevue Ave, St Louis, MO 63117 USA. OI Molnar, Miklos/0000-0001-9231-782X NR 25 TC 59 Z9 60 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUL PY 1999 VL 181 IS 1 BP 42 EP 49 DI 10.1016/S0002-9378(99)70434-5 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 218NK UT WOS:000081558500009 PM 10411794 ER PT J AU McNellis, D Alexander, D AF McNellis, D Alexander, D TI New opportunities for researchers in obstetrics and gynecology through programs supported by the National Institute of Child Health and Human Development SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE academic obstetrics and gynecology; research training; research career ID PHYSICIAN-SCIENTIST AB The organization of the National institute of Child Health and Human Development and its funding procedures are reviewed from the perspective of the specialty of obstetrics and gynecology. The opportunities for research training and career development recently made available by the National Institute of Child Health and Human Development are described. Active and productive use of these opportunities by the academic community is important. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP McNellis, D (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. NR 3 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUL PY 1999 VL 181 IS 1 BP 221 EP 225 DI 10.1016/S0002-9378(99)70463-1 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 218NK UT WOS:000081558500039 PM 10411823 ER PT J AU Hitzler, JK Witte, DP Jenkins, NA Copeland, NG Gilbert, DJ Naeve, CW Look, AT Morris, SW AF Hitzler, JK Witte, DP Jenkins, NA Copeland, NG Gilbert, DJ Naeve, CW Look, AT Morris, SW TI cDNA cloning, expression pattern, and chromosomal localization of Mlf1, murine homologue of a gene involved in myelodysplasia and acute myeloid leukemia SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID NON-HODGKINS-LYMPHOMA; STEM-CELL ORIGIN; HEMATOPOIETIC-CELLS; SIGNALING PROTEINS; KINASE-ACTIVITY; T-CELLS; 14-3-3-PROTEINS; FUSION; APOPTOSIS; RECEPTOR AB The NPM-MLF1 fusion protein is expressed in blasts from patients with myelodysplasia/acute myeloid leukemia (MDS/AML) containing the t(3;5) chromosomal rearrangement. Nucleophosmin (NPM), a previously characterized nucleolar phosphoprotein, contributes to two other fusion proteins found in lympho-hematopoietic malignancies, anaplastic large cell lymphoma (NPM-ALK) and acute promyelocytic leukemia (NPM-RAR alpha), By contrast, the function off the carboxy-terminal fusion partner, myelodysplasia/myeloid leukemia factor 1 (MLF1), is unknown. To aid in understanding normal MLF1 function, we isolated the murine cDNA, determined the chromosomal localization of Mlf1, and defined its tissue expression by in situ hybridization, Mlf1 was highly similar to its human homologue (86% and 84% identical nucleotide and amino acid sequence, respectively) and mapped to the central region of chromosome 3, within a segment lacking known mouse mutations. Mlf1 tissue distribution was restricted during both development and postnatal life, with high levels present only in skeletal, cardiac, and selected smooth muscle, gonadal tissues, and rare epithelial tissues including the nasal mucosa and the ependyma/choroid plexus in the brain. Mlf1 transcripts were undetectable in the lympho-hematopoietic organs of both the embryonic and adult mouse, suggesting that NPM-MLF1 contributes to the genesis of MDS/AML in part by enforcing the ectopic overexpression of MLF1 within hematopoietic tissues. C1 St Jude Childrens Res Hosp, Dept Expt Oncol, Memphis, TN 38105 USA. St Jude Childrens Res Hosp, Dept Hematol Oncol, Memphis, TN 38105 USA. St Jude Childrens Res Hosp, Ctr Biotechnol, Memphis, TN 38105 USA. Univ Tennessee, Dept Pediat, Coll Med, Memphis, TN 38163 USA. Univ Cincinnati, Med Ctr, Dept Pediat, Div Pathol, Cincinnati, OH 45267 USA. NCI, Mammalian Genet Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Morris, SW (reprint author), St Jude Childrens Res Hosp, Dept Expt Oncol, Room 5024,Thomas Tower,332 N Lauderdale St, Memphis, TN 38105 USA. FU NCI NIH HHS [CA 27165, CA 76301] NR 49 TC 18 Z9 21 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 JUL PY 1999 VL 155 IS 1 BP 53 EP 59 DI 10.1016/S0002-9440(10)65098-5 PG 7 WC Pathology SC Pathology GA 212HE UT WOS:000081210600009 PM 10393836 ER PT J AU Rice, AB Moomaw, CR Morgan, DL Bonner, JC AF Rice, AB Moomaw, CR Morgan, DL Bonner, JC TI Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosis in rats SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID SIGNAL-TRANSDUCTION PATHWAY; ASBESTOS-EXPOSED RATS; ACUTE LUNG INJURY; GENE-EXPRESSION; FACTOR-ALPHA; ALVEOLAR MACROPHAGES; CHRYSOTILE ASBESTOS; FACTOR-BETA; IN-VIVO; PDGF-A AB The proliferation of myofibroblasts is a central feature of pulmonary fibrosis. In this study we have used tyrosine kinase inhibitors of the tyrphostin class to specifically block autophosphorylation of the platelet-derived growth factor receptor (PDGF-R) or epidermal growth factor receptor (EGF-R). AG1296 specifically inhibited autophosphorylation of PDGF-R and blocked PDGF-stimulated [H-3]thymidine uptake by rat lung myofibroblasts in vitro. AG1478 was demonstrated as a selective blocker of EGF-R autophosphorylation and inhibited EGF-stimulated DNA synthesis in vitro. In a rat model of pulmonary fibrosis caused by intratracheal instillation of vanadium pentoxide (V2O5), intraperitoneal delivery of 50 mg/kg AG1296 or AG1478 in dimethylsulfoxide 1 hour before V2O5 instillation and again 2 days after instillation reduced the number of epithelial and mesenchymal cells incorporating bromodeoxyuridine (Brdu) by similar to 50% at 3 and 6 days after instillation. V2O5 instillation increased lung hydroxyproline fivefold 15 days after instillation, and AG1296 was more than 90% effective in preventing the increase in hydroxyproline, whereas AG1478 caused a 50% to 60% decrease in V2O5-stimulated hydroxyproline accumulation. These data provide evidence that PDGF and EGF receptor ligands are potent mitogens for collagen-producing mesenchymal cells during pulmonary fibrogenesis, and targeting tyrosine kinase receptors could offer a strategy for the treatment of fibrotic lung diseases. C1 NIEHS, Pulm Pathobiol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIEHS, Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Bonner, JC (reprint author), NIEHS, Pulm Pathobiol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 40 TC 113 Z9 124 U1 0 U2 4 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 JUL PY 1999 VL 155 IS 1 BP 213 EP 221 DI 10.1016/S0002-9440(10)65115-2 PG 9 WC Pathology SC Pathology GA 212HE UT WOS:000081210600026 PM 10393853 ER PT J AU Setsuda, J Teruya-Feldstein, J Harris, NL Ferry, JA Sorbara, L Gupta, G Jaffe, ES Tosato, G AF Setsuda, J Teruya-Feldstein, J Harris, NL Ferry, JA Sorbara, L Gupta, G Jaffe, ES Tosato, G TI Interleukin-18, interferon-gamma, IP-10, and Mig expression in Epstein-Barr virus-induced infectious mononucleosis and posttransplant lymphoproliferative disease SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID BONE-MARROW TRANSPLANTATION; NECROSIS IN-VIVO; LIVER-TRANSPLANTATION; INDUCIBLE PROTEIN-10; VIRAL INTERLEUKIN-10; T-CELLS; KAPPA-B; DISORDERS; RECIPIENTS; CYTOKINE AB T cell immunodeficiency plays an important role in the pathogenesis of posttransplant lymphoproliferative disease (PTLD) by permitting the unbridled expansion of Epstein-Barr virus (EBV)-infected B lymphocytes. However, factors other than T cell function may contribute to PTLD pathogenesis because PTLD infrequently develops even in the context of severe T cell immunodeficiency, and athymic mice that are T-cell-immunodeficient can reject EBV-immortalized cells. Here we report that PTLD tissues express significantly lower levels of IL-18, interferon-gamma (IFN-gamma), Mig, and RANTES compared to lymphoid tissues diagnosed with acute EBV-induced infectious mononucleosis, as assessed by semiquantitative RT-PCR analysis. Other cytokines and chemokines are expressed at similar levels. Immunohistochemistry confirmed that PTLD tissues contain less IL-18 and Mig protein than tissues with infectious mononucleosis. IL-18, primarily a monocyte product, promotes the secretion of IFN-gamma, which stimulates Mig and RANTES expression. Both IL-18 and Mig display antitumor activity in mice involving inhibition of angiogenesis, These results document greater expression of IL-18, IFN-gamma, Mig, and RANTES in lymphoid tissues with acute EBV-induced infectious mononucleosis compared to tissues with PTLD and raise the possibility that these mediators participate in critical host responses to EBV infection. C1 NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, NIH, Bldg 10,Room 2A33,10 Ctr Dr MSC 1500, Bethesda, MD 20892 USA. NR 49 TC 43 Z9 46 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 JUL PY 1999 VL 155 IS 1 BP 257 EP 265 DI 10.1016/S0002-9440(10)65119-X PG 9 WC Pathology SC Pathology GA 212HE UT WOS:000081210600030 PM 10393857 ER PT J AU Bissig, H Richter, J Desper, R Meier, V Schraml, P Schaffer, AA Sauter, G Mihatsch, MJ Moch, H AF Bissig, H Richter, J Desper, R Meier, V Schraml, P Schaffer, AA Sauter, G Mihatsch, MJ Moch, H TI Evaluation of the clonal relationship between primary and metastatic renal cell carcinoma by comparative genomic hybridization SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; COPY NUMBER CHANGES; BREAST-CANCER; INTRATUMOR HETEROGENEITY; CYTOGENETIC ANALYSIS; GENETIC-DIFFERENCES; BLADDER-CANCER; PRIMARY TUMORS; SOLID TUMORS; DNA-CONTENT AB The outcome of patients with renal cell carcinoma is limited by the development of metastasis after nephrectomy. To evaluate the genetic basis underlying metastatic progression of human renal cell carcinoma in vivo, we performed a comparative genomic hybridization analysis in 32 clear-cell renal-cell carcinoma metastases. The most common losses involved chromosomes 3p (25%), 4q (28%), 6q (28%), 8p (31%), and 9p (47%). The most common gains were detected at 17q (31%) and Xq (28%). There was one high-level gene amplification at chromosome 11q22-23, The mean number of aberrations in lymph node (4.8 +/- 2.8) and lung metastases (6.2 +/- 4.0) was lower than in other hematogenous metastases (11.5 +/- 8.7, P < 0.05), suggesting that hematogenous dissemination is linked to an acquisition of complex genomic alterations, As genetic differences between primary tumors and metastases give information on genetic changes that have contributed to the metastatic process, relative DNA sequence copy number changes in 19 matched tumor pairs were compared. Genomic changes, which frequently occurred in metastases but not in the corresponding primary tumor were losses of 8p and 9p and gains of 17q and Xq. An abnormal function of genes in these regions may contribute to the metastatic process. According to a statistical analysis of shared genetic changes in matched tumor pairs, a high probability of a common clonal progenitor was found in 11 of 19 patients (58%). Six metastases (32%) were genetically almost completely different from the primary, suggesting that detection of genomic alterations in primary tumors gives only a restricted view of the biological properties of metastatic renal cell carcinoma. C1 Univ Basel, Inst Pathol, CH-4003 Basel, Switzerland. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany. RP Moch, H (reprint author), Univ Basel, Inst Pathol, Schonbeinstr 40, CH-4003 Basel, Switzerland. RI Schaffer, Alejandro/F-2902-2012 NR 50 TC 86 Z9 88 U1 0 U2 3 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 JUL PY 1999 VL 155 IS 1 BP 267 EP 274 DI 10.1016/S0002-9440(10)65120-6 PG 8 WC Pathology SC Pathology GA 212HE UT WOS:000081210600031 PM 10393858 ER PT J AU Carballo, E Pitterle, DM Stumpo, DJ Sperling, RT Blackshear, PJ AF Carballo, E Pitterle, DM Stumpo, DJ Sperling, RT Blackshear, PJ TI Phagocytic and macropinocytic activity in MARCKS-deficient macrophages and fibroblasts SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE phagocytosis; macropinocytosis; myristoylated; alanine-rich; C kinase substrate ID PROTEIN-KINASE-C; RECEPTOR-MEDIATED PHAGOCYTOSIS; COLONY-STIMULATING FACTOR; MARROW-DERIVED MACROPHAGES; ABNORMAL BRAIN-DEVELOPMENT; NEURAL-TUBE DEFECTS; SUBSTRATE MARCKS; TYROSINE PHOSPHORYLATION; MEMBRANE ASSOCIATION; PHORBOL ESTERS AB Macrophages express high levels of the myristoylated, alanine-rich, C kinase substrate (MARCKS), an actin cross-linking protein. To investigate a possible role of MARCKS in macrophage function, fetal liver-derived macrophages were generated from wild-type and MARCKS knockout mouse embryos. No differences between the wild-type and MARCKS-deficient macrophages with respect to morphology (Wright's stain) or actin distribution (staining with rhodamine-phalloidin, under basal conditions or after treatment with phorbol esters, lipopolysaccharide, or both) were observed. We then evaluated phagocytosis mediated by different receptors: Fc receptors tested with IgG-coated sheep red blood cells, complement C3b receptors tested with C3b-coated yeast, mannose receptors tested with unopsonized zymosan, and nonspecific phagocytosis tested with latex beads. We also studied fluid phase endocytosis in macrophages and mouse embryo fibroblasts by using FITC-dextran to quantitate this process. In most cases, there were no differences between the cells derived from wild-type and MARCKS-deficient mice. However, a minor but significant and reproducible difference in rates of zymosan phagocytosis at 45-60 min was observed, with lower rates of phagocytosis in the MARCKS-deficient cells. Our data indicate that MARCKS deficiency may lead to slightly decreased rates of zymosan phagocytosis. C1 NIEHS, Off Clin Res, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), NIEHS, Off Clin Res, A2-05,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov NR 58 TC 15 Z9 15 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD JUL PY 1999 VL 277 IS 1 BP C163 EP C173 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 217QX UT WOS:000081511400017 PM 10409119 ER PT J AU Corleto, VD Weber, HC Jensen, RT AF Corleto, VD Weber, HC Jensen, RT TI Expression of somatostatin receptor subtypes on guinea pig gastric and colonic smooth muscle cells SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE colon; colonic motility; octreotide; cloning ID MESSENGER-RNA EXPRESSION; CHOLECYSTOKININ-OCTAPEPTIDE; OCTREOTIDE SCINTIGRAPHY; GASTROINTESTINAL-TRACT; MOLECULAR-CLONING; DISTAL COLON; RAT; TISSUE; INHIBITION; MUCOSAE AB In vivo and in vitro studies have demonstrated that somatostatin can influence motility and smooth muscle contractility of the stomach and colon. Recent studies have proposed that some of these effects may be mediated by somatostatin receptors (sst) directly on the smooth muscle cells. If this is correct, the sst receptor subtypes that are present are unknown. This study aimed to resolve these points. Because nucleotide sequences of guinea pig sst genes are unknown, we used sst subtype-specific primers based on comparisons of human and rat sst subtypes and performed RT-PCR of DNase I-treated total RNA from guinea pig total brain. PCR products were cloned in pCR II and sequenced and showed 87% (sst(1)), 90% (sst(2)), 90% (sst(3)), 99% (sst(4)), and 80% (sst(5)), respectively, nucleotide homology to the same region (transmembrane 4-6) of the human sst genes. Homology to rat sequences were lower. PCR products were obtained from first-strand cDNA derived from DNase I-treated RNA from dispersed guinea pig gastric and colonic smooth muscle cells. In gastric and colonic smooth muscle cells, we detected sst(1)-sst(3) and sst(5), and all were confirmed by sequencing. The presence of sst(4) was shown by Southern blot analysis and hybridization with a guinea pig sst-specific primer. RT-PCR from cultured colonic and gastric smooth muscle cells devoid of any neural elements gave identical results. These results demonstrate that in the guinea pig all five sst subtypes are present directly on gastric and colonic smooth muscle cells. Previous studies have suggested that a predominant sst(3) subtype on gastric and a sst5 subtype on colonic muscle cells mediated somatostatin's contractile effects, but the finding here that all five sst subtypes exist on both of these cells suggests that other sst subtypes have only a small or no contractile effect, sst subtypes in guinea pig have a different pharmacological profile from rat or human sst, or these other sst subtypes have some yet undescribed physiological function in muscle cells. C1 NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIDDK, Digest Dis Branch, NIH, Bldg 10,Rm 9C-103,10 Ctr Dr,MSC 1804, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov NR 45 TC 13 Z9 13 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD JUL PY 1999 VL 277 IS 1 BP G235 EP G244 PG 10 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 216UZ UT WOS:000081464000029 PM 10409172 ER PT J AU Solomon, SB Nikolic, SD Frater, RWM Yellin, EL AF Solomon, SB Nikolic, SD Frater, RWM Yellin, EL TI Contraction-relaxation coupling: determination of the onset of diastole SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE afterload; left ventricular relaxation ID LEFT-VENTRICULAR RELAXATION; SYSTOLIC PRESSURE; HEART; LOAD; MUSCLE; FAILURE; PUMP AB Left ventricular relaxation is dependent on afterload conditions during systole. An abrupt increase in afterload while the ventricle is actively contracting prolongs the duration of systole. An increase in afterload during ventricular relaxation shortens the duration of systole. Therefore, we hypothesized that the point during systole when an abrupt increase in afterload had no effect on the duration of systole represented the onset of ventricular relaxation. To determine when this point occurs, we performed aortic occlusions progressively throughout the duration of systole in six dogs. We determined the change in systolic time (t(sys)) after an intervention normalized to t(sys) Of a control beat (t(sys,i)/t(sys,c)) as a function of systolic occlusion time as a percentage of total systolic time (t(occ)/t(sys,c)), where t(sys) is the duration from time of left ventricular end-diastolic pressure to the time of minimum first derivative of left ventricular pressure. Our results show the onset of left ventricular relaxation during normal ejection occurs at 34 +/- 3% of systolic time and similar to 16% after the onset of ejection. Thus the beginning of relaxation occurs soon after the beginning of ejection, suggesting that relaxation is modulated by variable loading conditions during ejection, significantly before what has been conventionally been assumed to be the beginning of ventricular relaxation. C1 Yeshiva Univ Albert Einstein Coll Med, Dept Cardiothorac Surg, Bronx, NY 10461 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Physiol & Biophys, Bronx, NY 10461 USA. Stanford Univ, Sch Med, Palo Alto Med Fdn, Res Inst,Dept Cardiovasc & Thorac Surg, Palo Alto, CA 94306 USA. RP Solomon, SB (reprint author), NIH, Dept Crit Care Med, 10 Ctr Dr,Rm 7D43, Bethesda, MD 20892 USA. EM ssolomon@cc.nih.gov FU NHLBI NIH HHS [HL-49614] NR 27 TC 19 Z9 19 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUL PY 1999 VL 277 IS 1 BP H23 EP H27 PG 5 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 216KU UT WOS:000081442000004 PM 10409177 ER PT J AU Yang, TX Sun, DQ Huang, YNG Smart, A Briggs, JP Schnermann, JB AF Yang, TX Sun, DQ Huang, YNG Smart, A Briggs, JP Schnermann, JB TI Differential regulation of COX-2 expression in the kidney by lipopolysaccharide: role of CD14 SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE cyclooxygenase-2; renal inner medulla; transgenic mice ID ACTIVATED PROTEIN-KINASE; NITRIC-OXIDE SYNTHASE; COMPLEMENTARY-DNA; CYCLOOXYGENASE; ENDOTOXIN; INDUCTION; RAT; INFLAMMATION; CIRCULATION; MACROPHAGES AB Induction of the inducible cyclooxygenase isoform COX-2 is likely to be an important mechanism for increased prostaglandin production in renal inflammation. We examined the effect of lipopolysaccharide (LPS) on regional renal COX-2 expression in the rat. In the inner medulla, LPS injection (4 mg/kg ip) induced a twofold and 2.5-fold increase in the levels of COX-2 mRNA and COX-2 protein, respectively. In contrast, COX-2 expression in the renal cortex was not significantly altered. COX-2 promoter transgenic mice were created using the 2.7-kb flanking region of the rat COX-2 gene. In these animals, LPS injection induced reporter gene expression predominately in the inner medulla. The LPS receptor CD14, usually regarded as a monocyte/macrophage specific marker, was found to be abundantly expressed in the inner medulla and in dissected inner medullary collecting duct (IMCD) cells, suggesting that it may mediate medullary COX-2 induction. CD14 was present only at low levels in cortex and cortical segments, including glomeruli. Ln cultured cells,it was abundant in mouse IMCD (mIMCD-K2) cells and renal medullary interstitial cells, but largely undetectable in mesangial cells and M1 cells, a cell line derived from mouse cortical collecting ducts. In the mIMCD-K2 cell Line, LPS significantly induced COX-2 mRNA expression, with concomitant induction of CD14. LPS-stimulated COX-2 expression was reduced by the addition of an anti-CD14 monoclonal antibody to the culture medium. These results demonstrate that LPS selectively stimulates COX-2 expression in the renal inner medulla through a CD14-dependent mechanism. C1 NIDDK, NIH, Bethesda, MD 20892 USA. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48104 USA. Univ Michigan, Dept Physiol, Ann Arbor, MI 48104 USA. RP Schnermann, JB (reprint author), NIDDK, NIH, Bldg 10,Rm 4DA51,10 Ctr Dr, Bethesda, MD 20892 USA. EM jurgens@intra.niddk.nih.gov RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 FU NIDDK NIH HHS [DK-37448, DK-39255, DK-40042] NR 40 TC 13 Z9 14 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 JUL PY 1999 VL 277 IS 1 BP F10 EP F16 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 216AX UT WOS:000081419300002 PM 10409292 ER PT J AU Yang, TX Schnermann, JB Briggs, JP AF Yang, TX Schnermann, JB Briggs, JP TI Regulation of cyclooxygenase-2 expression in renal medulla by tonicity in vivo and in vitro SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE prostaglandin H synthase; inner medulla; hyperosmolality; prostaglandins; sodium chloride; promoter ID PROTEIN-TYROSINE PHOSPHORYLATION; COLLECTING TUBULE CELLS; MESSENGER-RNA; PROSTAGLANDIN SYNTHESIS; MDCK CELLS; HYPEROSMOTIC STRESS; COMPLEMENTARY-DNA; ALDOSE REDUCTASE; OSMOTIC-STRESS; GROWTH-FACTOR AB Renal medullary prostaglandins are believed to exert an important functional role in antagonizing vasopressin effects in dehydration. Studies were undertaken to determine the effect of hyperosmolality on cyclooxygenase (COX) isoform expression in the renal medulla. COX-1 and COX-2 mRNA and protein levels were determined by RT-PCR or Western blotting in Sprague-Dawley rats on varying water intakes, in Brattleboro rats and in Long-Evans controls. Over a wide range of urinary tonicity, COX-2 expression correlated closely with urine osmolality levels (R = 0.872). COX-1 levels did not vary. Immunolocalization showed that the stimulation of COX-2 expression by dehydration occurred predominantly in the collecting duct. Hypertonicity caused by addition of NaCl produced a dose- and time-dependent stimulation of COX-2 expression in mIMCD-K2 cells as well as in MDCK cells. COX-1 was unaffected. In the same cell lines, mannitol, sucrose, and raffinose also had a stimulatory effect. The tonicity-stimulated COX-2 expression in mIMCD-K2 cells was almost completely blocked by a tyrosine kinase inhibitor, genistein at 100 mu M. In MDCK cells transfected with a 2.7-kb COX-2 promoter and lacZ reporter construct, NaCl induced a twofold increase in beta-galactosidase activity. Using mIMCD-K2 cells, hypertonic NaCl (600 mosmol/kgH(2)O for 24 h) induced a 33-fold increase in PGE(2) release determined by enzyme immunoassay, an effect completely blocked by 3 mu M indomethacin or the COX-2-specific blocker N-(2-cyclohexy-4-nitrophenyl)methanesulfonamide (NS-398). We conclude that in inner medulla, COX-2 but not COX-1 is upregulated by hyperosmolality. C1 NIDDK, NIH, Bethesda, MD 20892 USA. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48104 USA. Univ Michigan, Dept Physiol, Ann Arbor, MI 48104 USA. RP Briggs, JP (reprint author), NIDDK, NIH, Bldg 31,Rm 9A17,31 Ctr Dr MSC 2560, Bethesda, MD 20892 USA. EM BriggsJ@hq.niddk.nih.gov RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 FU NIDDK NIH HHS [DK-37448, DK-39255, DK-40042] NR 43 TC 112 Z9 114 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 JUL PY 1999 VL 277 IS 1 BP F1 EP F9 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 216AX UT WOS:000081419300001 PM 10409291 ER PT J AU Mueller, TI Leon, AC Keller, MB Solomon, DA Endicott, J Coryell, W Warshaw, M Maser, JD AF Mueller, TI Leon, AC Keller, MB Solomon, DA Endicott, J Coryell, W Warshaw, M Maser, JD TI Recurrence after recovery from major depressive disorder during 15 years of observational follow-up SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 149th Annual Meeting of the American-Psychiatric-Association CY MAY 04-09, 1996 CL NEW YORK, NEW YORK SP Amer Psychiat Assoc ID PREDICTORS; RELAPSE; EPISODE; SEX AB Objective: The recurrence of an affective disorder in people who initially recover from major depressive disorder was characterized by using the unique longitudinal prospective follow-up data from the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression-Clinical Studies. Method: Up to 15 years of prospective follow-up data on the course of major depressive disorder were available for 380 subjects who recovered from an index episode of major depressive disorder and for 105 subjects who subsequently remained well for at least 5 years after recovery. Baseline demographic and clinical characteristics were examined as predictors of recurrence of an affective disorder, The authors also examined naturalistically applied antidepressant therapy. Results: A cumulative proportion of 85% (Kaplan-Meier estimate) of the 380 recovered subjects experienced a recurrence, as did 58% (Kaplan-Meier estimate) of those who remained well for at least 5 years. Female sex, a longer depressive episode before intake, more prior episodes, and never marrying were significant predictors of a recurrence. None of these or any other characteristic persisted as a predictor of recurrence in subjects who recovered and were subsequently well for at least 5 years. Subjects reported receiving low levels of antidepressant treatment during the index episode, which further decreased in amount and extent during the well interval. Conclusions: Few baseline demographic or clinical characteristics predict who will or will not experience a recurrence of an affective disorder after recovery from an index episode of major depressive disorder, even in persons with lengthy well intervals. Naturalistically applied levels of antidepressant treatment are well below those shown effective in maintenance pharmacotherapy studies. C1 Brown Univ, Sch Med, Dept Psychiat & Human Behav, Providence, RI 02906 USA. Brown Univ, NIMH, Collaborat Program Psychobiol Depress Clin Studie, Sch Med, Providence, RI 02906 USA. RP Mueller, TI (reprint author), Brown Univ, Butler Hosp, Sch Med, Dept Psychiat & Human Behav, 345 Blackstone Blvd, Providence, RI 02906 USA. RI Page, Andrew/G-5438-2012 OI Page, Andrew/0000-0003-3133-2844 FU NIMH NIH HHS [R01 MH025478] NR 20 TC 437 Z9 451 U1 3 U2 36 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 JUL PY 1999 VL 156 IS 7 BP 1000 EP 1006 PG 7 WC Psychiatry SC Psychiatry GA 211XM UT WOS:000081187200004 PM 10401442 ER PT J AU Cohen, RZ Seeman, MV Gotowiec, A Kopala, L AF Cohen, RZ Seeman, MV Gotowiec, A Kopala, L TI Earlier puberty as a predictor of later onset of schizophrenia in women SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID ESTROGEN; AGE; RAT; NEUROTRANSMISSION; EPIDEMIOLOGY; RELIABILITY; SENSITIVITY; PSYCHOSES; RECEPTORS; ACCURACY AB Objective: The aim of this study was to determine whether puberty plays a mediating role in onset of schizophrenia, The hypothesis was that there is an inverse relation between age at puberty (menarche) and age at onset in women, Method: Competent and consenting individuals with DSM-IV-defined schizophrenia or schizoaffective disorder and their mothers underwent a 45-minute interview to ascertain age at first odd behavior, age at first psychotic symptoms, age at first hospitalization, and ages at various indices of puberty. Information about substance use, head injury, perinatal trauma, and first-degree family history of schizophrenia was also obtained. Results: In the women (N=35), the earlier the age at menarche, the later the ages at both the first psychotic symptoms and the first hospitalization. There was no significant association between puberty and onset in the men (N=45). Other than gender, none of the examined variables played a role in the interaction of puberty and onset of illness. Conclusions: In women, early puberty (whether through hormonal or social influence) was associated with later onset of schizophrenia. This effect was not found in men; in fact, the trend was in the opposite direction. C1 Univ Toronto, Ctr Addict & Mental Hlth, Toronto, ON M5T 1R8, Canada. Johns Hopkins Univ, Natl Human Genome Res Inst, Baltimore, MD USA. Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada. RP Seeman, MV (reprint author), Univ Toronto, Ctr Addict & Mental Hlth, 250 Coll St, Toronto, ON M5T 1R8, Canada. NR 37 TC 56 Z9 58 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 JUL PY 1999 VL 156 IS 7 BP 1059 EP 1064 PG 6 WC Psychiatry SC Psychiatry GA 211XM UT WOS:000081187200014 PM 10401452 ER PT J AU Kumra, S Briguglio, C Lenane, M Goldhar, L Bedwell, J Venuchekov, J Jacobsen, LK Rapoport, JL AF Kumra, S Briguglio, C Lenane, M Goldhar, L Bedwell, J Venuchekov, J Jacobsen, LK Rapoport, JL TI Including children and adolescents with schizophrenia in medication-free research SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID CHILDHOOD-ONSET SCHIZOPHRENIA; NEUROLEPTIC WITHDRAWAL; METABOLITES AB Objective: There has been an increasing focus on the ethical issues raised by studies requiring the withdrawal of effective medication in schizophrenic adults. This article examines the risks and benefits of a medication-free period for pediatric patients with treatment-refractory schizophrenia who are participating in an ongoing study. Method: Between April 1993 and March 1998, 31 children and adolescents were admitted with a diagnosis of treatment-resistant, childhood-onset schizophrenia. Parental consent was obtained so that patients could participate in a medication-free research period. Patients were evaluated at screening, at the end of a 4-week washout, at the completion of a 6- to 8-week atypical neuroleptic trial, and at a 2- to 4-year follow-up. Results: At the completion of a 4-week drug-free period, seven patients (23%) were diagnosed with another disorder on the basis of data gained from the drug-free period and their lack of schizophrenic symptoms. Their revised diagnoses were posttraumatic stress disorder (N=1), an atypical psychosis labeled "multidimensionally impaired" (N=4), and personality disorder (N=2). At follow-up, three of these patients remained free of neuroleptic therapy, For eight patients (26%), the washout was curtailed because of rapid and severe deterioration of their schizophrenic symptoms. Conclusions: For children and adolescents with treatment-refractory schizophrenia, a medication-free period can be conducted safely for at least 4 weeks for inpatients. Such trials are useful on clinical grounds and for providing homogeneous patient groups for research. This study also highlights the necessity of having access to hospitalization to observe children and adolescents with psychotic symptoms while medication free. C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. Yale Univ, Sch Med, New Haven, CT USA. RP Rapoport, JL (reprint author), NIMH, Child Psychiat Branch, Bldg 10,Rm 3N202,10 Ctr Dr,MSC 1600, Bethesda, MD 20892 USA. NR 29 TC 15 Z9 15 U1 4 U2 4 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 JUL PY 1999 VL 156 IS 7 BP 1065 EP 1068 PG 4 WC Psychiatry SC Psychiatry GA 211XM UT WOS:000081187200015 PM 10401453 ER PT J AU Northridge, ME Yankura, J Kinney, PL Santella, RM Shepard, P Riojas, Y Aggarwal, M Strickland, P AF Northridge, ME Yankura, J Kinney, PL Santella, RM Shepard, P Riojas, Y Aggarwal, M Strickland, P CA Earth Crew TI Diesel exhaust exposure among adolescents in Harlem: A community-driven study SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; PARTICULATE AIR-POLLUTION; OBSTRUCTIVE PULMONARY-DISEASE; NEW-YORK-CITY; URINARY 1-HYDROXYPYRENE; RESPIRATORY-DISEASE; CHILDHOOD ASTHMA; PM10 POLLUTION; CHILDREN; HEALTH AB Objectives. This study sought individual-level data on diesel exhaust exposure and lung function among adolescents in Harlem as part of a community-driven research agenda. Methods. High school students administered in-person surveys to seventh grade students to ascertain information on demographics, asthma history, and self-reported and maternal smoking. Urine samples were assayed for l-hydroxypyrene (1-HP), a marker of diesel exhaust exposure, and cotinine, a marker of tobacco smoke exposure. Computer-assisted spirometry was used to measure lung function. Results. Three quarters (76%) of the participating students had detectable levels of 1-HP. Three students (13%) had an FEF25-75 of less than or equal to 80% of their predicted measurements, and 4 students (17%) had results between 80% and 90% of the predicted value, all of which are suggestive of possible lung impairment. Conclusions. These data suggest that most adolescents in Harlem are exposed to detectable levels of diesel exhaust, a known exacerbator and possible cause of chronic lung disorders such as asthma. Community-driven research initiatives are important for empowering communities to make needed changes to improve their environments and health. C1 NIEHS, Ctr Environm Hlth No Manhattan, New York, NY 10032 USA. Harlem Ctr Hlth Promot & Dis Prevent, New York, NY USA. W Harlem Environm Act, New York, NY USA. Johns Hopkins Sch Hyg & Publ Hlth, Baltimore, MD USA. RP Northridge, ME (reprint author), NIEHS, Ctr Environm Hlth No Manhattan, 60 Haven Ave,Level B-1, New York, NY 10032 USA. FU NIEHS NIH HHS [P30-ES03819] NR 41 TC 41 Z9 41 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 JUL PY 1999 VL 89 IS 7 BP 998 EP 1002 DI 10.2105/AJPH.89.7.998 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 209QG UT WOS:000081059100004 PM 10394306 ER PT J AU Alavanja, MCR Lubin, JH Mahaffey, JA Brownson, RC AF Alavanja, MCR Lubin, JH Mahaffey, JA Brownson, RC TI Residential radon exposure and risk of lung cancer in Missouri SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID NONSMOKING WOMEN; DESIGN AB Objectives. This study investigated residential radon exposure and lung I cancer risk, using both standard radon dosimetry and a new radon monitoring technology that, evidence suggests, is a better measure of cumulative radon exposure. Methods. Missouri women (aged 30 to 84 years) newly diagnosed with primary lung cancer during the period January 1, 1993, to January 31, 1994, were invited to participate in this population-based case-control study. Both indoor air radon detectors and CR-39 alpha-particle detectors (surface moni- tors) were used. Results. When surface monitors were used, a significant trend in lung cancer odds ratios was observed for 20-year time-weighted-average radon concentrations. Conclusions. When surface monitors were used, but not when standard radon dosimetry was used, a significant lung cancer risk was found for radon concentrations at and above the action level for mitigation of houses currently used in the United States (148 Bqm(-3)). The risk was below the action level used in Canada (750 Bqm(-3)) and many European countries (200-400 Bqm(-3)). C1 NCI, Div Can Epidemiol & Genet, Bethesda, MD 20892 USA. Pacific NW Lab, Richland, WA 99352 USA. St Louis Univ, Sch Publ Hlth, Dept Community Hlth, St Louis, MO 63103 USA. RP Alavanja, MCR (reprint author), NCI, Div Can Epidemiol & Genet, Execut Plaza S,Room 8000,Mail Stop 8000, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CP-21102] NR 26 TC 89 Z9 98 U1 0 U2 3 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 JUL PY 1999 VL 89 IS 7 BP 1042 EP 1048 DI 10.2105/AJPH.89.7.1042 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 209QG UT WOS:000081059100011 PM 10394313 ER PT J CA NICHD Early Child Care Res Network TI Child outcomes when child care center classes meet recommended standards for quality SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID INFANT; RATIO AB Objectives. This study assessed outcomes for children when child care centers meet recommended care standards. Methods. Data from the NICHD Study Of Early Child Care were used to examine the association between meeting standards for child-staff ratios, group sizes, caregiver training, and caregiver education and children's development at 24 and 36 months of age. Results. There were 5 major findings: (1) most classes observed did not meet all 4 recommended standards (compliance ranged from 10% at 6 months of age to 34% at 36 months of age); (2) linear associations were found between number of standards met and child outcomes, and this was more the case at 36 months than at 24 months of age; (3) there was no evidence of threshold effects; (4) children in classes that met more standards had better school readiness and language comprehension scores as well as fewer behavior problems at 36 months of age; and (5) child outcomes were predicted by child-staff ratio at 24 months and caregiver training and education at 36 months of age. Conclusions. Outcomes were better when children attended classes that met recommended child-staff ratios and recommended levels of caregiver training and education. C1 NICHHD, CHDB, Early Child Care Res Network, Bethesda, MD 20892 USA. RP NICHHD, CHDB, Early Child Care Res Network, Bldg 61 E,4B05,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 24 TC 0 Z9 0 U1 2 U2 5 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 JUL PY 1999 VL 89 IS 7 BP 1072 EP 1077 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 209QG UT WOS:000081059100016 ER PT J AU Bassily, S Frenck, RW Mohareb, EW Wierzba, T Savarino, S Hall, E Kotkat, A Naficy, A Hyams, KC Clemens, J AF Bassily, S Frenck, RW Mohareb, EW Wierzba, T Savarino, S Hall, E Kotkat, A Naficy, A Hyams, KC Clemens, J TI Seroprevalence of Helicobacter pylori among Egyptian newborns and their mothers: A preliminary report SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID PEPTIC-ULCER DISEASE; UNITED-STATES; INFECTION; CHILDREN; ACQUISITION; RISK; EPIDEMIOLOGY; PREVALENCE; INFANCY; COHORT AB Helicobacter pylori is one of the most common human bacterial infections in the world and children in the developing countries acquire H. pylori infection early in life. We prospectively evaluated the prevalence of serum antibodies to H. pylori in a cohort of pregnant women and their offspring. Mothers' sera were collected during the third trimester of pregnancy and sera from their offspring were collected when they were 7-9 months and 18 months of age. Pylori-Stat(TM), a commercially available ELISA kit, was used to detect antibodies to H. pylori in the serum of the subjects tested. Sera from 169 mothers were available for testing and 88% of these samples were positive for anti-H. pylori IgG. Of the 169 children tested, 13% of the infants 7-9 months of age and 25% of the children 18 months of age had serologic evidence of H. pylori infection. These data indicate that infection with N. pylori is common in Egypt and acquisition of infection occurs at a very young age. C1 USN, Med Res Unit 3, Cairo, Egypt. High Inst Publ Hlth, Alexandria, Egypt. NICHHD, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. USN, Med Res Inst, Bethesda, MD USA. RP Bassily, S (reprint author), USN, Med Res Unit 3, PSC 452,Box 5000, Cairo, Egypt. RI Savarino, Stephen/A-8030-2011 FU NICHD NIH HHS [Y1-HD-7186-02] NR 35 TC 24 Z9 30 U1 1 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DRIVE SUITE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUL PY 1999 VL 61 IS 1 BP 37 EP 40 PG 4 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 220MQ UT WOS:000081670100009 PM 10432052 ER PT J AU Tarr, PE Kuppens, L Jones, TC Ivanoff, B Aparin, PG Heymann, DL AF Tarr, PE Kuppens, L Jones, TC Ivanoff, B Aparin, PG Heymann, DL TI Considerations regarding mass vaccination against typhoid fever as an adjunct to sanitation and public health measures: Potential use in an epidemic in Tajikistan SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID VI-CAPSULAR POLYSACCHARIDE; CONTROLLED FIELD TRIAL; RESISTANT SALMONELLA-TYPHI; ENTERIC-COATED CAPSULES; INFECTIOUS-DISEASES; CHILDREN YOUNGER; REFUGEE SETTINGS; TY21A VACCINE; IMMUNIZATION; EFFICACY AB We report on the ongoing epidemic of typhoid fever in Tajikistan that started in 1996. It has involved more than 24,000 cases to date, and is characterized by multiple point sources, overflow of sewage, contaminated municipal water, and person-to-person spread. Of the Salmonella typhi isolates available for testing in western laboratories, more than 90% are multidrug-resistant (MDR). Most recently, 28 (82%) of 34 isolates are resistant to ciprofloxacin, representing the first reported epidemic of quinolone-resistant typhoid fever. In the past, mass immunization during typhoid fever epidemics has been discouraged. A review of this policy is recommended in light of the alarming emergence of quinolone-resistant strains of S. typhi, the availability of improved vaccines, and the ongoing epidemic in Tajikistan. Mass immunization may be a useful measure for the control of prolonged MDR typhoid fever epidemics, as an adjunct to correction of municipal infrastructure and public health intervention. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA USA. WHO, Div Emerging & Communicable Dis Surveillance Cont, CH-1211 Geneva 27, Switzerland. WHO, Vaccine Res & Dev Unit, Global Program Vaccines & Immunizat, CH-1211 Geneva, Switzerland. Clin Res Consultants, Basel, Switzerland. Natl Res Ctr, Inst Immunol, Moscow, Russia. RP Tarr, PE (reprint author), NIAID, NIH, 9000 Rockville Pike,10-11S231, Bethesda, MD 20892 USA. NR 80 TC 32 Z9 33 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DRIVE SUITE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUL PY 1999 VL 61 IS 1 BP 163 EP 170 PG 8 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 220MQ UT WOS:000081670100031 PM 10432074 ER PT J AU Glazner, GW Gressens, P Lee, SJ Gibney, G Gozes, I Gozes, Y Brenneman, DE Hill, JM AF Glazner, GW Gressens, P Lee, SJ Gibney, G Gozes, I Gozes, Y Brenneman, DE Hill, JM TI Activity-dependent neurotrophic factor: a potent regulator of embryonic growth and development SO ANATOMY AND EMBRYOLOGY LA English DT Article DE mouse; vasoactive intestinal peptide; postimplantation; growth factor; embryogenesis ID VASOACTIVE-INTESTINAL-PEPTIDE; CULTURED MOUSE EMBRYOS; NEURONAL SURVIVAL; ENVELOPE PROTEIN; SONIC-HEDGEHOG; NERVOUS-SYSTEM; MESSENGER-RNA; S-PHASE; EXPRESSION; RECEPTOR AB Activity-dependent neurotrophic factor is a potent, neuroprotective molecule released from astroglia following stimulation by vasoactive intestinal peptide and, at least in part, accounts for the neuroprotective actions of vasoactive intestinal peptide. As well as enhancing neuronal survival, vasoactive intestinal peptide is known to regulate embryonic growth during the early postimplantation period of development. The current study was designed to assess activity-dependent neurotrophic factor's role in the growth-regulatory properties of vasoactive intestinal peptide. Treatment of whole cultured day-9 mouse embryos with activity-dependent neurotrophic factor (10(-13) M) resulted in a growth of 3.1 somites, compared with 1.6 somites in control embryos after a 4 h incubation period. Significant increases were also seen in cross-sectional area, protein and DNA content and bromodeoxyuridine incorporation. Activity-dependent neurotrophic factor-treated embryos were morphologically indistinguishable from control embryos of the same size. Anti-activity-dependent neurotrophic factor ascites significantly inhibited growth. In addition, co-treatment of embryos with anti-activity-dependent neurotrophic factor ascites inhibited vasoactive intestinal peptide-stimulated growth. Although anti-vasoactive intestinal peptide treatment inhibited growth, it did not inhibit activity-dependent neurotrophic factor-induced growth. These data indicate that an activity-dependent neurotrophic factor-like substance is an endogenous and potent growth-promoting factor in the early postimplantation embryo and that vasoactive intestinal peptide-regulated growth of embryos occurs, at least in part, through the action of activity-dependent neurotrophic factor. C1 NICHHD, Sect Dev & Mol Pharmacol, Lab Dev Neurobiol, Bethesda, MD 20892 USA. Hop Robert Debre, Serv Neuropediat, F-75019 Paris, France. Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. Israel Inst Biol Res, IL-70450 Ness Ziona, Israel. RP Hill, JM (reprint author), NICHHD, Sect Dev & Mol Pharmacol, Lab Dev Neurobiol, Bethesda, MD 20892 USA. NR 41 TC 25 Z9 26 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-2061 J9 ANAT EMBRYOL JI Anat. Embryol. PD JUL PY 1999 VL 200 IS 1 BP 65 EP 71 DI 10.1007/s004290050260 PG 7 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 203AW UT WOS:000080685700007 PM 10395007 ER PT J AU Gilron, I Quirion, R Coderre, TJ AF Gilron, I Quirion, R Coderre, TJ TI Pre- versus postformalin effects of ketamine or large-dose alfentanil in the rat: Discordance between pain behavior and spinal Fos-like immunoreactivity 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 CENTRAL-NERVOUS-SYSTEM; DORSAL HORN NEURONS; SUBCUTANEOUS FORMALIN; PREEMPTIVE ANALGESIA; POSTOPERATIVE PAIN; CORD; EXPRESSION; MORPHINE; STIMULATION; NOCICEPTION AB The purpose of this animal investigation was to compare behavioral responses with spinal Fos-like immunoreactivity (FLI) after pre-versus postformalin administration of anesthetic doses of IV ketamine or alfentanil. Preformalin and postformalin injection (1.5% subcutaneously) treatment soups included nr saline control (1.5 mL/kg), ketamine (10 mg/kg), and alfentanil (170 mu g/kg), In the behavioral study soup, nociceptive behavior was evaluated 15-60 min after hindpaw formalin injection. in the spinal FLI study group, rats were perfused 2 h postformalin, and 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. Ketamine produced a selective preemptive analgesic effect in behavioral formalin experiments, yet failed to suppress spinal FLI. In contrast, alfentanil failed to demonstrate a selective preemptive analgesia in behavioral experiments, but did produce preemptive suppression of spinal FU. Together with previous data from our laboratory, we conclude that behavioral analgesia and spinal Fos expression may be uncoupled under certain circumstances. Implications: In this study, we compared pain reduction produced by IV drugs (ketamine or alfentanil) with the ability to prevent injury-induced spinal cord changes. We measured pain behavior and spinal Fos protein after rats received ketamine or alfentanil before versus after formalin injection. Fos inhibition patter ns did not clearly correlate with pain reduction, providing further evidence that Fos inhibition is not always predictive of behavioral analgesia. C1 Natl Inst Dent & Craniofacial Res, Pain Res Clin, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD 20892 USA. McGill Univ, Dept Psychiat, Montreal, PQ, Canada. Clin Res Inst Montreal, Pain Mechanisms Res Lab, Montreal, PQ H2W 1R7, Canada. Univ Montreal, Dept Med, Montreal, PQ, Canada. RP Gilron, I (reprint author), Natl Inst Dent & Craniofacial Res, Pain Res Clin, Pain & Neurosensory Mechanisms Branch, NIH, Bldg 10,Room 3C-434,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Coderre, Terence/B-4825-2012 NR 38 TC 27 Z9 27 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 JUL PY 1999 VL 89 IS 1 BP 128 EP 135 DI 10.1097/00000539-199907000-00022 PG 8 WC Anesthesiology SC Anesthesiology GA 210JJ UT WOS:000081101100022 PM 10389790 ER PT J AU Couse, JF Korach, KS AF Couse, JF Korach, KS TI Reproductive phenotypes in the estrogen receptor-alpha knockout mouse SO ANNALES D ENDOCRINOLOGIE LA English DT Article ID EPIDERMAL GROWTH-FACTOR; MESSENGER-RIBONUCLEIC-ACID; GENE DISRUPTION; TARGETED DISRUPTION; SIGNALING PATHWAYS; PURE ANTIESTROGEN; GRANULOSA-CELLS; TRANSGENIC MICE; DEFICIENT MICE; WILD-TYPE AB The generation and initial characterizations of the ER alpha KO and has proved exciting, however, it is worth noting that this model is relatively new to the field. These mice will undoubtedly prove invaluable to future studies of steroid hormones in normal development and function. The ER alpha KO mouse has been and continues to be utilized to further study the role of estrogen action in the cardiovascular system [44, 25, 26, 22], bone physiology [30], behavior [40, 43], the immune system [49], neurophysiology [47, 48], and adipogenesis [51]. Furthermore, studies of the documented << non-genomic >> effects of estradiol and progesterone in the brain [36] as well as ligand-independent actions involving cross-talk with other signaling systems will be advanced with further investigations using the ER alpha KO mouse. And finally, the ER alpha KO in combination with the recently developed ER beta KO mouse [31] will prove invalable in distinguishing the different roles that may exist between the two receptors in the estrogen signaling system. C1 NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Couse, JF (reprint author), NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. OI Korach, Kenneth/0000-0002-7765-418X NR 51 TC 50 Z9 56 U1 0 U2 1 PU MASSON EDITEUR PI MOULINEAUX CEDEX 9 PA 21 STREET CAMILLE DESMOULINS, ISSY, 92789 MOULINEAUX CEDEX 9, FRANCE SN 0003-4266 J9 ANN ENDOCRINOL-PARIS JI Ann Endocrinol. PD JUL PY 1999 VL 60 IS 2 BP 143 EP 148 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 224TM UT WOS:000081915300014 PM 10456188 ER PT J AU Weed, DL Coughlin, SS AF Weed, DL Coughlin, SS TI New ethics guidelines for epidemiology: Background and rationale SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE epidemiology; ethics; guidelines; professional practice; values ID HEALTH AB In the past decade, at least four sets of ethics guidelines for epidemiologists have been prepared by various national and international organizations. None, however, have been officially adopted by the American College of Epidemiology (ACE). Recently, the ACE asked its Ethics and Standards of Practice (ESOP) Committee to produce ethics guidelines. In this paper, we explain the context and rationale for this effort, describe the purpose and content of ethics guidelines in epidemiology, and discuss their strengths and weaknesses. Three issues that are central to the mission of ACE-education, policy, and advocacy-are inadequately addressed in existing ethics guidelines. In addition, ethics guidelines are not static documents; they should reflect the changing role of epidemiologists in society, including issues arising in emerging subspecialty areas. New, more dynamic, guidelines that emphasize core values, obligations, and virtues, may help to further define and legitimize the profession of epidemiology and will provide a foundation for the discussion of specific ethical issues in the classroom and in professional practice. Guidelines however, do not provide the final word on ethical issues. Specific degrees cisions in particular cases require judgments made upon reflection of the core values, obligations, and virtues described in the guidelines. From our review, we conclude that a new set of guidelines is reasonable and warranted. Published by Elsevier Science Inc. C1 NCI, EPS, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Div Canc Prevent & Control NCCDPHP, Atlanta, GA USA. RP Weed, DL (reprint author), NCI, EPS, Suite T-41,6130 Execut Blvd,MSC 7105, Bethesda, MD 20892 USA. NR 23 TC 14 Z9 14 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 JUL PY 1999 VL 9 IS 5 BP 277 EP 280 DI 10.1016/S1047-2797(99)00012-5 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 210BL UT WOS:000081085200001 PM 10976852 ER PT J AU Henkin, L Zaccaro, D Haffner, S Karter, A Revers, M Sholinsky, P Wagenknecht, L AF Henkin, L Zaccaro, D Haffner, S Karter, A Revers, M Sholinsky, P Wagenknecht, L TI Cigarette smoking, environmental tobacco smoke exposure and insulin sensitivity - The Insulin Resistance Atherosclerosis Study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE smoking; tobacco; smoke pollution. insulin; insulin resistance; atherosclerosis; epidemiologic study ID DEPENDENT DIABETES-MELLITUS; CORONARY-ARTERY DISEASE; GLUCOSE-TOLERANCE; RISK; POPULATION; AMERICANS; PLASMA AB PURPOSE: To investigate whether active smoking and/or exposure to environmental tobacco smoke (ETS) is associated with insulin sensitivity. METHODS: Insulin sensitivity and tobacco use history were measured in 1481 participants in the Insulin Resistance Atherosclerosis Study (IRAS). IRAS is a large mulitcenter epidemiologic study designed to explore the cross sectional relationships among insulin resistance, cardiovascular disease risk factors and behaviors, and disease in African-American, Hispanic, and non-Hispanic white men and women, aged 40-69 years, selected to represent a broad range of glucose tolerance. Multiple linear regression models and linear contrasts were employed to describe the association between smoking history, as assessed via structured interview, and insulin sensitivity, as assessed by an insulin modified frequently sampled intravenous glucose tolerance test (FSIGT) with minimal model analysis. RESULTS: Active smoking was not associated with insulin sensitivity.. Exposure to ETS was associated with lower insulin sensitivity. Specifically, for all participants combined, levels of S-1 were lower, indicating reduced insulin sensitivity, for those exposed to ETS when compared to those who were not exposed (p = 0.019). This association persisted for female participants (p = 0.013) and exhibited the same trend for males but failed to achieve statistical significance (p = 0.264). CONCLUSIONS: Our study did not reveal an association between active smoking and insulin sensitivity, as has been shown previously. The association between ETS exposure and insulin sensitivity is a puzzling finding which deserves further investigation in the longitudinal data from IRAS as well as in other populations. Published by Elsevier Science Inc. C1 Wake Forest Univ, Dept Publ Hlth Sci, Sch Med, Winston Salem, NC 27157 USA. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. Kaiser Permanente Div Res, Oakland, CA USA. Univ Colorado, Hlth Sci Ctr, Dept Prevent Med & Biometr, Denver, CO 80262 USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Henkin, L (reprint author), Wake Forest Univ, Dept Publ Hlth Sci, Sch Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. FU NHLBI NIH HHS [UO1-HL47887, UO1-HL47889, UO1-HL47890] NR 28 TC 50 Z9 51 U1 1 U2 3 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 JUL PY 1999 VL 9 IS 5 BP 290 EP 296 DI 10.1016/S1047-2797(99)00003-4 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 210BL UT WOS:000081085200004 PM 10976855 ER PT J AU Waldvogel, D van Gelderen, P Hallett, M AF Waldvogel, D van Gelderen, P Hallett, M TI Increased iron in the dentate nucleus of patients with Friedreich's ataxia SO ANNALS OF NEUROLOGY LA English DT Article ID CLINICAL-FEATURES; FRATAXIN; HOMOLOG AB Friedreich's ataxia (FA) is the most frequently inherited ataxia. To test the hypothesis that iron is increased in the cerebellum of patients with FA, we developed a multigradient echo magnetic resonance sequence for the three-dimensional imaging of brain icon-induced contrast. Relaxation rate (R2*) values in the unaffected globus pallidus were equal in FA patients and controls, although R2* values in the dentate nucleus of patients were significantly higher, which is most likely due to increased iron. C1 NINCDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. NINCDS, In Vivo Nucl Magnet Resonance Res Ctr, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINCDS, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. NR 20 TC 141 Z9 143 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JUL PY 1999 VL 46 IS 1 BP 123 EP 125 DI 10.1002/1531-8249(199907)46:1<123::AID-ANA19>3.0.CO;2-H PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 212DG UT WOS:000081200900018 PM 10401790 ER PT J AU Goldspiel, BR AF Goldspiel, BR TI Paclitaxel compatibility with ethylene vinyl acetate bags SO ANNALS OF PHARMACOTHERAPY LA English DT Letter C1 NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. RP Goldspiel, BR (reprint author), NIH, Ctr Clin, Dept Pharm, Bldg 10,Room 1N-257, Bethesda, MD 20892 USA. NR 2 TC 3 Z9 3 U1 0 U2 0 PU HARVEY WHITNEY BOOKS CO PI CINCINNATI PA PO BOX 42696, CINCINNATI, OH 45242 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD JUL-AUG PY 1999 VL 33 IS 7-8 BP 873 EP 874 DI 10.1345/aph.18328 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 227VE UT WOS:000082100000023 PM 10466923 ER PT J AU Masucci, IP Calis, KA Bartlett, DL Alexander, HR Horne, MK AF Masucci, IP Calis, KA Bartlett, DL Alexander, HR Horne, MK TI Thrombocytopenia after isolated limb or hepatic perfusions with melphalan; The risk of heparin-induced thrombocytopenia SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article DE thrombocytopenia; heparin ID CARDIOPULMONARY BYPASS-SURGERY; TUMOR-NECROSIS-FACTOR; MALIGNANT-MELANOMA; INTERFERON-GAMMA; ANTIBODIES; THROMBOSIS AB Background: Three cases of heparin-induced thrombocytopenia (HIT) were observed in patients undergoing isolated limb perfusion (ILP) with melphalan. This occurrence prompted the discontinuation of prophylactic postoperative heparin in ILP patients and its avoidance in patients undergoing isolated hepatic perfusion (IHP). The need to reassess these decisions led to a review of thrombocytopenia in both patient populations. Methods: Records of all patients treated with ILP or IHP at our institution from July 1992 through November 1996, were reviewed. Nine IHP patients were tested prospectively for heparin-related antibodies using serum samples obtained perioperatively and during the second postoperative week. Results: Thrombocytopenia (<100,000 platelets/mu L) developed postoperatively in 30% of 131 ILP patients and in 77% of 56 IHP patients. No cases of HIT were identified other than the three who had been previously diagnosed. The prevalence of HIT in heparinized ILP patients was 2.8% (3/108). All nine IHP patients developed heparin-related antibodies postoperatively. Conclusions: Because the prevalence of HIT following ILP is in the range observed in other clinical settings, postoperative heparin prophylaxis is an option. However, it probably should be limited to the first week, and daily platelet counts should be reviewed for a pattern of thrombocytopenia consistent with HIT. The prevalence of heparin-related antibodies after IHP is so high that prophylactic heparin should be avoided in this setting. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Pharm, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Clin Pathol, Bethesda, MD 20892 USA. RP Horne, MK (reprint author), NCI, Surg Branch, NIH, Rm 2C390,Bldg 10, Bethesda, MD 20892 USA. NR 21 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JUL-AUG PY 1999 VL 6 IS 5 BP 476 EP 480 DI 10.1007/s10434-999-0476-7 PG 5 WC Oncology; Surgery SC Oncology; Surgery GA 224AT UT WOS:000081874300013 PM 10458686 ER PT J AU Warner, HR AF Warner, HR TI Apoptosis: A two-edged sword in aging SO ANTICANCER RESEARCH LA English DT Review DE apoptosis; aging ID PROGRAMMED CELL-DEATH; INTERLEUKIN-1-BETA CONVERTING-ENZYME; MANGANESE SUPEROXIDE-DISMUTASE; ALZHEIMERS-DISEASE; IN-VIVO; LYMPHOPROLIFERATIVE SYNDROME; 1-BETA-CONVERTING ENZYME; INCREASES APOPTOSIS; HUMAN FIBROBLASTS; FAMILY PROTEASES AB It is now recognized that apoptosis plays an important role in many physiological processes, including aging and age-related diseases. Apoptosis plays both positive and negative roles in aging, and some of these roles are reviewed here. Of particular importance are the roles of apoptosis in reducing cancer incidence, and in promoting neurodegenerative disease. Therefore, the regulation of apoptosis is an inviting target for therapeutic interventions in aging and age-related disease. C1 NIA, Biol Aging Program, NIH, Bethesda, MD 20892 USA. RP Warner, HR (reprint author), NIA, Biol Aging Program, NIH, Gateway Bldg,Suite 2C231, Bethesda, MD 20892 USA. NR 70 TC 14 Z9 14 U1 3 U2 3 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDNTIOU-KALAMOU RD KAPANDRITI, POB 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD JUL-AUG PY 1999 VL 19 IS 4B BP 2837 EP 2842 PG 6 WC Oncology SC Oncology GA 274LV UT WOS:000084768100003 PM 10652562 ER PT J AU Kim, WH Lee, BL Kim, DK Kleinman, HK AF Kim, WH Lee, BL Kim, DK Kleinman, HK TI Laminin-1-adherent cancer cells show increased proliferation and decreased apoptosis in vivo SO ANTICANCER RESEARCH LA English DT Article DE colon cancer; laminin; apoptosis; adhesion selection ID LAMININ-BINDING PROTEIN; EXPRESSION; INTEGRIN; LINES; PROGRESSION; RECEPTOR; METASTASES; COMPLEXES; CARCINOMA; FAMILY AB Background. The growth rate of a tumor is dependent on both cell proliferation and cell loss. We have established subpopulations of human colon caneer cells with different in vivo growth rates by selecting the cells according to their adhesiveness to laminin-1 in vitro. Materials and methods. Laminin-l-adhesion selected colon cancer cells were injected into the cecal wall of nude mice. The tumors were examined 30 days later Cell proliferation was assessed by proliferating cell nuclear antigen (PCNA) index and apoptotic cells were labeled by digoxigenin-11-dUTP using terminal deoxynucleotidyl transferase. Results. The laminin-1-adherent cells, which formed larger tumors in vivo, showed increased proliferative activity and reduced apoptosis in comparison with the laminin-l-nonadherent cells. Conclusion. Laminin-1 may enhance the malignant behavior of colon cancer cells by accelerating proliferation as well as by decreasing cell loss. C1 Seoul Natl Univ, Coll Med, Dept Pathol, Seoul 119799, South Korea. Seoul Natl Univ, Coll Med, Dept Anat, Seoul 119799, South Korea. Seoul Natl Univ, Coll Med, Canc Res Ctr, Seoul 119799, South Korea. NIDR, Lab Craniofacial Malformat & Dev, NIH, Bethesda, MD 20892 USA. RP Kim, WH (reprint author), Seoul Natl Univ, Coll Med, Dept Pathol, 28 Yongon Dong, Seoul 119799, South Korea. RI Kim, Wooho/G-3703-2011; Seoul National University, Pathology/B-6702-2012; Lee, Byung Lan/J-5577-2012 NR 25 TC 13 Z9 13 U1 0 U2 0 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDNTIOU-KALAMOU RD KAPANDRITI, POB 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD JUL-AUG PY 1999 VL 19 IS 4B BP 3067 EP 3071 PG 5 WC Oncology SC Oncology GA 274LV UT WOS:000084768100035 PM 10652594 ER PT J AU Goldwasser, F Bae, I Pommier, Y Fornace, AJ AF Goldwasser, F Bae, I Pommier, Y Fornace, AJ TI Evidence of a reduced DNA topoisomerase II mRNA expression after ionizing radiation SO ANTICANCER RESEARCH LA English DT Article DE DNA damage; DNA topoisomerase II; transcription; ionizing radiation ID CELL-LINES; DAMAGING AGENTS; CANCER; P53; FRAGMENTATION; CAMPTOTHECIN; INDUCTION; GENE; RNA; CYTOTOXICITY AB DNA topoisomerase II (top2) is a nuclear enzyme which resolves the topological constraints during DNA metabolism and is the target of some of the most active drugs used in cancer chemotherapy. Top2 is regulated both transcriptionally and post- transcriptionally and its expression is coupled to cell cycle position. To explore the regulation of top2 after DNA damage, we studied the behavior of cell lines of the National Cancel Institute Anticancer Drug Screen, previously characterized for p53 status, in response to ionizing radiation. The kinetics of top2 mRNA expression were measured using quantitative hybridization. A profound and transient decrease of top2 mRNA after irradiation was detected within four hours in 30 % of the 25 cell lines tested This transient top2 decrease in mRNA expression occured independently of the p53 status of the cell lines and was not associated with increased apoptotic DNA fragmentation. This observation indicates that a transient decrease in top2 mRNA expression may occur after DNA damage and suggests the need for preferential schedule when planning the use of top2 inhibitors with ionizing radiation during combined radio-chemotherapy treatments. C1 NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Goldwasser, F (reprint author), Hop Paul Brousse, FSMSIT, Expt Therapeut & Translat Res Sect, Villejuif, France. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 34 TC 5 Z9 5 U1 0 U2 0 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDNTIOU-KALAMOU RD KAPANDRITI, POB 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD JUL-AUG PY 1999 VL 19 IS 4B BP 3167 EP 3171 PG 5 WC Oncology SC Oncology GA 274LV UT WOS:000084768100048 PM 10652607 ER PT J AU Lamb, DC Maspahy, S Kelly, DE Manning, NJ Geber, A Bennett, JE Kelly, SL AF Lamb, DC Maspahy, S Kelly, DE Manning, NJ Geber, A Bennett, JE Kelly, SL TI Purification, reconstitution, and inhibition of cytochrome P-450 sterol Delta(22)-desaturase from the pathogenic fungus Candida glabrata SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID AZOLE ANTIFUNGAL AGENTS; ERGOSTEROL BIOSYNTHESIS; RESISTANCE; YEAST; 14-ALPHA-DEMETHYLASE; METABOLISM; HYPOTHESIS; ALBICANS; MUTANTS; MODE AB Sterol Delta(22)-desaturase has been purified from a strain of Candida glabrata with a disruption in the gene encoding sterol 14 alpha-demethylase (cytochrome P-45051; CYP51). The purified cytochrome P-450 exhibited sterol Delta(22)-desaturase activity in a reconstituted system with NADPH-cytochrome P-450 reductase in dilaurylphosphatidylcholine, with the enzyme kinetic studies revealing a K-m for ergosta-5,7-dienol of 12.5 mu M and a V-max of 0.59 nmol of this substrate metabolized/min/nmol of P-450. This enzyme is encoded by CYP61 (ERG5) in Saccharomyces cerevisiae, and homologues have been shown in the Candida albicans and Schizosaccharomyces pombe genome projects. Ketoconazole, itraconazole, and fluconazole formed low-spin complexes with the ferric cytochrome and exhibited type II spectra, which are indicative of an interaction between the azole moiety and the cytochrome heme, The azole antifungal compounds inhibited reconstituted sterol Delta(22)-desaturase activity by binding to the cytochrome with a one-to-one stoichiometry, with total inhibition of enzyme activity occurring when equimolar amounts of azole and cytochrome P-450 were added. These results reveal the potential for sterol Delta(22)-desaturase to be an antifungal target and to contribute to the binding of drugs within the fungal cell. C1 Univ Wales, Inst Biol Sci, Aberystwyth SY23 3DA, Dyfed, Wales. Sheffield Childrens Hosp, Sheffield S10 2UH, S Yorkshire, England. NIAID, Clin Invest Lab, Bethesda, MD 20892 USA. RP Kelly, SL (reprint author), Univ Wales, Inst Biol Sci, Aberystwyth SY23 3DA, Dyfed, Wales. EM StevenKelly@abcr.ac.uk FU Wellcome Trust NR 23 TC 24 Z9 27 U1 1 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JUL PY 1999 VL 43 IS 7 BP 1725 EP 1728 PG 4 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 212HG UT WOS:000081210800032 PM 10390230 ER PT J AU Miller, MW Caracciolo, MR Berlin, WK Hanover, JA AF Miller, MW Caracciolo, MR Berlin, WK Hanover, JA TI Phosphorylation and glycosylation of nucleoporins SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE nuclear pore complex; N-acetylglucosamine; phosphorylation; p62; nucleoporin ID NUCLEAR-PORE COMPLEX; LINKED N-ACETYLGLUCOSAMINE; CASEIN KINASE-II; PROTEIN IMPORT; P62 COMPLEX; CELL-CYCLE; O-GLCNAC; TETRATRICOPEPTIDE REPEATS; CYTOPLASMIC PROTEINS; INVITRO TRANSFER AB The nuclear pore complex mediates macromolecular transport between the nucleus and cytoplasm. Many nuclear pore components (nucleoporins) are modified by both phosphate and O-linked N-acetylglucosamine (O-GlcNAc). Among its many functions, protein phosphorylation plays essential roles in cell cycle progression, The role of O-GlcNAc addition is unknown. Here, levels of nucleoporin phosphorylation and glycosylation during cell cycle progression are examined. Whereas nuclear pore glycoproteins are phosphorylated in a cell-cycle-dependent manner, levels of O-GlcNAc remain constant. The major nucleoporin p62 can be phosphorylated in vitro by protein kinase A and glycogen synthase kinase (GSK)-3 alpha but not by cyclin B/cdc2 or GSK-3 beta. The consensus sites of these kinases resemble sites which can be glycosylated by O-GlcNAc transferase. These data are consistent with a model that O-GlcNAc limits nucleoporin hyperphosphorylation during M-phase and hastens the resumption of regulated nuclear transport at the completion of cell division. (C) 1999 Academic Press. C1 Wright State Univ, Dept Biol Sci, Dayton, OH 45435 USA. NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Miller, MW (reprint author), Wright State Univ, Dept Biol Sci, Dayton, OH 45435 USA. NR 68 TC 70 Z9 71 U1 1 U2 5 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 JUL 1 PY 1999 VL 367 IS 1 BP 51 EP 60 DI 10.1006/abbi.1999.1237 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 214EZ UT WOS:000081316800007 PM 10375398 ER PT J AU Zhou, Y Gottesman, MM Pastan, I AF Zhou, Y Gottesman, MM Pastan, I TI The extracellular loop between TM5 and TM6 of P-glycoprotein is required for reactivity with monoclonal antibody UIC2 SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article ID TRANSIENT-EXPRESSION SYSTEM; MEMBRANE TOPOLOGY; VACCINIA VIRUS; TRANSMEMBRANE ORGANIZATION; MULTIDRUG-RESISTANCE; EPITOPE INSERTION; TERMINAL HALF; TRANSLATION; INHIBITION; TRANSPORT AB P-glycoprotein (P-gp), encoded by the MDR1 gene, is a plasma membrane transporter which confers resistance to many chemotherapeutic drugs. Monoclonal antibodies raised against P-gp have been used as tools to study P-gp topology and activity. Monoclonal antibody UIC2 recognizes a functional conformation of P-gp on the cell surface and blocks P-gp-mediated drug transport. Knowledge about the UIC2 epitope and the mechanism of its inhibitory effects may be helpful for understanding P-gp structure and developing P-gp inhibitors. In the present work, using several chimeras of MDR1 and MDR2, we found that the native sequence of the predicted extracellular loop between transmembrane domains (TM) 5 and 6 of P-gp is necessary, but not sufficient, for UIC2 reactivity. In addition, UIC2 reactivity is also affected by mutations in TM6, a region known to be involved in interactions of P-gp with substrates. These observations suggest that residues in the extracellular loop between TM5 and TM6 are directly involved in the display of the UIC2 epitope. Since TM6 has been shown to be actively involved in drug transport process, the proximity of this region to TM6 may help to explain why UIC2 binding is sensitive to the functional state of P-gp and why binding of UIC2 inhibits P-gp-mediated drug transport (C) 1999 Academic Press. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Room 4E16, Bethesda, MD 20892 USA. NR 23 TC 28 Z9 28 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JUL 1 PY 1999 VL 367 IS 1 BP 74 EP 80 DI 10.1006/abbi.1999.1221 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 214EZ UT WOS:000081316800010 PM 10375401 ER PT J AU Zullo, SJ Cerritos, A Merril, CR AF Zullo, SJ Cerritos, A Merril, CR TI Possible relationship between conditions associated with chronic hypoxia and brain mitochondrial DNA deletions; Reduction of genomic 8-hydroxyguanine levels in human brain tissues containing elevated levels of the human mitochondrial DNA(4977) deletion SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article ID DISEASE; DAMAGE C1 NIMH, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Zullo, SJ (reprint author), NIMH, Lab Biochem Genet, NIH, Bldg 10,Room 2D54, Bethesda, MD 20892 USA. NR 16 TC 1 Z9 1 U1 1 U2 1 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 JUL 1 PY 1999 VL 367 IS 1 BP 140 EP 142 DI 10.1006/abbi.1999.1224 PG 3 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 214EZ UT WOS:000081316800019 PM 10375410 ER PT J AU Toro, J Turner, M Gahl, WA AF Toro, J Turner, M Gahl, WA TI Dermatologic manifestations of Hermansky-Pudlak syndrome in patients with and without a 16-base pair duplication in the HPS1 gene SO ARCHIVES OF DERMATOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Pediatric-Dermatology CY FEB 26, 1998 CL ORLANDO, FLORIDA SP Soc Pediat Dermatol ID PALE EAR EP; OCULOCUTANEOUS ALBINISM; GRANULOMATOUS COLITIS; LOCUS HETEROGENEITY; HAIRLESS MICE; MOUSE; DAMAGE; SUNSCREENS; SKIN; POPULATION AB Background: Hermansky-Pudlak syndrome (HPS) consists of oculocutaneous albinism, a platelet storage pool deficiency, and lysosomal accumulation of ceroid lipofuscin. Patients with HPS from northwest Puerto Rico are homozygous for a 16-base pair (bp) duplication in exon 15 of HPS1, a gene on chromosome 10q23 known to cause the disorder. Objective: To determine the dermatologic findings of patients with PIPS. Design: Survey of inpatients with HPS by physical examination. Setting: National Institutes of Health Clinical Center, Bethesda, Md (a tertiary referral hospital). Patients: Sixty-five patients aged 3 to 54 years were diagnosed on the basis of the absence of platelet dense bodies in individuals with albinism and a bleeding diathesis. The presence of a 16-bp duplication in HPS1 was determined by polymerase chain reaction amplification; 40 patients were homozygous for the duplication and 25 lacked the duplication. All patients with the duplication were from northwest Puerto Rico; all patients without the duplication were non-Puerto Rican except 4 from central Puerto Rico. Results: Both patients homozygous for the 16-bp duplication and patients without the duplication displayed skin color ranging from white to light brown. Patients with the duplication, as well as those lacking the duplication, had hair color ranging from white to brown and eye color ranging from blue to brown. New findings in both groups of patients with HPS were melanocytic nevi with dysplastic features, acanthosis nigricans-like lesions in the axilla and neck, and trichomegaly. Eighty percent of patients with the duplication exhibited features of solar damage, including multiple freckles, stellate lentigines, actinic keratoses, and, occasionally, basal cell or squamous cell carcinomas. Only 8% of patients lacking the 16-bp duplication displayed these findings. As a group, the patients with the duplication lived closer to the equator than those without the duplication. Conclusion: Patients with PIPS exhibit wide variation in pigmentation and dermatologic findings. C1 NCI, Dermatol Branch, Bethesda, MD 20892 USA. NICHHD, Sect Human Biochem Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Turner, M (reprint author), NCI, Dermatol Branch, Bldg 10,Room 12N-238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. NR 46 TC 26 Z9 26 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 JUL PY 1999 VL 135 IS 7 BP 774 EP 780 DI 10.1001/archderm.135.7.774 PG 7 WC Dermatology SC Dermatology GA 215QZ UT WOS:000081395200004 PM 10411151 ER PT J AU Jaeger, AB Gramkow, A Hjalgrim, H Melbye, M Frisch, M AF Jaeger, AB Gramkow, A Hjalgrim, H Melbye, M Frisch, M TI Bowen disease and risk of subsequent malignant neoplasms - A population-based cohort study of 1147 patients SO ARCHIVES OF DERMATOLOGY LA English DT Article ID INTERNAL MALIGNANCY; CELL CARCINOMA; SKIN-CANCER AB Objective: To address the long-standing question of whether patients with Bowen disease are at increased risk of internal malignant neoplasms. Patients: A total, of 1147 Danish patients diagnosed between 1978 and 1993 as having Bowen disease at nongenital sites were followed up for 6463 person-years for cancer occurrence up to 16 years after the skin lesion. Main Outcome Measure: Standardized incidence ratios (SIRs)-the ratios of observed-to-expected numbers of cancer served as measures of relative risk. Results: The observed number of noncutaneous cancers occurring in the cohort (n = 115) was close to expected (n = 103.0) (SIR = 1.1; 95% confidence interval, [CI], 0.9-1.3), However, nonmelanoma skin cancer (SIR = 4.3; 95% CI, 3.5-5.4; n = 83), lip cancer (SIR = 8.2; 95% CI, 2.6-19.1; n = 5), and, among men, leukemia (SIR = 3.2; 95% CI, 1.04-7.5; n = 5) occurred in excess. Conclusions: Patients with Bowen disease do not appear to constitutionally be at any unusually high general cancer risk. The increased risk of invasive skin and lip cancers is likely due to the common risk factor of UV light. C1 Danish Epidemiol Sci Ctr, Dept Epidemiol Res, Statens Serum Inst, Copenhagen, Denmark. RP Frisch, M (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Executive Blvd, Rockville, MD 20852 USA. RI Frisch, Morten/E-9206-2016 OI Frisch, Morten/0000-0002-3864-8860 NR 21 TC 34 Z9 35 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 JUL PY 1999 VL 135 IS 7 BP 790 EP 793 PG 4 WC Dermatology SC Dermatology GA 215QZ UT WOS:000081395200007 PM 10411153 ER PT J AU Sanz-Gallardo, MI Guallar, E Van't Veer, P Longnecker, MP Strain, JJ Martin, BC Kardinaal, AFM Fernandez-Crehuet, J Thamm, M Kohlmeier, L Kok, FJ Martin-Moreno, JM AF Sanz-Gallardo, MI Guallar, E Van't Veer, P Longnecker, MP Strain, JJ Martin, BC Kardinaal, AFM Fernandez-Crehuet, J Thamm, M Kohlmeier, L Kok, FJ Martin-Moreno, JM TI Determinants of p,p '-dichlorodiphenyldichloroethane (DDE) concentration in adipose tissue in women from five European cities SO ARCHIVES OF ENVIRONMENTAL HEALTH LA English DT Article ID PERFORMANCE LIQUID-CHROMATOGRAPHY; POSTMENOPAUSAL BREAST-CANCER; FATTY-ACID COMPOSITION; POLYCHLORINATED-BIPHENYLS; MYOCARDIAL-INFARCTION; DIET; PCBS; ANTIOXIDANTS; POPULATION; RESIDUES AB To identify the determinants of p,p'-dichlorodiphenyldichloroethane (p,p'-DDE) in adipose tissue in subjects who participated in a cross-sectional study, we analyzed fatty acids, antioxidants, and p,p'-DDE in aspirates of adipose tissue of 328 postmenopausal women from 5 European countries. The overall mean of p,p'-DDE concentration was 1.66 mu g/g of fatty acids (95% confidence interval = 1.46, 1.88). In a multiple-regression analysis, the main predictors of log(10)(p,p'-DDE) were center of recruitment (p <.0001), adipose arachidic acid (p =.001), and adipose retinol (p =.04). These factors explained 14.9% of the overall variability of log(10)(p,p'-DDE), In our subjects, adipose tissue p,p'-DDE concentrations were only weakly related with biomarkers reflecting intake of fish and other foods. This result is consistent with the notion that p,p'-DDE exists in different foods and, given the widespread contamination of the food chain, is relatively evenly distributed among foods. C1 Inst Salud Carlos III, Natl Sch Publ Hlth, Dept Epidemiol & Bioestadist, Madrid 28029, Spain. Wageningen Univ Agr, Div Human Nutr & Epidemiol, Wageningen, Netherlands. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Univ Ulster, No Ireland Ctr Diet & Hlth, Coleraine BT52 1SA, Londonderry, North Ireland. Univ Zurich, Inst Social & Prevent Med, CH-8006 Zurich, Switzerland. TNO, Inst Toxicol & Nutr, NL-3700 AJ Zeist, Netherlands. Univ Malaga, Dept Prevent Med, E-29071 Malaga, Spain. Robert Koch Inst, Dept Hlth Risks & Prevent, D-1000 Berlin, Germany. Univ N Carolina, Dept Epidemiol & Nutr, Chapel Hill, NC USA. RP Guallar, E (reprint author), Inst Salud Carlos III, Escuela Nacl Sanidad, Dept Epidemiol & Bioestadist, Sinesio Delgado 8, Madrid 28029, Spain. RI Guallar, Eliseo/D-3807-2014; Martin-Moreno, Jose M./S-7733-2016; OI Guallar, Eliseo/0000-0002-4471-9565; Martin-Moreno, Jose M./0000-0002-8648-5541; Longnecker, Matthew/0000-0001-6073-5322 NR 31 TC 20 Z9 20 U1 0 U2 2 PU HELDREF PUBLICATIONS PI WASHINGTON PA 1319 EIGHTEENTH ST NW, WASHINGTON, DC 20036-1802 USA SN 0003-9896 J9 ARCH ENVIRON HEALTH JI Arch. Environ. Health PD JUL-AUG PY 1999 VL 54 IS 4 BP 277 EP 283 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 221JB UT WOS:000081723000007 ER PT J AU Rapoport, JL Giedd, JN Blumenthal, J Hamburger, S Jeffries, N Fernandez, T Nicolson, R Bedwell, J Lenane, M Zijdenbos, A Paus, T Evans, A AF Rapoport, JL Giedd, JN Blumenthal, J Hamburger, S Jeffries, N Fernandez, T Nicolson, R Bedwell, J Lenane, M Zijdenbos, A Paus, T Evans, A TI Progressive cortical change during adolescence in childhood-onset schizophrenia - A longitudinal magnetic resonance imaging study SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID BRAIN-DEVELOPMENT; SYNAPTIC DENSITY; CORTEX; MORPHOLOGY; MRI; REGISTRATION; SEGMENTATION; ADULTHOOD; CHILDREN AB Background: Adolescence provides a window to examine regional and disease-specific late abnormal brain development in schizophrenia. Because previous data showed progressive brain ventricular enlargement for a group of adolescents with childhood-onset schizophrenia at 2-year follow-up, with no significant changes for healthy controls, we hypothesized that there would be a progressive decrease in volume in other brain tissue in these patients during adolescence. Methods: To examine cortical change, we used anatomical brain magnetic resonance imaging scans for 15 patients with childhood-onset schizophrenia (defined as onset of psychosis by age 12 years) and 34 temporally yoked, healthy adolescents at a mean (SD) age of 13.17 (2.73) years at initial baseline scan and 17.46 (2.96) years at follow-up scan. Cortical gray and white matter volumes were obtained with an automated analysis system that classifies brain tissue into gray matter, white matter, and cerebrospinal fluid and separates the cortex into anatomically defined lobar regions. Results: A significant decrease in cortical gray matter volume was seen for healthy controls in the frontal (2.6%) and parietal (4.1%) regions. For the childhood-onset schizophrenia group, there was a decrease in volume in these regions (10.9% and 8.5%, respectively) as well as a 7% decrease in volume in the temporal gray matter. Thus, the childhood-onset schizophrenia group showed a distinctive disease-specific pattern (multivariate analysis of variance for change x region x diagnosis: F, 3.68; P = .004), with the frontal and temporal regions showing the greatest between-group differences. Changes in white matter volume did not differ significantly between the 2 groups. Conclusions: Patients with very early-onset schizophrenia had both a 4-fold greater decrease in cortical gray matter volume during adolescence and a disease specific pattern of change. Etiologic models for these patients' illness, which seem clinically and neurobiologically continuous with later-onset schizophrenia, must take into account both early and late disruptions of brain development. C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. NINDS, Biometry Branch, Bethesda, MD 20892 USA. McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada. RP Rapoport, JL (reprint author), NIMH, Child Psychiat Branch, Bldg 10,Room 3N202,10 Ctr Dr,MSC 1600, Bethesda, MD 20892 USA. EM rapoport@helix.nih.gov RI Giedd, Jay/A-3080-2008; Nicolson, Robert/E-4797-2011; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; Fernandez, Thomas/D-4295-2009 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Fernandez, Thomas/0000-0003-0830-022X NR 53 TC 266 Z9 269 U1 4 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD JUL PY 1999 VL 56 IS 7 BP 649 EP 654 DI 10.1001/archpsyc.56.7.649 PG 6 WC Psychiatry SC Psychiatry GA 212DP UT WOS:000081201800010 PM 10401513 ER PT J AU Nader, PR Stone, EJ Lytle, LA Perry, CL Osganian, SK Kelder, S Webber, LS Elder, JP Montgomery, D Feldman, HA Wu, M Johnson, C Parcel, GS Lucpker, RV AF Nader, PR Stone, EJ Lytle, LA Perry, CL Osganian, SK Kelder, S Webber, LS Elder, JP Montgomery, D Feldman, HA Wu, M Johnson, C Parcel, GS Lucpker, RV TI Three-year maintenance of improved diet and physical activity - The CATCH cohort SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID CARDIOVASCULAR HEALTH CATCH; SCHOOL-BASED INTERVENTION; ADOLESCENT TRIAL; RISK-FACTORS; PSYCHOSOCIAL DETERMINANTS; DISEASE PREVENTION; BLOOD-PRESSURE; UNITED-STATES; CHILD; PROMOTION AB Objective: To assess differences through grade 8 in diet, physical activity, and related health indicators of students who participated in the Child and Adolescent Trial for Cardiovascular Health (CATCH) school and family intervention from grades 3 through 5. Design: Follow-up of the 4-center, randomized, controlled field trial with 56 intervention and 40 control elementary schools. Participants: We studied 3714 (73%) of the initial CATCH cohort of 5106 students from ethnically diverse backgrounds in California, Louisiana, Minnesota, and Texas at grades 6, 7, and 8. Results: St lf-reported daily energy intake from fat at baseline was virtually identical in the control (32.7%) and intervention (32.6%) groups. At grade 5, the intake for controls remained at 32.2%, while the intake for the intervention group declined to 30.3% (P<.001). At grade 8, the between group differential was maintained (31.6% vs 30.6%, P = .01). Intervention students maintained significantly higher self-reported daily vigorous activity than control students (P = .001), although the difference declined from 13.6 minutes in grade 5 to 11.2, 10.8, and 8.8 minutes in grades 6, 7, and 8, respectively. Significant differences in favor of the intervention students also persisted at grade 8 for dietary knowledge and dietary intentions, but not for social support for physical activity. No impact on smoking behavior or stages of contemplating smoking was detected at grade 8. No significant differences were noted among physiologic indicators of body mass index, blood pressure, or serum lipid and cholesterol levels. Conclusion: The original CATCH results demonstrated that school-level interventions could modify school lunch and school physical education programs as well as influence student behaviors. This 3-year follow-up without further intervention suggests that the behavioral changes initiated during the elementary school years persisted to early adolescence for self-reported dietary and physical activity behaviors. C1 Univ Calif San Diego, Dept 0927, Div Community Pediat, La Jolla, CA 92037 USA. Natl Heart & Lung Inst, Bethesda, MD USA. Univ Minnesota, Div Epidemiol, Minneapolis, MN USA. New England Res Inst Inc, Watertown, MA USA. Univ Texas, Hlth Sci Ctr, Houston Ctr Hlth Promot Res & Dev, Houston, TX USA. Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA 70118 USA. San Diego State Univ, San Diego, CA 92182 USA. RP Nader, PR (reprint author), Univ Calif San Diego, Dept 0927, Div Community Pediat, 9500 Gilman Dr, La Jolla, CA 92037 USA. FU NHLBI NIH HHS [HL39927, HL39852, HL39870] NR 48 TC 203 Z9 208 U1 5 U2 22 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD JUL PY 1999 VL 153 IS 7 BP 695 EP 704 PG 10 WC Pediatrics SC Pediatrics GA 213UC UT WOS:000081290800005 PM 10401802 ER PT J AU Tracy, RP Arnold, AM Ettinger, W Fried, L Meilahn, E Savage, P AF Tracy, RP Arnold, AM Ettinger, W Fried, L Meilahn, E Savage, P TI The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly - Results from the Cardiovascular Health Study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE atherosclerosis; cardiovascular diseases; fibrinogen; risk factors; thrombosis ID ISCHEMIC-HEART-DISEASE; CORONARY-ARTERY DISEASE; COAGULATION-FACTOR-VII; PLASMA FACTOR-VII; MYOCARDIAL-INFARCTION; RISK FACTOR; PLASMINOGEN-ACTIVATOR; HEMOSTATIC FUNCTION; ATHEROSCLEROSIS; MEN AB Little is known about the prospective associations of fibrinogen, factor VII, or factor VIII with cardiovascular disease (CVD) and mortality in the elderly. At baseline in the Cardiovascular Health Study (5888 white and African American men and women; aged greater than or equal to 65 years), we measured fibrinogen, factor VIII, and factor VII. We used sex-stratified stepwise Cox survival analysis to determine relative risks (RRs) for CVD events and all-cause mortality (up to 5 years of follow-up), both unadjusted and adjusted for CVD risk factors and subclinical CVD. After adjustment, comparing the fifth quintile to the first, fibrinogen was significantly associated in men with coronary heart disease events (RR=2.1) and stroke or transient ischemic attack (RR=1.3), and also with mortality within 2.5 years of follow-up (RR=5.8) and later (RR=1.7). Factor VIII was significantly associated in men with coronary heart disease events (RR=1.5) and mortality (RR=1.8), and in women with stroke/transient ischemic attack (RR=1.4). For both factors, values were higher in those who died, whether causes were CVD-related or non-CVD-related, but highest in CVD death. Factor VII exhibited associations with incident angina (RR=1.44) in men and with death in women (RR, middle quintile compared with first=0.66). However, in general, factor VII was not consistently associated with CVD events in this population. We conclude that, if confirmed in other studies, the measurement of fibrinogen and/or factor VIII may help identify older individuals at higher risk for CVD events and mortality. C1 Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. Univ Vermont, Coll Med, Dept Biochem, Burlington, VT 05405 USA. Univ Vermont, Coll Med, Lab Clin Biochem Res, Burlington, VT 05405 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Winston Salem, NC 27103 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27103 USA. Johns Hopkins Univ, Dept Med, Baltimore, MD USA. Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. London Sch Hyg & Trop Med, Dept Epidemiol & Populat Sci, London WC1, England. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Tracy, RP (reprint author), CHS Coordinating Ctr, Century Sq,Suite 2025,1501 4th Ave, Seattle, WA 98101 USA. FU NHLBI NIH HHS [N01-HC-87080, N01-HC-87079, N01-HC-87081] NR 67 TC 162 Z9 162 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 JUL PY 1999 VL 19 IS 7 BP 1776 EP 1783 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 216BG UT WOS:000081420200025 PM 10397698 ER PT J AU Sabol, SZ Hamer, DH AF Sabol, SZ Hamer, DH TI An improved assay shows no association between the CYP2A6 gene and cigarette smoking behavior SO BEHAVIOR GENETICS LA English DT Article DE smoking; nicotine; cytochrome P450; CYP2A6 gene; genetics ID FAGERSTROM TOLERANCE QUESTIONNAIRE; CYTOCHROME-P450 2A6 CYP2A6; COUMARIN 7-HYDROXYLATION; NICOTINE DEPENDENCE; POLYMORPHISM; IDENTIFICATION AB Pianezza et al. (1998) reported an association between the CYP2A6 gene, which codes for the enzyme that metabolizes nicotine to cotinine, and cigarette smoking behavior. We attempted to replicate their findings by analyzing the CYP2A6 gene in a population of 385 individuals using the same two-step PCR assay described by Pianezza et al. but found no association between genotype and either smoking status or cigarette consumption. We then developed a single-step ge PCR method that is specific for the CYP2A6 locus and eliminates a high rate of false-positive mutations detected by the two-step assay. Although this assay gave a much lower frequency of mutant alleles, there was again no association of CYP2A6 genotype with smoking behavior. C1 NCI, Biochem Lab, Bethesda, MD 20892 USA. RP Hamer, DH (reprint author), NIH, Bldg 37,Room 4A13,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 20 TC 25 Z9 26 U1 0 U2 4 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD JUL PY 1999 VL 29 IS 4 BP 257 EP 261 DI 10.1023/A:1021642323602 PG 5 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 260WN UT WOS:000083976600006 ER PT J AU Masserano, JM Karoum, F Wyatt, RJ AF Masserano, JM Karoum, F Wyatt, RJ TI SR141716A, a CB1 cannabinoid receptor antagonist, potentiates the locomotor stimulant effects of amphetamine and apomorphine SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE cannabinoid; SR 141716A; amphetamine; apomorphine; locomotor activity ID RAT STRIATUM; BRAIN AB The intraperitoneal (i.p.) injection of apomorphine or d-amphetamine significantly increased locomotor activity in Sprague-Dawley rats. Prior administration of the cannabinoid receptor antagonist, SR 141716A significantly enhanced the stimulant effect of both d-amphetamine and apomorphine in a dose-dependent manner. Administration of SR 141716A alone had no effect on locomotor activity. These data indicate that endogenous cannabinoids exert an inhibitory action on the increase in locomotor activity produced by amphetamine and apomorphine. (C) 1999 Lippincott Williams & Wilkins. C1 NIMH, Neuropsychiat Branch, Bethesda, MD 20892 USA. RP Masserano, JM (reprint author), NIMH, Neuropsychiat Branch, 15 N Dr,MSC 2668,Bldg 15-K,Room 201, Bethesda, MD 20892 USA. NR 21 TC 39 Z9 39 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD JUL PY 1999 VL 10 IS 4 BP 429 EP 432 PG 4 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 220NK UT WOS:000081671900010 PM 10780811 ER PT J AU Sohrab, MH Hasan, CM Rashid, MA AF Sohrab, MH Hasan, CM Rashid, MA TI 6-substituted-7-oxygenated coumarins from the leaves of Micromelum minutum SO BIOCHEMICAL SYSTEMATICS AND ECOLOGY LA English DT Article DE Micromelum minutum; Rutaceae; coumarins; flavones C1 Univ Dhaka, Dept Pharm, Phytochem Res Lab, Dhaka 1000, Bangladesh. RP Rashid, MA (reprint author), NCI, SAIC Frederick, Frederick Canc Res & Dev Ctr, Bldg 560,Rm 32-63B,POB B, Frederick, MD 21702 USA. NR 8 TC 5 Z9 6 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0305-1978 J9 BIOCHEM SYST ECOL JI Biochem. Syst. Ecol. PD JUL PY 1999 VL 27 IS 5 BP 535 EP 537 DI 10.1016/S0305-1978(98)00119-7 PG 3 WC Biochemistry & Molecular Biology; Ecology; Evolutionary Biology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology; Evolutionary Biology GA 189QX UT WOS:000079917800011 ER PT J AU Li, AH Chang, L Ji, XD Melman, N Jacobson, KA AF Li, AH Chang, L Ji, XD Melman, N Jacobson, KA TI Functionalized congeners of 1,4-dihydropyridines as antagonist molecular probes for A(3) adenosine receptors SO BIOCONJUGATE CHEMISTRY LA English DT Article ID HIGH-AFFINITY; RAT-BRAIN; DERIVATIVES; AGONIST; CELLS; INHIBITOR; INDUCTION; APOPTOSIS; MYOCYTES; LIGANDS AB 4-Phenylethynyl-6-phenyl-1,4-dihydropyridine derivatives are selective antagonists at human A(3) adenosine receptors, with K-i values in a radioligand binding assay vs [I-125]AB-MECA [N-6-(4-amino-3-iodobenzyl)-5'-N-methylcarbamoyl-adenosine] in the submicromolar range. In this study, functionalized congeners of 1,4-dihydropyridines were designed as chemically reactive adenosine A(3) antagonists, for the purpose of synthesizing molecular probes for this receptor subtype. Selectivity of the new analogues for cloned human A(3) adenosine receptors was determined in radioligand binding in comparison to binding at rat brain A(1) and A(2A) receptors. Benzyl ester groups at the 3- and/or 5-positions and phenyl groups at the 2- and/or 5-positions were introduced as potential sites for chain attachment. Structure-activity analysis at A(3) adenosine receptors indicated that 3,5-dibenzyl esters, but not 2,6-diphenyl groups, are tolerated in binding. Ring substitution of the 5-benzyl ester with a 4-fluorosulfonyl group provided enhanced Ag receptor affinity resulting in a K-i value of 2.42 nM; however, a long-chain derivative containing terminal amine functionalization at the 4-position of the 5-benzyl ester showed only moderate affinity. This sulfonyl fluoride derivative appeared to bind irreversibly to the human A(3) receptor (1 h incubation at 100 nM resulting in the loss of 56% of the specific radioligand binding sites), while the binding of other potent dihydropyridines and other antagonists was generally reversible. At the 3-position of the dihydropyridine ring, an amine-functionalized chain attached at the 4-position of a benzyl ester provided higher A(3) receptor affinity than the corresponding 5-position isomer. This amine congener was also used as an intermediate in the synthesis of a biotin conjugate, which bound to A(3) receptors with a K-i value of 0.60 mu M. C1 NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bldg 8A,Room B1A-19, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031115-24, Z01 DK031117-20, Z99 DK999999] NR 36 TC 7 Z9 9 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD JUL-AUG PY 1999 VL 10 IS 4 BP 667 EP 677 DI 10.1021/bc9900136 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 219QC UT WOS:000081617100016 PM 10411465 ER PT J AU Tatusova, TA Karsch-Mizrachi, I Ostell, JA AF Tatusova, TA Karsch-Mizrachi, I Ostell, JA TI Complete genomes in WWW Entrez: data representation and analysis SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT 1st International Conference on Bioinformatics of Genome Regulation and Structure (BGRS 98) CY AUG 24-31, 1998 CL NOVOSIBIRSK, RUSSIA SP Inst Cytol & Genet, Novosibirst, Asia Pacific Bioinformat Network ID SEQUENCE; SPIROCHETE; ARCHAEON; PATHOGEN AB Motivation: The large amount of genome sequence data now publicily available can be accessed through the National Centre for Biotechnology Information (NCBI) Entrez search and retrieval system, making it possible to explore data of a breadth and scope exceeding traditional flatfile views. Results: Here we report recent improvements for completely sequenced genomes from viruses, bacteria, and yeast. Flexible web based views, precomputed relationships, and immediate access to analytical tools provide scientists with a portal into the new insights to be gained from completed genome sequences. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Tatusova, TA (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. NR 21 TC 72 Z9 73 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JUL-AUG PY 1999 VL 15 IS 7-8 BP 536 EP 543 DI 10.1093/bioinformatics/15.7.536 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 247GT UT WOS:000083213500003 PM 10487861 ER PT J AU Safrany, ST Caffrey, JJ Yang, XN Shears, SB AF Safrany, ST Caffrey, JJ Yang, XN Shears, SB TI Diphosphoinositol polyphosphates: The final frontier for inositide research? SO BIOLOGICAL CHEMISTRY LA English DT Review DE diphosphoinositol; inositol phosphates; MutT; signal transduction ID ASSEMBLY PROTEIN AP-2; PLANAR LIPID BILAYERS; DNA-SYNTHESIS; ION CHANNELS; IN-VITRO; PHOSPHATES; TETRAKISPHOSPHATE; KINASE; DICTYOSTELIUM; CELLS AB The diphosphoinositol polyphosphates comprise a group of highly phosphorylated compounds which have a rapid rate of metabolic turnover through tightly-regulated kinase/phosphohydrolase substrate cycles. The phosphohydrolases occur as multiple isoforms, the expression of which is apparently carefully controlled. Cellular levels of the diphosphoinositol polyphosphates are regulated by cAMP and cGMP in a protein kinase-independent manner. These inositides can also sense a specific mode of intracellular Ca2+ pool depletion. In this review, we will argue that these are characteristics of highly significant cellular molecules. C1 NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Shears, SB (reprint author), NIEHS, Lab Signal Transduct, POB 12233, Res Triangle Pk, NC 27709 USA. NR 59 TC 30 Z9 30 U1 0 U2 3 PU WALTER DE GRUYTER & CO PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 1431-6730 J9 BIOL CHEM JI Biol. Chem. PD JUL-AUG PY 1999 VL 380 IS 7-8 BP 945 EP 951 DI 10.1515/BC.1999.117 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 233QU UT WOS:000082438200027 PM 10494846 ER PT J AU Charney, DS Innis, RB Nestler, EJ Davis, KL Nemeroff, CB Weinberger, DR AF Charney, DS Innis, RB Nestler, EJ Davis, KL Nemeroff, CB Weinberger, DR TI Increasing public trust and confidence in psychiatric research SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material C1 Yale Univ, Sch Med, New Haven, CT 06520 USA. CUNY Mt Sinai Sch Med, New York, NY 10029 USA. Emory Univ, Sch Med, Atlanta, GA 30322 USA. NIMH, Bethesda, MD 20892 USA. RP Charney, DS (reprint author), Yale Univ, Sch Med, 333 Cedar St, New Haven, CT 06520 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 1 PY 1999 VL 46 IS 1 BP 1 EP 2 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 210KE UT WOS:000081103400001 PM 10394467 ER PT J AU Weinberger, DR AF Weinberger, DR TI Schizophrenia: New phenes and new genes SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID DOPAMINE; HYPOTHESIS C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,Room 4S235,MSC 1379, Bethesda, MD 20892 USA. NR 22 TC 28 Z9 29 U1 1 U2 2 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 JUL 1 PY 1999 VL 46 IS 1 BP 3 EP 7 PG 5 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 210KE UT WOS:000081103400003 PM 10394469 ER PT J AU Perera, L Darden, TA Pedersen, LG AF Perera, L Darden, TA Pedersen, LG TI Probing the structural changes in the light chain of human coagulation factor VIIa due to tissue factor association SO BIOPHYSICAL JOURNAL LA English DT Article ID GAMMA-CARBOXYGLUTAMIC ACID; MOLECULAR-DYNAMICS SIMULATION; BOVINE PROTHROMBIN FRAGMENT-1; SITE-DIRECTED MUTAGENESIS; K-DEPENDENT PROTEINS; GROWTH-FACTOR DOMAIN; MESH EWALD METHOD; EGF-LIKE DOMAIN; BLOOD-COAGULATION; FACTOR-IX AB The crystallographic structure of human coagulation factor VIIa/tissue factor complex bound with calcium ions was used to model the solution structure of the light chain of factor VIIa (residues 1-142) in the absence of tissue factor. The Amber force field in conjunction with the particle mesh Ewald summation method to accommodate long-range electrostatic interactions was used in the trajectory calculations. The estimated TF-free solution structure was then compared with the crystal structure of factor VIIa/tissue factor complex to estimate the restructuring of factor VIIa due to tissue factor binding. The solution structure of the light chain of factor VIIa in the absence of tissue factor is predicted to be an extended domain structure similar to that of the tissue factor-bound crystal. Removal of the EGF1-bound calcium ion is shown by simulation to lead to minor structural changes within the EGF1 domain, but also leads to substantial relative reorientation of the Gla and EGF1 domains. C1 Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Pedersen, LG (reprint author), Univ N Carolina, Dept Chem, CB 3290, Chapel Hill, NC 27599 USA. RI perera, Lalith/B-6879-2012; Pedersen, Lee/E-3405-2013 OI perera, Lalith/0000-0003-0823-1631; Pedersen, Lee/0000-0003-1262-9861 FU NHLBI NIH HHS [HL-0630] NR 78 TC 9 Z9 9 U1 0 U2 5 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUL PY 1999 VL 77 IS 1 BP 99 EP 113 DI 10.1016/S0006-3495(99)76875-X PG 15 WC Biophysics SC Biophysics GA 214RQ UT WOS:000081341700009 PM 10388743 ER PT J AU Kuznetsov, VA Puri, RK AF Kuznetsov, VA Puri, RK TI Kinetic analysis of high affinity forms of interleukin (IL)-13 receptors: Suppression of IL-13 binding by IL-2 receptor gamma chain SO BIOPHYSICAL JOURNAL LA English DT Article ID CELL CARCINOMA-CELLS; PSEUDOMONAS EXOTOXIN; B-CELLS; SURFACE; GROWTH; INTERNALIZATION; AGGREGATION; BIOSENSORS; DIFFUSION; COMPLEXES AB Interleukin-13 (IL-13) is a pleiotropic cytokine that controls growth, differentiation, and apoptosis of immune and tumor cells. To understand the mechanisms of interaction between IL-13 and IL-13 receptors (IL-13R), and the role of the IL-2 receptor common gamma chain (gamma(c)) in IL-13 binding and processing, we have examined IL-13 binding kinetics, dissociation/shedding, and internalization in renal cell carcinoma (RCC) cell lines. We observed a new phenomena in that the apparent rate of association, but not the dissociation, was strongly related to IL-13 concentration. We also observed cooperativity phenomena in IL-13 and IL-13R interaction in control RCC (MLneo) cells, but not in cells transfected with gamma(c) chain (MLgamma c). The number of IL-13 binding sites, the effective rate of ligand association, and the dissociation rate constants were reduced in gamma(c)-transfected cells compared to control RCC cells. Two forms of IL-13R were detected in these cell lines, which differed in the kinetics of endocytosis and dissociation/exocytosis. Only a small fraction of bound receptors (14-24%) was rapidly internalized and the same fraction of the ligand-receptor complexes was shed and/or dissociated. The expression of gamma(c) chain did not change any of these processes. A two independent high-affinity and moderate-affinity receptor model fit the kinetic observations in gamma(c)-transfected cells. However, in control cells, the binding kinetics were more complicated. A mathematical model that fit a set of kinetic and steady state data in control cells was selected from a set of possible models. This best-fit model predicts that 1) two different IL-13R are expressed on the cell membrane, 2) a minor fraction of IL-13R exist as microclusters (homodimers and/or heterodimers) without exogenous IL-13, 3) high morphological complexity of the gamma(c) negative control cell membrane affects the cooperativity phenomena of IL-13 binding, and 4) a large number of co-receptor molecules is present, which helps keep the ligand on the cell surface for a long period of time after fast IL-13 binding and provides a negative control for ligand binding via production of the high affinity inhibitor bound to IL-13. Our data demonstrate that gamma(c) exerts dramatic changes in the kinetic mechanisms of IL-13 binding. C1 US FDA, Ctr Biol Evaluat & Res, Lab Mol Tumour Biol, Div Cellular & Gene Therapies, Bethesda, MD 20892 USA. Russian Acad Sci, Inst Biochem Phys, Lab Math ImmunoBiophys, Moscow 117977, Russia. RP Puri, RK (reprint author), US FDA, Ctr Biol Evaluat & Res, Lab Mol Tumour Biol, Div Cellular & Gene Therapies, NIH Bldg 29B,Room 2NN10,29 Lincoln Dr,MSC 4555, Bethesda, MD 20892 USA. NR 45 TC 17 Z9 18 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 JUL PY 1999 VL 77 IS 1 BP 154 EP 172 DI 10.1016/S0006-3495(99)76879-7 PG 19 WC Biophysics SC Biophysics GA 214RQ UT WOS:000081341700013 PM 10388747 ER PT J AU Kirschner, LS Stratakis, CA AF Kirschner, LS Stratakis, CA TI Large-scale preparation of sequence-ready bacterial artificial chromosome DNA using QIAGEN (R) columns SO BIOTECHNIQUES LA English DT Article C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Kirschner, LS (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. NR 5 TC 22 Z9 22 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 JUL PY 1999 VL 27 IS 1 BP 72 EP + PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 214RJ UT WOS:000081341100015 PM 10407668 ER PT J AU Moscow, JA Huang, H Carter, C Hines, K Zujewski, J Cusack, G Chow, C Venzon, D Sorrentino, B Chiang, YW Goldspiel, B Leitman, S Read, EJ Abati, A Gottesman, MM Pastan, I Sellers, S Dunbar, C Cowan, KH AF Moscow, JA Huang, H Carter, C Hines, K Zujewski, J Cusack, G Chow, C Venzon, D Sorrentino, B Chiang, YW Goldspiel, B Leitman, S Read, EJ Abati, A Gottesman, MM Pastan, I Sellers, S Dunbar, C Cowan, KH TI Engraftment of MDR1 and NeoR gene-transduced hematopoietic cells after breast cancer chemotherapy SO BLOOD LA English DT Article ID BONE-MARROW CELLS; HIGH-DOSE CHEMOTHERAPY; DRUG RESISTANCE GENE; EX-VIVO EXPANSION; MULTIDRUG-RESISTANCE; PERIPHERAL-BLOOD; TRANSPLANTED MICE; IN-VIVO; EXPRESSION; THERAPY AB To determine whether the multidrug resistance gene MDR1 could act as a selectable marker in human subjects, we studied engraftment of peripheral blood progenitor cells (PBPCs) transduced with either MDR1 or the bacterial NeoR gene in six breast cancer patients. This study differed from previous MDR1 gene therapy studies in that patients received only PBPCs incubated in retroviral supernatants (no nonmanipulated PBPCs were infused), transduction of PBPCs was supported with autologous bone marrow stroma without additional cytokines, and a control gene (NeoR) was used for comparison with MDR1. Transduced PBPCs were infused after high dose alkylating agent therapy and before chemotherapy with MDR substrate drugs. We found that hematopoietic reconstitution can occur using only PBPCs incubated ex vivo, that the MDR1 gene product may play a role in engraftment, and that chemotherapy may selectively expand MDR1 gene transduced hematopoietic cells relative to NeoR transduced cells in some patients. This is a US government work. There are no restrictions on its use. C1 NHLBI, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. Genet Therapy Inc, Gaithersburg, MD USA. RP Cowan, KH (reprint author), Univ Nebraska, Med Ctr, Eppley Inst Res Canc, Eppley Canc Ctr, 600 S 42nd St, Omaha, NE 68198 USA. RI Venzon, David/B-3078-2008 NR 31 TC 112 Z9 117 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 JUL 1 PY 1999 VL 94 IS 1 BP 52 EP 61 PG 10 WC Hematology SC Hematology GA 212CF UT WOS:000081198200008 PM 10381498 ER PT J AU Manns, A Miley, WJ Waters, D Hanchard, B Wharfe, G Cranston, B Williams, E Blattner, WA AF Manns, A Miley, WJ Waters, D Hanchard, B Wharfe, G Cranston, B Williams, E Blattner, WA TI Prognostic significance of quantitative viral markers in adult T-cell leukemia lymphoma SO BLOOD LA English DT Letter ID INTERFERON-ALFA; CLASSIFICATION; ZIDOVUDINE C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, SAIC, Frederick Canc Res & Dev Ctr, Frederick, MD USA. Univ W Indies, Dept Hematol, Kingston 7, Jamaica. Univ W Indies, Dept Pathol, Kingston 7, Jamaica. Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. RP Manns, A (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 7 TC 3 Z9 3 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 JUL 1 PY 1999 VL 94 IS 1 BP 372 EP 373 PG 2 WC Hematology SC Hematology GA 212CF UT WOS:000081198200047 PM 10428547 ER PT J AU Lind, SE Pearce, LA Feinberg, WM Bovill, EG AF Lind, SE Pearce, LA Feinberg, WM Bovill, EG CA SPAF Investigators TI Clinically significant differences in the International Normalized Ratio measured with reagents of different sensitivities SO BLOOD COAGULATION & FIBRINOLYSIS LA English DT Article DE International Normalized Ratio; warfarin; International Sensitivity Index; thrombosis; anticoagulant therapy ID ORAL ANTICOAGULANT-THERAPY; PATIENTS RECEIVING WARFARIN; NATIVE PROTHROMBIN ANTIGEN; LYOPHILIZED PLASMAS; THROMBOPLASTIN REAGENTS; HEART-VALVES; FACTOR-VII; FACTOR-II; FACTOR-X; TIME AB `The International Normalized Ratio (INR) system was introduced a decade ago as a way of standardizing the results of prothrombin time testing for patients taking oral anticoagulants. A strong emphasis has been placed upon using thromboplastin reagents that are very sensitive to the effects of oral anticoagulants upon the prothrombin time [i.e. reagents with low International Sensitivity Index (ISI)]. In order to assess how well the INR system functions as currently used in clinical laboratories, we compared the INRs determined using thromboplastins of differing ISIs in samples collected during a large clinical trial of oral anticoagulation for atrial fibrillation (Stroke Prevention in Atrial Fibrillation III trial). Frozen plasma was subjected to prothrombin time testing using thromboplastins with ISIs ranging from 0.97 to 2.49. INRs were calculated using machine-specific ISIs and Westgard's rules were followed to maintain quality control. An unanticipated coagulometer failure allowed a determination of the effect of machine recalibration upon the INR of control plasmas. The correlation between each pair of INRs obtained from 1181 plasmas was high (> 0.9), but the differences between reagents were statistically different from zero (P<0.001 for pairwise comparisons). Plasmas had INRs within the therapeutic range (2.0-3.0) with one reagent but not with another in an average of 20% of instances. Among the 20% discordant pairings, 43% (8.5% of the total tested) showed a difference in INR of more than 0.2 INR units above or below the target range. Low ISI thromboplastins did not perform better in this pairwise comparison than other reagents or the locally determined INR. Recalibration of a coagulometer resulted in a significant change in the INRs obtained from control plasmas (P < 0.0001), which confirms and extends the observations of other authors concerning the sensitivity of the INR to coagulometer-related variables. There was a clinically significant difference in the INRs obtained with different thromboplastins, and low ISI reagents did not perform better than others. Since the risk of thrombosis rises sharply below the lower limit of the currently recommended target ranges, consideration should be given to narrowing the recommended range, or advising clinicians to aim for its mid-point. These findings illustrate the difficulties in imposing standardization upon coagulation testing after a test is in widespread use. Blood Coag Fibrinol 10:215-227 (C) 1999 Lippincott Williams & Wilkins. C1 Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05406 USA. NINDS, Div Stroke & Trauma, Bethesda, MD 20892 USA. Evanston Hosp, Dept Med, Evanston, IL USA. Northwestern Univ, Sch Med, Evanston, IL USA. Stat & Epidemiol Res Corp, Seattle, WA USA. Univ Arizona, Dept Neurol, Tucson, AZ USA. RP Bovill, EG (reprint author), Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05406 USA. FU NINDS NIH HHS [R01-NS24224] NR 47 TC 11 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0957-5235 J9 BLOOD COAGUL FIBRIN JI Blood Coagul. Fibrinolysis PD JUL PY 1999 VL 10 IS 5 BP 215 EP 227 DI 10.1097/00001721-199907000-00001 PG 13 WC Hematology SC Hematology GA 220DP UT WOS:000081649500001 PM 10456611 ER PT J AU Marx, SJ Agarwal, SK Heppner, C Kim, YS Kester, MB Goldsmith, PK Skarulis, MC Spiegel, AM Burns, AL Debelenko, LV Zhuang, Z Lubensky, IA Liotta, LA Emmert-Buck, MR Guru, SC Manickam, P Crabtree, JS Collins, FS Chandrasekharappa, SC AF Marx, SJ Agarwal, SK Heppner, C Kim, YS Kester, MB Goldsmith, PK Skarulis, MC Spiegel, AM Burns, AL Debelenko, LV Zhuang, Z Lubensky, IA Liotta, LA Emmert-Buck, MR Guru, SC Manickam, P Crabtree, JS Collins, FS Chandrasekharappa, SC TI The gene for multiple endocrine neoplasia type 1: Recent findings SO BONE LA English DT Article; Proceedings Paper CT 2nd Joint Meeting of the American-Society-for-Bone-and-Mineral-Research/International-Bone-and-Mi neral-Society CY DEC 01-06, 1998 CL SAN FRANCISCO, CALIFORNIA SP Amer Soc Bone & Mineral Res, Int Bone & Mineral Soc DE hyperparathyroid; gastrinoma; mesenchyme; tumor suppressor; oncogene; positional cloning; mutation ID TUMOR-SUPPRESSOR GENE; MEN1 GENE; PARATHYROID TUMORS; GERMLINE MUTATIONS; POSITIONAL CLONING; SOMATIC MUTATIONS; REGION; MICRODISSECTION; IDENTIFICATION; ANGIOFIBROMAS AB Multiple endocrine neoplasia type 1 (MEN1) is a promising model to understand endocrine and other tumors. Its most common endocrine expressions are tumors of parathyroids, entero-pancreatic neuro-endocrine tissue, and anterior pituitary. Recently, collagenomas and multiple angiofibromas of the dermis also have been recognized as very common. MEN1 can be characterized from different perspectives: (a) as a hormone (parathyroid hormone, gastrin, prolactin, etc,) excess syndrome with excellent therapeutic options; (b) as a syndrome with sometimes lethal outcomes from malignancy of entero-pancreatic neuro-endocrine or foregut carcinoid tissues; or (c) as a disorder than can give insight about cell regulation in the endocrine, the dermal, and perhaps other tissue systems. The MEN1 gene was identified recently by positional cloning, a comprehensive strategy of narrowing the candidate interval and evaluating all or most genes in that interval. This discovery has opened new approaches to basic and clinical issues. Germline MEN1 mutations have been identified in most MEN1 families, Germline MEN1 mutations were generally not found in families with isolated hyperparathyroidism or with isolated pituitary tumor, Thus, studies with the MEN1 gene helped establish that mutation of other gene(s) is likely causative of these two MEN1 phenocopies. MEN1 proved to be the gene most frequent L4 mutated in common-variety, nonhereditary parathyroid tumor, gastrinoma, insulinoma, or bronchial carcinoid. For example, in common-variety parathyroid tumors, mutation of several other genes (such as cyclin D1 and P53) has been found, but much less frequently than MEN1 mutation. The majority of germline and somatic MEN1 mutations predicted truncation of the encoded protein (menin). Such inactivating mutations strongly supported prior predictions that MEN1 is a tumor suppressor gene insofar as stepwise mutational inactivation of both copies can release a cell from normal growth suppression. Menin is principally a nuclear protein; menin interacts with junD, Future studies, such as discovery of menin's metabolic pathway, could lead to new opportunities in cell biology and in tumor therapy. (C) 1999 by Elsevier Science Inc. All rights reserved. C1 NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD USA. RP Marx, SJ (reprint author), NIDDKD, Metab Dis Branch, NIH, Bldg 10,Room 9C-101,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Agarwal, Sunita/D-1428-2016 OI Agarwal, Sunita/0000-0002-7557-3191 NR 41 TC 25 Z9 25 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD JUL PY 1999 VL 25 IS 1 BP 119 EP 122 DI 10.1016/S8756-3282(99)00112-X PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 213FU UT WOS:000081262700021 PM 10423035 ER PT J AU Boyce, BF Xing, L Franzoso, G Siebenlist, U AF Boyce, BF Xing, L Franzoso, G Siebenlist, U TI Required and nonessential functions of nuclear factor-kappa B in bone cells SO BONE LA English DT Article; Proceedings Paper CT 2nd Joint Meeting of the American-Society-for-Bone-and-Mineral-Research/International-Bone-and-Mi neral-Society CY DEC 01-06, 1998 CL SAN FRANCISCO, CALIFORNIA SP Amer Soc Bone & Mineral Res, Int Bone & Mineral Soc DE NF-kappa B; osteopetrosis; osteoclasts; lymphocytes; cytokines ID MICE LACKING; OSTEOCLAST DIFFERENTIATION; RHEUMATOID-ARTHRITIS; TRANSCRIPTION FACTOR; C-FOS; OSTEOPETROSIS; CYTOKINES; LIGAND; ACTIVATION; RECEPTOR AB Nuclear factor-kappa B (NF-kappa B) is a set of five polypeptide transcription factors, called p50, p52, p65 (also called Rel A), Rel B, and c-Rel, which regulate the expression of a variety of genes involved in immune and inflammatory responses, They were originally named because they were considered essential regulators of B cell kappa light chain expression. More recent studies indicate that NF-kappa B proteins are involved in the regulation of a variety of other cell functions, including cell proliferation, responses to stress, and apoptosis, NF-kappa B heterodimers reside in the cytoplasm of cells bound to inhibitory proteins, the two commonest of which are I kappa B alpha and I kappa B beta, which prevent NF-kappa B from entering the nucleus. When cells are stimulated, I kappa B is phosphorylated by specific I kappa B kinases and subsequently is ubiquitinated and degraded in proteosomes, This allows NF-kappa B to translocate to the nucleus to regulate the expression of a growing list of genes, including the proinflammatory cytokines, interleukin-1 (IL-1), IL-6, and tumor necrosis factor. IL-1 and tumor necrosis factor in turn also regulate the expression of NF-kappa B, Thus, once activated, NF-kappa B may be involved in upregulatory loops, which can amplify the effects of the initiating stimulus, Because these proinflammatory cytokines have been implicated in the pathogenesis of estrogen deficiency and inflammation-related bone loss, it is likely that NF-kappa B has a significant role in the increased generation and function of osteoclasts in these circumstances. However, an unexpected and essential role of NF-kappa B in the formation of osteoclasts during development was discovered recently after the generation of knockout mice, which lack the expression of the p50 and p52 subunits, This paper Kill describe recent studies that reveal an essential role for NF-kappa B signaling in the generation of osteoclasts and that suggest that NF-kappa B may also play a key central role in the activation and survival of osteoclasts in conditions in which osteoclastogenesis is upregulated, (C) 1999 by Elsevier Science Inc. All rights reserved. C1 Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78284 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Boyce, BF (reprint author), Univ Texas, Hlth Sci Ctr, Dept Pathol, 7703 Floyd Curl Dr, San Antonio, TX 78284 USA. NR 34 TC 72 Z9 73 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD JUL PY 1999 VL 25 IS 1 BP 137 EP 139 DI 10.1016/S8756-3282(99)00105-2 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 213FU UT WOS:000081262700025 PM 10423039 ER PT J AU Giannelli, G Pozzi, A Stetler-Stevenson, WG Gardner, HA Quaranta, V AF Giannelli, G Pozzi, A Stetler-Stevenson, WG Gardner, HA Quaranta, V TI MMP2-cleaved laminin-5 in mammary gland remodeling is regulated by sex steroids. SO BONE LA English DT Meeting Abstract C1 Scripps Res Inst, Dept Cell Biol, La Jolla, CA USA. Univ Bari, Inst Med Clin 2, I-70121 Bari, Italy. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RI giannelli, gianluigi/A-8169-2012; Stetler-Stevenson, William/H-6956-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808 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 8756-3282 J9 BONE JI Bone PD JUL PY 1999 VL 25 IS 1 MA 9 BP 157 EP 157 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 213FU UT WOS:000081262700038 ER PT J AU Riminucci, M Corsi, A Spiegel, A Shenker, A Majolagbe, A Robey, PG Bianco, P AF Riminucci, M Corsi, A Spiegel, A Shenker, A Majolagbe, A Robey, PG Bianco, P TI R201 mutations of the GNAS1 gene in isolated, non-MAS skeletal fibrous dysplasia and in a non-MAS ACTH-producing pituitary adenoma SO BONE LA English DT Meeting Abstract C1 Univ Aquila, I-67100 Laquila, Italy. NIDDK, NIH, Bethesda, MD USA. NIDR, NIH, Bethesda, MD 20892 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD JUL PY 1999 VL 25 IS 1 MA 12 BP 158 EP 158 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 213FU UT WOS:000081262700041 ER PT J AU Satomura, K Krebsbach, P Bianco, P Robey, PG AF Satomura, K Krebsbach, P Bianco, P Robey, PG TI Murine stromal cell lines that are at the same time committed and multipotential SO BONE LA English DT Meeting Abstract C1 NIDCR, NIH, Bethesda, MD 20892 USA. Univ Michigan, Sch Dent, Ann Arbor, MI 48108 USA. Univ Aquila, I-67100 Laquila, Italy. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD JUL PY 1999 VL 25 IS 1 MA 30 BP 163 EP 163 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 213FU UT WOS:000081262700059 ER PT J AU Barbeau, H McCrea, DA O'Donovan, MJ Rossignol, S Grill, WM Lemay, MA AF Barbeau, H McCrea, DA O'Donovan, MJ Rossignol, S Grill, WM Lemay, MA TI Tapping into spinal circuits to restore motor function SO BRAIN RESEARCH REVIEWS LA English DT Review DE locomotion; central pattern generator; spinal cord injury; functional neuromuscular stimulation; FNS; FES ID C3-C4 PROPRIOSPINAL NEURONS; BODY-WEIGHT SUPPORT; MEDULLARY RETICULAR-FORMATION; INTACT UNANESTHETIZED CAT; GROUP-I AFFERENTS; SPONTANEOUS RHYTHMIC ACTIVITY; CORD INJURED SUBJECTS; CHICK-EMBRYO; FICTIVE LOCOMOTION; UNRESTRAINED WALKING AB Motivated by the challenge of improving neuroprosthetic devices, the authors review current knowledge relating to harnessing the potential of spinal neural circuits, such as reflexes and pattern generators. If such spinal interneuronal circuits could be activated, they could provide the coordinated control of many muscles that is so complex to implement with a device that aims to address each participating muscle individually. The authors' goal is to identify candidate spinal circuits and areas of research that might open opportunities to effect control of human limbs through electrical activation of such circuits. David McCrea's discussion of the ways in which hindlimb reflexes in the cat modify motor activity may help in developing optimal strategies for functional neuromuscular stimulation (FNS), by using knowledge of how reflex actions can adapt to different conditions. Michael O'Donovan's discussion of the development of rhythmogenic networks in the chick embryo may provide clues to methods of generating rhythmic activity in the adult spinal cord. Serge Rossignol examines the spinal pattern generator fbr locomotion in cats, its trigger mechanisms, modulation and adaptation, and suggests how this knowledge can help guide therapeutic approaches in humans. Hugues Barbeau applies the work of Rossignol and others to locomotor training in human subjects who have suffered spinal cord injury (SCI) with incomplete motor function loss (IMFL). Michel Lemay and Warren Grill discuss some of the technical challenges that must be addressed by engineers to implement a neuroprosthesis using electrical stimulation of the spinal cord, particularly the control issues that would have to be resolved. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Univ Montreal, Ctr Rech Sci Neurol, Montreal, PQ H3T 1J4, Canada. NINDS, Sect Dev Neurobiol, Neural Control Lab, NIH, Bethesda, MD 20892 USA. Univ Manitoba, Spinal Cord Res Ctr, Dept Physiol, Winnipeg, MB R3E3J7, Canada. McGill Univ, Sch Phys & Occupat Therapy, Montreal, PQ H3G 1Y5, Canada. Case Western Reserve Univ, Dept Biomed Engn, Cleveland, OH 44106 USA. Case Western Reserve Univ, App Neural Control Lab, Cleveland, OH 44106 USA. RP Rossignol, S (reprint author), Univ Montreal, Ctr Rech Sci Neurol, Montreal, PQ H3T 1J4, Canada. RI o'donovan, michael/A-2357-2015; OI o'donovan, michael/0000-0003-2487-7547; Grill, Warren/0000-0001-5240-6588 FU NINDS NIH HHS [N01-NS-5-2331, N01-NS-8-2300] NR 191 TC 147 Z9 152 U1 2 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0173 J9 BRAIN RES REV JI Brain Res. Rev. PD JUL PY 1999 VL 30 IS 1 BP 27 EP 51 DI 10.1016/S0165-0173(99)00008-9 PG 25 WC Neurosciences SC Neurosciences & Neurology GA 217MZ UT WOS:000081504700002 PM 10407124 ER PT J AU Leyton, J Gozes, Y Pisegna, J Coy, D Purdom, S Casibang, M Zia, F Moody, TW AF Leyton, J Gozes, Y Pisegna, J Coy, D Purdom, S Casibang, M Zia, F Moody, TW TI PACAP(6-38) is a PACAP receptor antagonist for breast cancer cells SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE PACAP; VIP; breast cancer; proliferation ID CYCLASE-ACTIVATING POLYPEPTIDE; INTESTINAL-PEPTIDE VIP; ADENYLATE-CYCLASE; FUNCTIONAL EXPRESSION; SIGNAL-TRANSDUCTION; SPLICE VARIANTS; I RECEPTOR; RAT-BRAIN; LUNG; GROWTH AB The effects of pituitary adenylate cyclase activating polypeptide (PACAP) analogs were investigated using breast cancer cells. I-125-PACAP-27 bound with high affinity (Kd = 5 nM) to T47D cells (Bmax = 29,000 per cell). Specific I-125-PACAP-27 binding was inhibited half maximally by PACAP-27, PACAP-38, PACAP(6-38) and PACAP(28-38) with IC50 values of 8, 17, 750 and > 3000 nM, respectively. By RT-PCR, PACAP receptor mRNA was present in MCF-7 and T47D cell lines. Polyclonal antibodies to a PACAP receptor fragment (A-8-C) were elicited. The antibodies were affinity purified, recognized a 60-kDa protein by western blot, and stained malignant cells in breast cancer biopsy specimens by immunohistochemistry. PACAP-27 elevated the cAMP in T47D cells and the increase in cAMP caused by PACAP was inhibited by PACAP(6-38). PACAP-27 stimulated c-fos mRNA in T47D cells and the increase in c-fos gene expression caused by PACAP was reversed by PACAP(6-38). PACAP(6-38) inhibited colony formation using a soft agar assay and inhibited breast cancer xenograft growth in nude mice. These data suggest that PACAP(6-38) functions as a breast cancer PACAP receptor antagonist. C1 NCI, Dept Cell & Canc Biol, Med Branch, Rockville, MD 20850 USA. Israel Inst Biol Res, IL-70450 Ness Ziona, Israel. W Los Angeles Vet Affairs Med Ctr, CURE VA UCLA, Ctr Digest Dis, Los Angeles, CA 90073 USA. Tulane Univ, Sch Med, Med Branch, New Orleans, LA 70112 USA. George Washington Univ, Med Ctr, Dept Microbiol, Washington, DC 20037 USA. RP Leyton, J (reprint author), NCI, Dept Cell & Canc Biol, Med Branch, MCI 9610 Med Ctr, Rockville, MD 20850 USA. FU NIDDK NIH HHS [DK-36107] NR 41 TC 24 Z9 24 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 1999 VL 56 IS 2 BP 177 EP 186 PG 10 WC Oncology SC Oncology GA 239NW UT WOS:000082776400008 PM 10573110 ER PT J AU Kunkel, TA AF Kunkel, TA TI Defective DNA mismatch repair and cancer. SO BRITISH JOURNAL OF CANCER LA English DT Meeting Abstract C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUL PY 1999 VL 80 SU 2 MA S14 BP 4 EP 4 PG 1 WC Oncology SC Oncology GA 225JR UT WOS:000081955000014 ER PT J AU Pommier, Y AF Pommier, Y TI Topoisomerase I-induced DNA damage. SO BRITISH JOURNAL OF CANCER LA English DT Meeting Abstract C1 NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUL PY 1999 VL 80 SU 2 MA S16 BP 4 EP 4 PG 1 WC Oncology SC Oncology GA 225JR UT WOS:000081955000015 ER PT J AU Arris, CE Boyle, FT Calvert, AH Curtin, NJ Dewsbury, PJ Endicott, JA Gibson, AE Golding, BT Grant, S Griffin, RJ Johnson, LN Noble, MEM Newell, DR Sausville, E Schultz, R AF Arris, CE Boyle, FT Calvert, AH Curtin, NJ Dewsbury, PJ Endicott, JA Gibson, AE Golding, BT Grant, S Griffin, RJ Johnson, LN Noble, MEM Newell, DR Sausville, E Schultz, R TI In vitro growth activity of novel purine- and pyrimidine-based CDK1 and CDK2 inhibitors. SO BRITISH JOURNAL OF CANCER LA English DT Meeting Abstract C1 Univ Newcastle Upon Tyne, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. Univ Oxford, Oxford OX1 3QU, England. NCI, DTP, Washington, DC USA. Zeneca Pharmaceut, Macclesfield SK10 4TG, Cheshire, England. NR 0 TC 1 Z9 1 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUL PY 1999 VL 80 SU 2 MA 110 BP 11 EP 11 PG 1 WC Oncology SC Oncology GA 225JR UT WOS:000081955000036 ER PT J AU Alexandroff, AB Jackson, AM Paterson, T Haley, J Ross, JA Longo, DL Murphy, WJ James, K Taub, D AF Alexandroff, AB Jackson, AM Paterson, T Haley, J Ross, JA Longo, DL Murphy, WJ James, K Taub, D TI Expression of CD40 on carcinoma cells influences anti-tumour responses. SO BRITISH JOURNAL OF CANCER LA English DT Meeting Abstract C1 Univ Edinburgh, Dept Clin & Surg Sci, Edinburgh EH8 9YL, Midlothian, Scotland. Imperial Canc Res Fund, Res Unit, Leeds, W Yorkshire, England. SNBTS, Edinburgh, Midlothian, Scotland. NIA, Baltimore, MD 21224 USA. NCI, Frederick, MD 21701 USA. RI Jackson, Andrew/I-5929-2013 OI Jackson, Andrew/0000-0003-4739-4804 NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUL PY 1999 VL 80 SU 2 MA P229 BP 86 EP 86 PG 1 WC Oncology SC Oncology GA 225JR UT WOS:000081955000327 ER PT J AU Hargreaves, RHJ Winski, SL Ross, D Alley, M Sausville, EA McGown, AT Butler, J AF Hargreaves, RHJ Winski, SL Ross, D Alley, M Sausville, EA McGown, AT Butler, J TI RH1, pre-clinical studies SO BRITISH JOURNAL OF CANCER LA English DT Meeting Abstract C1 Christie Hosp NHS Trust, CRC, Sect Drug Dev & Imaging, Paterson Inst Canc Res, Manchester M20 9BX, Lancs, England. Univ Colorado, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci, Denver, CO 80262 USA. NCI, Dept Hlth & Human Sci, NIH, Bethesda, MD 20892 USA. Univ Salford, Dept Biol Sci, Salford M5 4WT, Lancs, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUL PY 1999 VL 80 SU 2 MA P267 BP 95 EP 95 PG 1 WC Oncology SC Oncology GA 225JR UT WOS:000081955000364 ER PT J AU Rusin, M Butkiewicz, D Malusecka, E Zborek, A Harasim, J Czyzewski, K Bennett, WP Shields, PG Weston, A Welsh, JA Krzyzowska-Gruca, S Chorazy, M Harris, CC AF Rusin, M Butkiewicz, D Malusecka, E Zborek, A Harasim, J Czyzewski, K Bennett, WP Shields, PG Weston, A Welsh, JA Krzyzowska-Gruca, S Chorazy, M Harris, CC TI Molecular epidemiological study of non-small-cell lung cancer from an environmentally polluted region of Poland SO BRITISH JOURNAL OF CANCER LA English DT Article DE p53; WAF1; GSTM1; CYP1A1; CYP2D6; tobacco smoke ID HYDROCARBON-DNA ADDUCTS; TUMOR-SUPPRESSOR GENE; S-TRANSFERASE GENES; GSTM1 NULL GENOTYPE; P53 MUTATIONS; POOR METABOLIZERS; STRAND BIAS; COAL-MINERS; SUSCEPTIBILITY; EXPOSURE AB The p53 mutation spectrum can generate hypotheses linking carcinogen exposure to human cancer. Although it is well-documented that tobacco smoking is a major cause of lung cancer, the contribution of air pollution is less well-established. We determined the molecular and immunohistochemical changes (p53 gene mutations, p53 protein accumulation and WAF1 protein expression) and genetic polymorphisms of GSTM1, CYP1A1 and CYP2D6 genes in a case series of non-small-cell lung cancers from Silesia. This region of southern Poland is highly industrialized with considerable environmental pollution. More than 50% of lung cancers (90/164) contained p53 mutations and 75% showed the combined alteration of the p53 gene and protein accumulation. Males occupationally exposed to coal-derived substances showed a relatively high frequency of squamous and large-cell carcinomas, relatively frequent mutations in codon 298 of p53 and a low frequency of p53 immunohistochemically positive tumours. Codon 298 GAG--> TAG mutations have rarely been found in lung cancers in other populations. We found no correlation between WAF1 protein expression and mutations in the p53 gene or p53 protein accumulation. No statistically significant relationship was found between p53 mutations and GSTM1, CYP1A1, CYP2D6 genotypes. Never smokers with lung cancers from Silesia had a higher frequency of G:C--> T:A transversions than previously reported of the p53 mutation spectrum in never smokers (6/15 vs 4/34; P = 0.06 by chi(2)). These data are a tentative indication that occupational and environmental exposure to polycyclic aromatic hydrocarbons, such as benzo(a)pyrene, in polluted air contributes to the molecular pathogenesis of lung cancer in never smokers. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Silesian Acad Med, Dept Thorac Surg, PL-41800 Zabrze, Poland. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Inst Oncol, Dept Tumor Biol, PL-44100 Gliwice, Poland. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. RI Shields, Peter/I-1644-2012 FU FIC NIH HHS [5F05 TW04836-03] NR 63 TC 20 Z9 23 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUL PY 1999 VL 80 IS 9 BP 1445 EP 1452 DI 10.1038/sj.bjc.6690542 PG 8 WC Oncology SC Oncology GA 212RL UT WOS:000081230000021 PM 10424749 ER PT J AU Setterfield, J Shirlaw, PJ Lazarova, Z Bryant, BM Bhogal, BS Harman, K Challacombe, SJ Black, MM AF Setterfield, J Shirlaw, PJ Lazarova, Z Bryant, BM Bhogal, BS Harman, K Challacombe, SJ Black, MM TI Paraneoplastic cicatricial pemphigoid SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Article DE antilaminin 5 cicatricial pemphigoid; gemcitabine; metastatic disease; non-small cell carcinoma of the lung; paraneoplastic disorder ID JUNCTIONAL EPIDERMOLYSIS-BULLOSA; HOMOZYGOUS NONSENSE MUTATION; BASEMENT-MEMBRANE; CHAIN GENE; EPILIGRIN; LAMININ-5; AUTOANTIBODIES; COMPONENT; CARCINOMA; FEATURES AB We report a 39-year-old woman with antiepiligrin cicatricial pemphigoid (CP) in association with non-small cell carcinoma of the lung. At presentation, mucosal lesions showed minimal response to combined systemic immunosuppressive agents. Following the diagnosis of non-small cell lung carcinoma and subsequent treatment with gemcitabine (a second-line chemotherapeutic agent), a significant reduction in both tumour mass and mucosal blistering was observed. Metastatic disease was subsequently associated with recurrent oral erosions. We believe this patient represents the first reported case of paraneoplastic CP. C1 St Thomas Hosp, St Johns Inst Dermatol, GKT, London SE1 7EH, England. Guys Hosp, Dept Oral Med & Pathol, GKT, London SE1 9RT, England. NIH, Dept Dermatol, Bethesda, MD 20892 USA. Greenwich Dist Hosp, Dept Oncol, London, England. RP Setterfield, J (reprint author), St Thomas Hosp, St Johns Inst Dermatol, GKT, London SE1 7EH, England. OI challacombe, stephen/0000-0002-7327-6927 NR 22 TC 26 Z9 27 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0007-0963 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD JUL PY 1999 VL 141 IS 1 BP 127 EP 131 PG 5 WC Dermatology SC Dermatology GA 219FT UT WOS:000081597800020 PM 10417528 ER PT J AU Rautalahti, MT Virtamo, JRK Taylor, PR Heinonen, OP Albanes, D Haukka, JK Edwards, BK Karkkainen, PA Stolzenberg-Solomon, RZ Huttunen, J AF Rautalahti, MT Virtamo, JRK Taylor, PR Heinonen, OP Albanes, D Haukka, JK Edwards, BK Karkkainen, PA Stolzenberg-Solomon, RZ Huttunen, J TI The effects of supplementation with alpha-tocopherol and beta-carotene on the incidence and mortality of carcinoma of the pancreas in a randomized, controlled trial SO CANCER LA English DT Article DE antioxidants; supplementation; beta-carotene; alpha-tocopherol; pancreatic carcinoma; prevention; clinical trial ID VITAMIN-E; PLASMA-LEVELS; RISK-FACTORS; SUBSEQUENT RISK; CANCER RISK; FOLLOW-UP; CARCINOGENESIS; ANTIOXIDANT; ALCOHOL; RETINOL AB BACKGROUND. Dietary components may be both causal and protective in cases of pancreatic carcinoma, but the preventive potential of single constituents has not been evaluated. The authors report the effects of alpha-tocopherol and beta-carotene supplementations on the rates of incidence of and mortality from pancreatic carcinoma in a randomized, controlled trial. METHODS. The 29,133 participants in the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study were male smokers who were ages 50-69 years at the time they were randomized into 1 of the following 4 intervention groups: dl-alpha-tocopherol (AT; 50 mg/day), beta-carotene (BC; 20 mg/day), both AT and BC, and placebo. The daily supplementation lasted for 5-8 years. Incident cancers were identified through the national Finnish Cancer Registry and death certificates of the Statistics Finland. Results were analyzed by supplementation with Cox regression models. RESULTS. Effects of both supplementations were statistically nonsignificant. The rate of incidence of pancreatic carcinoma was 25% lower for the men who received P-carotene supplements (n = 38) compared with the rate for those who did not receive beta-carotene (n = 51) (95% CI, -51% to 14%). Supplementation with alpha-tocopherol (n = 51) increased the rate of incidence by 34% (95% CI, -12% to 105%) compared with the rate for those who did not receive alpha-tocopherol. Mortality from pancreatic carcinoma during the follow-up, adjusted for stage and anatomic location of the tumor, was 19% (95% CI, -47% to 26%) lower among those who received beta-carotene and 11% (95% CI, -28% to 72%) higher among those who received alpha-tocopherol as compared with those who did not receive supplementation. CONCLUSIONS. Supplementation with beta-carotene or alpha-tocopherol does not have a statistically significant effect on the rate of incidence of pancreatic carcinoma or the rate of mortality caused by this disease. Cancer 1999;86:37-42. (C) 1999 American Cancer Society. C1 Natl Publ Hlth Inst, Helsinki, Finland. NCI, Bethesda, MD 20892 USA. Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. Univ Helsinki, Dept Pathol, Helsinki, Finland. RP Rautalahti, MT (reprint author), Canc Soc Finland, Liisankatu 21 B, SF-00170 Helsinki, Finland. RI Albanes, Demetrius/B-9749-2015; Haukka, Jari/G-1484-2014 OI Haukka, Jari/0000-0003-1450-6208 FU NCI NIH HHS [N01-CN-45165] NR 38 TC 54 Z9 55 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JUL 1 PY 1999 VL 86 IS 1 BP 37 EP 42 DI 10.1002/(SICI)1097-0142(19990701)86:1<37::AID-CNCR7>3.3.CO;2-6 PG 6 WC Oncology SC Oncology GA 209VR UT WOS:000081070400007 PM 10391561 ER PT J AU Chu, KC Baker, SG Tarone, RE AF Chu, KC Baker, SG Tarone, RE TI A method for identifying abrupt changes in US cancer mortality trends SO CANCER LA English DT Article DE cancer mortality; stepwise selection; piecewise regression analysis; cancer trends ID SURVIVAL AB BACKGROUND. Summaries of trends in cancer rates evaluated over a fixed, short period are informative, but methods that evaluate trends over a longer time period, identifying when changes occur as well as the magnitude of the changes, can provide additional information. METHODS. Cancer mortality trends from 1973-1995 were determined for more than 15 anatomic sites for white and black males and females using weighted piecewise linear regression analysis with a stepwise selection procedure. The dependent variable was the natural logarithm of the annual mortality rate, and the weight was the annual number of cancer deaths. The variability of estimated change points was examined by bootstrapping the residuals from the resulting models. RESULTS. For black males, cancer mortality rates declined in the 1990s due to decreases in lung, esophageal, oral cavity, and prostate cancer rates. However, there was no significant decline for cancer of the colon and rectum. For white males, cancer mortality rates declined in the 1990s due to declines in cancer of the lung and colon/rectum since the mid-1980s and declines in prostate cancer in the 1990s. For black females and white females, total cancer mortality rates declined, but not significantly. Cancer rates for all sites except the lung declined significantly in the 1990s for white, but not black, females due to declining trends for carcinoma of the colon and rectum since the mid-1980s and for breast cancer in the 1990s. CONCLUSIONS. A method for identifying major changes in cancer trends has been developed. Trends for cancer of the breast and colon/rectum indicate that gaps between rates for blacks and whites are widening. Cancer 1999;86:157-69. (C) 1999 American Cancer Society. C1 NCI, Off Special Populat Res, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, Biometry Branch, Bethesda, MD USA. NCI, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD USA. RP Chu, KC (reprint author), NCI, Off Special Populat Res, EPS Room 320,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 16 TC 15 Z9 16 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 0008-543X J9 CANCER JI Cancer PD JUL 1 PY 1999 VL 86 IS 1 BP 157 EP 169 DI 10.1002/(SICI)1097-0142(19990701)86:1<157::AID-CNCR22>3.0.CO;2-C PG 13 WC Oncology SC Oncology GA 209VR UT WOS:000081070400022 PM 10391576 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 (vol 43, pg 106, 1999) SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Correction C1 Brown Univ, Women & Infants Hosp, Providence, RI 02905 USA. NCI, Surg Branch, Gynecol Oncol Sect, 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. NR 1 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JUL PY 1999 VL 44 IS 1 BP 90 EP 90 PG 1 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 200HJ UT WOS:000080533300013 ER PT J AU Rizk, NP Chang, MY El Kouri, C Seth, P Kaiser, LR Albelda, SM Amin, KM AF Rizk, NP Chang, MY El Kouri, C Seth, P Kaiser, LR Albelda, SM Amin, KM TI The evaluation of adenoviral p53-mediated bystander effect in gene therapy of cancer SO CANCER GENE THERAPY LA English DT Article DE p53; gene therapy; bystander effect; adenovirus; cancer ID WILD-TYPE P53; TUMOR-SUPPRESSOR GENE; HUMAN-MALIGNANT MESOTHELIOMA; LUNG-CANCER; IN-VIVO; RECOMBINANT ADENOVIRUS; GLIOBLASTOMA CELLS; EXPRESSION; GROWTH; HEAD AB Because many tumors have mutated p53, one potential strategy proposed for cancer gene therapy is the introduction of the wild-type p53 gene into tumor cells. One puzzling aspect of this approach is that currently available gene transfer protocols result in a small percentage of tumor cells being transduced in vivo, thus implicating a "bystander effect" to achieve therapeutic efficacy. Because bystander effects in the context of p53-mediated gene therapy have not been well characterized, Lye evaluated the role of in vitro and in vivo bystander effects of adenovirally delivered p53 (AdWTp53), Using human tumor cell lines that did not express p53 protein but were infectible with adenovirus and showed sensitivity to p53-mediated apoptosis, we were unable to demonstrate an AdWTp53-mediated in vitro bystander effect, despite seeing strong bystander effects when cells were infected with an adenovirus containing the suicide gene herpes simplex virus thymidine kinase and treated with ganciclovir. In contrast, in vivo flank mixing studies using one of these cell lines showed a weak but significant p53-mediated bystander effect (a 40% inhibition of tumor growth). This bystander effect translated into a small survival advantage in an established intraperitoneal tumor model when tumor burden was low at the lime of viral instillation. The survival advantage was lost, however, when tumor burden was increased. This study indicates that treatment of human tumors using AdWTp53 may be possible; however, because of the weak bystander effect in vivo, effective treatment will likely require a large percentage of tumor cells to be transduced. C1 Univ Penn Hlth Syst, Thorac Oncol Res Lab, Dept Surg, Div Pulm & Crit Care, Philadelphia, PA 19104 USA. Univ Penn Hlth Syst, Dept Med, Philadelphia, PA 19104 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Amin, KM (reprint author), Hosp Univ Penn, Dept Surg, Thorac Oncol Res Lab, 810 Maloney Bldg,3600 Spruce St, Philadelphia, PA 19104 USA. FU NCI NIH HHS [CA-66726] NR 39 TC 22 Z9 23 U1 0 U2 2 PU STOCKTON PRESS PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD JUL-AUG PY 1999 VL 6 IS 4 BP 291 EP 301 DI 10.1038/sj.cgt.7700059 PG 11 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 214JR UT WOS:000081325300001 PM 10419047 ER PT J AU Rao, KVN Johnson, WD Bosland, MC Lubet, RA Steele, VE Kelloff, GJ McCormick, DL AF Rao, KVN Johnson, WD Bosland, MC Lubet, RA Steele, VE Kelloff, GJ McCormick, DL TI Chemoprevention of rat prostate carcinogenesis by early and delayed administration of dehydroepiandrosterone SO CANCER RESEARCH LA English DT Article ID METHYL-N-NITROSOUREA; LONG-TERM TREATMENT; INTRAEPITHELIAL NEOPLASIA; BREAST-CANCER; MAMMARY-GLAND; F344 RATS; INHIBITION; MICE; 3-BETA-METHYLANDROST-5-EN-17-ONE; TESTOSTERONE AB Two in vivo bioassays were conducted to evaluate the efficacy of dehydroepiandrosterone (DHEA) as an inhibitor of prostate carcinogenesis in rats. Prostate adenocarcinomas were induced in male Wistar-Unilever rats by a sequential regimen of cyproterone acetate and testosterone propionate, followed by a single i.v. injection of N-methyl-N-nitrosourea (MNU) and chronic androgen stimulation. In the first experiment, DHEA (1000 or 2000 mg/kg diet) was administered continuously to rats beginning 1 week before MNU exposure, In the second experiment, continuous administration of DHEA (2000 mg/kg diet) was begun either I week before, 20 weeks after, or 40 weeks after MNU exposure. Controls received basal diet without added DHEA, Studies were terminated at 13 months after MNU administration, and prostate cancer incidence was determined by histopathological evaluation of step sections of accessory sex glands. In the first study, continuous dietary administration of DHEA beginning 1 week before MNU resulted in a dose-related inhibition of prostate cancer induction. In the second experiment, comparable reductions in prostate cancer incidence were observed in groups exposed to DHEA beginning 1 week before, 20 weeks after, and 40 weeks after carcinogen exposure, These data demonstrate that nontoxic doses of DHEA confer significant protection against prostate carcinogenesis in rats. The efficacy of delayed administration of DHEA suggests that the compound confers protection against later stages of prostate cancer induction and can suppress the progression of existing preneoplastic lesions to invasive disease. C1 IIT, Res Inst, Expt Toxicol & Carcinogenesis Div, Chicago, IL 60616 USA. NYU, Sch Med, Dept Environm Med, New York, NY 10016 USA. NYU, Sch Med, Dept Urol, New York, NY 10016 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP McCormick, DL (reprint author), IIT, Res Inst, Expt Toxicol & Carcinogenesis Div, 10 W 35th St, Chicago, IL 60616 USA. EM dmccormick@iitri.org FU NCI NIH HHS [N01-CN-35566-02] NR 30 TC 63 Z9 66 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 1999 VL 59 IS 13 BP 3084 EP 3089 PG 6 WC Oncology SC Oncology GA 212BL UT WOS:000081196400014 PM 10397249 ER PT J AU Webber, MM Trakul, N Thraves, PS Bello-DeOcampo, D Chu, WW Storto, PD Huard, TK Rhim, JS Williams, DE AF Webber, MM Trakul, N Thraves, PS Bello-DeOcampo, D Chu, WW Storto, PD Huard, TK Rhim, JS Williams, DE TI A human prostatic stromal myofibroblast cell line WPMY-1: a model for stromal-epithelial interactions in prostatic neoplasia SO CARCINOGENESIS LA English DT Article ID SMOOTH-MUSCLE; TRANSFORMING GROWTH-FACTOR-BETA-1; GROWTH-FACTORS; DIFFERENTIATION; HYPERPLASIA; FIBROBLASTS; EXPRESSION; INDUCTION; CANCER; PROLIFERATION AB Here we report the characterization of an SV40 large-T antigen-immortalized stromal cell line, WPMY-1, derived from the same prostate as our previously described epithelial cell lines. The WPMY-1 cells mere determined to be myofibroblasts on the basis of co-expression of smooth muscle alpha-actin and vimentin, They also show positive staining for androgen receptor, large-T antigen, and positive but heterogeneous staining for p53 and pRb, Their growth is stimulated by the synthetic androgen mibolerone to 145% of control (100%). Platelet-derived growth factor BE, epidermal growth factor and basic fibroblast growth factor, at 10 ng/ml, stimulated growth to 138, 143 and 146% of control, respectively. Transforming growth factor-beta, at 10 ng/ml, inhibited serum-induced growth to 65% of control in the presence of 1% serum, and bFGF-induced growth to 30% of control. A serum-free medium was developed for optimal growth of WPMY-1 cells. They show anchorage-independent growth in soft agar, Studies on paracrine interactions show that myofibroblast-conditioned medium causes a marked inhibition of growth in WPE1-10 cells, while conditioned medium from WPE1-10 prostatic epithelial cells caused only a small increase in the growth of WPMY-1 cells. WPMY-1 cells secrete very low levels of MMP-9 but high levels of MMP-2, markedly higher than the epithelial cells, These epithelial and myofibroblast cell lines, derived from the same prostate, provide novel and useful models for studies on paracrine stromal-epithelial interactions in carcinogenesis, tumor progression, prevention and treatment of prostate cancer and benign prostatic hyperplasia. C1 Michigan State Univ, Dept Zool, E Lansing, MI 48824 USA. Michigan State Univ, Dept Med, E Lansing, MI 48824 USA. Michigan State Univ, Dept Pediat & Human Dev, E Lansing, MI 48824 USA. Georgetown Univ, Dept Radiat Med, Washington, DC 20057 USA. Sparrow Reg Canc Ctr, Lansing, MI USA. NCI, Lab Biochem Physiol, Frederick, MD 21701 USA. RP Webber, MM (reprint author), Michigan State Univ, Dept Zool, E Lansing, MI 48824 USA. NR 33 TC 60 Z9 61 U1 2 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 1999 VL 20 IS 7 BP 1185 EP 1192 DI 10.1093/carcin/20.7.1185 PG 8 WC Oncology SC Oncology GA 218JJ UT WOS:000081549200005 PM 10383888 ER PT J AU Tobi, SE Levy, DD Seidman, MM Kraemer, KH AF Tobi, SE Levy, DD Seidman, MM Kraemer, KH TI Sequence-dependent mutations in a shuttle vector plasmid replicated in a mismatch repair deficient human cell line SO CARCINOGENESIS LA English DT Article ID NONPOLYPOSIS COLORECTAL-CANCER; SOMATIC FRAMESHIFT MUTATIONS; DYSPLASTIC NEVUS SYNDROME; XERODERMA-PIGMENTOSUM; COLON-CANCER; EXCISION-REPAIR; ULTRAVIOLET HYPERMUTABILITY; MICROSATELLITE INSTABILITY; ESCHERICHIA-COLI; MAMMALIAN-CELLS AB We utilized a shuttle vector plasmid (pLSC) to assess the role of DNA sequence and mismatch repair on mutagenesis in human cells. pLSC contains an interrupted 29 bp mononucleotide poly(G) run within a bacterial suppressor tRNA gene, which acts as a highly sensitive mutagenic target for detection of base substitution and frameshift mutations. The frequency of spontaneous mutations in pLSC was found to be similar after replication in either the hMSH6 (GT binding protein) mismatch repair-deficient MT1 line or its parental, mismatch repair-proficient line, TK6, However, the classes of plasmid mutations showed distinct differences in the two cell lines. Single base deletions comprised 48% of the mutations in the 56 independent pLSC plasmids sequenced from MT1 cells while these represented only 18% of the 40 independent pLSC mutants sequenced from the wild-type TK6 cells (P = 0.001). Virtually all the deletions included the mononucleotide run. In contrast, in pSP189, which contains the unmodified supF tRNA without the mononucleotide sequence, no single base deletions were observed for either cell line (P < 0.001), UV treatment of pLSC and pSP189 resulted in a 12-140-fold increase in mutations in TK6 and MT1 cells. These were predominately single base substitution mutations without a large increase in deletion mutations in the mononucleotide run in pLSC, These data indicate that a mononucleotide poly(G) run promotes single base deletion mutations. This effect is enhanced in a hMSH6 mismatch repair-deficient cell line and is independent of UV-induced mutagenesis. C1 NCI, Mol Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Food Safety & Appl Nutr, Washington, DC 20204 USA. NIA, Mol Genet Lab, Baltimore, MD 21224 USA. RP Kraemer, KH (reprint author), NCI, Mol Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NR 57 TC 9 Z9 9 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 JUL PY 1999 VL 20 IS 7 BP 1293 EP 1301 DI 10.1093/carcin/20.7.1293 PG 9 WC Oncology SC Oncology GA 218JJ UT WOS:000081549200020 PM 10383903 ER PT J AU Kim, SG Liem, A Stewart, BC Miller, JA AF Kim, SG Liem, A Stewart, BC Miller, JA TI New studies on trans-anethole oxide and trans-asarone oxide SO CARCINOGENESIS LA English DT Article ID ISOLATED RAT HEPATOCYTES; DNA-SYNTHESIS ASSAY; CARCINOGENIC METABOLITE; SALMONELLA-TYPHIMURIUM; MOUSE-LIVER; EPOXIDE METABOLISM; ALPHA-ASARONE; BETA-ASARONE; ESTRAGOLE; SAFROLE AB The widespread use of naturally occurring alkenylbenzenes as flavoring and fragrance agents has led to a long-standing interest in their toxicity and carcinogenicity, Among them several allyl- and propenylbenzenes have been found to be mutagenic and carcinogenic. It has been shown that the carcinogenicity of several allylbenzenes can be related to the formation of electrophilic sulfuric acid esters following 1'-hydroxylation, Unlike the allylbenzenes, the mechanisms of carcinogenesis of propenylbenzenes such as anethole and asarone are not clear. It has been reported that one of the main metabolic pathways of trans-anethole is the epoxidation of the side chain 1,2-double bond, which was responsible for cytotoxicity but not for genotoxicity. However, we report here that synthetic trans-anethole oxide prepared from trans-anethole and dimethyldioxirane is not only mutagenic for Salmonella tester strains but is also carcinogenic in the induction of hepatomas in B6C3F1 mice and skin papillomas in CD-1 mice. Synthetic trans-asarone oxide was also carcinogenic in the induction of hepatomas as well as mutagenic for Salmonella strains, Further studies are needed on these side chain oxides of traits-anethole and trans-asarone as possible metabolites in the toxicity, mutagenicity and carcinogenicity of these and other propenylbenzenes. C1 Univ Wisconsin, Sch Med, Mcardle Lab Canc Res, Madison, WI 53706 USA. RP Kim, SG (reprint author), NIDDK, Mol Recognit Sect, LBC, NIH, Bethesda, MD 20892 USA. NR 39 TC 29 Z9 29 U1 2 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 1999 VL 20 IS 7 BP 1303 EP 1307 DI 10.1093/carcin/20.7.1303 PG 5 WC Oncology SC Oncology GA 218JJ UT WOS:000081549200021 PM 10383904 ER PT J AU Venugopal, M Callaway, A Snyderwine, EG AF Venugopal, M Callaway, A Snyderwine, EG TI 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) retards mammary gland involution in lactating Sprague-Dawley rats SO CARCINOGENESIS LA English DT Article ID FOOD-DERIVED CARCINOGEN; SERUM PROLACTIN LEVELS; DNA ADDUCT LEVELS; HETEROCYCLIC AMINES; CELL-DEATH; HIGH-FAT; TUMORIGENESIS; INDUCTION; HORMONE; TUMORS AB 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a compound from cooked meat, is an established mammary gland carcinogen in female rats. Four doses of PhIP (150 mg/kg, p.o., once per day) were given to lactating Sprague-Dawley rats separated from their 10-day-old pups to initiate involution of the gland, Twenty-four hours after the last dose, apoptotic index in the mammary gland, as measured by the TUNEL assay, was significantly higher in the gland from control rats than in the PhIP-treated rats (4.757 +/- 1.066 versus 1.905 +/- 0.248%; P < 0.05). In comparison with controls, alveoli in the mammary gland of PhIP-treated rats were also visibly larger and contained more secretory epithelial cells, The expression of Bar, a stimulator of apoptosis, and Bcl-2, an inhibitor of apoptosis, were quantitated by western blotting. Accordingly, Bar expression was 2.7-fold higher in control rats, whereas Bcl-2 expression was 3.1-fold higher in PhIP-treated rats, both changes being statistically different (Student's t-test, P < 0.05), Immunohistochemistry further confirmed a lower expression of Bas and higher expression of Bcl-2 in secretory alveolar epithelial cells of the PhIP-treated mammary gland. The findings are consistent with the notion that exposure to PhIP retarded involution via partial inhibition of programmed cell death, To investigate possible mechanisms for the inhibitory effects of PhIP on mammary gland involution, serum levels of prolactin, an important hormone for the maintenance of lactation, were measured in virgin rats with regular estrous cycles given PhIP (150 mg/kg, p.o.) on the morning of diestrous, After one estrous cycle, on proestrous morning, serum prolactin levels were 1.3-fold higher after PhIP than after control vehicle (one-way ANOVA, Fisher LSD multiple comparison test, P < 0.05), PhIP exposure during involution was associated with the induction of benign mammary tumors. Seven out of 12 rats developed fibroadenomas, and one developed a tubulopapillary carcinoma within 1 year of receiving PhIP administration during involution (150 mg/kg, p.o., once per day for 5 days), and a high-fat diet (23.5% corn oil). An increase in serum prolactin level and the effects on mammary gland apoptosis seen with PhIP may have implications for the mechanisms of carcinogenic targeting of PhIP to the mammary gland. C1 NCI, Chem Carcinogenesis Sect, Expt Carcinogenesis Lab, Div Basic Sci, Bethesda, MD 20892 USA. RP Snyderwine, EG (reprint author), NCI, Chem Carcinogenesis Sect, Expt Carcinogenesis Lab, Div Basic Sci, Bethesda, MD 20892 USA. NR 44 TC 18 Z9 18 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 1999 VL 20 IS 7 BP 1309 EP 1314 DI 10.1093/carcin/20.7.1309 PG 6 WC Oncology SC Oncology GA 218JJ UT WOS:000081549200022 PM 10383905 ER PT J AU Shane, BS deBoer, JG Glickman, BW Cunningham, ML AF Shane, BS deBoer, JG Glickman, BW Cunningham, ML TI Oxazepam is mutagenic in vivo in Big Blue (R) transgenic mice SO CARCINOGENESIS LA English DT Article ID CHEMICAL CARCINOGENESIS; B6C3F1 MICE; CELL-PROLIFERATION; MAMMALIAN-CELLS; DNA DAMAGE; MUTATIONS; LIVER; SPECTRUM; LACI; DEAMINATION AB Although oxazepam (Serax(R)), a widely used benzodiazepine anxiolytic, does not induce gene mutations iii vitro or chromosomal aberrations in vivo, it was found to be a hepatocarcinogen in a 2 year bioassay in B6C3F1 mice. Thus, it was of interest to determine whether this carcinogen is mutagenic in vivo. Male B6C3F1 Big Blue(R) transgenic mice were fed 2500 p.p.m. oxazepam or control diet alone for 180 days and killed on the nest day. The mutant frequency (MF) of lacI in control mice was 5.02 +/- 2.4 x 10(5), whereas the R;IF in the oxazepam-treated mice was 9.17 +/- 4.82 x 10(-5), a significant increase (P < 0.05). Correction of the mutant frequency of lacI from the oxazepam-treated mice for clonality resulted in a decrease in the mean mutant frequency to 8.15 +/- 2.54 x 10-5. Although the mutant frequency difference was small, sequencing of a random collection of the mutants from each oxazepam-exposed mouse showed a significant difference (P < 0.015) in the mutation spectrum compared with that from control mice, In the oxazepam-exposed mice, an increase in G:C-->T:A and G:C-->C:G transversions and a concomitant decrease in G:C-->A:T transitions were observed, Clonal expansion of mutations at guanines in 5'-CpG-3' sequencing contexts at three sites was noted. It is postulated that some of the mutations found in the oxazepam-derived spectrum were due to oxidative damage elicited by induction of CYP2B isozymes as the result of chronic oxazepam administration. This study demonstrates that the in vivo Big Blue(R) transgenic rodent mutation assay can detect mutations derived from a carcinogen that did not induce gene mutations in vitro or micronuclei in mouse bone marrow. Moreover, the sequencing of the recovered mutants can distinguish between the mutation spectrum from treated mice compared with that from control mice, thereby confirming the genotoxic consequences. C1 NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. Louisiana State Univ, Inst Environm Studies, Baton Rouge, LA 70803 USA. Univ Victoria, Ctr Environm Hlth, Victoria, BC V8W 3N5, Canada. RP Cunningham, ML (reprint author), NIEHS, Environm Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. FU NCI NIH HHS [CA72534-01] NR 38 TC 21 Z9 21 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 1999 VL 20 IS 7 BP 1315 EP 1321 DI 10.1093/carcin/20.7.1315 PG 7 WC Oncology SC Oncology GA 218JJ UT WOS:000081549200023 PM 10383906 ER PT J AU Chiou, Y Tomer, KB Smith, PC AF Chiou, Y Tomer, KB Smith, PC TI Effect of nonenzymatic glycation of albumin and superoxide dismutase by glucuronic acid and suprofen acyl glucuronide on their functions in vitro SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE acyl glucuronides; covalent binding; glycation; protein; albumin; superoxide dismutase ID HUMAN-SERUM-ALBUMIN; COVALENT BINDING; PLASMA-PROTEINS; ZOMEPIRAC GLUCURONIDE; UNITED-KINGDOM; CLOFIBRIC ACID; IN-VITRO; GLYCOSYLATION; DISCONTINUATIONS; COMPLICATIONS AB Acyl glucuronides bind irreversibly to plasma proteins, and one mechanism proposed for this covalent binding is similar to that for glycation of protein by reducing sugars. Because glycation of protein by glucose and other reducing sugars can alter protein function, this lead to the hypothesis that the glycation of proteins by acyl glucuronides may cause similar effects. When human serum albumin (HSA) was incubated with 0.5 M glucose for 5 days, the unbound fractions of diazepam and warfarin were increased by 41 and 35%, respectively, less than that caused by glucuronic acid which increased the unbound fractions by 90% for diazepam and 420% for warfarin. When HSA was incubated with suprofen glucuronide (SG) at a much lower concentration of 0.005 M for only 24 h, the effects on the unbound fractions of diazepam and warfarin to HSA were altered dramatically with increases of 340 and 230%, respectively. After incubation of superoxide dismutase (SOD) with 0.5 or 1 M reducing sugars for 14 days, the enzyme activity decreased to 82 and 61% of initial levels at day 14, respectively, whereas glucuronic acid almost completely inactivated the enzyme activity over the same period. Even at a very low concentration (0.005 M) of SG, SOD activity was reduced significantly to 11% of initial levels by day 14, which was comparable to the effect by 0.5 and 1.0 M concentrations of glucuronic acid. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and matrix associated laser desorption:ionization time of flight mass spectrometry indicated that several equivalents of reducing sugars or SG became attached to albumin after incubation. These results suggest that acyl glucuronides may affect the function of proteins by the formation of glycated protein in vivo and may be associated with the toxicity of xenobiotics metabolized to labile acyl glucuronides. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. NIEHS, Lab Mol Biophys, Res Triangle Pk, NC 27709 USA. RP Smith, PC (reprint author), Univ N Carolina, Sch Pharm, CB 7360, Chapel Hill, NC 27599 USA. RI Tomer, Kenneth/E-8018-2013 FU NIGMS NIH HHS [GM 41828] NR 44 TC 28 Z9 28 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JUL 1 PY 1999 VL 121 IS 2 BP 141 EP 159 DI 10.1016/S0009-2797(99)00098-8 PG 19 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 212MT UT WOS:000081221000002 PM 10418961 ER PT J AU Guerrero, C Ghosh, A Lecuona, E Ridge, K Santos, E Sznajder, JI AF Guerrero, C Ghosh, A Lecuona, E Ridge, K Santos, E Sznajder, JI TI Dopamine regulates NA,K-adenosine triphosphatase in alveolar epithelial cells via the mitogen-activated protein kinase/extracellular-signal-regulated kinase pathway SO CHEST LA English DT Article; Proceedings Paper CT 41st Annual Thomal L Petty Aspen Lung Conference on Acute Lung Injury CY JUN 03-06, 1998 CL ASPEN, COLORADO SP 3M Pharmaceut, Alliance Pharmaceut Corp, Astra USA, Bayer Pharmaceut Div, Boehringer Ingelheim Pharmaceut Inc, Bristol-Myers Squibb Oncol, Dura Pharmaceut, Eli Lilly & Co Inc, Genetech Inc, Glaxo Wellcome, Hoechst Marion Roussel Inc, Human Genome Sci Inc, Invitrogen Corp, Key Pharmaceut, Merck Res Labs & Merck Frosst Canada, NEXSTAR Pharmaceut Inc, Novartis Pharmaceut Corp, Ohmeda Inc, Ortho-McNeil Pharmaceut Inc, PathoGenesis Corp, Pfizer Inc, Pharmacia & Upjohn, Rhone-Poulenc Rorer Pharmaceut, Roche Labs, Sanofi Winthrop Inc, Schering Corp, Teijin Ltd, Wallace Labs, Zeneca Pharmaceut, Francis Families Fdn, Respiratory Distress Syndrome Fdn, Aspen Lung Conf Endowment Fund ID LIQUID CLEARANCE; ALPHA-SUBUNITS; TRANSPORT C1 Univ Illinois, Michael Reese Hosp, Div Pulm & Crit Care Med, Chicago, IL USA. NCI, NIH, Bethesda, MD 20892 USA. RP Sznajder, JI (reprint author), Michael Reese Hosp & Med Ctr, Dept Med, 2929 S Ellis Ave,Baum 101, Chicago, IL 60616 USA. RI Guerrero, Carmen/F-1776-2010 OI Guerrero, Carmen/0000-0002-8747-6831 FU NHLBI NIH HHS [HL-48129] NR 11 TC 3 Z9 3 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD JUL PY 1999 VL 116 IS 1 SU S BP 88S EP 89S DI 10.1378/chest.116.suppl_1.88S PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 220CC UT WOS:000081646100052 PM 10424607 ER PT J AU Leonard, HL Swedo, SE Garvey, M Beer, D Perlmutter, S Lougee, L Karitani, M Dubbert, B AF Leonard, HL Swedo, SE Garvey, M Beer, D Perlmutter, S Lougee, L Karitani, M Dubbert, B TI Postinfectious and other forms of obsessive-compulsive disorder SO CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article ID AUTOIMMUNE NEUROPSYCHIATRIC DISORDERS; CHRONIC TIC DISORDER; 7-YEAR FOLLOW-UP; RHEUMATIC-FEVER; TOURETTES-SYNDROME; DOUBLE-BLIND; STREPTOCOCCAL INFECTIONS; ANTINEURONAL ANTIBODIES; SYDENHAMS CHOREA; FAMILY HISTORY AB The search for subtypes of obsessive-compulsive disorder (OCD) has led to increased appreciation of the importance of distinguishing early (prepubertal) versus later onset, and of tie-related versus non-tie related subtypes, as well as postinfectious forms of the disorder. How these apparent typologies relate to each other remains to be elucidated. Careful longitudinal clinical descriptive studies, as well as the ongoing application of genetic, neuroimaging, and immunologic techniques, promise to advance our understanding of how genotype and environmental factors interact to produce the diverse clinical forms of OCD and to point the way to more effective treatment. C1 Rhode Isl Hosp, Div Child & Adolescent Psychiat, Providence, RI 02903 USA. Brown Univ, Sch Med, Dept Psychiat & Human Behav, Providence, RI 02912 USA. NIMH, Pediat & Dev Neuropsychiat Branch, Bethesda, MD 20892 USA. RP Leonard, HL (reprint author), Rhode Isl Hosp, Div Child & Adolescent Psychiat, 593 Eddy St, Providence, RI 02903 USA. NR 59 TC 17 Z9 18 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 1056-4993 J9 CHILD ADOL PSYCH CL JI Child Adolesc. Psychiatr. N. Am. PD JUL PY 1999 VL 8 IS 3 BP 497 EP + PG 16 WC Psychiatry SC Psychiatry GA 221MM UT WOS:000081730900006 PM 10442228 ER PT J AU Bornstein, MH Selmi, AM Haynes, OM Painter, KM Marx, ES AF Bornstein, MH Selmi, AM Haynes, OM Painter, KM Marx, ES TI Representational abilities and the wearing status of child/mother dyads SO CHILD DEVELOPMENT LA English DT Article ID SYMBOLIC PLAY; LANGUAGE IMPAIRMENT; PRETEND PLAY; 2ND YEAR; CHILDREN; MOTHERS; DEAF; TODDLERS; INFANTS; CHILDHOOD AB Two representational abilities, expressive and receptive language and symbolic play, were assessed in multiple formats in hearing and deaf 2-year-old children of hearing and deaf mothers. Based on maternal report, hearing children of hearing and deaf mothers produced more words than deaf children of hearing mothers, hearing children of hearing mothers more words than deaf children of deaf mothers, and deaf children of deaf mothers more words than deaf children of hearing mothers. Based on experimenter assessments, hearing children in both groups produced and comprehended more words than deaf children in both groups. By contrast, no differences emerged among these groups in child solitary symbolic play or in child-initiated or mother-initiated child collaborative symbolic play; all groups also increased equivalently in symbolic play between solitary and collaborative play. Representational language and symbolic play were unrelated in hearing children of hearing mothers and in deaf children of deaf mothers, but the 2 abilities were associated in children in the 2 child/mother mismatched hearing status groups. These findings are placed in the context of a proposed developing modularity of verbal and nonverbal symbol systems, and the implications of hearing status in communicative exchanges between children and their mothers in diverse hearing and deaf dyads are explored. C1 NICHHD, NIH, Bethesda, MD 20892 USA. San Jose State Univ, San Jose, CA 95192 USA. RP Bornstein, MH (reprint author), NICHHD, NIH, Bldg 31,Room B2B15,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 100 TC 13 Z9 14 U1 0 U2 0 PU BLACKWELL PUBLISHERS PI MALDEN PA 350 MAIN STREET, STE 6, MALDEN, MA 02148 USA SN 0009-3920 J9 CHILD DEV JI Child Dev. PD JUL-AUG PY 1999 VL 70 IS 4 BP 833 EP 852 DI 10.1111/1467-8624.00060 PG 20 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 221PH UT WOS:000081735100003 PM 10446723 ER PT J AU Cutler, JA AF Cutler, JA TI The effects of reducing sodium and increasing potassium intake for control of hypertension and improving health SO CLINICAL AND EXPERIMENTAL HYPERTENSION LA English DT Article; Proceedings Paper CT International Expert Meeting on Hypertension CY SEP 28-OCT 01, 1998 CL FUKUOKA, JAPAN SP WHO, Int Soc Hypertens, Japan Cardiovascular Res Fdn, Japanese Soc Hypertens, Japanese Pharmaceut Mfg Assoc, Astra Hassle AB, Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Glaxo Wellcome SpA, Knoll AG, Merck & Co Inc, Novartis Pharma AG, Pfizer Pharmaceut, Hoffmann - La Roche Ltd, Sanofi, Servier Int DE blood pressure; nutrition; epidemiology; clinical trials ID LEFT-VENTRICULAR MASS; BLOOD-PRESSURE; DIETARY-SODIUM; SALT INTAKE; NUTRITIONAL FACTORS; WEIGHT-LOSS; REDUCTION; TRIALS; METAANALYSIS; MAGNESIUM AB From a world-wide, population perspective, the problem of excessive blood pressure levels for optimal cardiovascular health is immense and growing. Evidence from animal experimentation, observational epidemiology, and randomized clinical trials strongly supports efforts to change nutritional factors in desirable directions, especially to lower dietary salt and increase potassium intake. C1 NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Cutler, JA (reprint author), NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. NR 36 TC 5 Z9 5 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1064-1963 J9 CLIN EXP HYPERTENS JI Clin. Exp. Hypertens. PD JUL-AUG PY 1999 VL 21 IS 5-6 BP 769 EP 783 DI 10.3109/10641969909061007 PG 15 WC Pharmacology & Pharmacy; Peripheral Vascular Disease SC Pharmacology & Pharmacy; Cardiovascular System & Cardiology GA 217RK UT WOS:000081512600027 PM 10423100 ER PT J AU Tedla, N Dwyer, J Truskett, P Taub, D Wakefield, D Lloyd, A AF Tedla, N Dwyer, J Truskett, P Taub, D Wakefield, D Lloyd, A TI Phenotypic and functional characterization of lymphocytes derived from normal and HIV-1-infected human lymph nodes SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE HIV-1; lymph nodes; flow cytometry; lymphocytes; adhesion molecules ID MEMORY T-CELLS; HIV-INFECTION; ADHESION MOLECULES; ENDOTHELIAL-CELLS; EXPRESSION; MIGRATION; ANTIGEN; SUBSETS; VIRUS; AIDS AB Lymph nodes are the major site of cell-to-cell transmission and replication of HIV-1. Trafficking of CD4(+) T lymphocytes into lymph nodes provides a continual supply of susceptible target lymphocytes, and conversely, recruitment of CD8(+) T lymphocytes may be critical for the host response that attempts to control HIV-1 replication. The present study was undertaken as no detailed assessment of lymphocyte subpopulations in HIV-1-infected lymph nodes has previously been reported. Peripheral blood and single-cell suspensions prepared from lymph nodes of patients with HIV-1 and control subjects were analysed using three-colour flow cytometry. Approximately 80% of the lymphocytes in control lymph nodes were CD3(+) T lymphocytes, of which over 65% were CD4(+). The majority of the CD4(+) and CD8(+) T lymphocytes obtained from both lymph nodes and blood of control subjects were immunologically naive (CD45RA(+)). By contrast, in HIV-1-infected patients there was a significant reduction in the proportion of CD4(+) T lymphocytes and an expansion of the CD8(+) T lymphocyte subset in both lymph nodes and peripheral blood. Furthermore, a high proportion of these T lymphocytes displayed a marker for immunological memory (CD45RO(+)). T lymphocytes derived from HIV-1-infected lymph nodes also showed altered expression of the adhesion molecules, L-selectin and very late antigen-4 (VLA-4), but not leucocyte function-associated antigen-1 (LFA-1). In an in vitro adhesion assay, lymphocytes from HIV-1- infected nodes were significantly more adhesive than control lymphocytes on fibronectin, as well as recombinant human intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) substrates. This combination of altered lymphocyte subpopulations in the HIV-1-infected lymph nodes, as well as enhanced adhesion phenotype and function, suggests that T lymphocyte traffic to lymph nodes in HIV disease may be an important determinant of pathogenesis. C1 Univ New S Wales, Sch Pathol, Inflammat Res Unit, Sydney, NSW 2052, Australia. Prince Wales Hosp, Div Med, Randwick, NSW 2031, Australia. Prince Wales Hosp, Dept Surg, Randwick, NSW 2031, Australia. NIA, Baltimore, MD 21224 USA. RP Lloyd, A (reprint author), Univ New S Wales, Sch Pathol, Inflammat Res Unit, Sydney, NSW 2052, Australia. NR 41 TC 18 Z9 20 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 JUL PY 1999 VL 117 IS 1 BP 92 EP 99 PG 8 WC Immunology SC Immunology GA 228VZ UT WOS:000082157500014 PM 10403921 ER PT J AU Cowan, KH Moscow, JA Huang, H Zujewski, JA O'Shaughnessy, J Sorrentino, B Hines, K Carter, C Schneider, E Cusack, G Noone, M Dunbar, C Steinberg, S Wilson, W Goldspiel, B Read, EJ Leitman, SF McDonagh, K Chow, C Abati, A Chiang, Y Chang, YN Gottesman, MM Pastan, I Nienhuis, A AF Cowan, KH Moscow, JA Huang, H Zujewski, JA O'Shaughnessy, J Sorrentino, B Hines, K Carter, C Schneider, E Cusack, G Noone, M Dunbar, C Steinberg, S Wilson, W Goldspiel, B Read, EJ Leitman, SF McDonagh, K Chow, C Abati, A Chiang, Y Chang, YN Gottesman, MM Pastan, I Nienhuis, A TI Paclitaxel chemotherapy after autologous stem-cell transplantation and engraftment of hematopoietic cells transduced with a retrovirus containing the multidrug resistance complementary DNA (MDR1) in metastatic breast cancer patients SO CLINICAL CANCER RESEARCH LA English DT Article ID BONE-MARROW CELLS; HIGH-DOSE CHEMOTHERAPY; EX-VIVO EXPANSION; LONG-TERM PROTECTION; GENE-TRANSFER; REPOPULATING CELLS; PERIPHERAL-BLOOD; TRANSGENIC MICE; DRUG-RESISTANCE; DIHYDROFOLATE-REDUCTASE AB The MDR1 multidrug resistance gene confers resistance to natural-product anticancer drugs including paclitaxel. We conducted a clinical gene therapy study to determine whether retroviral-mediated transfer of MDR1 in human hematopoietic cells would result in stable engraftment, and possibly expansion, of cells containing this gene after treatment with myelosuppressive doses of paclitaxel, Patients with metastatic breast cancer who achieved a complete or partial remission after standard chemotherapy were eligible for the study. Hematopoietic stem cells (HSCs) were collected by both peripheral blood apheresis and bone marrow harvest after mobilization with a single dose of cyclophosphamide (4 g/m(2)) and daily filgrastim therapy (10 mu g/kg/day). After enrichment for CD34+ cells, one-third of each collection was incubated ex vivo for 72 h with a replication-incompetent retrovirus containing the MDR1 gene (G1MD) in the presence of stem-cell factor, interleukin 3, and interleukin 6, The remaining CD34+ cells were stored without further manipulation. All of the CD34+ cells were reinfused for hematopoietic rescue after conditioning chemotherapy with ifosfamide, carboplatin, and etoposide regimen,. After hematopoietic recovery, patients received six cycles of paclitaxel (175 mg/m(2) every 3 weeks). Bone marrow and serial peripheral blood samples were obtained and tested for the presence of the MDR1 transgene using a PCR assay. Six patients were enrolled in the study and four patients received infusion of genetically altered cells. The ex vivo transduction efficiency, estimated by the PCR assay, ranged from 0.1 to 0.5%. Three of the four patients demonstrated engraftment of cells containing the MDR1 transgene. The estimated percentage of granulocytes containing the MDR1 transgene ranged from a maximum of 9% of circulating nucleated cells down to the limit of detection of 0.01%, One patient remained positive for the MDR1 transgene throughout all six cycles of paclitaxel therapy, whereas the other 2 patients showed a decrease in the number of cells containing the transgene to undetectable levels. Despite the low level of engraftment of MDR1-marked cells, a correlation was observed between the relative number of granulocytes containing the MDR1 transgene and the granulocyte nadir after paclitaxel therapy. No adverse reactions to the genetic manipulation procedures were detected. Therefore, engraftment of human HSCs transduced with the MDR1 gene can be achieved. However, the overall transduction efficiency and stable engraftment of gene-modified HSCs must be improved before MDR1 gene therapy and in vivo selection with anticancer drugs can be reliably used to protect cancer patients from drug-related myelosuppression. C1 NCI, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Genet Therapy Inc, Gaithersburg, MD 20878 USA. RP Cowan, KH (reprint author), Eppley Inst Res Canc, 600 S 42nd St, Omaha, NE 68198 USA. EM kcowan@unmc.edu NR 45 TC 106 Z9 115 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL PY 1999 VL 5 IS 7 BP 1619 EP 1628 PG 10 WC Oncology SC Oncology GA 217TG UT WOS:000081514600004 PM 10430060 ER PT J AU Bhalla, KN Kumar, GN Walle, UK Ibrado, AM Javed, T Stuart, RK Reed, C Arbuck, SG Walle, T AF Bhalla, KN Kumar, GN Walle, UK Ibrado, AM Javed, T Stuart, RK Reed, C Arbuck, SG Walle, T TI Phase I and pharmacologic study of a 3-hour infusion of paclitaxel followed by cisplatinum and 5-fluorouracil in patients with advanced solid tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID COLONY-STIMULATING FACTOR; HUMAN LIVER-MICROSOMES; CELL LUNG-CANCER; OVARIAN-CANCER; TAXOL METABOLISM; ANTITUMOR AGENTS; BREAST-CANCER; TRIAL; PHARMACOKINETICS; CARCINOMA AB A Phase I and pharmacological study of paclitaxel administered as an outpatient, 3-h i.v. infusion just before a 5-day regimen of daily cisplatinum (CP) and a continuous infusion of 5-fluorouracil (5-FU) was performed in patients with advanced solid tumors. A secondary objective was to determine the objective response rate to this regimen, Forty-two patients were enrolled and were evaluable for toxicities. Eighteen patients were previously untreated, whereas the rest had received prior treatment with radiation (J, H. Schiller et at, J, Clin, Oncol,, 12: 241-248, 1994), chemotherapy (M. J, Kennedy et al,, Clin, Cancer Res., 4: 349-356, 1998), or both modalities (J, Ii, Schiller et al., J, Clin, Oncol,, 12: 241-248, 1994). The paclitaxel dose was escalated from 100-135-170-200-225 to 250 mg/m(2), whereas i.v. 5-FU and CP doses were fixed at 1.0 g/m(2)/day continuous infusion and 20 mg/m(2)/day, respectively, daily for 5 days. Granulocyte colony-stimulating factor (G-CSF; 5 mu g/kg/day) was administered s.c. from day 6, routinely after 250 mg/m(2) dose of paclitaxel or after a lower dose of paclitaxel if ANC <500/mu l or febrile neutropenia was observed. Patients were treated every 28 days, Plasma and urine samples were collected to determine the pharmacokinetics of paclitaxel. In previously untreated patients, the maximally tolerated dose of paclitaxel in the drug regimen was determined to be 170 mg/m(2) without and 250 mg/m(2) with G-CSF support. At the higher dose level, mucositis and thrombocytopenia were dose-limiting, In previously treated patients, these toxicities were observed at all dose levels of paclitaxel greater than or equal to 135 mg/m(2). With increasing doses of paclitaxel, a disproportionate increase in the peak concentrations, as well as the area under plasma concentration time-curve, was seen. This nonlinearity was due to saturable total body clearance and volume of distribution of paclitaxel (P < 0.001). The apparent plasma elimination half-life was unaffected by the dose of paclitaxel, CP and 5-FU had no apparent effect on the metabolism of paclitaxel, Among 32 patients evaluable for response, 22 demonstrated an objective response, including five complete remissions. Therefore, a regimen of 3-h infusion of 250 mg/m(2) paclitaxel before CP and FU is tolerable with G-CSF (as above) support in previously untreated patients. The regimen also seems to be highly active against breast and esophageal cancers. C1 Univ Miami, Sch Med, Sylvester Comprehens Canc Ctr, Div Clin & Translat Res, Miami, FL 33136 USA. Med Univ S Carolina, Dept Pharmacol, Charleston, SC 29425 USA. Med Univ S Carolina, Div Hematol Oncol, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Surg, Charleston, SC 29425 USA. NCI, NIH, Rockville, MD 20852 USA. RP Bhalla, KN (reprint author), Univ Miami, Sch Med, Sylvester Comprehens Canc Ctr, Div Clin & Translat Res, 1550 NW 10th Ave,M710, Miami, FL 33136 USA. OI Stuart, Robert/0000-0001-7549-8008 NR 38 TC 9 Z9 10 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL PY 1999 VL 5 IS 7 BP 1723 EP 1730 PG 8 WC Oncology SC Oncology GA 217TG UT WOS:000081514600019 PM 10430075 ER PT J AU Small, EJ Reese, DM Um, B Whisenant, S Dixon, SC Figg, WD AF Small, EJ Reese, DM Um, B Whisenant, S Dixon, SC Figg, WD TI Therapy of advanced prostate cancer with granulocyte macrophage colony-stimulating factor SO CLINICAL CANCER RESEARCH LA English DT Article ID RENAL-CELL CARCINOMA; PHASE-II TRIAL; TUMOR VACCINES; LNCAP MODEL; ANTIGEN; IMMUNOTHERAPY; POTENT AB Granulocyte macrophage colony-stimulating factor is a pleiotropic cytokine capable of inducing systemic immune responses against experimental and human tumors. To evaluate the efficacy of GM-CSF treatment in patients with hormone-refractory prostate cancer, we conducted sequential Phase II studies in 36 men with progressive disease after androgen deprivation and antiandrogen withdrawal. In a first cohort of patients (n = 23), GM-CSF was administered s.c. at a dose of 250 mu g/m(2) daily for 14 days of a 28-day treatment period. After we observed oscillating prostate-specific antigen (PSA) responses in several patients in this first cohort, a second trial was performed in which patients (n = 13) received maintenance GM-CSF (250 mu g/m(2) three times weekly) after the first 14 days of daily GM-CSF, All patients were treated until disease progression. Response was assessed by evaluation of serial changes in serum PSA and sequential imaging studies. In cohort I, 10 of 22 patients (45%) had a PSA versus time plot with a sawtooth pattern, with PSA declining during GM-CSF therapy and climbing during the off-therapy period; 5 patients had at least two consecutive declines in PSA, with a median response duration of 3.5 months. All but one patient in cohort II experienced a decline in PSA (median decline, 32%), but a PSA decline greater than 50% and sustained for more than 6 weeks was seen in only one patient, who had a >99% decline in PSA and an improvement in bone scan lasting for 14+ months, Changes in PSA levels could not be attributed to direct or indirect effects of GM-CSF on the PSA assay or down-regulation of PSA expression by GM-CSF, Toxicity was very mild, consisting primarily of transient constitutional symptoms and injection site reactions. These data suggest that GM-CSF may have antitumor activity in advanced prostate cancer, and the use of GM-CSF may be a confounding variable when PSA responses are used as an end point in clinical trials evaluating new regimens for the treatment of advanced prostate cancer. C1 Univ Calif San Francisco, Mt Zion Canc Ctr, Dept Med, Urol Oncol Program, San Francisco, CA 94115 USA. NCI, Med Branch, Bethesda, MD 20892 USA. RP Small, EJ (reprint author), Univ Calif San Francisco, Mt Zion Canc Ctr, Dept Med, Urol Oncol Program, 2356 Sutter St,5th Floor, San Francisco, CA 94115 USA. RI Figg Sr, William/M-2411-2016 NR 17 TC 103 Z9 105 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL PY 1999 VL 5 IS 7 BP 1738 EP 1744 PG 7 WC Oncology SC Oncology GA 217TG UT WOS:000081514600021 PM 10430077 ER PT J AU Srivastava, RK Srivastava, AR Cho-Chung, YS Longo, DL AF Srivastava, RK Srivastava, AR Cho-Chung, YS Longo, DL TI Synergistic effects of retinoic acid and 8-chloro-adenosine 3 ',5 '-cyclic monophosphate on the regulation of retinoic acid receptor beta and apoptosis: Involvement of mitochondria SO CLINICAL CANCER RESEARCH LA English DT Article ID BREAST-CANCER CELLS; DEPENDENT PROTEIN-KINASE; AMP RESPONSE ELEMENT; PERMEABILITY TRANSITION; LUNG-CANCER; POLY(ADP-RIBOSE) POLYMERASE; CATALYTIC SUBUNIT; GROWTH ARREST; CYTOCHROME-C; EXPRESSION AB In advanced or recurrent malignant diseases, retinoic acid (RA) is not effective, even at doses that are toxic to the host, In late stages of breast cancer, patients do not respond to RA because the expression of RA receptor beta (RAR beta) is lost. In the present study, the intracellular mechanism(s) of synergistic effects of RA and a site-selective cyclic AMP (cAMP) analogue, 8-chloro-adenosine 3',5'-cyclic monophosphate (8-Cl-cAMP), on growth inhibition and apoptosis in breast cancer cells was examined, Our data demonstrated that hormone-dependent MCF-7 cells, but not hormone-independent MDA-MB-231 cells, are sensitive to RA-induced growth inhibition and apoptosis. Introduction of the RAR beta gene into MDA-MB-231 cells resulted in a gain of RA sensitivity. 8-Cl-cAMP acted synergistically with all-trans-RA in inducing and activating RAR beta gene expression that correlates with the reduction in mitochondrial membrane potential, redistribution of cytochrome c, activation of caspases, cleavage of poly (ADP-ribose) polymerase and DNA-dependent protein kinase (catalytic subunit), and induction of apoptosis, Mutations in the cAMP response element-related motif within the RAR beta promoter resulted in loss of synergy in RAR beta transcription. In addition, inhibition of RAR beta expression by an antisense construct also blocked the antitumor effects of RA + 8-Cl-cAMP, Thus, RAR beta can mediate RA and/or cAMP action in breast cancer cells by promoting apoptosis, Therefore, loss of RAR beta expression may contribute to the tumorigenicity of human mammary epithelial cells, These findings suggest that RA and 8-Cl-cAMP act in a synergistic fashion and may have potential for combination biotherapy for the treatment of malignant diseases. C1 NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. NCI, Cellular Biochem Sect, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. RP Srivastava, RK (reprint author), NIA, Immunol Lab, NIH, Box 28,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 59 TC 11 Z9 12 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL PY 1999 VL 5 IS 7 BP 1892 EP 1904 PG 13 WC Oncology SC Oncology GA 217TG UT WOS:000081514600041 PM 10430097 ER PT J AU Sacks, FM Appel, LJ Moore, TJ Obarzanek, E Vollmer, WM Svetkey, LP Bray, GA Vogt, TM Cutler, JA Windhauser, MM Lin, PH Karanja, N AF Sacks, FM Appel, LJ Moore, TJ Obarzanek, E Vollmer, WM Svetkey, LP Bray, GA Vogt, TM Cutler, JA Windhauser, MM Lin, PH Karanja, N TI A dietary approach to prevent hypertension: A review of the Dietary Approaches to Stop Hypertension (DASH) study SO CLINICAL CARDIOLOGY LA English DT Article DE hypertension; nutrition; blood pressure; Dietary Approaches to Stop Hypertension ID BLOOD-PRESSURE; NUTRITIONAL FACTORS; POTASSIUM; TRIAL; WOMEN AB Background Populations eating mainly vegetarian diets have lower blood pressure levels than those eating omnivorous diets. Epidemiologic findings suggest that eating fruits and vegetables lowers blood pressure. Hypothesis: Two hypotheses were tested: (1) that high intake of fruits and vegetables lowers blood pressure, and (2) that an overall dietary pattern (known as the DASH diet, or DASH combination diet) that is high in fruits, vegetables, nuts, and low-fat dairy products, emphasizes fish and chicken rather than red meat, and is low in saturated fat, cholesterol, sugar, and refined carbohydrate lowers blood pressure. Methods: Participants were 459 adults with untreated systolic blood pressure < 160 mmHg and diastolic blood pressure 80-95 mmHg. After a 3-week run-in on a control diet typical of Americans, they were randomized to 8 weeks receiving either the control diet, or a diet rich in fruits and vegetables, or the DASH diet. The participants were given all of their foods to eat, and body weight and sodium intake were held constant. Blood pressure was measured at the clinic and by 24-h ambulatory monitoring. Results: The DASH diet lowered systolic blood pressure significantly in the total group by 5.5/3.0 mmHg, in African Americans by 6.9/3.7 mmHg, in Caucasians by 3.3/2.4 mmHg, in hypertensives by 11.6/5.3 mmHg, and in nonhypertensives by 3.5/2.2 mmHg. The fruits and vegetables diet also reduced blood pressure in the same subgroups, but to a lesser extent. The DASH diet lowered blood pressure similarly throughout the day and night. Conclusions: The DASH diet may offer an alternative to drug therapy in hypertensives and, as a population approach, may prevent hypertension, particularly in African Americans. C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Johns Hopkins Univ, Baltimore, MD USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. Duke Univ, Med Ctr, Durham, NC USA. Kaiser Permanente, Ctr Hlth Res, Portland, OR USA. NHLBI, Bethesda, MD 20892 USA. RP Sacks, FM (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. NR 11 TC 59 Z9 68 U1 1 U2 8 PU CLINICAL CARDIOLOGY PUBL CO PI MAHWAH PA PO BOX 832, MAHWAH, NJ 07430-0832 USA SN 0160-9289 J9 CLIN CARDIOL JI Clin. Cardiol. PD JUL PY 1999 VL 22 IS 7 SU 3 BP 6 EP 10 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 214BH UT WOS:000081307400002 ER PT J AU Remaley, AT Sampson, ML DeLeo, JM Remaley, NA Farsi, BD Zweig, MH AF Remaley, AT Sampson, ML DeLeo, JM Remaley, NA Farsi, BD Zweig, MH TI Prevalence-value-accuracy plots: A new method for comparing diagnostic tests based on misclassification costs SO CLINICAL CHEMISTRY LA English DT Article ID ROC CURVE AB The clinical accuracy of diagnostic tests commonly is assessed by ROC analysis. ROC plots, however, do not directly incorporate the effect of prevalence or the value of the possible test outcomes on test performance, which are two important factors in the practical utility of a diagnostic test. We describe a new graphical method, referred to as a prevalence-value-accuracy (PVA) plot analysis, which includes, in addition to accuracy, the effect of prevalence and the cost of misclassifications (false positives and false negatives) in the comparison of diagnostic test performance. PVA plots are contour plots that display the minimum cost attributable to misclassifications (z-axis) at various optimum decision thresholds over a range of possible values for prevalence (x-axis) and the unit cost ratio (UCR; y-axis), which is an index of the cost of a false-positive vs a false-negative test result. Another index based on the cost of misclassifications can be derived from PVA plots for the quantitative comparison of test performance. Depending on the region of the PVA plot that is used to calculate the misclassification cost index, it can potentially lead to a different interpretation than the ROC area index on the relative value of different tests. A PVA-threshold plot, which is a variation of a PVA plot, is also described for readily identifying the optimum decision threshold at any given prevalence and UCR. In summary, the advantages of PVA plot analysis are the following: (a) it directly incorporates the effect of prevalence and misclassification costs in the analysis of test performance; (b) it yields a quantitative index based on the costs of misclassifications for comparing diagnostic tests; (c) it provides a way to restrict the comparison of diagnostic test performance to a clinically relevant range of prevalence and UCR; and (d) it can be used to directly identify an optimum decision threshold based on prevalence and misclassification costs. (C) 1999 American Association for Clinical Chemistry. C1 NIH, Ctr Clin, Dept Clin Pathol, Bethesda, MD 20892 USA. Ctr Informat Technol, Bethesda, MD 20892 USA. NEI, Bethesda, MD 20892 USA. NHLBI, Bethesda, MD 20892 USA. RP Remaley, AT (reprint author), NIH, Ctr Clin, Dept Clin Pathol, Bldg 10 2C-433, Bethesda, MD 20892 USA. NR 10 TC 21 Z9 21 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUL PY 1999 VL 45 IS 7 BP 934 EP 941 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 213RB UT WOS:000081286100003 PM 10388467 ER PT J AU Seman, LJ DeLuca, C Jenner, JL Cupples, LA McNamara, JR Wilson, PWF Castelli, WP Ordovas, JM Schaefer, EJ AF Seman, LJ DeLuca, C Jenner, JL Cupples, LA McNamara, JR Wilson, PWF Castelli, WP Ordovas, JM Schaefer, EJ TI Lipoprotein(a)-cholesterol and coronary heart disease in the Framingham Heart Study SO CLINICAL CHEMISTRY LA English DT Article ID LP(A) LIPOPROTEIN; MYOCARDIAL-INFARCTION; PLASMA LIPOPROTEIN(A); REPLACEMENT THERAPY; APOLIPOPROTEIN-B; ARTERY DISEASE; RISK FACTOR; MEN; CHOLESTEROL; QUANTIFICATION AB Background: Increased plasma lipoprotein(a) [Lp(a)] concentrations have been reported to be an independent risk factor for coronary heart disease (CHD) in some prospective studies, but not in others. These inconsistencies may relate to a lack of standardization and the failure of some immunoassays to measure all apolipoprotein(a) isoforms equally. Methods: We measured plasma Lp(a)-cholesterol [Lp(a)C] in a Caucasian population of offspring and spouses of the Framingham Heart Study participants, using a lectin-based assay (Lipopro(TM)). We compared the prevalence of increased Lp(a)-C to the presence of sinking pre-beta-lipoprotein (SPB). We also related Lp(a)-C concentrations to the prevalence of CHD risk in the entire population. Results: The mean (+/- SD) Lp(a)-C concentration in the Framingham population (n = 3121) was 0.186 +/- 0.160 mmol/L, with no significant gender or age differences. The mean Lp(a)-C concentrations in the absence or presence of SPB were 0.158 +/- 0.132 mmol/L and 0.453 +/- 0.220 mmol/L, respectively (P <0.0001). The mean Lp(a)C concentration in men with CHD (n = 156) was 0.241 +/- 0.204 mmol/L, which was significantly (P <0.001) higher, by 34%, than in controls. The odds ratio for CHD risk in men with Lp(a)-C greater than or equal to 0.259 mmol/L (greater than or equal to 10 mg/dL), after adjusting for age, HDL-cholesterol, LDL-cholesterol, smoking, diabetes, blood pressure, and body mass index, was 2.293 (confidence interval, 1.55-3.94; P <0.0005). Lp(a)-C values correlated highly with a Lp(a)mass immunoassay [Apotek(TM) Lp(a); r = 0.832; P <0.0001; n = 1000]. Conclusions: An increased Lp(a)-C value greater than or equal to 0.259 mmol/L (greater than or equal to 10 mg/dL) is an independent CHD risk factor in men with a relative risk of more than 2, but was inconclusive in women. Lp(a)-C measurements offer an alternative to Lp(a)-mass immunoassays and can be performed on automated analyzers. (C) 1999 American Association for Clinical Chemistry. C1 New England Med Ctr, Div Endocrinol Diabet Metab & Mol Med, Boston, MA 02111 USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. Tufts Univ, Human Nutr Res Ctr Aging, Jean Mayer USDA, Lipid Metab Lab, Boston, MA 02111 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA 02118 USA. NHLBI, Framingham Heart Study, NIH, Framingham, MA 01702 USA. RP Seman, LJ (reprint author), New England Med Ctr, Div Endocrinol Diabet Metab & Mol Med, Box 216,750 Washington St, Boston, MA 02111 USA. OI Ordovas, Jose/0000-0002-7581-5680 FU NCRR NIH HHS [M01-RR00054]; NIA NIH HHS [T32AG00209] NR 42 TC 73 Z9 80 U1 0 U2 3 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 JUL PY 1999 VL 45 IS 7 BP 1039 EP 1046 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 213RB UT WOS:000081286100016 PM 10388480 ER PT J AU Slavotinek, A Clayton-Smith, J AF Slavotinek, A Clayton-Smith, J TI Brachydactyly type B: case report and further evidence for clinical heterogeneity SO CLINICAL DYSMORPHOLOGY LA English DT Article DE brachydactyly type B; apical dystrophy; Sorsby syndrome ID ADAMS-OLIVER SYNDROME; ONYCHODYSPLASIA-DYSPHALANGISM SYNDROME; DISTAL LIMB HYPOPLASIA; MENTAL-RETARDATION; DIGITAL ANOMALIES; NAIL DYSPLASIA; SHORT STATURE; DEFECTS; SCALP; FEATURES AB We present a male child with digital and radiographic findings consistent with brachydactyly type B. His left hand had 2-4 syndactyly, shortened first and fifth digits and single palmar and fifth finger flexion creases. The nail on the second finger was hypoplastic. The right hand had a small thumb and curving of the second finger towards the midline. The left foot had a short left hallux with an absent nail, 2-4 syndactyly and an absent toe. His right foot had a short, dorsiflexed hallux with a hypoplastic nail, 2-3 syndactyly and an overlapping toe. Radiographs showed asymmetrical hypoplasia of the middle and terminal phalanges and there were no extra-articular findings to suggest Sorsby syndrome. Brachydactyly type B has classically been described as hypoplasia or absence of the terminal phalanges with absent nails. Although other digital anomalies have previously been described with brachydactyly type B, the absent digit, atypical syndactyly and marked asymmetry in this child make this case a good illustration of the clinical heterogeneity that can be associated with this type of brachdactyly. We provide a brief review of syndromes in which similar digital malformations have been reported. Clin Dysmorphol 8: 165-171 (C) 1999 Lippincott Williams & Wilkins. C1 St Marys Hosp, Dept Med Genet, Manchester M13 0JH, Lancs, England. St Marys Hosp, Reg Genet Serv, Manchester M13 0JH, Lancs, England. RP Slavotinek, A (reprint author), Natl Human Genome Res Inst, NIH, Bldg 49, Bethesda, MD 20814 USA. NR 36 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0962-8827 J9 CLIN DYSMORPHOL JI Clin. Dysmorphol. PD JUL PY 1999 VL 8 IS 3 BP 165 EP 171 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 267EE UT WOS:000084343300002 PM 10457848 ER PT J AU Slavotinek, A Clayton-Smith, J Kerr, B AF Slavotinek, A Clayton-Smith, J Kerr, B TI Unilateral tibial aplasia, pre-axial polysyndactyly, vertebral anomalies and imperforate anus SO CLINICAL DYSMORPHOLOGY LA English DT Letter DE tibial aplasia; preaxial polysyndactyly ID MESODERMAL DYSPLASIA SPECTRUM; UNUSUAL FACIES SYNDROME; VARIABILITY; HEMIMELIA; VACTERL AB Tibial hemimelia is a rare malformation that can be isolated or found with other skeletal abnormalities. We describe a fetus with unilateral tibial aplasia, ipsilateral pre-axial polysyndactyly and femoral hypoplasia, ventriculomegaly, anal atresia and rib and vertebral anomalies. We believe that this combination of malformations has not previously been described. Clin Dysmorphol 8: 223-225 (C) 1999 Lippincott Williams & Wilkins. C1 Univ Manchester, St Marys Hosp, Dept Med Genet, Reg Genet Serv, Manchester M13 0JH, Lancs, England. RP Slavotinek, A (reprint author), Natl Human Genome Res Inst, NIH, Bldg 49, Bethesda, MD 20814 USA. NR 17 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0962-8827 J9 CLIN DYSMORPHOL JI Clin. Dysmorphol. PD JUL PY 1999 VL 8 IS 3 BP 223 EP 225 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 267EE UT WOS:000084343300014 PM 10457860 ER PT J AU Weng, NP AF Weng, NP TI Telomeres, telomerase, and lymphocyte replicative life span SO CLINICAL IMMUNOLOGY LA English DT Editorial Material ID T-CELL TURNOVER; HIV-INFECTION; LENGTH; CD4(+) C1 NIA, Immunol Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Weng, NP (reprint author), NIA, Immunol Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. NR 12 TC 2 Z9 3 U1 0 U2 0 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 JUL PY 1999 VL 92 IS 1 BP 1 EP 2 DI 10.1006/clim.1999.4741 PG 2 WC Immunology SC Immunology GA 216PY UT WOS:000081452100001 PM 10413646 ER PT J AU Cohn, DL Fisher, EJ Peng, GT Hodges, JS Chesnut, J Child, CC Franchino, B Gibert, CL El-Sadr, W Hafner, R Korvick, J Ropka, M Heifets, L Clotfelter, J Munroe, D Horsburgh, CR AF Cohn, DL Fisher, EJ Peng, GT Hodges, JS Chesnut, J Child, CC Franchino, B Gibert, CL El-Sadr, W Hafner, R Korvick, J Ropka, M Heifets, L Clotfelter, J Munroe, D Horsburgh, CR CA Terry Beirn Community Program Clin R TI A prospective randomized trial of four three-drug regimens in the treatment of disseminated Mycobacterium avium complex disease in AIDS patients: Excess mortality associated with high-dose clarithromycin SO CLINICAL INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 4th Conference on Retroviruses and Opportunistic Infections CY JAN 22-31, 1997 CL WASHINGTON, D.C. ID HUMAN-IMMUNODEFICIENCY-VIRUS; IMMUNE-DEFICIENCY-SYNDROME; COMBINATION THERAPY; INFECTED PATIENTS; IN-VITRO; BACTEREMIA; ETHAMBUTOL; RIFABUTIN; CLOFAZIMINE; SURVIVAL AB The optimal regimen for treatment of Mycobacterium avium complex (MAC) disease has not been established. Eighty-five AIDS patients with disseminated MAC disease were randomized to receive a three-drug regimen of clarithromycin, rifabutin or clofazimine, and ethambutol. Two dosages of clarithromycin, 500 or 1,000 mg twice daily (b.i.d.), were compared. The Data and Safety Monitoring Board recommended discontinuation of the clarithromycin dosage comparison and continuation of the rifabutin vs. clofazimine comparison. After a mean follow-up of 4.5 months, 10 (22%) of 45 patients receiving clarithromycin at 500 mg b.i.d. had died (70 deaths per 100 person-years) compared with 17 (43%) of 30 patients receiving clarithromycin at 1,000 mg b.i.d. (158 deaths per 100 person-years) (relative risk, 2.43; 95% confidence interval, 1.11-5.34; P = .02). After 10.4 months, 20 (49%) of 41 patients receiving rifabutin had died (81 deaths per 100 person-years) compared with 23 (52%) of 44 patients receiving clofazimine (94 deaths per 100 person-years) (relative risk, 1.20; 95% confidence interval, 0.65-2.19; P = .56). Bacteriologic outcomes were similar among treatment groups. In treating MAC disease in AIDS patients, the maximum dose of clarithromycin should be 500 mg b.i.d. C1 Denver Community Program Clin Res AIDS, Denver, CO USA. Richmond AIDS Consortium, Richmond, VA USA. Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. Social & Sci Syst, Rockville, MD USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Washington Reg AIDS Program, Washington, DC USA. Columbia Univ Coll Phys & Surg, Harlem Hosp Ctr, New York, NY 10032 USA. NIAID, Bethesda, MD 20892 USA. Natl Inst Nursing Res, NIH, Bethesda, MD USA. Natl Jewish Med & Res Ctr, Denver, CO USA. Louisiana Community AIDS Res Program, New Orleans, LA USA. Emory Univ, Sch Med, Atlanta, GA USA. RP Cohn, DL (reprint author), Denver Publ Hlth, 605 Bannock St, Denver, CO 80204 USA. FU NIAID NIH HHS [AI-45228, AI-45234, AI-55258] NR 45 TC 39 Z9 40 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 JUL PY 1999 VL 29 IS 1 BP 125 EP 133 DI 10.1086/520141 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 220UF UT WOS:000081685300022 PM 10433575 ER PT J AU Winterer, G Ziller, M Dorn, H Frick, K Mulert, C Dahhan, N Herrmann, WM Coppola, R AF Winterer, G Ziller, M Dorn, H Frick, K Mulert, C Dahhan, N Herrmann, WM Coppola, R TI Cortical activation, signal-to-noise ratio and stochastic resonance during information processing in man SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE EEG; event-related potentials; N100; information processing; reaction time; cortical activation; signal-to-noise ratio; stochastic resonance ID EVOKED-POTENTIALS; EEG; VARIABILITY; RESPONSES; INTENSITY; BRAIN AB Objectives: The goal of this study was to determine the relation between EEG, event-related potentials and information processing as measured by an acoustical choice reaction time task. In particular, we wanted to find out to what extent reaction-time performance is related to the pre-stimulus EEG activity (frequency domain) and the magnitude of signal power as well as noise power (stimulus-uncorrelated activity) after the tones (time domain). Materials and methods: For parametrization, EEG-activity was factorized across pre-defined frequency bands and 19 electrode positions, applying spectral power and coherence analysis. Signal power was estimated by calculating the mean power of the evoked single sweeps. Noise power was computed by subtracting the latter minus the power of the average evoked potential. We investigated 254 healthy subjects who had to perform an acoustical choice reaction task during running EEG. Results: In the frequency domain, it was found that high frontally pronounced delta-power in the pre-stimulus EEG correlates with fast reaction-time performance, which was regarded as the expression of a readiness potential in the frequency domain, reflecting increased cortical activation. In the time domain, fast reaction times were found to be correlated with the amplitude of the event-related potential N100 as well as with the signal power and signal-to-noise ratio of the evoked activity. This result pointed to the frequently described relation between evoked signals and information processing. In accordance with the theory of stochastic resonance, we also found a positive correlation between the magnitude of noise power after the stimulus and reaction-time performance. Besides, noise power was found to be positively correlated with pre-stimulus cortical activation (mainly in the delta and alphal frequency band), whereas no relation was found between pre-stimulus EEG and the signal power of the event-related activity, except for a weak relation to the alpha2 power. Conclusion: Our findings support the notion that information processing is not only dependent on signal strength but also on a certain amount of basic noise, reflecting the overall energy state of the brain. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 Free Univ Berlin, Dept Psychiat, Lab Clin Psychophysiol, D-14050 Berlin, Germany. NIMH, NIH, Bethesda, MD 20892 USA. RP Winterer, G (reprint author), Free Univ Berlin, Dept Psychiat, Lab Clin Psychophysiol, Eschenallee 3, D-14050 Berlin, Germany. RI Mulert, Christoph/F-2576-2012 NR 50 TC 59 Z9 60 U1 1 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD JUL PY 1999 VL 110 IS 7 BP 1193 EP 1203 DI 10.1016/S1388-2457(99)00059-0 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 212LX UT WOS:000081219100004 PM 10423185 ER PT J AU Conwit, RA Stashuk, D Tracy, B McHugh, M Brown, WF Metter, EJ AF Conwit, RA Stashuk, D Tracy, B McHugh, M Brown, WF Metter, EJ TI The relationship of motor unit size, firing rate and force SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE firing rate; force generation; motor unit activation; EMG signal decomposition ID ISOMETRIC CONTRACTIONS AB Objective: Using a clinical electromyographic (EMG) protocol, motor units were sampled from the quadriceps femoris during isometric contractions at fixed force levels to examine how average motor unit size and firing rate relate to force generation. Methods: Mean firing rates (mFRs) and sizes (mean surface-detected motor unit action potential (mS-MUAP) area) of samples of active motor units were assessed at various force levels in 79 subjects. Results: MS-MUAP size increased linearly with increased force generation, while mFR remained relatively constant up to 30% of a maximal force and increased appreciably only at higher force levels. A relationship was found between muscle force and mS-MUAP area (r(2) = 0.67), mFR (r(2) = 0.38), and the product of mS-MUAP area and mFR (mS-MUAP mFR) (r(2) = 0.70), Conclusions: The results support the hypothesis that motor units are recruited in an orderly manner during forceful contractions, and that in large muscles only at higher levels of contraction ( > 30% MVC) do mFRs increase appreciably. MS-MUAP and mFR can be assessed using clinical EMG techniques and they may provide a physiological basis for analyzing the role of motor units during muscle force generation. (C) 1999 Elsevier Science ireland Ltd. All rights reserved. C1 Johns Hopkins Bayview Med Ctr, Dept Neurol, Baltimore, MD 21224 USA. Univ Waterloo, Dept Syst Design Engn, Waterloo, ON N2L 3G1, Canada. Univ Colorado, Dept Kinesiol, Boulder, CO 80309 USA. New England Med Ctr, Neuromuscular Div, Boston, MA 02111 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Conwit, RA (reprint author), Johns Hopkins Bayview Med Ctr, Dept Neurol, 4940 Eastern Ave, Baltimore, MD 21224 USA. NR 18 TC 44 Z9 44 U1 0 U2 7 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD JUL PY 1999 VL 110 IS 7 BP 1270 EP 1275 DI 10.1016/S1388-2457(99)00054-1 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 212LX UT WOS:000081219100011 PM 10423192 ER PT J AU Sulzbacher, S Farwell, JR Temkin, N Lu, AS Hirtz, DG AF Sulzbacher, S Farwell, JR Temkin, N Lu, AS Hirtz, DG TI Late cognitive effects of early treatment with phenobarbital SO CLINICAL PEDIATRICS LA English DT Article ID SPINAL-CORD NEURONS; CONTROLLED TRIAL; DOUBLE-BLIND; INTRAVENTRICULAR HEMORRHAGE; ANTIEPILEPTIC DRUGS; NEONATAL SEIZURES; FEBRILE SEIZURES; ANTICONVULSANT; DIAZEPAM; CHILDREN AB We previously reported that IQ was significantly lowered in a group of toddler-aged children randomly assigned to receive phenobarbital or placebo for febrile seizures and there was no difference in the febrile seizure recurrence rate. We retested these children 3-5 years later, after they had entered school, to determine whether those effects persisted over the longer term and whether later school performance might be affected. On follow-up testing of 139 (of the original n=217) Western Washington children who had experienced febrile seizures, we found that the phenobarbital group scored significantly lower than the placebo group on the Wide Range Achievement Test (WRAT-R) reading achievement standard score (87.6 vs 95.6; p=0.007). There was a nonsignificant mean difference of 3.71 IQ points on the Stanford-Binet, with the phenobarbital-treated group scoring lower (102.2 vs 105.7; p=0.09). There were five children in our sample with afebrile seizures during the 5-year period after the end of the medication trial. Two had been assigned to phenobarbital, and three had been in the placebo group, We conclude there may be a long-term adverse cognitive effect of phenobarbital on the developmental skills (language/verbal) being acquired during the period of treatment and no beneficial effect on the rate of febrile seizure recurrences or later nonfebrile seizures. C1 Univ Washington, Sch Med, Dept Psychiat, Seattle, WA USA. Univ Washington, Sch Med, Dept Pediat, Seattle, WA USA. Univ Washington, Sch Med, Dept Neurol Surg, Seattle, WA USA. NINDS, Bethesda, MD 20892 USA. RP Sulzbacher, S (reprint author), Childrens Hosp & Reg Med Ctr, Psychiat Dept CH 13, POB C-5371, Seattle, WA 98105 USA. FU NINDS NIH HHS [N01-NS-2-2395, NS24641-02] NR 36 TC 84 Z9 90 U1 1 U2 4 PU WESTMINSTER PUBL INC PI GLEN HEAD PA 708 GLEN COVE AVE, GLEN HEAD, NY 11545 USA SN 0009-9228 J9 CLIN PEDIATR JI Clin. Pediatr. PD JUL PY 1999 VL 38 IS 7 BP 387 EP 394 DI 10.1177/000992289903800702 PG 8 WC Pediatrics SC Pediatrics GA 215VA UT WOS:000081403100002 PM 10416094 ER PT J AU Berti, R Jacobson, S AF Berti, R Jacobson, S TI Role of viral infection in the aetiology of multiple sclerosis - Status of current knowledge and therapeutic implications SO CNS DRUGS LA English DT Article ID POLYMERASE CHAIN-REACTION; LEPTOMENINGEAL CELL-LINE; CANINE-DISTEMPER VIRUS; HUMAN HERPESVIRUS-6; CAUSAL AGENT; DISEASE; ANTIBODIES; SYSTEM; IDENTIFICATION; RETROVIRUSES AB Multiple sclerosis (MS) is a chronic disease of the CNS that typically begins in late adolescence or early adulthood. It is highly variable in its expression and severity. The cause of MS is unknown, but both genetic and environmental factors have been implicated in its pathogenesis. It is known that viruses can induce chronic neurological disease, but the pathogenetic process in unclear. A viral cause for MS has been postulated, but to date no single virus has been confirmed to be associated with the disease. Although most viral candidates are no longer considered as possible aetiological agents in MS, a few are still being investigated. C1 NINDS, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, NIH, Bldg 10,Room 5-B16,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 62 TC 13 Z9 13 U1 0 U2 0 PU ADIS INTERNATIONAL LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 10, NEW ZEALAND SN 1172-7047 J9 CNS DRUGS JI CNS Drugs PD JUL PY 1999 VL 12 IS 1 BP 1 EP 7 DI 10.2165/00023210-199912010-00001 PG 7 WC Clinical Neurology; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 216CU UT WOS:000081424100001 ER PT J AU Martin, LD Bratton, SL O'Rourke, PP AF Martin, LD Bratton, SL O'Rourke, PP TI Clinical uses and controversies of neuromuscular blocking agents in infants and children SO CRITICAL CARE MEDICINE LA English DT Review DE neuromuscular blocking agents; neuromuscular depolarizing agents; neuromuscular nondepolarizing agents; neuromuscular junction; newborn; infant; child; review ID INTENSIVE-CARE UNIT; RESPIRATORY-DISTRESS SYNDROME; HYALINE-MEMBRANE DISEASE; BLOOD-FLOW VELOCITY; EXTRAJUNCTIONAL ACETYLCHOLINE RECEPTORS; PLASMA LAUDANOSINE CONCENTRATIONS; OPIOID BARBITURATE ANESTHESIA; NITROUS-OXIDE HALOTHANE; CRITICALLY ILL PATIENTS; MECHANICAL VENTILATION AB Objective: To review the pharmacology of neuromuscular blocking drugs (NMBDs), their use in critically ill or injured infants and children, and the relevance of developmental changes in neuromuscular transmission. Data Sources: Computerized search of the medical literature. Study Selection: Studies specifically examining the following were reviewed: a) the developmental changes in neuromuscular transmission; b) the pharmacokinetics and pharmacodynamics of all clinically available NMBDs in neonates, infants, children, and adults; and c) clinical experience with NMBDs in the critical care setting. Particular attention was directed toward studies in the pediatric population. Data Synthesis: Neuromuscular transmission undergoes maturational changes during the first 2 months of life. Alterations in body composition and organ function affect the pharmacokinetics and pharmacodynamics of the NMBDs throughout active growth and development Numerous NMBDs have been developed during the last two decades with unique pharmacologic profiles and potential clinical advantages. The NMBDs are routinely used in critically ill or injured patients of all ages. This widespread use is associated with rare but significant: clinical complications, such as prolonged weakness, Conclusions: Significant gaps in our knowledge of the pharmacokinetics and pharmacodynamics of NMBDs in infants and children continue to exist. Alterations in electrolyte balance and organ-specific drug metabolism may contribute to complications with the use of NMBDs in the critical care arena. C1 Univ Washington, Sch Med, Dept Anesthesiol, Seattle, WA 98195 USA. Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. NIH, Off Sci Policy, Bethesda, MD 20892 USA. RP Martin, LD (reprint author), Childrens Hosp, Dept Anesthesia & Crit Care, CH-05,4800 Sand Point Way NE, Seattle, WA 98105 USA. NR 128 TC 18 Z9 18 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JUL PY 1999 VL 27 IS 7 BP 1358 EP 1368 DI 10.1097/00003246-199907000-00030 PG 11 WC Critical Care Medicine SC General & Internal Medicine GA 224NZ UT WOS:000081906300020 PM 10446832 ER PT J AU Ryba, NJP AF Ryba, NJP TI Pheromone reception: A complex map of activation in the brain SO CURRENT BIOLOGY LA English DT Article ID MULTIGENE FAMILY; MAMMALS AB Recent studies of the projection pattern made by sensory neurons involved in mammalian pheromone reception have shown that there is a map of activation in the brain, but this pheromone map appears far more complex than the equivalent map in the main olfactory system responsible for the sense of smell. C1 Natl Inst Dent & Craniofacial Res, Taste & Smell Unit, NIH, Bethesda, MD 20892 USA. RP Ryba, NJP (reprint author), Natl Inst Dent & Craniofacial Res, Taste & Smell Unit, NIH, Bethesda, MD 20892 USA. NR 10 TC 1 Z9 1 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 JUL 1 PY 1999 VL 9 IS 13 BP R472 EP R474 DI 10.1016/S0960-9822(99)80298-X PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 212UD UT WOS:000081234500007 PM 10395534 ER PT J AU St Georgiev, V AF St Georgiev, V TI Parasitic infections. Treatment and developmental therapeutics. 1. Necatoriasis SO CURRENT PHARMACEUTICAL DESIGN LA English DT Review ID CUTANEOUS LARVA-MIGRANS; MEMBRANE GLYCOPROTEIN-IIB; SOIL-TRANSMITTED NEMATODES; ANCYLOSTOMA-CEYLANICUM; AMERICANUS INFECTION; TRICHURIS-TRICHIURA; IRON-DEFICIENCY; HUMAN HOOKWORM; INTESTINAL HELMINTHIASIS; PLATELET ACTIVATION AB Necator americanus is a nematode hookworm of the family Ancylostomatidae, subfamily Necatorinae. This nematode parasite, which is distinguished by two chitinous cutting plates in the buccal cavity and fused male copulatory spicules, is the causative agent of necatoriasis, a hookworm disease prevalent in the Americas as well as in the tropical regions of Africa, southern Asia. and Polynesia. The adult parasites attached to the villi of the small intestines will suck blood causing abdominal discomfort, diarrhea and cramps, anorexia, weight loss, and in advanced disease, hypochromic microcytic anemia. Hookworm infections in man, especially in children, are one of the leading causes of iron-deficiency anemia resulting directly from intestinal capillary blood loss following the feeding activities of fourth-stage (L-4) larva and adult worms. Another clinical manifestation often associated with hookworm infections is cutaneous larva migrans (CLM). It is a well recognized, usually self-limiting condition caused by the infectious larvae of nematodes. CLM is characterized by skin eruption and represents a clinical description rather than a definitive diagnosis. Of the hookworm parasites, the dog and cat worm Ancylostoma braziliense is the most common causing CLM, although many other species have been implicated. The major subject of this review article will be discussion of the evolution of therapies and treatment of human necatoriasis and the development of experimental infections with N. americanus. Difference in the clinical efficacies of mebendazole and albendazole will be discussed along with drug resistance of N. americanus. C1 NIAID, NIH, Bethesda, MD 20892 USA. RP St Georgiev, V (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 140 TC 0 Z9 0 U1 0 U2 2 PU BENTHAM SCIENCE PUBL BV PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1381-6128 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD JUL PY 1999 VL 5 IS 7 BP 545 EP 554 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 231KC UT WOS:000082306400005 ER PT J AU Erlichman, B Howard, OMZ AF Erlichman, B Howard, OMZ TI CD27 signals through PKC in human B cell lymphomas SO CYTOKINE LA English DT Article DE CD27; PKC; B cell; lymphoma; signal transduction ID TUMOR-NECROSIS-FACTOR; FACTOR-RECEPTOR FAMILY; CD27/CD70 INTERACTION; T-CELLS; MONOCLONAL-ANTIBODIES; GROWTH-INHIBITION; PROTEIN-KINASE; ANTIGEN CD27; ACTIVATION; LIGAND AB Tumour necrosis factor receptor (TNFR) superfamily members play critical roles in the regulation of cell proliferation and death. One member of the TNFR superfamily, CD27, is unique because it is the only covalently linked homodimer in the family. CD27 and its cellular ligand, CD70, have been implicated in the regulation of T cell and B cell interactions that lead to cellular activation and regulation of immunoglobulin expression. Due to the unique nature of CD27, me chose to screen a number of B cell lymphoma cell lines for CD27 and CD70 expression and evaluate CD27 activation by antibody cross-linking Two cell lines, HT and SU-4, showed greater cellular proliferation when CD27 was cross-lined and this correlated with increased PKC activation. Additionally, in the HT cell line cell surface expression of IgG was increased by CD27 cross-linking. Thus we have identified cellular systems for the study of CD27 signal transduction that will allow definition of the CD27 signal cascade of some B cell lymphomas, (C) 1999 Academic Press. C1 NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21701 USA. NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Div Basic Sci, Frederick, MD 21701 USA. RP Howard, OMZ (reprint author), NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21701 USA. RI Howard, O M Zack/B-6117-2012 OI Howard, O M Zack/0000-0002-0505-7052 NR 41 TC 2 Z9 2 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 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 1999 VL 11 IS 7 BP 476 EP 484 DI 10.1006/cyto.1998.0449 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 215EB UT WOS:000081368000003 PM 10419648 ER PT J AU Becker, KG AF Becker, KG TI Comparative genetics of type 1 diabetes and autoimmune disease - Common loci, common pathways? SO DIABETES LA English DT Article ID SYSTEMIC LUPUS-ERYTHEMATOSUS; GENOME-WIDE SEARCH; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; CHEDIAK-HIGASHI-SYNDROME; MULTIPLE-SCLEROSIS; RHEUMATOID-ARTHRITIS; SUSCEPTIBILITY LOCI; THYROID-DISEASE; INSULIN; GENES AB Genome-scale analysis in type 1 diabetes has resulted in a number of non-major histocompatibility complex loci of varying levels of statistical significance. In no case has a specific gene been proven to be the source of genetic linkage at any candidate locus. Comparative analysis of the position of loci for type 1 diabetes with candidate loci from other autoimmune/inflammatory diseases shows considerable overlap. This supports a hypothesis that the underlying genetic susceptibility to type 1 diabetes may be shared with other clinically distinct autoimmune diseases such as systemic lupus erythemastosus, multiple sclerosis, and Crohn's Disease. C1 NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Becker, KG (reprint author), NIA, Gerontol Res Ctr, NIH, Room 4-101,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Becker, Kevin/0000-0002-6794-6656 NR 68 TC 103 Z9 104 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUL PY 1999 VL 48 IS 7 BP 1353 EP 1358 DI 10.2337/diabetes.48.7.1353 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 208YD UT WOS:000081019300001 PM 10389838 ER PT J AU Folsom, AR Rasmussen, ML Chambless, LE Howard, G Cooper, LS Schmidt, MI Heiss, G AF Folsom, AR Rasmussen, ML Chambless, LE Howard, G Cooper, LS Schmidt, MI Heiss, G CA ARIC Study Investigators TI Prospective associations of fasting insulin, body fat distribution, and diabetes with risk of ischemic stroke SO DIABETES CARE LA English DT Article ID IMPROVED LIPOLYTIC EFFICIENCY; CARDIOVASCULAR-DISEASE; ENZYMATIC DETERMINATION; ATHEROSCLEROSIS RISK; ADIPOSE-TISSUE; MEN BORN; FOLLOW; HYPERTENSION; PARTICIPANTS; COMMUNITIES AB OBJECTIVE - We tested the hypothesis that diabetes, body fat distribution, and (in nondiabetic subjects) fasting insulin levels are positively associated with ischemic stroke incidence in the general population RESEARCH DESIGN AND METHODS - As part of the Atherosclerosis Risk in Communities (ARIC) Study we measured diabetes by using fasting glucose criteria, waist and hip circumferences, and fasting insulin levels with a radioimmunoassay in >12,000 adults aged 45-64 years who had no cardiovascular disease at baseline. We followed them for 6-8 years for ischemic stroke occurrence (n = 191). RESULTS - After adjustment for age, sex, race, ARIC community, smoking, and education level, the relative risk of ischemic stroke was 3.70 (95% CI 2.7-5.1) for diabetes, 1.74 (1.4-2.2) for a 0.11 increment of waist-to-hip ratio, and 1.19 (1.1-1.3) for a 50-pmol/l increment of fasting insulin among nondiabetic subjects. Ischemic stroke incidence was nor statistically significantly associated with BMI (comparably adjusted relative risk = 1.15, 95% CI 0.97-1.36). With adjustment for other stroke risk factors (some of which may mediate the effects of diabetes, fat distribution, and hyperinsulinemia), the relative risks for diabetes, waist-to-hip ratio, and fasting insulin level were 2.22 (95% CI 1.5-3.2), 1.08 (0.8-1.4), and 1.14 (1.01-1.3), respectively CONCLUSION - Diabetes is a strong risk factor for ischemic stroke. Aspects of insulin resistance, as reflected by elevated waist-to-hip ratios and elevated fasting insulin levels, may also contribute to a greater risk of ischemic stroke. C1 Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55454 USA. Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth, Winston Salem, NC USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Fed Rio Grande Sul, Dept Social Med, Porto Alegre, RS, Brazil. RP Folsom, AR (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Suite 300,1300 S 2nd St, Minneapolis, MN 55454 USA. FU NHLBI NIH HHS [N01-HC-55015, N01-HC-55018, N01-HC-55016] NR 28 TC 206 Z9 209 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 JUL PY 1999 VL 22 IS 7 BP 1077 EP 1083 DI 10.2337/diacare.22.7.1077 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 208XZ UT WOS:000081018900012 PM 10388971 ER PT J AU Liang, FX Kachar, B Ding, MX Zhai, ZH Wu, XR Sun, TT AF Liang, FX Kachar, B Ding, MX Zhai, ZH Wu, XR Sun, TT TI Urothelial hinge as a highly specialized membrane: detergent-insolubility, urohingin association, and in vitro formation SO DIFFERENTIATION LA English DT Article DE bladder epithelium; urothelium; uroplakin; differentiation; quick-freeze deep-etch ID MAMMALIAN URINARY-BLADDER; ASYMMETRIC UNIT MEMBRANE; 3-DIMENSIONAL STRUCTURE; PLASMA-MEMBRANE; UROPLAKIN-I; DIFFERENTIATION; CELLS; EPITHELIUM; EXPRESSION; PROTEINS AB Urothelial surface is covered by numerous plaques (consisting of asymmetric unit membranes or AUM) that are interconnected by ordinary looking hinge membranes. We describe an improved method for purifying bovine urothelial plaques using 2% sarkosyl and 25 mM NaOH to remove contaminating membrane and peripheral proteins selectively. Highly purified plaques interconnected by intact hinge areas were obtained, indicating that the hinges are as detergent-insoluble as the plaques. These plaque/hinge preparations contained uroplakins, an as yet uncharacterized 18-kDa plaque-associated protein, plus an 85-kDa glycoprotein that is known to be hinge-associated in situ. Examination of the isolated, in vitro-resealed bovine AUM vesicles by quick freeze deep-etch showed that each AUM particle consists of a 16-nm, luminally exposed "head" anchored to the lipid bilayer via a 9-nm transmembranous "tail", and that an AUM plaque can break forming several smaller plaques separated by newly formed particle-free, hingelike areas. These data lend support to our recently proposed three-dimensional model of mouse urothelial plaques. In addition, our findings suggest that urothelial plaques are dynamic structures that can rearrange giving rise to new plaques with intervening hinges; that the entire urothelial apical surface (both plaque and hinge areas) is highly specialized; and that these two membrane domains may be equally important in fulfilling some of the urothelial functions. C1 NYU, Sch Med, Ronald Perelman Dept Dermatol, Epithelial Biol Unit, New York, NY 10016 USA. NIDODS, Sect Struct Cell Biol, NIH, Bethesda, MD 20892 USA. Beijing Univ, Coll Life Sci, Dept Cell Biol & Genet, Beijing 100871, Peoples R China. NYU, Sch Med, Dept Urol, New York, NY USA. NYU, Sch Med, Dept Microbiol, New York, NY 10010 USA. Vet Adm Med Ctr Manhattan, New York, NY 10010 USA. NYU, Sch Med, Kaplan Comprehens Canc Ctr, New York, NY USA. NYU, Sch Med, Dept Pharmacol, New York, NY USA. RP Sun, TT (reprint author), NYU, Sch Med, Ronald Perelman Dept Dermatol, Epithelial Biol Unit, 550 1st Ave, New York, NY 10016 USA. FU NIDDK NIH HHS [DK39753, DK47529, DK49469] NR 43 TC 26 Z9 26 U1 0 U2 2 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0301-4681 J9 DIFFERENTIATION JI Differentiation PD JUL PY 1999 VL 65 IS 1 BP 59 EP 69 DI 10.1046/j.1432-0436.1999.6510059.x PG 11 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 219UB UT WOS:000081624500005 PM 10448713 ER PT J AU Dorschner, MO Phillips, RB AF Dorschner, MO Phillips, RB TI Comparative analysis of two Nramp loci from rainbow trout SO DNA AND CELL BIOLOGY LA English DT Article ID NATURAL-RESISTANCE; MACROPHAGE PROTEIN-1; INTRACELLULAR PARASITES; GENE; SEQUENCE; CLONING; TRANSPORTER; EXPRESSION; CANDIDATE; INFECTION AB Innate resistance to intracellular parasites is controlled in part by Nramp1 (Natural resistance-associated macrophage protein 1) in mammals and birds. To isolate Nramp homologs from rainbow trout, a combination of library screening and rapid amplification of cDNA ends was performed. Two closely related Nramp loci, designated OmNramp alpha and OmNramp beta, were cloned and characterized. OmNramp alpha and OmNramp beta encode two highly conserved proteins of 585 and 558 amino acids, respectively. Deduced amino acid seqences showed that the OmNramp alpha and OmNramp beta proteins share 90% of their residues and contain all of the signature features of the Nramp family of proteins: 12 transmembrane domains, two N-linked glycosylation sites, and a conserved transport motif. Phylogenetic analysis supported a close relation to Nramp2 proteins, a related member of the Nramp family. Despite this relation, juvenile trout expressed OmNramp alpha in a manner consistent with an Nramp1 homolog and OmNramp beta similar to an Nramp2 locus. Both trout loci were expressed at relatively high amounts in the ovaries of juveniles, a finding not reported in the investigations of previously characterized mammalian and avian homologs. These results suggest a role for Nramp loci in the follicular development of teleost fishes, as well as in mammals. Because salmonid fishes are ancestral tetraploids, fragments of OmNramp alpha and OmNramp beta were isolated from smelt, a diploid relative, to determine whether the trout loci represent duplicates of a single gene. Homologous sequences for both loci were found in smelt, supporting the hypothesis that OmNramp alpha and OmNramp beta are indeed independent loci that were present before the chromosomal duplication of salmonids. The isolation of Nramp loci from rainbow trout may eventually produce a genetic tool for the control of disease in aquaculture operations. Determining the involvement of trout homologs in innate immunity may also provide insight regarding the evolution of host resistance to pathogens. C1 Univ Wisconsin, Dept Biol Sci, Milwaukee, WI 53204 USA. Univ Wisconsin, NIEHS, Marine & Freshwater Biomed Res Facil, Milwaukee, WI 53204 USA. RP Dorschner, MO (reprint author), Univ Washington, Div Med Genet, Box 357720,1959 NE Pacific St, Seattle, WA 98195 USA. NR 44 TC 42 Z9 46 U1 0 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1044-5498 J9 DNA CELL BIOL JI DNA Cell Biol. PD JUL PY 1999 VL 18 IS 7 BP 573 EP 583 DI 10.1089/104454999315123 PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity GA 220UY UT WOS:000081686900006 PM 10433556 ER PT J AU Harper, JL Daly, JW AF Harper, JL Daly, JW TI Inhibitors of store-operated calcium channels: Imidazoles, phenothiazines, and other tricyclics SO DRUG DEVELOPMENT RESEARCH LA English DT Article DE SOC channel; miconazole; trifluoperazine; clozapine ID CAPACITATIVE CA2+ ENTRY; CELLS; INFLUX; SK-AND-F-96365; MECHANISMS; ACTIVATION; PATHWAY AB Imidazoles, such as SKF 96365, clotrimazole, and miconazole, have represented the major class of inhibitors of store-operated calcium (SOC) channels. In HL60 cells, ATP and thapsigargin cause depletion of intracellular calcium stores, resulting in activation of SOC channels. Tricyclic phenothiazines and other tricyclics, such as amitriptyline and clozapine, were found to inhibit SOC channels of HL60 cells, with trifluoperazine being of comparable potency to the imidazoles. The effects of the imidazoles and tricyclics on intracellular calcium levels in HL60 cells were compared. In addition to inhibiting SOC channels, imidazoles, in particular, miconazole, caused a marked release of intracellular calcium, apparently from the same intracellular pool depleted by ATP and thapsigargin. The phenothiazines and the other two tricyclics caused little or no release of intracellular calcium compared to that caused by miconazole. However, these compounds did cause a significant decrease in the release of intracellular calcium elicited by subsequent addition of ATP or thapsigargin. Loperamide, which appears to selectively and positively modulate activated SOC channels, augments the elevation of intracellular calcium elicited by the imidazoles and, to a lesser extent, the tricyclics. The augmentation of calcium levels by loperamide indicated that these agents had, through release of intracellular calcium, caused activation of SOC channels. Published 1999 Wiley-Liss, Inc. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Harper, JL (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bldg 8,Rm 1A15, Bethesda, MD 20892 USA. RI Harper, Jacquie/A-8920-2014 NR 24 TC 11 Z9 11 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 0272-4391 J9 DRUG DEVELOP RES JI Drug Dev. Res. PD JUL PY 1999 VL 47 IS 3 BP 107 EP 117 DI 10.1002/(SICI)1098-2299(199907)47:3<107::AID-DDR1>3.0.CO;2-7 PG 11 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 228TM UT WOS:000082151800001 ER PT J AU Lanza, DL Code, E Crespi, CL Gonzalez, FJ Yost, GS AF Lanza, DL Code, E Crespi, CL Gonzalez, FJ Yost, GS TI Specific dehydrogenation of 3-methylindole and epoxidation of naphthalene by recombinant human CYP2F1 expressed in lymphoblastoid cells SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID PNEUMOTOXIN 3-METHYLINDOLE; SUBSTRATE-SPECIFICITY; REACTIVE INTERMEDIATE; METABOLISM; CYTOCHROME-P450; CDNA; CYTOTOXICITY; PROMUTAGENS; ENZYMES; CLONING AB 3-Methylindole (3MI) is a naturally occurring pulmonary toxin that requires metabolic activation, Previous studies have shown that 3MI-induced pneumotoxicity resulted from cytochrome P-450-catalyzed dehydrogenation of 3MI to an electrophilic methylene imine (3-methyleneindolenine), which covalently bound to cellular macromolecules. Multiple cytochrome P-450s are capable of metabolizing 3MI to several different metabolites, including oxygenated products. In the present study, the role of human CYP2F1 in the metabolism of 3MI was examined to determine whether it catalyzes dehydrogenation rather than hydroxylation or ring oxidation. Metabolism was examined using microsomal fractions from human lymphoblastoid cells that expressed the recombinant human CYP2F1 P-450 enzyme. Expression of CYP2F1 in the lymphoblastoid cells proved to be an appropriate expression system for this enzyme. Products were analyzed using HPLC and the mercapturate, 3-[(N-acetylcystein-S-yl)methyl]indole, of the reactive intermediate was identified and quantified. Product analysis showed that human CYP2F1 efficiently catalyzed the dehydrogenation of 3MI to the methylene imine without detectable formation of indole-3-carbinol or 3-methyloxindole. High substrate concentrations of 3MI strongly inhibited production of the dehydrogenated product, a result that may indicate the existence of mechanism-based inhibition of CYP2F1 by 3MI. Recombinant CYP2F1 demonstrated remarkable selectivity for the bioactivation of 3MI to the putative dehydrogenated reactive electrophile. Bioactivation of naphthalene to its pneumotoxic epoxide by CYP2F1 was also demonstrated. C1 Univ Utah, Dept Pharmacol & Toxicol, Salt Lake City, UT 84112 USA. Gentest Corp, Woburn, MA USA. NCI, Lab Metab, NIH, Bethesda, MD USA. RP Yost, GS (reprint author), Univ Utah, Dept Pharmacol & Toxicol, 30 S 2000 E,Room 201, Salt Lake City, UT 84112 USA. FU NHLBI NIH HHS [HL13645]; NIEHS NIH HHS [P42-ES-04675-10] NR 19 TC 73 Z9 79 U1 1 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD JUL PY 1999 VL 27 IS 7 BP 798 EP 803 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 211CT UT WOS:000081142900007 PM 10383923 ER PT J AU Buckley, LA Coleman, DP Burgess, JP Thomas, BF Burka, LT Jeffcoat, R AF Buckley, LA Coleman, DP Burgess, JP Thomas, BF Burka, LT Jeffcoat, R TI Identification of urinary metabolites of isoprene in rats and comparison with mouse urinary metabolites SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID SPECIES-DIFFERENCES; B6C3F1 MICE; BUTADIENE METABOLITES; INHALATION EXPOSURE; 1,3-BUTADIENE; CARCINOGENICITY; ACIDS; DISPOSITION; TOXICOLOGY; TOXICITY AB Isoprene, a major commodity chemical used in production of polyisoprene elastomers, has been shown to be carcinogenic in rodents. Similar to findings for the structurally related compound butadiene, mice are more susceptible than rats to isoprene-induced toxicity and carcinogenicity. Although differences in uptake, and disposition of isoprene in rats and mice have been described, its in vivo biotransformation products have not been characterized in either species. The purpose of these studies was to identify the urinary metabolites of isoprene in Fischer 344 rats and compare these metabolites with those formed in male B6C3F(1) mice. After i.p. administration of 64 mg [C-14]isoprene/kg to rats and mice, isoprene was excreted unchanged in breath (similar to 50%) or as urinary metabolites (similar to 32%). In rats isoprene was primarily excreted in urine as 2-hydroxy-2-methyl-3-butenoic acid (53%), 2-methyl-3-buten-1,2-diol (23%), and the C-1 glucuronide conjugate or 2-methyl-3-buten-1, 2-diol (13%). These metabolites are consistent with preferential oxidation of isoprene's methyl-substituted vinyl group. No oxidation of the unsubstituted vinyl group was observed. In addition to the isoprene metabolites found in rat urine, mouse urine contained numerous other isoprene metabolites with a larger percentage (25%) of total urinary radioactivity associated with an unidentified, polar fraction than in the rat (7%). Unlike butadiene, there was no evidence that glutathione conjugation played a significant role in the metabolism of isoprene in rats. Because of the unidentified metabolites in mouse urine, involvement of glutathione in the metabolism of isoprene in mice cannot be delineated. C1 Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Jeffcoat, R (reprint author), Res Triangle Inst, POB 12194, Res Triangle Pk, NC 27709 USA. OI Thomas, Brian/0000-0002-0097-4804 FU NIEHS NIH HHS [N01-ES-15329] NR 36 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD JUL PY 1999 VL 27 IS 7 BP 848 EP 854 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 211CT UT WOS:000081142900015 PM 10383931 ER PT J AU Teipel, SJ Bartenstein, P Alexander, GE Moller, HJ Rapoport, SI Hampel, H AF Teipel, SJ Bartenstein, P Alexander, GE Moller, HJ Rapoport, SI Hampel, H TI In vivo neuroreceptor imaging and applications for Alzheimer's disease SO DRUG NEWS & PERSPECTIVES LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; LIVING HUMAN-BRAIN; MUSCARINIC ACETYLCHOLINE-RECEPTORS; BENZODIAZEPINE BINDING-SITES; IN-VIVO; NICOTINIC RECEPTORS; DOPAMINE-RECEPTORS; C-11 RACLOPRIDE; SENILE DEMENTIA; FRONTAL-CORTEX AB A large body of evidence from neuropathological studies in Alzheimer's disease (AD) on postmortem brains has demonstrated impairment of specific neurotransmitter systems, especially of the cholinergic system. These studies, however, reflect end stages of the disease and permit only limited inference of the temporal sequence and cognitive and behavioral effects of deficits in neurotransmission. Since 1979, positron emission tomography (PET) has evolved into a powerful tool to visualize neuroreceptor binding in the living human brain and to quantify neuroreceptor density and ligand-receptor binding kinetics. Assessment of binding characteristics and receptor availability is essentially based on compartment models or saturation kinetic analysis derived from autoradiographic studies. This article describes the mathematical assumptions underlying these models and the biochemical characteristics that have to be met by a ligand to allow mapping of specific binding in PET. From this methodological basis, we review the present state of in vivo neuroreceptor imaging in AD. The majority of studies have focused on the cholinergic system, showing a decrease of nicotinic binding sites in frontal and temporal cortex in AD that was partially reversible through administration of central cholinergic drugs. As will be shown, interpretation of these results is severely limited by methodological difficulties. Recent studies have further demonstrated alterations of serotonin and opioid receptor availability in AD. We conclude with a discussion of the requirements that should be met by future studies on neurotransmission alterations in AD and outline possible future perspectives for these studies with respect to differential diagnosis and selective assessment of drug action and efficacy. (C) 1999 Prous Science. All rights reserved. C1 Univ Munich, Dept Psychiat, Geriatr Res Branch, Dementia & Neuroimaging Res Grp, D-80336 Munich, Germany. Univ Munich, Dept Psychiat, Memory Clin, D-80336 Munich, Germany. Univ Munich, Res Unit D2, Dementia & Neuroimaging Sect, D-80336 Munich, Germany. Tech Univ Munich, Dept Nucl Med, D-81675 Munich, Germany. NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. NR 88 TC 0 Z9 0 U1 3 U2 3 PU PROUS SCIENCE, SA PI BARCELONA PA PO BOX 540, PROVENZA 388, 08025 BARCELONA, SPAIN SN 0214-0934 J9 DRUG NEWS PERSPECT JI Drug News Perspect. PD JUL PY 1999 VL 12 IS 6 BP 341 EP 350 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 225NA UT WOS:000081966600003 ER PT J AU Reddy, SM Sinha, VR Reddy, DS AF Reddy, SM Sinha, VR Reddy, DS TI Novel oral colon-specific drug delivery systems for pharmacotherapy of peptide and nonpeptide drugs SO DRUGS OF TODAY LA English DT Review ID ACTIVE ULCERATIVE-COLITIS; PERACYLATED BETA-CYCLODEXTRINS; STEADY-STATE PHARMACOKINETICS; HUMAN GASTROINTESTINAL-TRACT; PHARMACEUTICAL DOSAGE FORMS; INFLAMMATORY BOWEL-DISEASE; MIGRATING MOTOR COMPLEX; 5-AMINO SALICYLIC-ACID; DEXTRAN ESTER PRODRUGS; IN-VITRO EVALUATION AB The increasing number of peptide and protein drugs being investigated demands the development of dosage forms which exhibit site-specific release. Delivery of drugs into systemic circulation through colonic absorption represents a novel mode of introducing peptide and protein drug molecules and drugs that are poorly absorbed from the upper gastrointestinal (GI) tract. Oral colon-specific drug delivery systems offer obvious advantages over parenteral administration. Colon targeting is naturally of value for the topical treatment of diseases of the colon such as Crohn's disease, ulcerative colitis and colorectal cancer. Sustained colonic release of drugs can be useful in the treatment of nocturnal asthma, angina and arthritis. Peptides, proteins, oligonucleotides and vaccines are the potential candidates of interest for colon-specific drug delivery. Sulfasalazine, ipsalazide and olsalazine have been developed as colon-specific delivery systems for the treatment of inflammatory bower disease (IBD). The vast microflora and distinct enzymes present in the colon are being increasingly exploited to release drugs in the colon. Although the large intestine is a potential site for absorption of drugs, some difficulties are involved in the effective local delivery of drugs to the colon bypassing the stomach and small intestine. Furthermore, differential pH conditions and long transit time during the passage of drug formulations from mouth to colon create numerous technical difficulties in the safe delivery of drugs to the colon. However, recent developments in pharmaceutical technology, including coating drugs with pH-sensitive and bacterial degradable polymers, embedding in bacterial degradable matrices and designing into prodrugs, have provided renewed hope to effectively target drugs to the colon. The use of pH changes is analogous to the more common enteric coating and consists of employing a polymer with an appropriate pH solubility profile. The concept of using pH as a trigger to release a drug in the colon is based on the pH conditions that vary continuously down the GI tract. Polysaccharide and azopolymer coating, which is refractory in the stomach and small intestine yet degraded by the colonic bacteria, have been used as carriers for colon-specific targeting. Finally, the availability of optimal preclinical models and clinical methods fueled the rapid development and evaluation of colon-specific drug delivery systems for clinical use. Future studies may hopefully lead to further refinements in the technology of colon-specific drug delivery systems and improve the pharmacotherapy of peptide drugs. (C) 1999 Prous Science. Ail rights reserved. C1 Panjab Univ, Inst Pharmaceut Sci, Chandigarh 160014, India. RP NINDS, Epilepsy Res Branch, NIH, Bldg 10,Rm 5N-250,10 Ctr Dr,MSC 1408, Bethesda, MD 20892 USA. OI Reddy, Samba/0000-0003-2735-9550 NR 293 TC 60 Z9 62 U1 1 U2 30 PU PROUS SCIENCE, SAU-THOMSON REUTERS PI BARCELONA PA 398 PROVENCA, 08025 BARCELONA, SPAIN SN 1699-3993 EI 1699-4019 J9 DRUG TODAY JI Drugs Today PD JUL PY 1999 VL 35 IS 7 BP 537 EP 580 PG 44 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 235MB UT WOS:000082544500005 PM 12973398 ER PT J AU Golding, A Chandler, S Ballestar, E Wolffe, AP Schlissel, MS AF Golding, A Chandler, S Ballestar, E Wolffe, AP Schlissel, MS TI Nucleosome structure completely inhibits in vitro cleavage by the V(D)J recombinase SO EMBO JOURNAL LA English DT Article DE accessibility; chromatin; nucleosome; V(D)J recombination ID TRANSCRIPTION FACTOR-BINDING; KAPPA-GENE REARRANGEMENT; IN-VITRO; HISTONE ACETYLATION; CORE PARTICLE; RAG2 PROTEINS; B-CELLS; 2 STEPS; DNA; CHROMATIN AB Lineage specificity and temporal ordering of immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangement are reflected in the accessibility of recombination signal sequences (RSSs) within chromatin to in vitro cleavage by the V(D)J recombinase. In this report, we investigated the basis of this regulation by testing the ability of purified RAG1 and RAG2 proteins to initiate cleavage on positioned nucleosomes containing RSS substrates. We found that nicking and double-strand DNA cleavage of RSSs positioned on the face of an unmodified nucleosome are entirely inhibited. This inhibition was independent of translational position or rotational phase and could not be overcome either by addition of the DNA-bending protein HMG-1 or by the use of hyperacetylated histones, me suggest that the nucleosome could act as the stable unit of chromatin which limits recombinase accessibility to potential RSS targets, and that actively rearranging gene segments might be packaged in a modified or disrupted nucleosome structure. C1 Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RP Schlissel, MS (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA. OI Golding, Amit/0000-0003-3659-6654 FU NIAID NIH HHS [R01 AI 40227] NR 60 TC 117 Z9 118 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JUL 1 PY 1999 VL 18 IS 13 BP 3712 EP 3723 DI 10.1093/emboj/18.13.3712 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 218CP UT WOS:000081535900018 PM 10393186 ER PT J AU De Luca, F Baron, J AF De Luca, F Baron, J TI Skeletal maturation SO ENDOCRINOLOGIST LA English DT Review ID MALE PRECOCIOUS PUBERTY; GROWTH-FACTOR-I; BONE-AGE; POSTNATAL-GROWTH; THYROID-HORMONE; HYPOTHYROIDISM; CHILDREN; INSULIN; HEIGHT; SPIRONOLACTONE AB The term "skeletal maturation" refers to the developmental process by which the skeleton is gradually transformed from cartilage into bone. There is a concordance between the rate of skeletal maturation and the rates of other developmental processes, such as linear growth, the decline in growth potential, and puberty. Thus, the radiographic assessment of skeletal maturation is a useful indicator of the overall developmental tempo. The rate of skeletal maturation is determined by endocrine, paracrine, nutritional, and genetic factors. Factors extrinsic to the skeleton tend to regulate bone growth and bone maturation in a concordant fashion. This correlation between skeletal growth and skeletal maturation has diagnostic implications; short stature with delayed bone maturation suggests a defect extrinsic to the skeleton, The rate of skeletal maturation also correlates with the rate of loss of growth potential. This correlation is used clinically to predict final height. There is an additional concordance between the rates of skeletal maturation and pubertal development in many pathological conditions, Possible biological explanations for these various concordances are discussed. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Pediat, Div Pediat Endocrinol, Baltimore, MD USA. RP Baron, J (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr MSC 1862, Bethesda, MD 20892 USA. NR 52 TC 12 Z9 13 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1051-2144 J9 ENDOCRINOLOGIST JI Endocrinologist PD JUL-AUG PY 1999 VL 9 IS 4 BP 286 EP 293 DI 10.1097/00019616-199907000-00008 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 219LR UT WOS:000081609200008 ER PT J AU Wang, YH Lee-Kwon, W Martindale, JL Adams, L Heller, P Egan, JM Bernier, M AF Wang, YH Lee-Kwon, W Martindale, JL Adams, L Heller, P Egan, JM Bernier, M TI Modulation of CCAAT/enhancer-binding protein-alpha gene expression by metabolic signals in rodent adipocytes SO ENDOCRINOLOGY LA English DT Article ID WHITE ADIPOSE-TISSUE; GLUCAGON-LIKE PEPTIDE-1; NECROSIS-FACTOR-ALPHA; PYRUVATE-KINASE GENE; FATTY-ACID SYNTHASE; 3T3-L1 ADIPOCYTES; INSULIN-RESISTANCE; C/EBP-ALPHA; HEXOSAMINE BIOSYNTHESIS; GLUCOSE-TRANSPORTER AB The transcription factor CCAAT/enhancer-binding protein-alpha (C/EBP alpha) is a positive modulator of transcription for several adipocyte-specific genes that play a role in energy metabolism. However, there is little information available regarding the regulation of its expression by metabolic signals. Exposure to insulin for 5-24 h attenuated C/EBP alpha expression when 3T3-L1 adipocytes were incubated in 24 mM glucose, but not in 5.7 mar glucose. Nuclear run-on transcription assays indicated a transcriptional repression of C/EBP alpha: gene, but not that of C/EBP beta. Glucosamine, a product of the hexosamine pathway, in the presence of low glucose mimicked high glucose's ability to reduce C/EBP alpha messenger RNA expression in insulin-treated cells. Similar results were obtained with xylitol, an activator of the pentose phosphate pathway. There was no correlation between the accumulation of hexosamine pathway metabolites (e.g. UDP-N-acetylhexosamines) and/or changes in intracellular protein glycosylation with the ability of high glucose, glucosamine, or xylitol to down-regulate C/EBP alpha gene expression. None of these treatments caused a reduction in intracellular ATP levels. Stable transfection of 3T3-L1 cells with the 5'-flanking 468-bp sequence of the mouse C/EBP alpha gene fused to luciferase demonstrated that promoter activity was also reduced by these nutrients. Of interest, treatment of rats with glucose or glucosamine led to a reduction in C/EBP alpha messenger RNA levels in epididymal, but not omental, fat. Taken together, these results suggest that metabolic signals serve to down-regulate C/EBP alpha expression both in vitro and in vivo. C1 NIA, Diabet Sect, Gerontol Res Ctr, NIH,Lab Clin Invest, Baltimore, MD 21224 USA. NIA, Biol Chem Lab, NIH, Baltimore, MD 21224 USA. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Bernier, M (reprint author), NIA, Diabet Sect, Gerontol Res Ctr, NIH,Lab Clin Invest, 5600 Nathan Shock Dr,Box 23, Baltimore, MD 21224 USA. EM bernierm@vax.grc.nia.nih.gov OI Bernier, Michel/0000-0002-5948-368X NR 52 TC 9 Z9 9 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 JUL PY 1999 VL 140 IS 7 BP 2938 EP 2947 DI 10.1210/en.140.7.2938 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 208JL UT WOS:000080987200002 PM 10385384 ER PT J AU Hentunen, TA Jackson, SH Chung, H Reddy, SV Lorenzo, J Choi, SJ Roodman, GD AF Hentunen, TA Jackson, SH Chung, H Reddy, SV Lorenzo, J Choi, SJ Roodman, GD TI Characterization of immortalized osteoclast precursors developed from mice transgenic for both bcl-X-L and simian virus 40 large T antigen SO ENDOCRINOLOGY LA English DT Article ID CELL-LINES; IN-VITRO; MOUSE; BONE; MARROW; DIFFERENTIATION; ACTIVATION; EXPRESSION; GENERATION; RESORPTION AB We recently developed an immortalized osteoclast (OCL) precursor cell line that forms large numbers of OCLs. This cell line was derived from mice doubly transgenic for bcl-X-L, and large T antigen that was targeted to cells in the OCL lineage (bcl-X-L/Tag cells). We have now characterized these cells in terms of their surface and enzymatic phenotype, responsiveness to osteotropic factors, and differentiation potential. The bcl-X-L/Tag cells expressed interleukin-l receptors 1 and 2, gelatinase B (MMP9), as well as Mac-1, CD16/CD32 (Fc gamma receptors), CD45.2 (common leukocyte marker), CD86 (costimulatory molecule expressed on B cells, follicular dendritic cells, and thymic epithelium), major histocompatibility complex I, and nonspecific esterase when cocultured with MC3T3E1 cells. However, they did not express the antigens for F4/80 (mature macrophage/dendritic cell marker) by immunostaining. Treatment of bcl;X-L/Tag cells, cocultured with MC3T3E1 cells, with the combination of 1,25-dihydroxyvitamin D-3, and dexamethasone induced high levels of OCL formation. The bcl-X-L/Tag cells formed large numbers of OCLs when cultured with RANK ligand and macrophage colony-stimulating factor in the absence of feeder cells. In the absence of RANK ligand and a feeder cell layer, 100% of the cells differentiated into F4/80-positive cells. However, neither PTH nor PTH-related protein enhanced OCL formation by bcl-X-L/Tag cells even when they were cocultured with primary osteoblasts, suggesting that they differ from primary mouse bone mat-row cells in their responsiveness to PTWPTK-related protein. Thus, bcl-X-L/Tag cells have many of the properties of primary mouse OCL precursors and should be very useful for studies of OCL differentiation and divergence of OCL precursors from the macrophage lineage. C1 Audie L Murphy Mem Vet Adm Med Ctr, Res Serv 151, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Med, Div Hematol, San Antonio, TX 78284 USA. NIH, Bethesda, MD 20892 USA. Vet Adm Med Ctr, Dept Res, Newington, CT 06111 USA. RP Roodman, GD (reprint author), Audie L Murphy Mem Vet Adm Med Ctr, Res Serv 151, 7400 Merton Minter Blvd, San Antonio, TX 78284 USA. EM roodman@uthscsa.edu NR 19 TC 21 Z9 22 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 JUL PY 1999 VL 140 IS 7 BP 2954 EP 2961 DI 10.1210/en.140.7.2954 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 208JL UT WOS:000080987200004 PM 10385386 ER PT J AU Tajima, T Ma, XM Bornstein, SR Aguilera, G AF Tajima, T Ma, XM Bornstein, SR Aguilera, G TI Prenatal dexamethasone treatment does not prevent alterations of the hypothalamic pituitary adrenal axis in steroid 21-hydroxylase deficient mice SO ENDOCRINOLOGY LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; II CORTICOSTEROID RECEPTORS; ADRENOCORTICAL AXIS; EXPOSURE ALTERS; ADULT-RATS; HYPERPLASIA; STRESS; FETAL; GENE; EXPRESSION AB A major difficulty in the clinical management of congenital adrenal hyperplasia (CAH) is adjustment of glucocorticoid doses to suppress ACTH and androgens without causing iatrogenic hypercortisolism. The possibility that structural alterations of the adrenal or a dysfunction of the hypothalamic pituitary adrenal (HPA) axis caused by glucocorticoid deficiency during fetal Life contribute to this problem was studied in 2 l-hydroxylase deficient mice caused by deletion of the cytochrome P-450 21-hydroxylase gene. Homozygotes showed about 200-fold elevations in plasma progesterone, hyperplastic adrenal cortices lacking zonation, and structural alterations of adrenocortical mitochondria. Histochemical studies showed increases in hypothalamic CRH messenger RNA (mRNA) and immunoreactive (ir) CRH, and pituitary POMC mRNA in homozygous mice. VP mRNA levels in PVN perikarya were normal, but irVP in parvicellular terminals of the median eminence was increased in homozygotes. Prenatal dexamethasone treatment (0.5 to 2 mu g/day) prevented the increases in CRH mRNA, whereas dexamethasone only partially decreased POMC mRNA levels, and had no effect on serum progesterone levels. The data suggest that intrauterine glucocorticoid deficiency in CAH causes hyperactivity of the hypothalamic-pituitary-corticotroph aids and insensitivity to glucocorticoid feedback. These studies in 21-hydroxylase deficient mice may provide new insights on the mechanism, clinical manifestations and management of some types of human CAH. C1 NICHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Aguilera, G (reprint author), NICHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr MSC 1862, Bethesda, MD 20892 USA. EM aguilerg@exchange.nih.gov RI Toshihiro, Tajima/A-5720-2012 NR 54 TC 18 Z9 18 U1 0 U2 2 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 JUL PY 1999 VL 140 IS 7 BP 3354 EP 3362 DI 10.1210/en.140.7.3354 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 208JL UT WOS:000080987200051 PM 10385433 ER PT J AU Usdin, TB Hilton, J Vertesi, T Harta, G Segre, G Mezey, E AF Usdin, TB Hilton, J Vertesi, T Harta, G Segre, G Mezey, E TI Distribution of the parathyroid hormone 2 receptor in rat: Immunolocalization reveals expression by several endocrine cells SO ENDOCRINOLOGY LA English DT Article ID MESSENGER RIBONUCLEIC-ACIDS; IN-SITU LOCALIZATION; PTH/PTHRP RECEPTOR; INSULIN-SECRETION; CYTOSOLIC CALCIUM; PANCREATIC-ISLETS; MEDIAL CISTERNAE; GOLGI-APPARATUS; PEPTIDE PTHRP; SOMATOSTATIN AB The PTH2 receptor is a G protein-coupled receptor selectively activated by PTH. We are studying the receptors distribution to guide the investigation of its physiological function. We have now generated an antibody from a C-terminal peptide sequence of the PTH2 receptor and used this to study its cellular distribution. Labeling with the antibody identified a number of endocrine cells expressing the PTH2 receptor, including thyroid parafollicular cells, pancreatic islet D cells, and some gastrointestinal peptide synthesizing cells. There was complete overlap of PTH2 receptor labeling with somatostatin in pancreatic islets, and partial overlap with somatostatin in thyroid parafollicular cells and in the gastrointestinal tract. Furthermore, observations made previously by in situ hybridization histochemistry, including expression throughout the cardiovascular system, as well as by discrete populations of cells within the gastrointestinal tract and reproductive system were confirmed. These data suggest a broad role for the PTH2 receptor, especially within the endocrine system, and provide a basis for experimental exploration of its physiology. C1 Natl Inst Mental Hlth, Genet Lab, Bethesda, MD 20892 USA. Natl Inst Neurol Dis & Stroke, BAsic Neurosci Program, Bethesda, MD 20892 USA. Natl Inst Hlth, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Usdin, TB (reprint author), Natl Inst Mental Hlth, Genet Lab, Bldg 36,Room 3D06,36 Convent Dr MSC4094, Bethesda, MD 20892 USA. EM usdin@codon.nih.gov NR 44 TC 46 Z9 46 U1 0 U2 2 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 JUL PY 1999 VL 140 IS 7 BP 3363 EP 3371 DI 10.1210/en.140.7.3363 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 208JL UT WOS:000080987200052 PM 10385434 ER PT J AU Wang, J Zhou, J Powell-Braxton, L Bondy, C AF Wang, J Zhou, J Powell-Braxton, L Bondy, C TI Effects of Igf1 gene deletion on postnatal growth patterns SO ENDOCRINOLOGY LA English DT Article ID FACTOR-I GENE; MICE; HORMONE; DEFICIENCY; EXPRESSION AB This study documents the temporal and organ-specific effects of Igf1 gene deletion on postnatal growth patterns. Igf1-/- mice are 63 +/- 4% the size of wildtype (wt) littermates at birth and this ratio persists through postnatal day 20 (P20). After P20, Igf1-/- mice virtually stop growing, while wt littermates double in size from P20 to P40, after which their growth markedly decelerates. As a result, 'full-grown' Igf1-/- mice are less than one third the size of wt littermates. Igf1 gene deletion has disproportionate effects on organ growth. For example, at P10 and P40, Igf1-/- body weights are 63% and 31% of wt, respectively, while Igf1-/- lungs weigh only 34% and 22% of wt at these ages. In contrast, the Igf1-/- heart is disproportionately enlarged, representing similar to 85% of wt at P10 and similar to 56% at P40. Igf1-/- kidney, spleen and liver are slightly but significantly increased in size relative to the degree of reduction in Igf1-/- body weight. These data demonstrate that Igf1 has two major phases or modes of growth promotion. There is an early, growth hormone (GH)-independent Igf1 growth augmentation during perinatal development, responsible for about 35% of growth prior to P20. Then there are later effects due to GH-induced Igf1, which are responsible for increasing animal size by similar to 100% between P20 and 40. The fact that there is virtually no GH-induced growth in the Igf1-/- mice supports the view that Igf1 mediates GH's major effects on somatic growth. Finally, this study shows that Igf1 has discordant effects on pulmonary and cardiac growth parameters, with relative hypoplasia of Igf1-/- lungs and hypertrophy of Igf1-/- hearts. C1 NICHD, NIH, Dev Endocrinol Branch, Bethesda, MD 20892 USA. Genentech Inc, Cardiovasc Res Dept, San Francisco, CA USA. RP Wang, J (reprint author), NICHD, NIH, Dev Endocrinol Branch, Bethesda, MD 20892 USA. NR 10 TC 59 Z9 59 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 JUL PY 1999 VL 140 IS 7 BP 3391 EP 3394 DI 10.1210/en.140.7.3391 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 208JL UT WOS:000080987200056 PM 10385438 ER PT J AU Abernathy, CO Liu, YP Longfellow, D Aposhian, HV Beck, B Fowler, B Goyer, R Menzer, R Rossman, T Thompson, C Waalkes, M AF Abernathy, CO Liu, YP Longfellow, D Aposhian, HV Beck, B Fowler, B Goyer, R Menzer, R Rossman, T Thompson, C Waalkes, M TI Arsenic: Health effects, mechanisms of actions, and research issues SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE S-adenosylmethionine; arsenic; arsenate; arsenite; dimethylarsinic acid; heat shock proteins; heme oxygenase; monomethylarsonic acid ID ENZYMATIC METHYLATION; EPITHELIAL-CELLS; DRINKING-WATER; WEST-BENGAL; PREVALENCE; EXPOSURE; HUMANS; INDIA; MODEL AB A meeting on the health effects of arsenic (As), its modes of action, and areas in need of future research was held in Hunt Valley, Maryland, on 22-24 September 1997. Exposure to As in drinking water has been associated with the development of skin and internal cancers and noncarcinogenic effects such as diabetes, peripheral neuropathy, and cardiovascular diseases. There is little data on specific mechanism(s) of action for As, but a great deal of information on possible modes of action. Although arsenite [As(III)] can inhibit more than 200 enzymes, events underlying the induction of the noncarcinogenic effects of As are not understood. With respect to carcinogenicity, As can affect DNA repair, methylation of DNA, and increase radical formation and activation of the protooncogene c-myc, but none of these potential pathways have widespread acceptance as the principal etiologic event. In addition, there are no accepted models for the study of As-induced carcinogenesis. At the final meeting session we considered research needs. Among the most important areas cited were a) As metabolism and its interaction with cellular constituents; b) possible bioaccumulation of As; c) interactions with other metals; d) effects of As on genetic material; e) development of animal models and cell systems to study effects of As; and f) a better characterization of human exposures as related to health risks. Some of the barriers to the advancement of As research included an apparent lack of interest in the United States on As research; lack of relevant animal models; difficulty with adoption of uniform methodologies; lack of accepted biomarkers; and the need for a central storage repository for stored specimens. C1 US EPA, Off Water & Res & Dev, Washington, DC USA. NCI, Div Canc Biol, Bethesda, MD USA. Univ Arizona, Tucson, AZ USA. Gradient Corp, Cambridge, MA USA. Univ Maryland, Catonsville, MD USA. NYU, Med Ctr, Tuxedo Pk, NY USA. NIEHS, Res Triangle Pk, NC USA. NIEHS, NCI, Inorgan Carcinogenesis Sect, Res Triangle Pk, NC USA. RP Abernathy, CO (reprint author), Off Sci & Technol 4304, Room 1037 E Tower,401 M St, Washington, DC 20460 USA. EM abernathy.charles@epa.gov NR 30 TC 360 Z9 374 U1 8 U2 83 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 JUL PY 1999 VL 107 IS 7 BP 593 EP 597 DI 10.2307/3434403 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 216DX UT WOS:000081426900033 PM 10379007 ER PT J AU Huff, J AF Huff, J TI Animal and human carcinogens SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter ID CANCER C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Huff, J (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM huff1@niehs.nih.gov NR 12 TC 12 Z9 12 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 JUL PY 1999 VL 107 IS 7 BP A341 EP A342 DI 10.2307/3434380 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 216DX UT WOS:000081426900003 PM 10405250 ER PT J AU Suk, WA Anderson, BE AF Suk, WA Anderson, BE TI A holistic approach to environmental health research SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 NIEHS, Off Program Dev, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. RP Suk, WA (reprint author), NIEHS, Off Program Dev, Div Extramural Res & Training, POB 12233, Res Triangle Pk, NC 27709 USA. NR 0 TC 7 Z9 7 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 JUL PY 1999 VL 107 IS 7 BP A338 EP A339 DI 10.2307/3434378 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 216DX UT WOS:000081426900001 PM 10379011 ER PT J AU Parker, AS Cerhan, JR Putnam, SD Cantor, KP Lynch, CF AF Parker, AS Cerhan, JR Putnam, SD Cantor, KP Lynch, CF TI A cohort study of farming and risk of prostate cancer in Iowa SO EPIDEMIOLOGY LA English DT Article DE cohort studies; farming; prostatic neoplasms; occupations; histology; diet; alcohol drinking; smoking ID PESTICIDE APPLICATORS; SWEDISH AGRICULTURE; FARMERS AB Although farming has been linked to prostate cancer mortality, few investigations have addressed its association with prostate cancer incidence. We followed a population-based cohort of 1,177 cancer free men for up to 9 years and identified 81 incident prostate cancers. Men whose usual occupation was farmer were at an increased risk of prostate cancer after adjust ment for age, smoking, alcohol, and dietary factors (RR = 1.7; 95% CI 1.0-2.7). Exclusion of well differentiated, localized tumors slightly strengthened the association (RR = 2.0; 95% CI = 1.1-3.6). Risk was confined to older (age 70+ years) farmers (RR = 2.2; 95% CI = 1.1-4.3); we found no evidence of an effect among younger farmers (RR = 1.0; 95% CI = 0.4-2.1). C1 Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. Univ Iowa, Coll Med, Dept Prevent Med & Environm Hlth, Iowa City, IA USA. NCI, Occupat Epidemiol Branch, Bethesda, MD 20892 USA. RP Cerhan, JR (reprint author), Mayo Clin, Dept Hlth Sci Res, 200 1st St SW, Rochester, MN 55905 USA. FU NCI NIH HHS [R21 CA/ES69838, N01-CP-51026]; NIEHS NIH HHS [P30 ES05605] NR 22 TC 32 Z9 33 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD JUL PY 1999 VL 10 IS 4 BP 452 EP 455 DI 10.1097/00001648-199907000-00019 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 208JK UT WOS:000080987100019 PM 10401883 ER PT J AU Hatch, EE Lubin, JH Tarone, RE Wacholder, S Kleinerman, RA Linet, MS Kaune, WT AF Hatch, EE Lubin, JH Tarone, RE Wacholder, S Kleinerman, RA Linet, MS Kaune, WT TI Childhood leukemia and electrical appliances - The authors reply SO EPIDEMIOLOGY LA English DT Letter ID ACUTE LYMPHOBLASTIC-LEUKEMIA; EXPOSURE C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM Factors, Richland, WA 99352 USA. RP Hatch, EE (reprint author), NCI, Div Canc Epidemiol & Genet, 6130 Execut Blvd EPN 408, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD JUL PY 1999 VL 10 IS 4 BP 465 EP 467 DI 10.1097/00001648-199907000-00023 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 208JK UT WOS:000080987100023 ER PT J AU Gennaro, V Finkelstein, MM Ceppi, M Fontana, V Montanaro, F Perrotta, A Puntoni, R Silvano, S AF Gennaro, V Finkelstein, MM Ceppi, M Fontana, V Montanaro, F Perrotta, A Puntoni, R Silvano, S TI Lung tumors attributable to asbestos among oil refinery workers SO EPIDEMIOLOGY LA English DT Meeting Abstract C1 Natl Canc Inst, Genoa, Italy. Ontario Minst Labour, Toronto, ON, Canada. AUSL 5, Occupat Hyg & Safety Dpt, La Spezia, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD JUL PY 1999 VL 10 IS 4 MA 180O BP S76 EP S76 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 208JK UT WOS:000080987100210 ER PT J AU Kamel, F Boyes, WK Gladen, BC Alavanja, MCR Sandler, DP AF Kamel, F Boyes, WK Gladen, BC Alavanja, MCR Sandler, DP TI Visual dysfunction and pesticide use SO EPIDEMIOLOGY LA English DT Meeting Abstract C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD JUL PY 1999 VL 10 IS 4 MA 353O BP S123 EP S123 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 208JK UT WOS:000080987100383 ER PT J AU Little, R Zadorozhnaja, T Mendel, N Gladen, BC Hulchiy, L Miller, RK Kennicult, M AF Little, R Zadorozhnaja, T Mendel, N Gladen, BC Hulchiy, L Miller, RK Kennicult, M TI Mercury in 200 placentas from urban Ukraine SO EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD JUL PY 1999 VL 10 IS 4 MA 281P BP S103 EP S103 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 208JK UT WOS:000080987100311 ER PT J AU Puntoni, R Merlo, F Ceppi, M Reggiardo, G Borsa, L Valerio, G AF Puntoni, R Merlo, F Ceppi, M Reggiardo, G Borsa, L Valerio, G TI A historical cohort mortality study among shipyard workers in Genoa, Italy (1960-1995). SO EPIDEMIOLOGY LA English DT Meeting Abstract C1 Natl Canc Inst, Genoa, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD JUL PY 1999 VL 10 IS 4 MA 181O BP S76 EP S76 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 208JK UT WOS:000080987100212 ER PT J AU Tabacova, S Little, R Balabaeva, L AF Tabacova, S Little, R Balabaeva, L TI Maternal exposure to phthalates and complications of pregnancy SO EPIDEMIOLOGY LA English DT Meeting Abstract C1 Natl Ctr Hyg, Sofia, Bulgaria. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 15 Z9 17 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD JUL PY 1999 VL 10 IS 4 MA 368O BP S127 EP S127 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 208JK UT WOS:000080987100398 ER PT J AU Ward, MH Prince, JR Stewart, PA Zahm, SH AF Ward, MH Prince, JR Stewart, PA Zahm, SH TI Estimating exposure to pesticides among migrant farm workers: Results from a feasibility study SO EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD JUL PY 1999 VL 10 IS 4 MA 361P BP S125 EP S125 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 208JK UT WOS:000080987100391 ER PT J AU Bottner, A Eisenhofer, G Friberg, P Rundqvist, B Bornstein, SR AF Bottner, A Eisenhofer, G Friberg, P Rundqvist, B Bornstein, SR TI Hyperleptinaemia does not correlate with plasma catecholamine levels in chronic heart failure SO EUROPEAN HEART JOURNAL LA English DT Letter ID LEPTIN SECRETION C1 Univ Leipzig, Dept Internal Med 3, D-7010 Leipzig, Germany. Natl Inst Hlth, Clin Neurosci Branch, Bethesda, MD USA. Univ Gothenburg, Dept Clin Physiol, Gothenburg, Sweden. NICHHD, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Bottner, A (reprint author), Univ Leipzig, Dept Internal Med 3, D-7010 Leipzig, Germany. RI Korner, Antje/B-3988-2015 OI Korner, Antje/0000-0001-6001-0356 NR 11 TC 10 Z9 10 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD JUL PY 1999 VL 20 IS 14 BP 1051 EP 1052 DI 10.1053/euhj.1999.1590 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 213CC UT WOS:000081253600013 PM 10381857 ER PT J AU Murphy, E Cross, HR Steenbergen, C AF Murphy, E Cross, HR Steenbergen, C TI Na+/H+ and Na+/Ca2+ exchange: their role in the rise in cytosolic free [Ca2+] during ischaemia and reperfusion SO EUROPEAN HEART JOURNAL SUPPLEMENTS LA English DT Article; Proceedings Paper CT Symposium on the Cardiac Na+/H+ Exchanger at the XVI World Congress of the International-Society-for-Heart-Research CY MAY, 1998 CL RHODES, GREECE DE HOE-694; HOE-642; amiloride; preconditioning; pH ID SODIUM-HYDROGEN-EXCHANGE; PERFUSED RAT-HEART; CARDIAC CONTRACTILE FUNCTION; MYOCARDIAL ISCHEMIC-INJURY; FREE CALCIUM-CONCENTRATION; REDUCES INFARCT SIZE; GUINEA-PIG HEARTS; INTRACELLULAR SODIUM; H+ EXCHANGE; POSTISCHEMIC RECOVERY AB A rise in Ca-i occurs during ischaemia. During the first 30 min of ischaemia, this rise does not appear to be due to Ca2+ entry via Ca2+ channels or Ca2+ release from the SR. The increase in Ca-i appears to be due to Ca2+ entry via Na+/Ca2+ exchange, secondary to a rise in Na-i during ischaemia. The mechanism responsible for the rise in Na-i is controversial. There appears to be some entry via noninactivating voltage-gated Na+ channels and some entry via NHE, although the exact relative percentage may depend on the metabolic activity of the cell and the magnitude of the fall in pH(i). Inhibition of the rise in Na-i during ischaemia (whether by inhibition of Na+ channels, inhibition of NHE, or a combination of both) reduces the subsequent rise in Ca-i and is cardioprotective. There is also convincing data suggesting that NHE is stimulated at the start of reflow. Inhibition of NHE at the start of reflow slows the rate of recovery of intracellular pH, but there is no measurable change in Na-i at the start of reflow, unless the Na+/K+ ATPase is inhibited. However, although the increased Na+ entry on reflow does not measurably alter bulk Na-i, it appears to enhance Na+/Ca2+ exchange and this can cause a transient increase in Ca-i on reflow. Inhibitors of NHE are cardioprotective if administered before or during ischaemia. Addition of NHE inhibitors only at the start of reflow is less protective; this is attributed to either slow delivery of the inhibitor to the myocyte or to the need for combined inhibition of NHE during ischaemia as well as for reflow for optimal protection. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. Duke Univ, Dept Pathol, Durham, NC 27710 USA. RP Murphy, E (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, MD-D2-03,Box 1223, Res Triangle Pk, NC 27709 USA. NR 104 TC 9 Z9 9 U1 1 U2 3 PU W B SAUNDERS CO LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1520-765X J9 EUR HEART J SUPPL JI Eur. Heart J. Suppl. PD JUL PY 1999 VL 1 IS K BP K18 EP K30 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 213CF UT WOS:000081253900004 ER PT J AU Strunnikov, AV Jessberger, R AF Strunnikov, AV Jessberger, R TI Structural maintenance of chromosomes (SMC) proteins - Conserved molecular properties for multiple biological functions SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Review DE SMC proteins; chromosome condensation; sister chromatid cohesion; DNA recombination; gene dosage compensation; chromatin dynamics; cell cycle ID SISTER-CHROMATID COHESION; DOSAGE COMPENSATION COMPLEX; NEMATODE X-CHROMOSOME; STRAND-BREAK REPAIR; MITOTIC CHROMOSOME; SCHIZOSACCHAROMYCES-POMBE; SACCHAROMYCES-CEREVISIAE; SCAFFOLD PROTEIN; DNA-REPLICATION; BUDDING YEAST AB The evolutionarily-conserved eukaryotic SMC (structural maintenance of chromosomes) proteins are ubiquitous chromosomal components in prokaryotes and eukaryotes. The eukaryotic SMC proteins form two kind of heterodimers: the SMC1/SMC3 and the SMC2/SMC4 types. These heterodimers constitute an essential part of higher order complexes, which are involved in chromatin and DNA dynamics. The two most prominent and best-characterized complexes an cohesin and condensin, necessary for sister chromatid cohesion and chromosome condensation. Hen we discuss these functions together with additional roles in gene dosage compensation and DNA recombination. C1 Basel Inst Immunol, CH-4005 Basel, Switzerland. NICHD, Lab Mol Embryol, NIH, Bethesda, MD USA. RP Jessberger, R (reprint author), Basel Inst Immunol, Grenzacherstr 487, CH-4005 Basel, Switzerland. OI Strunnikov, Alexander/0000-0002-9058-2256 NR 73 TC 134 Z9 136 U1 0 U2 4 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 JUL PY 1999 VL 263 IS 1 BP 6 EP 13 DI 10.1046/j.1432-1327.1999.00509.x PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 217BZ UT WOS:000081480800002 PM 10429180 ER PT J AU Farr, KA Cohen-Fix, O AF Farr, KA Cohen-Fix, O TI The metaphase to anaphase transition - A case of productive destruction SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Review DE cell cycle; mitosis; anaphase promoting complex; cyclosome; mitotic checkpoint; protein degradation ID SPINDLE ASSEMBLY CHECKPOINT; SISTER-CHROMATID SEPARATION; POLE BODY DUPLICATION; SACCHAROMYCES-CEREVISIAE; PROMOTING COMPLEX; BUDDING YEAST; FISSION YEAST; UNATTACHED KINETOCHORES; CYCLIN PROTEOLYSIS; MITOTIC CHECKPOINT AB The metaphase to anaphase transition is a point of no return; the duplicated sister chromatids segregate to the future daughter cells, and any mistake in this process may be deleterious to both progeny. At the heart of this process lies the anaphase inhibitor, which must be degraded in order for this transition to take place. The degradation of the anaphase inhibitor occurs via the ubiquitin-degradation pathway, and it involves the activity of the cyclosome/anaphase promoting complex (APC). The fidelity of the metaphase to anaphase transition is ensured by several different regulatory mechanisms that modulate the activity of the cyclosome/APC. Great advancements have been mode in this field in the past few years, but many questions still remain to be answered. C1 NIDDK, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Cohen-Fix, O (reprint author), NIDDK, Mol & Cellular Biol Lab, NIH, 8 Ctr Dr,Bldg 8,Room 319, Bethesda, MD 20892 USA. NR 52 TC 14 Z9 14 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 JUL PY 1999 VL 263 IS 1 BP 14 EP 19 DI 10.1046/j.1432-1327.1999.00510.x PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 217BZ UT WOS:000081480800003 PM 10429181 ER PT J AU Mahalingam, B Louis, JM Reed, CC Adomat, JM Krouse, J Wang, YF Harrison, RW Weber, IT AF Mahalingam, B Louis, JM Reed, CC Adomat, JM Krouse, J Wang, YF Harrison, RW Weber, IT TI Structural and kinetic analysis of drug resistant mutants of HIV-1 protease SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Article DE drug resistance; HIV-1; aspartic protease; crystal structure ID HUMAN-IMMUNODEFICIENCY-VIRUS; GAG-POL POLYPROTEIN; TYPE-1 PROTEASE; HUMAN-IMMUNODEFICIENCY-VIRUS-1 PROTEASE; CRYSTAL-STRUCTURES; IN-VIVO; MUTATIONS; VARIANTS; INHIBITORS; MUTAGENESIS AB Mutants of HIV-1 protease that are commonly selected on exposure to different drugs, V82S, G48V, N88D and L90M, showed reduced catalytic activity compared to the wild-type protease on cleavage site peptides, CA-p2, p6(pol)-PR and PR-RT, critical for viral maturation. Mutant V82S is the least active (2-20% of wild-type protease), mutants N88D, R8Q. and L90M exhibit activities ranging from 20 to 40% and G48V from 50 to 80% of the wild-type activity. In contrast, D30N is variable in its activity an different substrates (10-110% of wild-type), with the PR-RT site bring the most affected. Mutants K45I and M46L, usually selected in combination with other mutations, showed activities that are similar to (60-110%) or greater than (110-530%) wild-type, respectively. No direct relationship was observed between catalytic activity, inhibition, and structural stability. The mutants D30N and V82S were similar to wild-type protease in their stability toward urea denaturation, while R8Q, G48V, and L90M showed 1.5 to 2.7-fold decreased stability, and N88D and K45I showed 1.6 to 1.7-fold increased stability. The crystal structures of R8Q, K45I and L90M mutants complexed with a CA-p2 analog inhibitor were determined at 2.0, 1.55 and 1.88 Angstrom resolution respectively, and compared to the wild-type structure. The intersubunit hydrophobic contacts observed in the crystal structures are in good agreement with the relative structural stability of the mutant proteases. All these results suggest that viral resistance does not arise by a single mechanism. C1 Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Weber, IT (reprint author), Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Microbiol & Immunol, 233 S 10th St, Philadelphia, PA 19107 USA. FU NIAID NIH HHS [AI41380]; NIGMS NIH HHS [R01 GM062920] NR 36 TC 96 Z9 97 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD JUL PY 1999 VL 263 IS 1 BP 238 EP 245 DI 10.1046/j.1432-1327.1999.00514.x PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 217BZ UT WOS:000081480800031 PM 10429209 ER PT J AU Lissowska, J Groves, FD Sobin, LH Fraumeni, JF Nasierowska-Guttmejer, A Radziszewski, J Regula, J Hsing, AW Zatonski, W Blot, WJ Chow, WH AF Lissowska, J Groves, FD Sobin, LH Fraumeni, JF Nasierowska-Guttmejer, A Radziszewski, J Regula, J Hsing, AW Zatonski, W Blot, WJ Chow, WH TI Family history and risk of stomach cancer in Warsaw, Poland SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE case-control study; family history; Poland; stomach cancer ID HELICOBACTER-PYLORI INFECTION; GASTRIC-CANCER; ATROPHIC GASTRITIS; CARCINOMA; POPULATION; MUTATIONS; ACCURACY; MUCOSA; JAPAN AB In a population-based case-control study of stomach cancer conducted in Warsaw, Poland, 464 cases and 480 controls were interviewed to evaluate the role of family history and other risk factors. A greater than threefold increase in risk was associated with a history of stomach cancer in a first degree relative (OR = 3.5; 95% CI = 2.0-6.2), but no excess risk was seen with other forms of cancer. The risk associated with familial occurrence was not significantly modified by gender, age or ABO blood type, and did not vary with Lauren histologic classification. Our findings add to evidence for a familial predisposition to both diffuse and intestinal types of gastric cancer, Further studies are needed to identify the susceptibility genes and environmental exposures that may account for the familial tendency to stomach cancer. (C) 1999 Lippincott Williams & Wilkins. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Ctr Canc, Div Canc Epidemiol & Prevent, Warsaw, Poland. M Sklodowska Curie Inst Oncol, Warsaw, Poland. Armed Forces Inst Pathol, Div Gastrointestinal Pathol, Washington, DC 20306 USA. Ctr Canc, Div Histopathol, Warsaw, Poland. Ctr Canc, Div Upper Digest Tract Canc, Warsaw, Poland. Ctr Canc, Med Ctr Postgrad Educ, Dept Gastroenterol, Warsaw, Poland. Int Epidemiol Inst, Rockville, MD USA. RP Chow, WH (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8100, Bethesda, MD 20892 USA. OI Lissowska, Jolanta/0000-0003-2695-5799 FU NCI NIH HHS [N01-CP-05626, N02-CP-40501, N02-CP-71103] NR 32 TC 46 Z9 46 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-8278 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD JUL PY 1999 VL 8 IS 3 BP 223 EP 227 DI 10.1097/00008469-199906000-00010 PG 5 WC Oncology SC Oncology GA 220PR UT WOS:000081674800010 PM 10443951 ER PT J AU Singer, DS Zinger, H Kohn, LD Mozes, E AF Singer, DS Zinger, H Kohn, LD Mozes, E TI Differing MHC class I requirements for induction and propagation of experimental systemic lupus erythematosus SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE MHC class I; systemic lupus erythematosus; chimeras; CD1; neonatal Fc receptor ID BETA(2)-MICROGLOBULIN-DEFICIENT MICE; IGG CATABOLISM; DEFICIENT MICE; T-CELLS; ENCEPHALOMYELITIS; MOLECULES; RESPONSES; RECEPTORS AB Mice deficient in beta 2-microglobulin expression are resistant to the induction of experimental systemic lupus erythematosus (SLE). The present studies were designed to identify the beta 2-microglobulin-dependent cell surface molecule(s) that confers sensitivity to experimental SLE, and to determine its role in disease development. We report hat mice lacking the transporter associated with antigen presentation (TAP(-/-))were also resistant to disease, whereas CD1(-/-) and CD8(-/-) mice were susceptible; susceptibility also did not correlate with neonatal Fc receptor or HEPH expression. These data indicate that disease susceptibility is determined by expression of MHC class I. Furthermore, by analyzing both adoptive transfer and radiation bone marrow chimeras, we demonstrate that MHC class I expression is necessary for propagation of disease, but not for induction of pathogenic cells. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. NIDDK, Biochem & Metab Lab, NIH, Bethesda, MD USA. RP Singer, DS (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B-36, Bethesda, MD 20892 USA. NR 29 TC 13 Z9 16 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 JUL PY 1999 VL 29 IS 7 BP 2259 EP 2268 DI 10.1002/(SICI)1521-4141(199907)29:07<2259::AID-IMMU2259>3.0.CO;2-1 PG 10 WC Immunology SC Immunology GA 215ET UT WOS:000081369500023 PM 10427989 ER PT J AU Albeck, DS Backman, C Veng, L Friden, P Rose, GM Granholm, ACE AF Albeck, DS Backman, C Veng, L Friden, P Rose, GM Granholm, ACE TI Acute application of NGF increases the firing rate of aged rat basal forebrain neurons SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Review DE acetylcholine; Alzheimer's disease; medial septum; neurodegeneration; neurotrophins ID NERVE GROWTH-FACTOR; BLOOD-BRAIN-BARRIER; ANTITRANSFERRIN RECEPTOR ANTIBODY; SEPTO-HIPPOCAMPAL NEURONS; TRANSFERRIN RECEPTOR; CHOLINERGIC NEURONS; NEUROTROPHIC FACTOR; ALZHEIMERS-DISEASE; NUCLEUS BASALIS; SPATIAL MEMORY AB Nerve growth factor (NGF) has been widely used in animal models to ameliorate age-related neurodegeneration, but it cannot cross the blood-brain barrier (BBB). NGF conjugated to an antibody against the transferrin receptor (OX-26) crosses the BBB and affects the biochemistry and morphology of NGF-deprived basal forebrain neurons. The rapid actions of NGF, including electrophysiological effects on these neurons, are not well understood. In the present study, two model systems in which basal forebrain neurons either respond dysfunctionally to NGF (aged rats) or do not have access to target-derived NGF (intraocular transplants of forebrain neurons) were tested. One group of transplanted and one group of aged animals received unconjugated OX-26 and NGF comixture as a control, while other groups received replacement NGF in the form of OX-26-NGF conjugate during the 3 months preceding the electrophysiological recording session. Neurons from animals in both the transplanted and aged control groups showed a significant increase in firing rate in response to acute NGF application, while none of the conjugate-treated groups or young intact rats showed any response. After the recordings, forebrain transplants and aged brains were immunocytochemically stained for the low-affinity NGF receptor. All conjugate treatment groups showed significantly greater staining intensity compared to controls. These data from both transplants and aged rats in situ indicate that NGF-deprived basal forebrain neurons respond to acute NGF with an increased firing rate. This novel finding may have importance even for long-term biological effects of this trophic factor in the basal forebrain. C1 Univ Colorado, Hlth Sci Ctr, Dept Basic Sci & Oral Res, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Neurosci Program, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, Denver, CO 80262 USA. NIDA, Intramural Res Program, Baltimore, MD 21224 USA. Peridontix, Watertown, MA 02172 USA. RP Albeck, DS (reprint author), Campus Box C286,4200 E 9th Ave, Denver, CO 80262 USA. RI backman, cristina/C-1276-2013 FU NIA NIH HHS [AG12122, AG04418, AG15239, R01 AG010755] NR 106 TC 23 Z9 26 U1 2 U2 2 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JUL PY 1999 VL 11 IS 7 BP 2291 EP 2304 DI 10.1046/j.1460-9568.1999.00644.x PG 14 WC Neurosciences SC Neurosciences & Neurology GA 211NT UT WOS:000081175400010 PM 10383618 ER PT J AU Phan, VL Su, TP Privat, A Maurice, T AF Phan, VL Su, TP Privat, A Maurice, T TI Modulation of steroidal levels by adrenalectomy castration and inhibition of neurosteroid synthesis enzymes affect sigma(1) receptor-mediated behaviour in mice SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE sigma(1) receptor; neurosteroids; Trilostane; Finasteride; learning and memory; spontaneous alternation; passive avoidance ID METHYL-D-ASPARTATE; INDUCED LEARNING IMPAIRMENT; INDUCED NEURONAL ACTIVATION; CONDITIONED FEAR STRESS; DEHYDROEPIANDROSTERONE-SULFATE; RAT-BRAIN; 3-BETA-HYDROXYSTEROID DEHYDROGENASE; (+)-SKF-10,047 BINDING; NEUROACTIVE NEUROSTEROIDS; MK-801-INDUCED IMPAIRMENT AB The interaction between neurosteroids and sigma(1) (sigma(1)) receptors may be of therapeutic interest during physiological or pathological ageing, particularly concerning their neuromodulatory role on cognitive functions. Neurosteroids modulate memory processes through a mechanism involving interactions with GABA(A), N-methyl-D-aspartate and/or sigma(1) receptors. To measure the contribution of endogenous neurosteroid levels to the antiamnesic effects of sigma(1) agonists, we investigated the effects of inhibitors of key enzymes involved in neurosteroid synthesis, in adrenalectomized/castrated (AdX/CX) mice to avoid the effect of circulating steroids. Trilostane, a 3 beta-hydroxysteroid-deshydrogenase inhibitor, blocks the pregnenolone to progesterone conversion and leads to a decrease of progesterone. Finasteride, a 5 alpha-reductase inhibitor, blocks the progesterone to 5 alpha-pregnane-3,20-dione conversion and leads to an accumulation of progesterone. The in vivo binding of (+)-[H-3]SKF-10 047 to sigma(1) sites was measured in the mouse hippocampus and cortex. The attenuating effect of the selective sigma(1) agonist PRE-084 (0.1-3 mg/kg) against dizocilpine (0.15 mg/kg)-induced learning impairment was examined using spontaneous alternation behaviour, step-down passive avoidance and place learning in the elevated plus-maze. The in vivo (+)-[H-3]SKF-10 047 binding appeared significantly increased in AdX/CX mice and after trilostane treatment (10 mg/kg twice a day, 7 days), compared with sham-operated animals. The finasteride treatment (25 mg/kg, 7 days) significantly decreased binding levels. The learning deficits induced by dizocilpine were not affected by the treatments. The antiamnesic effect of PRE-084 was facilitated in AdX/CX mice and even more after trilostane treatment, as several parameters for animals treated with both PRE-084 and dizocilpine returned to control values. The PRE-084 effect was blocked after finasteride. These results confirmed that endogenous neurosteroidal levels modulate sigma(1) receptor-mediated behaviour directly, and revealed that, among neurosteroids, progesterone may be the main modulator of sigma(1) receptors. C1 ENSCM, INSERM, U336, Montpellier 5, France. NIDA, Cellular Pathobiol Unit, Mol Neuropsychiat Sect, Div Intramural Res,NIH, Baltimore, MD 21224 USA. RP Maurice, T (reprint author), ENSCM, INSERM, U336, 8 Rue Ecole Normale, F-34296 Montpellier 5, France. NR 79 TC 40 Z9 41 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JUL PY 1999 VL 11 IS 7 BP 2385 EP 2396 DI 10.1046/j.1460-9568.1999.00656.x PG 12 WC Neurosciences SC Neurosciences & Neurology GA 211NT UT WOS:000081175400020 PM 10383628 ER PT J AU Li, YX Schaffner, AE Barker, JL AF Li, YX Schaffner, AE Barker, JL TI Astrocytes regulate the developmental appearance of GABAergic and glutamatergic postsynaptic currents in cultured embryonic rat spinal neurons SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE Ca2+ currents; cell culture; differentiation; synapses ID INHIBITORY SYNAPTIC CURRENTS; CALCIUM-CHANNEL TYPES; DORSAL HORN NEURONS; HIPPOCAMPAL-NEURONS; IN-VITRO; CELLS; CORD; GABA; DIFFERENTIATION; TRANSMISSION AB The effects of astrocytes on the emergence of synaptic transients and excitable membrane properties in cultured, embryonic, rat ventral spinal neurons were studied with electrical and optical recording techniques. Neurons on astrocytes had significantly longer neurites and an accelerated rate of growth in surface membrane during the initial 24 h in culture compared to neurons on poly-D-lysine (PDL). GABAergic (GABA, gamma-aminobutyric acid) and glutamatergic transients appeared spontaneously in co-cultured neurons by 24 h. GABAergic quanta did not appear in neurons on PDL until 4 days in culture, and glutamatergic transients did not emerge until 7 days in culture. Astrocyte-conditioned medium (ACM) partially mimicked the effects of direct astrocytic contact. GABAergic transients appeared by 2 days, and glutamatergic signals by 4 days in neurons on PDL exposed to ACM. All of the spontaneous, synaptic-like transients were eliminated by tetrodotoxin or Ca-o(2+)-free saline, implicating voltage-dependent cation channels in their generation. Astrocytes immediately and significantly increased the density of voltage-dependent Na+ currents compared to neurons on PDL, but by the end of 24 h, Na+ current densities were identical. Electrophysiological and optical recording revealed comparable densities of high-voltage-activated (HVA) Ca2+ currents on both co-cultured neurons and neurons on PDL throughout the first week. However, neurons on astrocytes had significantly greater contributions of P/Q-type currents and lesser contributions of L-type currents beginning at 24 h and continuing for 7 days. The contribution of N-type current was significantly more in co-cultured neurons only at 24 h. Thus, in vitro, astrocytes help to differentiate specific excitable membrane properties in spinal neurons, along with GABAergic and glutamatergic forms of synaptic transmission. C1 NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Li, YX (reprint author), NINDS, Neurophysiol Lab, NIH, Bldg 36,Rm 4C-02, Bethesda, MD 20892 USA. NR 41 TC 16 Z9 16 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JUL PY 1999 VL 11 IS 7 BP 2537 EP 2550 DI 10.1046/j.1460-9568.1999.00679.x PG 14 WC Neurosciences SC Neurosciences & Neurology GA 211NT UT WOS:000081175400035 PM 10383643 ER PT J AU Adali, O Carver, GC Philpot, RM AF Adali, O Carver, GC Philpot, RM TI The effect of arginine-428 mutation on modulation of activity of human liver flavin monooxygenase 3 (FMO3) by imipramine and chlorpromazine SO EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY LA English DT Article; Proceedings Paper CT 16th European Workshop on Drug Metabolism CY JUN 21-26, 1998 CL COPENHAGEN, DENMARK SP European Soc Biochem Pharmacol DE flavin-containing monooxygenases; FMO3; liver; human; imipramine; chlorpromazine ID KIDNEY MICROSOMES; N-OXIDATION; GENE FAMILY; METABOLISM; RABBIT; METHIONINE; FORM AB This study was carried out to investigate the molecular basis for modulation of recombinant FMO3-catalyzed activity by the tricyclicantidepressants, imipramine and chlorpromazine. A mutant of human liver FMO3 (T428R) was formed by site-directed mutagenesis and characterized along with the native enzyme in order to elucidate a possible structure-function relationship. Functional properties of native and T428R human FMO3s were studied with methimazole as substrate. Both enzymes catalyzed the S-oxidation of methimazole with the same Km value. Imipramine modulated the activities of the native and T428R human FMO3s differently; the activity of the native FMO3 was increased at all concentrations, whereas the activity of the mutant enzyme was inhibited at concentrations above 300 mu M. Chlorpromazine activated the native enzyme at all concentrations of methimazole but activated the mutant enzyme only at high substrate concentrations. The direction (activation or inhibition) and extend of modulation of FMO3 activity is not only dependent on the concentration of the modulator, it is also dependent on the substrate concentration. This study confirms our previous findings with FMO1 that position 428 is important in the interaction of the FMO with modulators. C1 Middle E Tech Univ, Dept Biol, TR-06531 Ankara, Turkey. Natl Inst Environm Hlth Sci, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Adali, O (reprint author), Middle E Tech Univ, Dept Biol, TR-06531 Ankara, Turkey. NR 27 TC 0 Z9 0 U1 0 U2 1 PU GUSTAV FISCHER VERLAG PI JENA PA VILLENGANG 2, D-07745 JENA, GERMANY SN 0940-2993 J9 EXP TOXICOL PATHOL JI Exp. Toxicol. Pathol. PD JUL PY 1999 VL 51 IS 4-5 BP 271 EP 276 PG 6 WC Pathology; Toxicology SC Pathology; Toxicology GA 233AH UT WOS:000082403000002 PM 10445381 ER PT J AU Lundberg, MS Crow, MT AF Lundberg, MS Crow, MT TI Age-related changes in the signaling and function of vascular smooth muscle cells SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE atherosclerosis; vascular injury; vascular smooth muscle cells; intima; neointima; TGF-beta 1; bFGF; PDGF; calcium; calmodulin-dependent protein kinases; integrins ID PROTEIN-KINASE-II; FIBROBLAST GROWTH-FACTOR; GLYCATION END-PRODUCTS; ATHEROSCLEROTIC LESIONS; OXIDANT STRESS; MIGRATION; INJURY; PROLIFERATION; DYSFUNCTION; INHIBITION AB Aging is an independent risk factor for the development of atheroscelrosis, a vascular abnormality that plays a significant role in the development of many cardiovascular disorders. Animal experiments have demonstrated that aging predisposes the vasculature to advanced atherosclerotic disease and vessel injury and that this predisposition is a function of age-associated changes in the vessel wall itself. Because vascular smooth muscle cells play important roles in the pathogenesis of many vascular disorders, identifying age-associated differences in the way these cells respond to extracellular clues has been an area of active research. Currently, the most remarkable differences in intracellular signaling between vascular smooth muscle cells isolated from young and old animals are related to the control of cell migration through the CamKII pathways and the accelerated transition of older vascular smooth muscle cells from the contractile to the synthetic phenotype. These differences may be due to alternative signaling pathways revealed by the inability of older cells to respond to inhibitors, such as transforming growth factor (TGF)-beta 1, or to altered interactions with the extracellular matrix resulting from age-associated shifts in integrin expression or changes in the matrix composition of blood vessels. The exact role that thew alterations have in explaining age-associated differences in the response of the vessel wall to injury and its increased susceptibility to developing advanced atherosclerotic lesions remains to be determined but will be guided by studies on intracellular signaling mechanisms. (C) 1999 Elsevier Science Inc. All rights reserved. C1 NIA, Vasc Biol Unit, Cardiovasc Sci Lab, Gerontol Res Ctr,NIH, Baltimore, MD 21224 USA. RP Crow, MT (reprint author), NIA, Vasc Biol Unit, Cardiovasc Sci Lab, Gerontol Res Ctr,NIH, Baltimore, MD 21224 USA. NR 39 TC 37 Z9 38 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD JUL PY 1999 VL 34 IS 4 BP 549 EP 557 DI 10.1016/S0531-5565(99)00036-4 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 226VQ UT WOS:000082043700008 PM 10817810 ER PT J AU Keller, JR Gooya, JM Smith, MR Dermott, JM Weiler, SR AF Keller, JR Gooya, JM Smith, MR Dermott, JM Weiler, SR TI P205 (D3): A nuclear protein induced during the differentiation of hematopoietic progenitor cells with growth inhibitory properties. SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 SAIC, IRSP, Frederick, MD USA. NCI, FCRDC, Frederick, MD USA. NCI, LMI, Frederick, MD USA. LTI Inc, Rockville, MD USA. NIH, LI, Baltimore, MD 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 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 1999 VL 27 IS 7 SU 1 MA 62 BP 52 EP 52 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 209CM UT WOS:000081030100063 ER PT J AU Linnekin, D Ashman, L Ferrao, P Chian, R Keller, J AF Linnekin, D Ashman, L Ferrao, P Chian, R Keller, J TI Signaling mechanisms of an oncogenic form of c-Kit in hematopoietic cells SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 FCRDC, NCI, DBS, Basic Res Lab, Frederick, MD USA. Inst Med & Vet Sci, Adelaide, SA 5000, Australia. RI ASHMAN, LEONIE/G-7631-2013 OI ASHMAN, LEONIE/0000-0003-3559-3611 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 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 1999 VL 27 IS 7 SU 1 MA 79 BP 56 EP 56 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 209CM UT WOS:000081030100080 ER PT J AU Schwartz, GN Fukazawa, M Gress, RE AF Schwartz, GN Fukazawa, M Gress, RE TI Modulatory effects of MIG chemokine on P16(INK4A) (CDKN2) expression in CD34+cells stimulated with IL-3 and IGF-II. SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 NCI, Med Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 1999 VL 27 IS 7 SU 1 MA 232 BP 98 EP 98 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 209CM UT WOS:000081030100233 ER PT J AU Drize, NJ Todria, TV Manakova, TE Gerasimova, LP Drutskaya, MS Chertkov, JL Alimzhanov, MB Kuprash, DV Turetskaya, RL Rajewsky, K Pfeffer, K Nedospasov, SA AF Drize, NJ Todria, TV Manakova, TE Gerasimova, LP Drutskaya, MS Chertkov, JL Alimzhanov, MB Kuprash, DV Turetskaya, RL Rajewsky, K Pfeffer, K Nedospasov, SA TI Altered hematopoiesis in mice with combined LT TNF deficiencies SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Hematol Sci Ctr, Moscow, Russia. Moscow State Univ, Belozersky Inst Phys Chem Biol, Moscow, Russia. Russian Acad Sci, VA Engelhardt Mol Biol Inst, Moscow 117901, Russia. SAIC Frederick, IRSP, NCI, FCRDC, Frederick, MD USA. Univ Cologne, Inst Genet, D-5000 Cologne, Germany. Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, D-8000 Munich, Germany. RI Nedospasov, Sergei/J-5936-2013; Nedospasov, Sergei/L-1990-2015; Kuprash, Dmitry/O-4899-2015; Nedospasov, Sergei/Q-7319-2016 OI Kuprash, Dmitry/0000-0002-1488-4148; 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 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 1999 VL 27 IS 7 SU 1 MA 256 BP 104 EP 104 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 209CM UT WOS:000081030100258 ER PT J AU Barrett, J Childs, R Clave, E Epperson, D Bahceci, E Contentin, N Jayasekera, D AF Barrett, J Childs, R Clave, E Epperson, D Bahceci, E Contentin, N Jayasekera, D TI Durable remissions of chronic myeloid leukemias following low intensity preparative regimens due solely to an allogeneic graft-vs-leukemia effect: Are myeloablative regimens necessary? SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 NHLBI, Bone Marrow Transplant Unit, Hematol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 1999 VL 27 IS 7 SU 1 MA 360 BP 131 EP 131 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 209CM UT WOS:000081030100362 ER PT J AU Takenaka, T Hendrickson, CS Tworek, DM Tudor, M Schiffmann, R Brady, RO Medin, JA AF Takenaka, T Hendrickson, CS Tworek, DM Tudor, M Schiffmann, R Brady, RO Medin, JA TI Enzymatic and functional correction along with long-term enzyme secretion from transduced bone marrow hematopoietic stem progenitor and stromal cells derived from patients with Fabry disease SO EXPERIMENTAL HEMATOLOGY LA English DT Article DE Fabry disease; retroviral gene transfer; CD34(+) cells; long-term bone marrow culture ID HUMAN ALPHA-GALACTOSIDASE; MEDIATED GENE-TRANSFER; EX-VIVO EXPANSION; RETROVIRAL VECTOR; ENDOTHELIAL-CELLS; GAUCHER PATIENTS; IN-VITRO; TRANSPLANTATION; DEFICIENCY; EXPRESSION AB Fabry disease is a lysosomal storage disorder that is due to a deficiency in alpha-galactosidase A (alpha-gal A). Previously we have shown that a recombinant retrovirus synthesized for the transfer of the human alpha-gal A coding sequence was able to engineer enzymatic correction of the hydrolase deficiency in fibroblasts and lymphoblasts from Fabry patients. The corrected cells secreted alpha-gal A that was taken up and utilized by uncorrected bystander cells, thus demonstrating metabolic cooperativity. In separate experiments we used transduced murine bone marrow cells and successfully tested and quantitated this phenomenon in vivo. In the present studies, which were designed to bring this therapeutic approach closer to clinical utility, we establish that cells originating from the bone marrow of numerous Fabry patients and normal volunteers can be effectively transduced and that these target cells demonstrate metabolic cooperativity. Both isolated CD34(+)-enriched cells and long-term bone marrow culture cells, including nonadherent hematopoietic cells and adherent stromal cells, were transduced. The transferred gene generates increased intracellular alpha-gal A enzyme activity in these cells. Further, it causes functional correction of lipid accumulation and provides for longterm alpha-gal A secretion. Collectively, these results indicate that a multifaceted gene transfer approach to bone marrow cells may be of therapeutic benefit for patients with Fabry disease. (C) 1999 International Society for Experimental Hematology. Published by Elsevier Science Inc. C1 Univ Illinois, Dept Med, Hematol Oncol Sect, Chicago, IL 60607 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Medin, JA (reprint author), Univ Illinois, Dept Med, Hematol Oncol Sect, MBRB Room 3150 M-C 734,900 S Ashland Ave, Chicago, IL 60607 USA. NR 38 TC 26 Z9 29 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 1999 VL 27 IS 7 BP 1149 EP 1159 DI 10.1016/S0301-472X(99)00050-8 PG 11 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 207ZT UT WOS:000080966200005 PM 10390190 ER PT J AU Horwitz, ME Malech, HL Anderson, SM Girard, LJ Bodine, DM Orlic, D AF Horwitz, ME Malech, HL Anderson, SM Girard, LJ Bodine, DM Orlic, D TI Granulocyte colony-stimulating factor mobilized peripheral blood stem cells enter into G(1) of the cell cycle and express higher levels of amphotropic retrovirus receptor mRNA SO EXPERIMENTAL HEMATOLOGY LA English DT Article DE cell cycle; amphotrophic receptor; retrovirus; stem cell; granulocyte colony-stimulating factor ID APE LEUKEMIA-VIRUS; BONE-MARROW; PROGENITOR CELLS; CD34(+) CELLS; MESSENGER-RNA; GENE-TRANSFER; AUTOLOGOUS TRANSPLANTATION; HEMATOPOIETIC PROGENITORS; FUNCTIONAL-HETEROGENEITY; SURFACE RECEPTORS AB We compared the cell cycle status and expression of mRNA for the amphotropic retroviral receptor in hematopoietic stem cells isolated from bone marrow and cytokine mobilized peripheral blood, CD34(+) cells from six normal volunteers were enriched by immune selection from steady-state bone marrow and granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood (10 mu g/kg/day for 5 days), Cell cycle status of the phenotypically primitive CD34(+)CD38(-) hematopoietic stem cell population was analyzed using a four-color flow cytometry technique that distinguished the G(0), G(1), and S/G(2)/M phases of the cell cycle, Semiquantitative reverse transcriptase-polymerase chain reaction was performed to measure mRNA expression of the amphotropic retroviral receptor. Peripheral blood hematopoietic stem cells had 2.6-fold more cells in the G(1) phase of the cell cycle compared to steady-state bone marrow. Furthermore, lineage(-)CD34(+)CD38(-) cells from G-CSF mobilized peripheral blood had a fourfold higher level of amphotropic retrovirus receptor mRNA. In conclusion, we found that CD34(+)CD38(-) hematopoietic stem cells isolated from G-CSF mobilized peripheral blood differ from those isolated from steady-state bone marrow in that a significant proportion have entered the G(1) phase of the cell cycle and express higher levels of amphotropic receptor mRNA. These biologic properties are consistent with the reported rapid recovery of hematopoietic function following transplantation with peripheral blood hematopoietic stem cells and make these cells a preferred target for retroviral-based gene transfer. (C) 1999 International Society for Experimental Hematology. Published by Elsevier Science Inc. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Hematopoiesis Sect, NIH, Bethesda, MD USA. RP Horwitz, ME (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Room 11N113, Bethesda, MD 20892 USA. NR 41 TC 18 Z9 19 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 1999 VL 27 IS 7 BP 1160 EP 1167 DI 10.1016/S0301-472X(99)00049-1 PG 8 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 207ZT UT WOS:000080966200006 PM 10390191 ER PT J AU Chaudhuri, AR St Jeor, S Maciejewski, JP AF Chaudhuri, AR St Jeor, S Maciejewski, JP TI Apoptosis induced by human cytomegalovirus infection can be enhanced by cytokines to limit the spread of virus SO EXPERIMENTAL HEMATOLOGY LA English DT Article DE HCMV; apoptosis; Fas; interferon; cytokines ID TUMOR-NECROSIS-FACTOR; FAS ANTIGEN EXPRESSION; HUMAN-IMMUNODEFICIENCY-VIRUS; INTERFERON-GAMMA; FACTOR-ALPHA; HUMAN MACROPHAGES; IMMUNE-RESPONSES; GLYCOPROTEIN-B; T-CELLS; LYMPHOCYTES AB Fas-mediated apoptosis is one of the immune effector pathways leading to the elimination of virus infected cells. In vivo, apoptotic signals are delivered to virus infected cells by Fas-L and other cytokines secreted by specific T lymphocytes. Cellular immune response appears to be essential in prevention of human cytomegalovirus (HCMV) disease. We have hypothesized that HCMV infection might directly or indirectly result in upregulation of Fas receptor and in the presence of Fas ligand, lead to apoptosis of infected cells. We show that infection of human fibroblasts with HCMV is associated with up-modulation of Fas-R process that could be further potentiated by interferon (IFN-gamma). Using DNA agarose gel electrophoresis, terminal dideoxy transferase reaction, and annexin assay, we demonstrated that in a productive HCMV infection of human fibroblasts, loss of cell viability was not only due to virus-mediated cell lysis but also to due to apoptosis, IFN-gamma induced relative HCMV resistance and prevented loss in cell viability. In contrast, anti-Fas monoclonal antibody CH11, serving as Fas agonist, resulted in an accelerated loss in viability of infected cells, IFN-gamma in combination with CH11 further increased the rate of apoptosis and compared to cultures with CH11 only, this effect was not restricted to only infected cells. While IFN-gamma did not affect the number of cells expressing immediate early antigen, it markedly reduced structural protein expression. IFN-gamma in combination with CH11, decreased the expression of HCMV matrix protein pp65, reduced the amount of HCMV DNA and infectious virus produced, Our results are consistent with the theory that cells infected with HCMV can be eliminated by immune effector cells via Fas-mediated apoptosis, IFN-gamma, in addition to its intrinsic antiviral activity, primes HCMV infected cells to the action of Fas ligand and Fas-mediated apoptosis. (C) 1999 International Society for Experimental Hematology. Published by Elsevier Science Inc. C1 Univ Nevada, Sch Med, Dept Microbiol, Reno, NV 89557 USA. Univ Nevada, Sch Med, Dept Internal Med, Cell & Mol Biol Program, Reno, NV 89557 USA. RP Maciejewski, JP (reprint author), NHLBI, Hematol Branch, Bldg 10,7C 108, Bethesda, MD 20892 USA. NR 35 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 1999 VL 27 IS 7 BP 1194 EP 1203 DI 10.1016/S0301-472X(99)00044-2 PG 10 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 207ZT UT WOS:000080966200010 PM 10390195 ER PT J AU Kawahara, N Ruetzler, CA Mies, G Klatzo, I AF Kawahara, N Ruetzler, CA Mies, G Klatzo, I TI Cortical spreading depression increases protein synthesis and upregulates basic fibroblast growth factor SO EXPERIMENTAL NEUROLOGY LA English DT Article DE cortical spreading depression; cerebral glucose utilization; cerebral protein synthesis; basic FGF; ischemic tolerance ID CEREBRAL GLUCOSE-UTILIZATION; FIBRILLARY ACIDIC PROTEIN; REDUCES INFARCT SIZE; RAT-BRAIN; NEURONAL DAMAGE; MESSENGER-RNA; BLOOD-FLOW; ISCHEMIC TOLERANCE; HIPPOCAMPAL-NEURONS; POTASSIUM-CHLORIDE AB Protective effects of cortical spreading depression (CSD) against ischemic damage have been demonstrated in cortex when elicited at either 24 h or 3 days prior to ischemia. The present study was carried out to investigate possible mechanisms of neuroprotection following CSD. In Sprague-Dawley rats, 5 M KCl, 5 M NaCl, or physiological saline was applied to the cortex for 1 h. Repetitive CSD waves were elicited only in the KCl group. Measurements of cerebral glucose utilization demonstrated a marked reduction in affected cortex and subcortical regions in both the NaCl and the KCl groups, whereas cortical and hippocampal protein synthesis was discretely increased only in the KCl group. Immunohistochemistry of GFAP demonstrated a rapid activation in reactive astrocytes at 3 days in the KCl group whereas only a discrete activation was observed in the NaCl group, Similar changes were observed for basic fibroblast growth factor. Our results suggest that CSD-induced ischemic tolerance is not due to a reduction in energy metabolism but rather is associated with an upregulation of trophic factors and glial cell activation which might provide a mechanism for a long-lasting neuroprotection. (C) 1999 Academic Press. C1 NINDS, Stroke Branch, Bethesda, MD 20892 USA. Max Planck Inst Neurol Res, Cologne, Germany. RP Kawahara, N (reprint author), Univ Tokyo, Dept Neurosurg, Fac Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138655, Japan. NR 57 TC 35 Z9 36 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUL PY 1999 VL 158 IS 1 BP 27 EP 36 DI 10.1006/exnr.1999.7091 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 218PW UT WOS:000081561800003 PM 10448415 ER PT J AU Conejero, C Wright, R Freed, W AF Conejero, C Wright, R Freed, W TI Glutamate and antimitotic agents induce differentiation, p53 activation, and apoptosis in rodent neostriatal cell lines immortalized with the tsA58 allele of SV40 large T antigen SO EXPERIMENTAL NEUROLOGY LA English DT Article DE SV40 large T antigen; cell lines; apoptosis; p53; PC12 cell ID WILD-TYPE P53; BREAST-TUMOR CELLS; MYELOID-LEUKEMIA CELLS; NEURONAL DIFFERENTIATION; CONSTITUTIVE EXPRESSION; TOPOISOMERASE-II; STRAND BREAKAGE; GENE-EXPRESSION; PRECURSOR CELLS; GROWTH ARREST AB The tsA58 allele of SV40 large T antigen has the ability to immortalize cells, which is thought to be due, in part, to binding of p53 protein by T antigen at 33 degrees C. At the nonpermissive temperature (39.5 degrees C), it is thought that p53 is released, inducing growth arrest, vulnerability to apoptosis, and loss of the immortal phenotype. In cell lines derived from the rat neostriatum immortalized with tsA58, the toxic agents Adriamycin, cytosine arabinoside, and glutamate induced apoptosis and increased p53 activity and differentiation. The apoptosis and p53-inducing effects of the drugs were not greater at 39.5 degrees C compared to 33 degrees C, suggesting that p53 is not effectively blocked even at 33 degrees C. Growth arrest was not induced under most treatment conditions despite p53 induction. On the other hand, process extension was enhanced at 39.5 degrees C compared to 33 degrees C. Therefore, these cell lines are temperature sensitive with respect to differentiation, but not growth regulation or apoptosis. (C) 1999 Academic Press. C1 NIDA, Cellular Neurobiol Branch, Dev & Plast Sect, Baltimore, MD 21224 USA. RP Conejero, C (reprint author), NIDA, Cellular Neurobiol Branch, Dev & Plast Sect, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 91 TC 7 Z9 7 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUL PY 1999 VL 158 IS 1 BP 109 EP 120 DI 10.1006/exnr.1999.7083 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 218PW UT WOS:000081561800010 PM 10448422 ER PT J AU Bornstein, SR Tajima, T Eisenhofer, G Haidan, A Aguilera, G AF Bornstein, SR Tajima, T Eisenhofer, G Haidan, A Aguilera, G TI Adrenomedullary function is severely impaired in 21-hydroxylase-deficient mice SO FASEB JOURNAL LA English DT Article DE 21-OH deficiency; adrenal medulla; catecholamine synthesis ID CONGENITAL ADRENAL-HYPERPLASIA; NEURAL CREST DERIVATIVES; CHROMAFFIN CELLS; ADRENOCORTICAL-CELLS; SPLANCHNIC NERVE; INTRAADRENAL INTERACTIONS; LEARNING-DISABILITIES; PRENATAL TREATMENT; CORTICAL-CELLS; GROWTH-FACTORS AB Deficiency of 21-hydroxylase (21-OH), one of the most common genetic defects in humans, causes low glucocorticoid and mineralocorticoid production by the adrenal cortex, but the effect of this disorder on the adrenomedullary system is unknown. Therefore, we analyzed the development, structure, and function of the adrenal medulla in 21-OH-deficient mice, an animal model resembling human congenital adrenal hyperplasia, Chromaffin cells of el-OH-deficient mice exhibited ultrastructural features of neuronal transdifferentiation with reduced granules, increased rough endoplasmic reticulum and small neurite outgowth. Migration of chromaffin cells in the adrenal to form a central medulla was impaired. Expression of phenylethanolamine-N-methyltransferase (PNMT) was reduced to 27 +/- 9% (P<0.05), as determined by quantitative TaqMan polymerase chain reaction, and there was a significant reduction of cells staining positive for PNMT in the adrenal medulla of the 21-OH-deficient mice, Adrenal contents of epinephrine were decreased to 30 +/- 2% (P<0.01) whereas norepinephrine and dopamine levels were reduced to 57 +/- 4% (P<0.01) and 50 +/- 9% (P<0.05), respectively. 21-OH-deficient mice demonstrate severe adrenomedullary dysfunction, with alterations in chromaffin cell migration, development, structure, and catecholamine synthesis. This hitherto unrecognized mechanism may contribute to the frequent clinical, mental, and therapeutic problems encountered in humans with this genetic disease. C1 NICHD, Dev Endocrinol Branch, NIH, Sect Endocrine Physiol, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. Univ Leipzig, Dept Internal Med, D-7010 Leipzig, Germany. RP Bornstein, SR (reprint author), NICHD, Dev Endocrinol Branch, NIH, Sect Endocrine Physiol, Bldg 10,Rm 10n262,10 Ctr Dr MSC 1862, Bethesda, MD 20892 USA. NR 71 TC 44 Z9 44 U1 2 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUL PY 1999 VL 13 IS 10 BP 1185 EP 1194 PG 10 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 213GR UT WOS:000081264800007 PM 10385609 ER PT J AU Aravind, L Ponting, CP AF Aravind, L Ponting, CP TI The cytoplasmic helical linker domain of receptor histidine kinase and methyl-accepting proteins is common to many prokaryotic signalling proteins SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE histidine kinase; chemotaxis; PP2C-like phosphatase; adenylyl cyclase; PAS domain; regulator of receptor function; sequence analysis ID ESCHERICHIA-COLI; ASPARTATE CHEMORECEPTOR; MUTATIONAL ANALYSIS; CHEMOTAXIS PROTEINS; OSMOSENSOR ENVZ; REGION; IDENTIFICATION; COMMUNICATION; CONSERVATION; SUPERFAMILY AB Mutations in the cytoplasmic linker regions of receptor histidine kinase and chemoreceptor proteins have been shown previously to significantly impair receptor functions. Here we demonstrate significant sequence similarities between these regions in numerous histidine kinases, methyl-accepting proteins, adenylyl cyclases and other prokaryotic signalling proteins. It is suggested that these 'HAMP domains' possess roles of regulating the phosphorylation or methylation of homodimeric receptors by transmitting the conformational changes in periplasmic ligand-binding domains to cytoplasmic signalling kinase and methyl-acceptor domains. (C) 1999 Published by Elsevier Science B.V. All rights reserved. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Texas A&M Univ, Dept Biol, College Stn, TX 77843 USA. RP Ponting, CP (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. NR 37 TC 251 Z9 260 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1097 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD JUL 1 PY 1999 VL 176 IS 1 BP 111 EP 116 DI 10.1111/j.1574-6968.1999.tb13650.x PG 6 WC Microbiology SC Microbiology GA 214JE UT WOS:000081324200017 PM 10418137 ER PT J AU Bialkowski, K Bialkowska, A Anderson, LM Kasprzak, KS AF Bialkowski, K Bialkowska, A Anderson, LM Kasprzak, KS TI Higher activity of 8-oxo-2 '-deoxyguanosine 5 '-triphosphate pyrophosphohydrolase (8-oxo-dGTPase) coincides with lower background levels of 8-oxo-2 '-deoxyguanosine in DNA of fetal compared with maternal mouse organs SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE 8-oxo-dGTPase; MTH1; MutT; 8-oxo-2 '-deoxyguanosine; oxidative DNA damage; mutagenesis; free radicals ID MUTAGENIC SUBSTRATE; ESCHERICHIA-COLI; NUCLEOSIDE TRIPHOSPHATASE; OXIDATIVE DAMAGE; MUTT PROTEIN; HUMAN-CELLS; CLONING; CDNA; 8-HYDROXYDEOXYGUANOSINE; TRANSVERSION AB Mammalian homologues of Escherichia coli MutT, a protein having 8-oxo-2'-deoxyguanosine 5'-triphosphate pyrophosphohydrolase (8-oxo-dGTPase) activity, are thought to play the same role in preventing the incorporation of promutagenic 8-oxo-2'-deoxyguanosine (8-oxo-dG) into DNA. One could thus expect that higher activity of 8-oxo-dGTPase should correlate with a lower background level of 8-oxo-dG in nuclear DNA. During transplacental carcinogenesis experiments, in control healthy Swiss mice on day 18 of gestation we found consistently lower levels of 8-oxo-dG in DNA in fetal livers and lungs (1.74 +/- 0.04 SE and 1.49 +/- 0.08 SE 8-oxo-dG/10(5) dG, respectively; pooled organs of fetuses of 8 dams) as compared with maternal organs (3.05 +/- 0.20 SE and 3.08 +/- 0.17 SE 8-oxo-dG/105 dG, respectively; n = 8). The 8-oxo-dGTPase activity determination in the same organs revealed that the lower levels of 8-oxo-dG in fetal DNA did, indeed, coincide with higher 8-oxo-dGTPase activity (48.8 +/- 2.6 SE and 52.5 +/- 2.5 SE U/mg protein in livers and lungs, respectively); and vice versa, higher 8-oxo-dG levels in DNA of maternal organs were associated with lower levels of 8-oxo-dGTPase activity (24.3 +/- 1.3 SE and 4.7 +/- 0.6 SE U/mg protein, as above). Without excluding other reasons for the relatively low 8-oxo-dG background in DNA of fetal tissues (e.g., higher level of antioxidants and antioxidative enzymes; more efficient DNA repair), this inverse relationship may support or at least does not contradict the concept of a guardian role of 8-oxo-dGTPase against 8-oxo-dGTP mutagenicity in mammalian cells. (C) 1999 Elsevier Science Inc. C1 NCI, FCRDC, Comparat Carcinogenesis Lab, Ft Detrick, MD 21702 USA. SAIC Frederick, Intramural Res Support Program, Frederick, MD USA. Univ Sch Med Sci, Dept Clin Biochem, Bydgoszcz, Poland. Univ Sch Med Sci, Dept Pathophysiol, Bydgoszcz, Poland. RP Bialkowski, K (reprint author), NCI, FCRDC, Comparat Carcinogenesis Lab, Bldg 538,Rm 205E, Ft Detrick, MD 21702 USA. RI Bialkowski, Karol/E-2328-2014; Bialkowska, Aneta/G-9280-2014 FU NCI NIH HHS [N01-CO-56000] NR 27 TC 18 Z9 19 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL PY 1999 VL 27 IS 1-2 BP 90 EP 94 DI 10.1016/S0891-5849(99)00040-4 PG 5 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 220FW UT WOS:000081654800012 PM 10443924 ER PT J AU Dikalov, S Fink, B Skatchkov, M Bassenge, E AF Dikalov, S Fink, B Skatchkov, M Bassenge, E TI Comparison of glyceryl trinitrate-induced with pentaerythrityl tetranitrate-induced in vivo formation of superoxide radicals: Effect of vitamin C SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE superoxide radical; nitric oxide; organic nitrates; nitrate tolerance; spin trap; vitamin C; free radicals ID VASCULAR SMOOTH-MUSCLE; NITRATE TOLERANCE; NITRIC-OXIDE; IN-VIVO; ENDOTHELIAL DYSFUNCTION; HEART-FAILURE; PEROXYNITRITE; SUPPLEMENTATION; VASODILATION; ACTIVATION AB Glyceryl trinitrate (GTN) and pentaerythrityl tetranitrate (PETN) are among the most known organic nitrates that are used in cardiovascular therapy as vasodilators. However, anti-ischemic therapy with organic nitrates is complicated by the induction of nitrate tolerance. When nitrates are metabolized to release nitric oxide (NO), there is considerable coproduction of superoxide radicals in vessels leading to inactivation of NO. However, nitrate-induced increase of superoxide radical formation in vivo has not been reported. In this work, the authors studied the in vivo formation of superoxide radicals induced by treatment with PETN or GTN and determined the antioxidant effect of vitamin C. The formation of superoxide radicals was determined by the oxidation of 1-hydroxy-3-carboxy-pyrrolidine (CP-H) to paramagnetic 3-carboxy-proxyl (CP) using electron spin resonance spectroscopy. CP-H (9 mg/kg intravenous bolus and 0.225 mg/kg per minute continuous intravenous GTN or PETN 130 mu g/kg) were infused into anesthetized rabbits. Every 5 min, blood samples were obtained from Arteria carotis to measure the CP formation. Both PETN and GTN showed similar vasodilator effects. Formation of CP in blood after infusions of GTN and PETN were 2.0 +/- 0.4 mu M and 0.98 +/- 0.23 mu M, respectively. Pretreatment with 30 mg/kg vitamin C led to a significant decrease in CP formation: 0.27 +/- 0.14 mu M (vitamin C plus GTN) and 0.34 +/- 0.15 mu M (vitamin C plus PETN). Pretreatment of animals with superoxide dismutase (15,000 units/kg) significantly inhibited nitrate-induced nitroxide formation. Therefore, in vivo infusion of GTN or PETN in rabbits increased the formation of superoxide radicals in the vasculature. PETN provoked a minimal stimulation of superoxide radical formation without simultaneous development of nitrate tolerance. The data suggest that the formation of superoxide radicals induced by organic nitrate correlates with the development of nitrate tolerance. The effect of vitamin C on CP formation leads to the conclusion that vitamin C can be used as an effective antioxidant for protection against nitrate-induced superoxide radical formation in vivo. (C) 1999 Elsevier Science Inc. C1 Russian Acad Sci, Inst Chem Kinet & Combust, Novosibirsk 630090, Russia. Univ Freiburg, Inst Appl Physiol, Freiburg, Germany. RP Dikalov, S (reprint author), NIEHS, MD F002,POB 12233, Durham, NC 27709 USA. NR 33 TC 43 Z9 44 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL PY 1999 VL 27 IS 1-2 BP 170 EP 176 DI 10.1016/S0891-5849(99)00066-0 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 220FW UT WOS:000081654800021 PM 10443933 ER PT J AU Ried, T Heselmeyer-Haddad, K Blegen, H Schrock, E Auer, G AF Ried, T Heselmeyer-Haddad, K Blegen, H Schrock, E Auer, G TI Genomic changes defining the genesis, progression, and malignancy potential in solid human tumors: A phenotype genotype correlation SO GENES CHROMOSOMES & CANCER LA English DT Review ID MOLECULAR CYTOGENETIC ANALYSIS; HIGH GENETIC INSTABILITY; NUCLEAR-DNA CONTENT; CHROMOSOMAL-ABERRATIONS; COLORECTAL TUMORIGENESIS; HYBRIDIZATION REVEALS; INSITU HYBRIDIZATION; CERVICAL CARCINOMAS; RECURRENT PATTERN; UTERINE CERVIX AB The transition of normal epithelium to invasive carcinoma occurs sequentially. In colorectal and cervical carcinogenesis, this transition is reflected by histomorphologically defined grades of increasing dysplasia that untreated may progress to invasive disease. In an attempt to understand the role of chromosomal aberrations during tumorigenesis we have applied comparative genomic hybridization using DNA extracted from defined stages of colorectal and cervical tumors, from low- and high-grade astrocytic tumors and from diploid and aneuploid breast carcinomas. Genetic instability, as measured by the number of chromosomal copy alterations per case, increases significantly at the transition from precursor lesions to invasive carcinomas and continues to increase with tumor stage. Aggressive tumors have a higher number of copy alterations per case. High-level copy number changes (amplifications) become more prevalent in advanced-stage disease. Subtractive karyograms of chromosomal gains and losses were used to map tumor stage-specific chromosomal aberrations and clearly showed that nonrandom chromosomal aberrations occur during disease progression. In colorectal and cervical tumors, chromosomal copy number changes were correlated with nuclear DNA content, proliferative activity, expression levels of the tumor suppressor gene TP53, and the cyclin-dependent kinase inhibitor P21/WAFI, as well as the presence of viral genomes, Here we summarize and review the results of this comprehensive phenotype/genotype correlation and discuss the relevance of stage-specific chromosomal aberrations with respect to diagnostic applications. Published 1999 Wiley-Liss, Inc.dagger. C1 Karolinska Hosp & Inst, Canc Centrum, Dept Pathol, Div Cell & Mol Anal, S-17176 Stockholm, Sweden. NIH, Natl Human Genome Res Inst, Bethesda, MD USA. RP Auer, G (reprint author), Karolinska Hosp & Inst, Canc Centrum, Dept Pathol, Div Cell & Mol Anal, S-17176 Stockholm, Sweden. NR 38 TC 212 Z9 214 U1 0 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD JUL PY 1999 VL 25 IS 3 BP 195 EP 204 DI 10.1002/(SICI)1098-2264(199907)25:3<195::AID-GCC1>3.0.CO;2-8 PG 10 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 202CR UT WOS:000080635000001 PM 10379865 ER PT J AU Weaver, ZA McCormack, SJ Liyanage, M du Manoir, S Coleman, A Schrock, E Dickson, RB Ried, T AF Weaver, ZA McCormack, SJ Liyanage, M du Manoir, S Coleman, A Schrock, E Dickson, RB Ried, T TI A recurring pattern of chromosomal aberrations in mammary gland tumors of MMTV-cmyc transgenic mice SO GENES CHROMOSOMES & CANCER LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; PRIMARY BREAST-CANCER; C-MYC; MOUSE MAMMARY; COPY NUMBER; TUMORIGENESIS; AMPLIFICATION; INSTABILITY; CARCINOMAS; GENE AB Mice carrying the MMTV-cmyc transgene develop mammary tumors at 9 to 12 months of age, Little is known about karyotypic changes in this model of human breast cancer. We have developed and applied molecular cytogenetic techniques to study chromosomal aberrations that occur in these tumors, namely, comparative genomic hybridization and spectral karyotyping. Cell lines from eight tumors were established and analyzed, four of which carried a heterozygous p53 mutation. All of the tumor cell lines revealed increases in ploidy and/or multiple numerical and structural chromosomal aberrations. No consistent differences were observed between cmyclp53(+/+) and cmyclp53(+/-) tumors, suggesting that cmyc induces karyotype instability independent of p53 status. Loss of whole chromosome (Chr) 4 was detected in five of the eight tumors. Parts of Chr 4 are syntenic to human 1p31-p36, a region that is also deleted in human breast carcinomas, Four tumors carried translocations involving the distal portion of Chr I I (syntenic to human chromosome arm 17q), including two translocations T(X; I I), with cytogenetically identical breakpoints. We compare the pattern of chromosomal aberrations with human breast cancers, find similarities in several syntenic regions, and discuss the potential of an interspecies cytogenetic map of chromosomal gains and losses. Published 1999 Wiley-Liss, Inc.dagger. C1 Natl Human Genome Res Inst, Genome Technol Branch, NIH, Bethesda, MD USA. Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC USA. NCI, Genet Lab, Bethesda, MD 20892 USA. RP Weaver, ZA (reprint author), NCI, Dept Genet, Div Clin Sci, 49 Convent Dr, Bethesda, MD 20892 USA. FU ADAMHA HHS [CRADA 9512-8] NR 28 TC 62 Z9 62 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD JUL PY 1999 VL 25 IS 3 BP 251 EP 260 DI 10.1002/(SICI)1098-2264(199907)25:3<251::AID-GCC7>3.0.CO;2-3 PG 10 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 202CR UT WOS:000080635000007 PM 10379871 ER PT J AU Taetle, R Aickin, M Yang, LM Panda, L Emerson, J Roe, D Adair, L Thompson, F Liu, Y Wisner, L Davis, JR Trent, J Alberts, DS AF Taetle, R Aickin, M Yang, LM Panda, L Emerson, J Roe, D Adair, L Thompson, F Liu, Y Wisner, L Davis, JR Trent, J Alberts, DS TI Chromosome abnormalities in ovarian adenocarcinoma: I. Nonrandom chromosome abnormalities from 244 cases SO GENES CHROMOSOMES & CANCER LA English DT Article ID SOLID TUMORS; HUMAN CANCER; ABERRATIONS; CARCINOMA; NEOPLASIA; REARRANGEMENTS; EXPRESSION; LEUKEMIA; MALIGNANCIES; BAND AB Cytogenetics provides important insights into the molecular pathogenesis of human cancers. Although extensive data exist on recurring cytogenetic abnormalities in hematologic cancers, data on individual solid tumor types remain limited. Previous studies of ovarian carcinoma indicated the presence of multiple, complex clonal chromosome abnormalities. Cytogenetics remains one of a few techniques capable of detecting these multiple, simultaneously occurring genetic abnormalities. We describe cytogenetic abnormalities from a series of 244 primary ovarian cancer specimens referred to a single institution. A total of 201/244 cases had fully characterized clonal chromosome abnormalities, of which 134 showed clonal chromosome breakpoints. We used a novel statistical technique to detect nonrandom chromosome breakpoints at the level of chromosome regions. Nonrandom occurrence of chromosome breakpoints was detected at regions 1p1*, 1q1*, 1p2*, 1p2*, 1p3*, 1q3, 3p1*, 1q4*, 6q1*, 6p2, 6q2, 7p1*, 7q1, 7p2*, 11p1*, 11q1, 11q2*, 12p1, 12q2*, 13p1, and 19q1. Simultaneous occurrence of multiple abnormalities was common. However, 120/134 cases had breakpoints at one or more of 13 commonly involved regions (*), suggesting a hierarchy of genetic abnormalities. Among clinical and tumor variables that predict patient survival, tumor grade was significantly associated with the presence of chromosome breakpoints. In additional studies, we show that nonrandom chromosome abnormalities are associated with impaired survival in ovarian cancer and that specific, nonrandomly involved chromosome regions retain significant effects on survival when analyses are controlled for important clinical variables. Additional specific chromosome abnormalities in this series are described, including chromosome gains and losses in near-diploid cases and homogeneously staining regions. These results suggest that recurring, nonrandom chromosome abnormalities are important in the pathogenesis and/or progression of ovarian cancers, and target areas of the genome for molecular genetic studies. (C) 1999 Wiley-Liss, Inc. C1 Univ Arizona, Arizona Canc Ctr, Dept Med, Tucson, AZ 85724 USA. Univ Arizona, Arizona Canc Ctr, Dept Pathol, Tucson, AZ 85724 USA. Natl Human Genome Res Inst, Canc Genet Lab, Bethesda, MD USA. RP Taetle, R (reprint author), Univ Arizona, Arizona Canc Ctr, Dept Med, 1515 N Campbell Ave, Tucson, AZ 85724 USA. FU NCI NIH HHS [CA41183, CA23074]; NIEHS NIH HHS [NIH-ES-95-32] NR 46 TC 54 Z9 54 U1 2 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD JUL PY 1999 VL 25 IS 3 BP 290 EP 300 DI 10.1002/(SICI)1098-2264(199907)25:3<290::AID-GCC12>3.0.CO;2-G PG 11 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 202CR UT WOS:000080635000012 PM 10379876 ER PT J AU Whalen, WA Yoon, JH Shen, RL Dhar, R AF Whalen, WA Yoon, JH Shen, RL Dhar, R TI Regulation of mRNA export by nutritional status in fission yeast SO GENETICS LA English DT Article ID DEPENDENT PROTEIN-KINASE; NUCLEAR-PORE COMPLEX; MESSENGER-RNA EXPORT; SCHIZOSACCHAROMYCES-POMBE; SACCHAROMYCES-CEREVISIAE; NUCLEOCYTOPLASMIC TRANSPORT; FUNCTIONALLY INTERACTS; GLUCOSE REPRESSION; PKA1 GENE; NUCLEOPORIN AB We have isolated a mutation in nup184(nup184-1) that is synthetically lethal with the mRNA export defective rae1-167 mutation in Schizosaccharomyces pombe. The consequence of the synthetic lethality is a defect in mRNA export. The predicted Nup184p is similar to Nup188p of Saccharomyces cerevisiae, and a Nup184-GFP fusion localizes to the nuclear periphery in a punctate pattern. The Delta nup184 null mutant is viable and also is synthetically lethal with rae1-167. In a rae1(+) background, both the nup184-1 and Delta nup184 mutations confer sensitivity to growth in nutrient-rich medium (YES) that is accompanied by nuclear poly(A)(+) RNA accumulation. Removal of the cAMP-dependent protein kinase, Pka1p, relieved the growth and mRNA export defects of nup184 mutants when grown in nutrient-rich medium. The activation of Pka1p is necessary, but not sufficient, to cause the severe poly(A)(+) RNA export defects when nup184 mutant cells are incubated in YES, suggesting nutritional status carl also regulate poly(A)(+) RNA export. Our results suggest that the regulation of poly(A)(+) RNA export by Pka1p kinase appears to be indirect, via a translation-dependent step, but post-translationally; in response to YES. C1 NCI, Basic Sci Lab, NIH, Bethesda, MD 20892 USA. NCI, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP NCI, Basic Sci Lab, NIH, Bldg 41,Rm B506, Bethesda, MD 20892 USA. EM dharr@dce41.nei.nih.gov RI Shen, Rulong/E-4079-2011 NR 53 TC 16 Z9 17 U1 0 U2 0 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 JUL PY 1999 VL 152 IS 3 BP 827 EP 838 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 214RT UT WOS:000081341900002 PM 10388805 ER PT J AU Kasravi, A Walter, MF Brand, S Mason, JM Biessmann, H AF Kasravi, A Walter, MF Brand, S Mason, JM Biessmann, H TI Molecular cloning and tissue-specific expression of the mutator2 gene (mu2) in Drosophila melanogaster SO GENETICS LA English DT Article ID MEIOTIC RECOMBINATION; RNA LOCALIZATION; CHROMOSOME ENDS; CELL-DIVISION; DNA-SEQUENCES; BICOID RNA; OOGENESIS; HOMOLOG; CHECKPOINTS; TRANSPORT AB We present here the molecular cloning and characterization of the mutator2 (mu2) gene of Drosophila melanogaster together with further genetic analyses of its mutant phenotype. mu2 functions in oogenesis during meiotic recombination, during repair of radiation damage in mature oocytes, and in proliferating somatic cells, where mu2 mutations cause an increase in somatic recombination. Our data show that mu2 represents a novel component in the processing of double strand breaks (DSBs) in female meiosis. mu2 does not code for a DNA repair enzyme because mu2 mutants are not hypersensitive to DSB-inducing agents. We have mapped and cloned the mu2 gene and rescued the mu2 phenotype by germ-line transformation with genomic DNA fragments containing the mu2 gene. Sequencing its cDNA demonstrates that mu2 encodes a novel 139-kD protein, which is highly basic in the carboxy half and carries three nuclear localization signals and a helix-loop-helix domain. Consistent with the sex-specific mutant phenotype, the gene is expressed in ovaries but not in testes. During oogenesis its RNA is rapidly transported from the nurse cells into the oocyte where it accumulates specifically at the anterior margin. Expression is also prominent in diploid proliferating cells of larval somatic tissues. Our genetic and molecular data are consistent with the model that mu2 encodes a structural component of the oocyte nucleus. The MU2 protein may be involved in controlling chromatin structure and thus may influence the processing of DNA DSBs. C1 Univ Calif Irvine, Ctr Dev Biol, Irvine, CA 92697 USA. Univ Dundee, Dept Anat & Physiol, Dundee DD1 4HN, Scotland. NIEHS, Genet Mol Lab, Res Triangle Pk, NC 27709 USA. RP Biessmann, H (reprint author), Univ Calif Irvine, Ctr Dev Biol, Irvine, CA 92697 USA. NR 62 TC 8 Z9 9 U1 0 U2 0 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD JUL PY 1999 VL 152 IS 3 BP 1025 EP 1035 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 214RT UT WOS:000081341900018 PM 10388821 ER PT J AU Lin, JP Hirsch, R Jacobsson, LTH Scott, WW Ma, LD Pillemer, SR Knowler, WC Kastner, DL Bale, SJ AF Lin, JP Hirsch, R Jacobsson, LTH Scott, WW Ma, LD Pillemer, SR Knowler, WC Kastner, DL Bale, SJ TI Genealogy construction in a historically isolated population: Application to genetic studies of rheumatoid arthritis in the Pima Indian SO GENETICS IN MEDICINE LA English DT Article DE genealogic approach; rheumatoid arthritis; kinship coefficient; inbreeding coefficient; Pima Indians ID LINKAGE DISEQUILIBRIUM; NATIVE-AMERICANS; ASSOCIATION; PREVALENCE; ADMIXTURE; HAPLOTYPE; DISEASES; COMMON; LOCUS; RATS AB Purpose: Due to the characteristics of complex traits, many traits may not be amenable to traditional epidemiologic methods. We illustrate an approach that defines an isolated population as the "unit" for carrying out studies of complex disease. We provide an example using the Pima Indians, a relatively isolated population, in which the incidence and prevalence of Type 2 diabetes, gallbladder disease, and rheumatoid arthritis (RA) are significantly increased compared with the general U.S. population. A previous study of RA in the Pima utilizing traditional methods failed to detect a genetic effect on the occurrence of the disease. Methods: Our approach involved constructing a genealogy for this population and using a genealogic index to investigate familial aggregation. We developed an algorithm to identify biological relationships among 88 RA cases Versus 4,000 subsamples of age-matched individuals from the same population. Kinship coefficients were calculated for ail possible pairs of RA cases, and similarly for the subsamples. Results: The sum of the kinship coefficient among all combination of RA pairs, 5.92, was significantly higher than the average of the 4,000 subsamples, 1.99 (p < 0.001), and was elevated over that of the subsamples to the level of second cousin, supporting a genetic effect in the familial aggregation. The mean inbreeding coefficient for the Pima was 0.00009, similar to that reported for other populations; none of the RA cases were inbred. Conclusions: The Pima genealogy can be anticipated to provide valuable information for the genetic study of diseases other than RA. Defining an isolated population as the "unit" in which to assess familial aggregation may be advantageous, especially if there are a limited number of cases in the study population. C1 NIAMSD, NIH, Bethesda, MD 20892 USA. Univ Lund, Malmo, Sweden. Johns Hopkins Univ, Baltimore, MD 21218 USA. NIDDKD, NIH, Phoenix, AZ USA. RP Lin, JP (reprint author), Skin Biol Lab, Genet Studies Sect, Bldg 6,Room 429,6 Ctr Dr,MSC 2757, Bethesda, MD 20892 USA. NR 41 TC 10 Z9 10 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD JUL-AUG PY 1999 VL 1 IS 5 BP 187 EP 193 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 248HX UT WOS:000083270000005 PM 11256671 ER PT J AU Grimbacher, B Dutra, AS Holland, SM Fischer, RE Pao, M Gallin, JI Puck, JM AF Grimbacher, B Dutra, AS Holland, SM Fischer, RE Pao, M Gallin, JI Puck, JM TI Analphoid marker chromosome in a patient with hyper-IgE syndrome, autism, and mild mental retardation SO GENETICS IN MEDICINE LA English DT Article DE analphoid; centromere; chromosome 4q21; immunodeficiency; immunoglobulin E; interstitial deletion; Job syndrome; marker ring chromosome ID FATHER-CHILD INCOMPATIBILITY; INTERSTITIAL DELETION; PIEBALD TRAIT; LONG ARM; RETARDED-CHILD; JOBS SYNDROME; GC-SYSTEM; DEL(4)(Q12Q21.1); GENE; KIT AB Hyper-IgE syndrome with recurrent infections (HIES) is a primary immunodeficiency disease characterized by recurrent skin and lung abscesses and extreme elevations of serum IgE, but also involving dentition, bones, and connective tissue. Although the etiology of HIES is unknown, autosomal dominant inheritance has been observed in multiple kindreds. A 17 year old male with sporadic HIES, autism, and mild mental retardation was found to have a supernumerary marker chromosome in peripheral blood lymphocytes and shin fibroblasts. Microdissection and FISH analysis of the marker chromosome showed that it was derived from a small interstitial deletion of one homologue of chromosome 4q21. Lack of hybridization of probes specific for telomeres and alphoid centromeres, including a centromere 4 specific probe, established that the marker was an analphoid ring chromosome. Comparative genotyping of transformed B-cell subclones with (M+) and without (M-) the marker chromosome showed loss of the maternal alleles in M- cells between markers D4S1569 and D4S3010. FISH using YAC clones from 4q21 confirmed the size and location of the interstitial deletion. Thus our patient's phenotypes were associated with de novo formation of a marker chromosome containing 15-20 cM of DNA deleted from his maternally derived chromosome 4. Proximal chromosome 4q therefore is a candidate region for disease genes for both HIES and autism. Identification of genes disrupted or lost during the formation of the marker chromosome as well as linkage studies in kindreds with HIES or autism may help us to understand the etiology of these complex phenotypes. C1 NHGRI, Immunol Genet Sect, GMBB, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Psychiat, Washington, DC 20010 USA. RP Puck, JM (reprint author), NHGRI, Immunol Genet Sect, GMBB, NIH, Bldg 49,Room 3A14,49 Convent Dr, Bethesda, MD 20892 USA. NR 51 TC 19 Z9 19 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD JUL-AUG PY 1999 VL 1 IS 5 BP 213 EP 218 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 248HX UT WOS:000083270000010 PM 11256675 ER PT J AU Makarova, KS Aravind, L Galperin, MY Grishin, NV Tatusov, RL Wolf, YI Koonin, EV AF Makarova, KS Aravind, L Galperin, MY Grishin, NV Tatusov, RL Wolf, YI Koonin, EV TI Comparative genomics of the archaea (Euryarchaeota): Evolution of conserved protein families, the stable core, and the variable shell SO GENOME RESEARCH LA English DT Article ID POLYPEPTIDE-ASSOCIATED COMPLEX; DEPENDENT RNA-POLYMERASES; ESCHERICHIA-COLI; DNA-POLYMERASE; METHANOBACTERIUM-THERMOAUTOTROPHICUM; HYPERTHERMOPHILIC ARCHAEON; BACTERIAL GENOMES; DUPLICATED GENES; MITOTIC CONTROL; PSI-BLAST AB Comparative analysis of the protein sequences encoded in the Four euryarchaeal species whose genomes have been sequenced completely (Methanococcus jannaschii, Methanobacterium thermoautotrophicum, Archaeoglobus fulgidus, and Pyrococcus horikoshii) revealed 1326 orthologous sets, of which 543 are represented in all four species. The proteins that belong to these conserved euryarchaeal Families comprise 31%-35% of the gene complement and may be considered the evolutionarily stable core of the archaeal genomes. The core gene set includes the great majority of genes coding for proteins involved in genome replication and expression, but only a relatively small subset of metabolic functions. For many gene families that are conserved in all euryarchaea, previously undetected orthologs in bacteria and eukaryotes were identified. A number of euryarchaeal synapomorphies (unique shared characters) were identified; these are protein families that possess sequence signatures or domain architectures that are conserved in ail euryarchaea but are not Found in bacteria or eukaryotes. In addition, euryarchaea-specific expansions of several protein and domain families were detected. In tel ms of their appal ent phylogenetic affinities, the archaeal protein families split into bacterial and eukaryotic families. The majority of the proteins that have only eukaryotic orthologs or show the greatest similarity to their eukaryotic counterparts belong to the core set. The families of euryarchaeal genes that are conserved in only two or three species constitute a relatively mobile component of the genomes whose evolution should have involved multiple events of lineage-specific gene loss and horizontal gene transfer. Frequently these proteins have detectable orthologs only in bacteria or show the greatest similarity to the bacterial homologs, which might suggest a significant role of horizontal gene transfer from bacteria in the evolution of the euryarchaeota. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Uniformed Serv Univ Hlth Sci, Dept Pathol, FE Hebert Sch Med, Bethesda, MD 20814 USA. Texas A&M Univ, Dept Biol, College Stn, TX 77843 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 NR 93 TC 201 Z9 211 U1 3 U2 11 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 JUL PY 1999 VL 9 IS 7 BP 608 EP 628 PG 21 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 218KG UT WOS:000081551300002 PM 10413400 ER PT J AU Mintz, L Galperin, E Pasmanik-Chor, M Tulzinsky, S Bromberg, Y Kozak, CA Joyner, A Fein, A Horowitz, M AF Mintz, L Galperin, E Pasmanik-Chor, M Tulzinsky, S Bromberg, Y Kozak, CA Joyner, A Fein, A Horowitz, M TI EHD1 - An EH-domain-containing protein with a specific expression pattern SO GENOMICS LA English DT Article ID GROWTH-FACTOR-I; BARDET-BIEDL-SYNDROME; TYROSINE KINASE SUBSTRATE; ARTICULAR CHONDROCYTES; MEDIATED ENDOCYTOSIS; TRANSGENIC MICE; EPS15 HOMOLOGY; SH3 DOMAIN; IGF-I; INSULIN AB A cDNA that is a member of the eps15 homology (EH)-domain-containing family and is expressed differentially in testis was isolated from mouse and human. The corresponding genes map to the centromeric region of mouse chromosome 19 and to the region of conserved synteny on human chromosome 11q13. Northern analysis revealed two RNA species in mouse. In addition to the high levels in testis, expression was noted in kidney, heart, intestine, and brain. In human, three RNA species were evident. The smaller one was predominant in testis, while the largest species was evident in other tissues as well. The predicted protein sequence has an EH domain at its C-terminus, including an EF, a Ca2+ binding motif, and a central coiled-coil structure, as well, as a nucleotide binding consensus site at its N-terminus. As such, it is a member of the EH-domain-containing protein family and was designated EHD1 (EH domain-containing 1). In cells in tissue culture, we localized EHD1 as a green fluorescent protein fusion protein, in transferrin-containing, endocytic vesicles, Immunostaining of different adult mouse organs revealed major expression of EHD1 in germ cells in meiosis, in the testes, in adipocytes,and in specific retinal layers. Results of ia situ hybridization to whole embryos and immunohistochemical analyses indicated that EHD1 expression was already noted at day 9.5 in the limb buds and pharyngeal arches-and at day 10.5 in sclerotomes, at various elements of the branchial apparatus (mandible and hyoid), and in the occipital region. At day 15.5 ERD1 expression peaked in cartilage, preceding hypertrophy and ossification, and at day 17.5 there was no expression in the bones. The EHD1 gene is highly con-served between nematode, Drosophila, mouse, and human. Its predicted protein structure and cellular localization point to the possibility that EHD1 participates in ligand-induced endocytosis. (C) 1999 Academic Press. C1 Tel Aviv Univ, Dept Cell Res & Immunol, Sackler Sch Med, IL-69978 Ramat Aviv, Israel. Tel Aviv Univ, Dept Physiol, Sackler Sch Med, IL-69978 Ramat Aviv, Israel. Tel Aviv Univ, Dept Embryol, Sackler Sch Med, IL-69978 Ramat Aviv, Israel. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. NYU, Med Ctr, Skirball Inst Biomol Med, Dev Genet Program, New York, NY 10016 USA. RP Horowitz, M (reprint author), Tel Aviv Univ, Dept Cell Res & Immunol, Sackler Sch Med, IL-69978 Ramat Aviv, Israel. NR 49 TC 63 Z9 66 U1 1 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 JUL 1 PY 1999 VL 59 IS 1 BP 66 EP 76 DI 10.1006/geno.1999.5800 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 217XX UT WOS:000081525200009 PM 10395801 ER PT J AU Sharief, FS Vojta, PJ Ropp, PA Copeland, WC AF Sharief, FS Vojta, PJ Ropp, PA Copeland, WC TI Cloning and chromosomal mapping of the human DNA polymerase theta (POLQ), the eighth human DNA polymerase SO GENOMICS LA English DT Article ID TRYPANOSOMATID CRITHIDIA-FASCICULATA; CROSS-LINKING AGENTS; BASE EXCISION-REPAIR; FANCONI-ANEMIA; HUMAN GENOME; IN-VITRO; GENE; BETA; MUS308; IDENTIFICATION AB We have cloned the cDNA for the eighth human DNA polymerase, DNA polymerase theta. The human cDNA encodes a putative DNA polymerase of 1762 amino acids with a calculated molecular mass of 198 kDa. The derived protein sequence is homologous to the Drosophila melanogaster mus308 protein product, a putative DNA polymerase-helicase involved in repair of interstrand crosslinks. The C-terminal region contains the canonical DNA polymerase motifs A, B, and C found in the family A type of DNA polymerases, which includes Escherichia coli polymerase I. The N-terminal region contains a putative ATP binding domain but not motifs for a helicase. The gene was mapped by radiation hybrid analysis to chromosome 3q within an interval flanked by proximal marker D3S1303 and distal marker D3S3576 and, based on proximity to a gene that has been mapped cylogenetically, within band 3q13.31. (C) 1999 Academic Press. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Off Sci Director, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, Mol Genet Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 32 TC 85 Z9 88 U1 0 U2 4 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD JUL 1 PY 1999 VL 59 IS 1 BP 90 EP 96 DI 10.1006/geno.1999.5843 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 217XX UT WOS:000081525200012 PM 10395804 ER PT J AU Butler, RN August, P Ferdinand, KC Phillips, RA Roccella, EJ AF Butler, RN August, P Ferdinand, KC Phillips, RA Roccella, EJ TI Hypertension: Drug therapy options for older patients - Part 3 SO GERIATRICS LA English DT Editorial Material ID MEN AB For the older patient with uncomplicated hypertension, JNC-VI recommends a low-dose thiazide diuretic as first-line drug therapy. If control is not achieved,it is often necessary to add a second or third agent. Cardioselective beta blockers are useful with concomitant coronary artery disease and are compelling post-MI. ACE inhibitors are useful in combination with a diuretic and for patients with congestive heart failure. Angiotensin II receptor blockers have some of the benefits of ACE inhibitors and a side effect profile similar to placebo. Alpha blockers can be very effective, especially when combined with calcium channel blockers or beta blockers. The dihydropyridine calcium antagonists have been shown to reduce morbidity and the incidence of stroke. Whatever the drug therapy, blood pressure controling older patients reduces the risk of stroke, coronary artery disease, and congestive heart failure. C1 Mt Sinai Med Ctr, Dept Geriatr & Adult Dev, New York, NY 10029 USA. Int Longev Ctr US, New York, NY USA. Cornell Univ Med Coll, New York, NY USA. Cornell Univ, New York Hosp, Div Hypertens, New York, NY USA. Xavier Univ, Coll Pharm, New Orleans, LA USA. Heartbeats Life Ctr, New Orleans, LA USA. Mt Sinai Med Ctr, Zena & Michael A Wiener Cardiovasc Inst, Hypertens Program, New York, NY 10029 USA. Mt Sinai Med Ctr, Zena & Michael A Wiener Cardiovasc Inst, Cardiac Hlth Program, New York, NY 10029 USA. NHLBI, Natl High Blood Pressure Educ Program, NIH, Bethesda, MD 20892 USA. RP Butler, RN (reprint author), Mt Sinai Med Ctr, Dept Geriatr & Adult Dev, New York, NY 10029 USA. NR 9 TC 1 Z9 1 U1 0 U2 0 PU ADVANSTAR COMMUNICATIONS PI DULUTH PA 131 W FIRST ST, DULUTH, MN 55802 USA SN 0016-867X J9 GERIATRICS JI Geriatrics PD JUL PY 1999 VL 54 IS 7 BP 27 EP + PG 5 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 214ZQ UT WOS:000081357800013 PM 10431597 ER PT J AU Brown, MR Chuaqui, R Vocke, CD Berchuck, A Middleton, LP Emmert-Buck, MR Kohn, EC AF Brown, MR Chuaqui, R Vocke, CD Berchuck, A Middleton, LP Emmert-Buck, MR Kohn, EC TI Allelic loss on chromosome arm 8p: Analysis of sporadic epithelial ovarian tumors SO GYNECOLOGIC ONCOLOGY LA English DT Article; Proceedings Paper CT 30th Annual Meeting of the Society-of-Gynecologic-Oncologists CY MAR 20-24, 1999 CL SAN FRANCISCO, CA SP Soc Gynecol Oncologists ID GENE AMPLIFICATION; PRIMARY BREAST; FREQUENT LOSS; HETEROZYGOSITY; CANCER; CARCINOMAS; MUTATIONS; 8P12-21; LOCI AB Objective. Our objective was to determine the frequency of allelic loss at 8p21 in sporadic epithelial ovarian cancer. We recently described allelic loss at this locus in 7/9 ovarian cancers from patients with BRCA1 gene mutations. Methods, We anonymously obtained and examined 40 unselected invasive epithelial ovarian cancers and 5 low-malignant-potential (LMP) ovarian tumors for loss of heterozygosity (LOH) at 8p12-22, Pure epithelial and stromal cell populations were procured selectively by laser capture microdissection and extracted DNA was amplified with polymorphic microsatellite markers spanning the region of interest. Results. LOH was highest (50%) at marker D8S136 located at 8p21 with 15 of 30 informative cases exhibiting an allelic deletion. None of the LMP tumors evaluated showed LOH at 8p12-22. A trend toward more frequent LOH at 8p12-22 was identified with increasing disease aggressiveness from LMP to early stage invasive ovarian cancer to advanced stage invasive ovarian cancer (Lehman's test, P(2) < 0.024). Conclusions. Fifty percent allelic loss at the distal portion of 8p21 has not been reported to date for sporadic epithelial ovarian carcinomas, The higher rate of loss in our cohort, in contrast to previous allelotyping studies, is due likely to analysis from homogenous cell populations. These results, in concert with our previous study of BRCA1 mutation-positive patients, suggest a tumor suppressor gene locus at 8p21 for epithelial ovarian cancer. C1 NCI, Pathol Lab, Bethesda, MD 20892 USA. NCI, Pathogenet Unit, Pathol Lab, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Div Gynecol Oncol, Durham, NC 27710 USA. RP Brown, MR (reprint author), NCI, Pathol Lab, Bldg 10,Room 2A33,10 Ctr Dr,MDC 1500, Bethesda, MD 20892 USA. NR 26 TC 44 Z9 44 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUL PY 1999 VL 74 IS 1 BP 98 EP 102 DI 10.1006/gyno.1999.5439 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 217CX UT WOS:000081483200016 PM 10385558 ER PT J AU Jennings, JR Maricq, HR Canner, J Thompson, B Freedman, RR Wise, R Kaufmann, PG AF Jennings, JR Maricq, HR Canner, J Thompson, B Freedman, RR Wise, R Kaufmann, PG TI A thermal vascular test for distinguishing between patients with Raynaud's phenomenon and healthy controls SO HEALTH PSYCHOLOGY LA English DT Article DE Raynaud's Phenomenon; Nielsen test; cold sensitivity; automation; Stroop color-word test ID SYSTOLIC BLOOD-PRESSURE; DOUBLE-BLIND CROSSOVER; FINGER COOLING TEST; COLD; NIFEDIPINE; TRIAL; SCLERODERMA; DISEASE; STRESS AB This study tested the reliability and validity of a diagnostic thermal vascular test (TVT) for patients with Raynaud's Phenomenon (:RP). The TVT examined digital blood pressure responses to combined cooling and occlusion and was developed as part of the Raynaud's Treatment Study, a multicenter clinical trial comparing the efficacy of biofeedback and pharmacological treatment. A computerized system permitted efficient, accurate, and uniform testing at different geographical sites. A comparison of 199 patients with RP and 52 healthy controls is reported. The TVT showed a sensitivity of 79% and a specificity of 88%. Test-retest reliability was acceptable (r = .80). Addition of a psychological challenge failed to improve the discrimination between patients with RP and controls. The TVT separated patients with RP and controls as well as or better than existing tests and did so with enhanced ease of operation. C1 Univ Pittsburgh, Pittsburgh, PA 15260 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Wayne State Univ, Detroit, MI 48202 USA. Johns Hopkins Univ, Med Ctr, Baltimore, MD 21218 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Newark, NJ 07103 USA. Clin Trials & Surveys Corp, Clin Coordinating Ctr, Baltimore, MD USA. Publ Hlth Serv, US Dept HHS, Drug Distribut Ctr, Indian Hlth Serv,Supply Ctr, Perry Point, MD USA. NHLBI, Div Epidemiol & Clin Applicat, Behav Med Res Grp, Project Off, Bethesda, MD 20892 USA. Univ Cincinnati, Cincinnati, OH 45221 USA. Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Hanover, NH 03756 USA. NIA, Bethesda, MD 20892 USA. Duke Univ, Durham, NC 27706 USA. Henry Ford Hosp, Detroit, MI 48202 USA. RP Jennings, JR (reprint author), Western Psychiat Inst & Clin, 3811 Ohara St,E-1329, Pittsburgh, PA 15213 USA. OI Wise, Robert/0000-0002-8353-2349 FU NHLBI NIH HHS [N01-HC-25121] NR 26 TC 6 Z9 6 U1 1 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 J9 HEALTH PSYCHOL JI Health Psychol. PD JUL PY 1999 VL 18 IS 4 BP 421 EP 426 DI 10.1037/0278-6133.18.4.421 PG 6 WC Psychology, Clinical; Psychology SC Psychology GA 217YA UT WOS:000081525500014 PM 10431945 ER PT J AU Matsumoto, A Yeo, AET Shih, JWK Tanaka, E Kiyosawa, K Alter, HJ AF Matsumoto, A Yeo, AET Shih, JWK Tanaka, E Kiyosawa, K Alter, HJ TI Transfusion-associated TT virus infection and its relationship to liver disease SO HEPATOLOGY LA English DT Article ID HEPATITIS-G VIRUS; NON-A; NON-B; NON-C; SEQUENCES; ANTIBODY AB TT virus (TTV) has been proposed as the causative agent of non-A to E hepatitis, We studied the association between TTV viremia and biochemical evidence of hepatitis in blood donors and prospectively-followed patients. TTV was found in 7.5% of 402 donors and in 11.0% of 347 patients before transfusion. The rate of new TTV infections was 4.7% in 127 nontransfused, and 26.4% in 182 transfused patients (P < .0001), The risk of infection increased with the number of units transfused (P < .0001), The rate of new TTV infections in 13 patients with non-A to E hepatitis (23.2%) was almost identical to the rate in 124 patients who were transfused, but did not develop hepatitis (21.8%). Of 45 patients with acute hepatitis C, 40.0% were simultaneously infected with TTV, TTV did not worsen the biochemical severity (mean ALT: 537 in TTV+; 550 in TTV-) or persistence of hepatitis C. In non-A to E cases, the mean ALT was 182 in those TTV-positive and 302 in TTV-negatives. No consistent relationship between alanine transaminase level and TTV DNA level was observed in 4 patients with long-term, sequential samples. Of 21 viremic subjects, 67% cleared TTV within 5 years (38% in 1 year); 33% were viremic throughout follow-up extending to 22 years. We conclude that TTV is a very common, often persistent infection that is transmitted by transfusion and by undefined nosocomial routes. We found no association between TTV and non-A to E hepatitis and no effect of TTV on the severity or duration of coexistent hepatitis C, TTV may not be a primary hepatitis virus. C1 Ctr Clin, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. Shinshu Univ, Sch Med, Dept Internal Med 2, Matsumoto, Nagano 390, Japan. RP Alter, HJ (reprint author), Ctr Clin, Dept Transfus Med, NIH, Bldg 10,1C-711, Bethesda, MD 20892 USA. NR 22 TC 93 Z9 100 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUL PY 1999 VL 30 IS 1 BP 283 EP 288 DI 10.1002/hep.510300118 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 211FW UT WOS:000081151000038 PM 10385668 ER PT J AU Metral, CJ Janini, GM Muschik, GM Issaq, HJ AF Metral, CJ Janini, GM Muschik, GM Issaq, HJ TI A computer method for predicting the electrophoretic mobility of peptides SO HRC-JOURNAL OF HIGH RESOLUTION CHROMATOGRAPHY LA English DT Article DE electrophoresis; electrophoretic mobilities; CZE; MEKC; peptides ID CAPILLARY ZONE ELECTROPHORESIS; PROTEINS; PH AB A computer model is presented for the prediction of the electrophoretic mobilities of peptides from physical constants derived from their amino acid sequences. The model assumes that the electrophoretic mobility can be represented by a product of four functions according to the relation: l(comp) = l(L)w(W)q(Q)c(CC), where L (a length parameter) is represented by the number of amino acid residues of the peptide, W (a width parameter) is represented by the average residue mass, Q = the charge of the peptide, and CC = the position of the center of charge relative to the center of mass. The model was used to calculate the electrophoretic mobilities of peptides in a 50 mM phosphate buffer at pH 2.5. Sixty-four test peptides ranging in size from 2 to 39 amino acid residues were used for this study. The calculated mobilities show excellent correlation with experimental measurements with a correlation coefficient greater than 0.98. C1 NCI, SAIC Frederick, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. RP Metral, CJ (reprint author), NCI, SAIC Frederick, Frederick Canc Res & Dev Ctr, POB B, Ft Detrick, MD 21702 USA. NR 13 TC 9 Z9 9 U1 1 U2 1 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0935-6304 J9 HRC-J HIGH RES CHROM JI HRC-J. High Resolut. Chromatogr. PD JUL PY 1999 VL 22 IS 7 BP 373 EP 378 PG 6 WC Chemistry, Analytical SC Chemistry GA 212GA UT WOS:000081207900002 ER PT J AU Feinendegen, LE AF Feinendegen, LE TI The role of adaptive responses following exposure to ionizing radiation SO HUMAN & EXPERIMENTAL TOXICOLOGY LA English DT Article ID CELL; MECHANISMS; TISSUE; REPAIR; RISK C1 NIH, Ctr Clin, Dept Nucl Med, Bethesda, MD 20892 USA. RP Feinendegen, LE (reprint author), NIH, Ctr Clin, Dept Nucl Med, Bethesda, MD 20892 USA. NR 37 TC 28 Z9 29 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0144-5952 J9 HUM EXP TOXICOL JI Hum. Exp. Toxicol. PD JUL PY 1999 VL 18 IS 7 BP 426 EP 432 DI 10.1191/096032799678840309 PG 7 WC Toxicology SC Toxicology GA 219JD UT WOS:000081603400003 PM 10454071 ER PT J AU Yamamoto, T Nanba, E Ninomiya, H Higaki, K Taniguchi, M Zhang, HD Akaboshi, S Watanabe, Y Takeshima, T Inui, K Okada, S Tanaka, A Sakuragawa, N Millat, G Vanier, MT Morris, JA Pentchev, PG Ohno, K AF Yamamoto, T Nanba, E Ninomiya, H Higaki, K Taniguchi, M Zhang, HD Akaboshi, S Watanabe, Y Takeshima, T Inui, K Okada, S Tanaka, A Sakuragawa, N Millat, G Vanier, MT Morris, JA Pentchev, PG Ohno, K TI NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C SO HUMAN GENETICS LA English DT Article ID FIBROBLASTS; COMPLEMENTATION; HETEROGENEITY; GANGLIOSIDE AB Complementary and genomic DNAs isolated from the fibroblasts of 10 Japanese (7 late infantile, 2 juvenile, and 1 adult form of the disease) and one Caucasian patient with Niemann-Pick disease type C were analyzed for mutations in the NPC1 gene. Fourteen novel mutations were found including small deletions and point mutations. A one-base deletion and a point mutation caused splicing errors. The mutations were not clustered in any particular region of the gene and were found both in and out of the transmembrane domains. Three patients were homozygous, five were compound heterozygous, and the remaining three were suspected of being compound hetrozygous with an unknown error in one of their NPC I alleles. Of the 14 mutations, the G1553A substitution that caused a splicing error of exon 9 appeared to be relatively common in Japanese patients, because two patients were homozygous and one patient was compound heterozygous for this mutation. C1 Tottori Univ, Ctr Gene Res, Yonago, Tottori 6838503, Japan. Tottori Univ, Sch Life Sci, Dept Neurobiol, Yonago, Tottori, Japan. Tottori Univ, Fac Med, Inst Neurol Sci, Div Child Neurol, Yonago, Tottori 683, Japan. Tottori Univ, Fac Med, Inst Neurol Sci, Div Neurol, Yonago, Tottori 683, Japan. Osaka Univ, Sch Med, Dept Pediat, Osaka 553, Japan. Osaka City Univ, Sch Med, Dept Pediat, Osaka 545, Japan. Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Inherited Metab Dis, Tokyo, Japan. Lyon Sud Med Sch, Dept Biochem, Lyon, France. Lyon Sud Med Sch, INSERM, U189, Lyon, France. NINDS, NIH, Bethesda, MD 20892 USA. RP Yamamoto, T (reprint author), Tottori Univ, Ctr Gene Res, 86 Nishi Machi, Yonago, Tottori 6838503, Japan. NR 22 TC 46 Z9 48 U1 1 U2 2 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 JUL-AUG PY 1999 VL 105 IS 1-2 BP 10 EP 16 DI 10.1007/s004390051057 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 229PM UT WOS:000082203000003 PM 10480349 ER PT J AU Panguluri, RCK Brody, LC Modali, R Utley, K Adams-Campbell, L Day, AA Whitfield-Broome, C Dunston, GM AF Panguluri, RCK Brody, LC Modali, R Utley, K Adams-Campbell, L Day, AA Whitfield-Broome, C Dunston, GM TI BRCA1 mutations in African Americans SO HUMAN GENETICS LA English DT Article ID BREAST-CANCER; OVARIAN-CANCER; MURINE BRCA1; SEQUENCE; GENE; INDIVIDUALS; FAMILIES AB The breast cancer predisposing gene, BRCA1, was analyzed for germline mutations in 45 African American families at high-risk for hereditary breast cancer. Patients were considered high-risk if they had a family history of the disease, early onset breast cancer, bilateral breast cancer, or breast and ovarian cancer. The entire BRCA1 coding and flanking intron regions have been examined by single stranded conformation polymorphism analysis followed by sequencing of variant bands. Eleven different BRCA1 germline mutations/variations were identified in 7 patients from the 45 high-risk families. Two pathogenic, protein-truncating mutations were detected in exon 11. A ten base pair tandem duplication, 943ins10, was present in a woman with breast and ovarian cancer whose first-degree relatives had prostate cancer. A four base pair deletion, 3450de14, was detected in a breast cancer patient with five cases of breast cancer in the family; two of the proband's sisters with breast cancer also carried the same mutation. Four amino acid substitutions (Lys1183Arg, Leu1564Pro, Gln1785His, and Glu1794Asp) and four nucleotide substitutions in intron 22 (IVS22+78 C/A, IVS22+67 T/C, IVS22+8 T/A and IVS22+7 T/C) were observed in patients and not in control subjects. One early onset breast cancer patient carried five distinct BRCA1 variations, two amino acid substitutions and three substitutions in intron 22. An amino acid substitution in exon 11, Ser1140Gly, was identified in 3 different unrelated patients and in 6 of 92 control samples. The latter probably represents a benign polymorphism. C1 Howard Univ, Coll Med, Dept Biochem & Mol Biol, Washington, DC 20059 USA. Howard Univ, Coll Med, Human Immunogenet Lab, Washington, DC USA. Howard Univ, Coll Med, Dept Microbiol, Washington, DC USA. Natl Human Genome Res Inst, Bethesda, MD USA. BioServe Biotechnol, Laurel, MD USA. Howard Univ, Ctr Canc, Washington, DC 20059 USA. RP Whitfield-Broome, C (reprint author), Howard Univ, Coll Med, Dept Biochem & Mol Biol, 520 W St NW, Washington, DC 20059 USA. FU NCI NIH HHS [R01 CA557720]; NCRR NIH HHS [G12 RR03048] NR 29 TC 51 Z9 52 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 JUL-AUG PY 1999 VL 105 IS 1-2 BP 28 EP 31 DI 10.1007/s004390051059 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 229PM UT WOS:000082203000005 PM 10480351 ER PT J AU Ida, H Rennert, OM Iwasawa, K Kobayashi, M Eto, Y AF Ida, H Rennert, OM Iwasawa, K Kobayashi, M Eto, Y TI Clinical and genetic studies of Japanese homozygotes for the Gaucher disease L444P mutation SO HUMAN GENETICS LA English DT Article ID ACID BETA-GLUCOSIDASE; HUMAN GLUCOCEREBROSIDASE GENE; BONE-MARROW TRANSPLANTATION; NORRBOTTNIAN TYPE; JEWISH; IDENTIFICATION; POLYMORPHISM; HETEROGENEITY; EXPRESSION; PREVALENCE AB In patients originally genotyped as homoallelic for the Gaucher disease (GD) L444P (1448C) mutation, we sought to confirm previously reported phenotypic differences between Caucasians and Japanese, to determine the prevalence and phenotypic impact of recombinant alleles, and to explore the phenotypic influence of genetic background. We therefore analyzed data from longer-ten clinical follow-up, more comprehensive genotyping and polymorphism and mitochondrial DNA (mtDNA) testing in all known Japanese L444P homozygotes (n = 15). Our studies demonstrated that, of 12 patients in our series originally diagnosed with non-neuronopathic GD, 9 developed neurological signs/symptoms during follow-up (at a mean of 14 years 11 months +/- 11 years 4 months). Of three patients originally diagnosed with acute neuronopathic (type 2) GD, all three were compound heterozygotes for L444P and the complex allele RecNci I. In the entire series, Pvu II and liver erythrocyte pyruvate kinase (PKLR) polymorphism and prevalence of the 9 bp mtDNA deletion were heterogeneous, and these background genetic factors could not predict phenotypic expression. Our data suggest that, in Japanese as in Caucasian patients, the L444P/L444P genotype is highly associated with subacute neuronopathic (type 3) GD, and the presence of a complex allele together with an L444P allele leads to type 2 disease. Our findings also underline the importance of comprehensive genotyping (particularly testing for recombinant alleles), longterm follow-up and careful neurological examination in patients with early-onset GD. Such measures ultimately may improve genotype/phenotype correlations and, with them, genetic counseling and therapeutic decision making. C1 Jikei Univ, Sch Med, Dept Pediat, Minato Ku, Tokyo 105, Japan. NICHHD, Ctr Res Mothers & Children, NIH, Bethesda, MD 20892 USA. RP Ida, H (reprint author), Jikei Univ, Sch Med, Dept Pediat, Minato Ku, 3-25-8 Nishi Shinbashi, Tokyo 105, Japan. NR 36 TC 28 Z9 29 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 JUL-AUG PY 1999 VL 105 IS 1-2 BP 120 EP 126 DI 10.1007/s004390051073 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 229PM UT WOS:000082203000019 PM 10480365 ER PT J AU Philibert, RA Winfield, SL Damschroder-Williams, P Tengstrom, C Martin, BM Ginns, EI AF Philibert, RA Winfield, SL Damschroder-Williams, P Tengstrom, C Martin, BM Ginns, EI TI The genomic structure and developmental expression patterns of the human OPA-containing gene (HOPA) SO HUMAN GENETICS LA English DT Article ID MENTAL-RETARDATION; X-CHROMOSOME; TRINUCLEOTIDE REPEATS; DUPLICATION; SEQUENCES AB We determined the genomic organization of the human OPA-containing gene (HOPA) and characterized its developmental expression. The gene encoding HOPA, which contains a rare polymorphism tightly associated with non-specific mental retardation, is 25 kb in length and consists of 44 exons. A promoter scan analysis demonstrates two possible transcription initiation sites without TATA boxes upstream from the putative translation initiation start site. Several informative polymorphisms are evident in the sequence including a large pentanucleotide repeat. Northern blot analysis of the gene transcript and its murine orthologue, MOPA-1, demonstrates that only one transcript is expressed throughout the soma and the CNS, and that the transcript is highly expressed during early fetal development. We conclude that the delineation of the function of the HOPA gene locus merits further study. C1 Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. NIMH, Clin Neurosci Branch, Bethesda, MD 20892 USA. Rinnekoti Fdn, Lab Cytogenet, SF-02980 Espoo, Finland. RP Philibert, RA (reprint author), Univ Iowa, Dept Psychiat, Room 2-126B Psychiat Res MEB, Iowa City, IA 52242 USA. NR 18 TC 21 Z9 22 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 JUL-AUG PY 1999 VL 105 IS 1-2 BP 174 EP 178 DI 10.1007/s004390051084 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 229PM UT WOS:000082203000030 PM 10480376 ER PT J AU Quintanilla-Martinez, L Franklin, JL Guerrero, I Krenacs, L Naresh, KN Rama-Rao, C Bhatia, K Raffeld, M Magrath, IT AF Quintanilla-Martinez, L Franklin, JL Guerrero, I Krenacs, L Naresh, KN Rama-Rao, C Bhatia, K Raffeld, M Magrath, IT TI Histological and immunophenotypic profile of nasal NK T cell lymphomas from Peru: High prevalence of p53 overexpression SO HUMAN PATHOLOGY LA English DT Article DE nasal lymphomas; NK T cell; EBV; p53; CD56 ID EPSTEIN-BARR-VIRUS; NON-HODGKINS-LYMPHOMAS; NATURAL-KILLER; NASOPHARYNGEAL CARCINOMA; POLYMORPHIC RETICULOSIS; MALIGNANT-LYMPHOMAS; GENE-MUTATIONS; HONG-KONG; EXPRESSION; PROTEIN AB Nasal NK/T-cell lymphoma is a unique form of lymphoma highly associated with Epstein-Barr virus (EBV). These lymphomas are rare in Western populations and much more prevalent in some Asian and Latin American countries. Although there are several sizable studies from Asian countries, the same is not true from South America. The aim of this study was to analyze a series of 32 cases of nasal T-cell lymphoma from Peru and to further extend the characterization of this disease. Immunohistochemistry was performed on paraffin sections using the following antibodies: CD20 (L26), CD45RO, CD3, Ki67, CD57, CD56, TIA-1, bcl-2, and p53. The presence of EBV was investigated with immunohistochemical analysis for latent membrane protein (LMP)-1 and in situ hybridization using an antisense riboprobe to EBER 1. The 32 patients included 18 men and 14 women (M:F ratio, 1.2:1), with a median age of 43 years (11 to 72). Three categories were identified: (1) Nasal NK/T cell lymphomas (28 cases): The morphology ranged from small or medium-sized cells to large transformed cells. Necrosis was present in 86% of the cases, and angioinvasion was seen in 36% of the cases. All cases were positive for CD45RO, CD3, and for TIA-1. CD56 was positive in 21 of 27 cases (78%), and CD57 was negative in all cases. EBER 1 positivity was identified in most of the tumor cells in 27 of 28 cases (96%), including the six cases in which CD56 was negative. Overexpression of p53 was detected in 24 cases (86%). (2) Blastic NK cell lymphoma (1 case): The neoplastic cells resembled those of lymphoblastic lymphoma. CD56 and CD45RO were positive; TIA-1, TdT, and EBER-1 were negative. (3) Peripheral T-cell lymphoma (PTCL) unspecified (3 cases): CD56, TIA-1, and EBER-1 were negative. Nasal lymphomas from Peru with a T cell phenotype are predominantly EBV-associated NK/T cell lymphomas, similar to those described in Asian countries. The expression of CD56, TIA-1, and EBER-1, in combination, are very useful markers for the diagnosis of nasal NK/T cell lymphoma in paraffin-embedded tissue. The differential diagnosis of T-cell lymphomas in the nasal region should include rare cases of PTCL unspecified and the blastic variant of NK cell lymphoma. P53 is overexpressed in 86% of the cases. The significance of this finding with regard to clinical behavior and prognosis remains to be determined. This is a US government work. There are no restrictions on its use. C1 NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. Inst Nacl Enfermedades Neoplasicas, Lima, Peru. RP Raffeld, M (reprint author), NCI, Hematopathol Sect, Pathol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Krenacs, Laszlo/L-8063-2014 OI Krenacs, Laszlo/0000-0001-6541-3031 NR 40 TC 70 Z9 74 U1 1 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD JUL PY 1999 VL 30 IS 7 BP 849 EP 855 DI 10.1016/S0046-8177(99)90147-8 PG 7 WC Pathology SC Pathology GA 215BG UT WOS:000081361600017 PM 10414505 ER PT J AU Kalantaridou, SN Braddock, DT Patronas, NJ Nelson, LM AF Kalantaridou, SN Braddock, DT Patronas, NJ Nelson, LM TI Treatment of autoimmune premature ovarian failure SO HUMAN REPRODUCTION LA English DT Article DE autoimmune lymphocytic oophoritis; autoimmune premature ovarian failure; glucocorticoids; osteonecrosis; return of ovarian function ID ADDISONS-DISEASE; T-CELLS; ANTIBODIES; OOPHORITIS; AUTOANTIBODIES; MENOPAUSE; IDENTIFICATION; PREVALENCE; PREGNANCY; NECROSIS AB There is no known immunosuppressive therapy for autoimmune premature ovarian failure that has been proven safe and effective by prospective randomized placebo-controlled study. Nevertheless, immunosuppression using corticosteroids has been used on an empirical basis for this condition. Here we present two cases of young women with premature ovarian failure who were treated with glucocorticoids in the hopes of restoring fertility. The first case illustrates the potential benefit of such therapy, and the second case illustrates a potential risk. The first patient with histologically proven autoimmune oophoritis was treated with alternate day glucocorticoid treatment. She had return of menstrual bleeding six times and ovulatory progesterone concentrations four times over a 16 week period. The second patient with presumed but unconfirmed autoimmune ovarian failure was referred to us after having been treated with a 9 month course of corticosteroids. During that treatment her menses did not resume. The corticosteroid treatment was complicated by iatrogenic Cushing syndrome and osteonecrosis of the knee. Identifying patients with autoimmune premature ovarian failure presents the opportunity to restore ovarian function by treating these patients with the proper immune medullation therapy. On the other hand, potent immune medullation therapy can have major complications. Corticosteroid therapy for autoimmune premature ovarian failure should be limited to use in placebo-controlled trials designed to evaluate the safety and efficacy of such treatment. C1 NICHHD, Sect Womens Hlth Res, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NCI, Div Clin Sci, Pathol Lab, NIH, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Kalantaridou, SN (reprint author), NICHHD, Sect Womens Hlth Res, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NR 53 TC 37 Z9 39 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD JUL PY 1999 VL 14 IS 7 BP 1777 EP 1782 DI 10.1093/humrep/14.7.1777 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 221XC UT WOS:000081751900025 PM 10402388 ER PT J AU Dunson, DB Baird, DD Wilcox, AJ Weinberg, CR AF Dunson, DB Baird, DD Wilcox, AJ Weinberg, CR TI Day-specific probabilities of clinical pregnancy based on two studies with imperfect measures of ovulation SO HUMAN REPRODUCTION LA English DT Article DE basal body temperature; fecundability; fertile interval; ovulation; urinary ID MENSTRUAL-CYCLE; CONCEPTION; SPERM; FERTILITY; SURVIVAL; SEX AB Two studies have related the timing of sexual intercourse (relative to ovulation) to day-specific fecundiability. The first was a study of Catholic couples practising natural family planning in London in the 1950s and 1960s and the second was of North Carolina couples attempting to become pregnant in the early 1980s. The former identified ovulation based on the ovulatory shift in the basal body temperature, while the latter used urinary assays of hormones. We use a statistical model to correct for error in identifying ovulation and to re-estimate the length of the fertile window and day-specific fecundabilities. We estimate the same 6-day fertile interval in both studies after controlling for error. After adjusting for error both data sets showed the highest estimate of the probability of pregnancy on the day prior to ovulation and both fell close to zero after ovulation. Given that the fertile interval is before ovulation, methods that anticipate ovulation by several days (such as the assessment of cervical mucus) would be particularly useful for couples who want to time their intercourse either to avoid or facilitate conception. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Dunson, DB (reprint author), NIEHS, Biostat Branch, MD A3-03, Res Triangle Pk, NC 27709 USA. OI Wilcox, Allen/0000-0002-3376-1311; Baird, Donna/0000-0002-5544-2653 NR 22 TC 103 Z9 104 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD JUL PY 1999 VL 14 IS 7 BP 1835 EP 1839 DI 10.1093/humrep/14.7.1835 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 221XC UT WOS:000081751900037 PM 10402400 ER PT J AU Chernomordik, V Hattery, D Gannot, I Gandjbakhche, AH AF Chernomordik, V Hattery, D Gannot, I Gandjbakhche, AH TI Inverse method 3-D reconstruction of localized in vivo fluorescence - Application to Sjogren syndrome SO IEEE JOURNAL OF SELECTED TOPICS IN QUANTUM ELECTRONICS LA English DT Article DE diffusion processes; fluorescence; image reconstruction; inverse problems; molecular tagging; random media; tissue optics ID TISSUE; MEDIA; MODEL AB The development of specific fluorescently labeled cell surface markers have opened the possibility of specific and quantitative noninvasive diagnosis of tissue changes. We are developing a fluorescence scanning imaging system that can perform a "noninvasive optical biopsy" of the Sjogren syndrome (SS) which may replace the currently used histological biopsy. The diagnosis of SS is based on the quantification of the number of topical preadministered fluorescent antibodies which specifically bind to the lymphocytes infiltrating the minor salivary glands. We intend to scan the lower lip, and for each position of the scan, generate a two-dimensional (2-D) image of fluorescence using a charge-coupled del ice (CCD) camera. We have shown previously that our diffuse fluorescent photon migration theory predicts adequately the positions and strengths of one and two fluorescent targets embedded at different depths in tissue-like phantoms, An inverse reconstruction algorithm based on our theoretical findings has been written in C++ and uses 2-D images to predict the strength and location of embedded fluorophores. However, due to large numbers of variables, which include the optical properties of the tissue at the excitation and emission wavelengths, and the positions and strengths of an unknown number of fluorophore targets, the validity of the final result depends on assumptions (such as the number of targets) and the input values for the optical parameters. Our results show that the number of fluorophore targets reconstructed for each scan is limited to two, and at least the scattering coefficient at the excitation wavelength is needed a priori to obtain good results. The latter can be obtained by measurements of spatially resolved diffuse reflectance at the excitation wavelength that provides the product of the absorption and scattering coefficients. C1 NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. George Washington Univ, Dept Elect & Comp Engn, Washington, DC 20052 USA. Tel Aviv Univ, Dept Biomed Engn, Fac Engn, IL-69978 Tel Aviv, Israel. RP Chernomordik, V (reprint author), NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. NR 12 TC 20 Z9 20 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 1077-260X J9 IEEE J SEL TOP QUANT JI IEEE J. Sel. Top. Quantum Electron. PD JUL-AUG PY 1999 VL 5 IS 4 BP 930 EP 935 DI 10.1109/2944.796313 PG 6 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA 248CM UT WOS:000083257800009 ER PT J AU Kyriacou, SK Davatzikos, C Zinreich, SJ Bryan, RN AF Kyriacou, SK Davatzikos, C Zinreich, SJ Bryan, RN TI Nonlinear elastic registration of brain images with tumor pathology using a biomechanical model SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE brain atlas; biomechanics; finite elements; inverse methods; registration; surgical planning ID FINITE-ELEMENT ANALYSIS; HYPERELASTIC MEMBRANES; DEFORMABLE MODELS AB A biomechanical model of the brain is presented, using a finite-element formulation. Emphasis is given to the modeling of the soft-tissue deformations induced by the growth of tumors and its application to the registration of anatomical atlases, with images from patients presenting such pathologies. First, an estimate of the anatomy prior to the tumor growth is obtained through a simulated biomechanical contraction of the tumor region. Then a normal-to-normal atlas registration to this estimated pre-tumor anatomy is applied. Finally, the deformation from the tumor-growth model is applied to the resultant registered atlas, producing an atlas that has been deformed to fully register to the patient images. The process of tumor growth is simulated in a nonlinear optimization framework, which is driven by anatomical features such as boundaries of brain structures. The deformation of the surrounding tissue is estimated using a nonlinear elastic model of soft tissue under the boundary conditions imposed by the skull, ventricles, and the falx and tentorium. A preliminary-two dimensional (2-D) implementation is presented in this paper, and tested on both simulated and patient data. One of the long-term goals of this work is to use anatomical brain atlases to estimate the locations of important brain structures in the brain and to use these estimates in pre-surgical and radiosurgical planning systems. C1 Johns Hopkins Univ, Sch Med, Dept Radiol, Neuroimaging Lab, Baltimore, MD 21287 USA. NIH, Diagnost Radiol Clin Ctr, Bethesda, MD 20892 USA. RP Johns Hopkins Univ, Sch Med, Dept Radiol, Neuroimaging Lab, Baltimore, MD 21287 USA. RI Bryan, R. Nick/P-1661-2014 FU NIA NIH HHS [R01 AG14971-0251] NR 34 TC 102 Z9 104 U1 0 U2 8 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 EI 1558-254X J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD JUL PY 1999 VL 18 IS 7 BP 580 EP 592 DI 10.1109/42.790458 PG 13 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 238MJ UT WOS:000082713800003 PM 10504092 ER PT J AU Morgan, PN Iannuzzelli, RJ Epstein, FH Balaban, RS AF Morgan, PN Iannuzzelli, RJ Epstein, FH Balaban, RS TI Real-time cardiac MRI using DSP's SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Letter DE cardiac; digital signal processing; magnetic resonance imaging ID IMAGE-RECONSTRUCTION; EJECTION FRACTION; DATA ACQUISITION; SCANNER; SYSTEM AB A real-time cardiac magnetic resonance imaging (MRI) system has been implemented using digital signal processing (DSP) technology. The system enables real-time acquisition, processing, and display of ungated cardiac movies at moderate video rates of 20 images/s. A custom graphical user interface (GUI) provides interactive control of data acquisition parameters and image display functions. Images can be compressed into moving-picture experts group (MPEG) movies, but are displayed on the console without compression during the scan. Compared to existing real-time MRI systems, implementation with DSP's allows rapid parallel computations, fast data transfers, and greater system flexibility, including the ability to scale to multiple channels, at the expense of somewhat higher component cost. C1 Texas A&M Univ, Dept Elect Engn, College Stn, TX 77843 USA. Johns Hopkins Univ, Appl Phys Lab, Air Def Syst Dept, Laurel, MD 20723 USA. NHLBI, Cardiac Energet Lab, Bethesda, MD 20892 USA. RP Morgan, PN (reprint author), Texas A&M Univ, Dept Elect Engn, College Stn, TX 77843 USA. RI Balaban, Robert/A-7459-2009 OI Balaban, Robert/0000-0003-4086-0948 NR 20 TC 7 Z9 7 U1 0 U2 1 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 JUL PY 1999 VL 18 IS 7 BP 649 EP 653 DI 10.1109/42.790464 PG 5 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 238MJ UT WOS:000082713800009 PM 10504098 ER PT J AU Reiner, SL Seder, RA AF Reiner, SL Seder, RA TI Dealing from the evolutionary pawnshop: How lymphocytes make decisions SO IMMUNITY LA English DT Review ID CD4(+) T-CELLS; POSITION-EFFECT VARIEGATION; INTERFERON-GAMMA PRODUCTION; TRANSCRIPTION FACTOR GATA-3; IFN-GAMMA; CENTROMERIC HETEROCHROMATIN; ERYTHROPOIETIN RECEPTOR; PHENOTYPE DEVELOPMENT; IL-4-PRODUCING CELLS; GENE-EXPRESSION C1 Univ Chicago, Gwen Knapp Ctr Lupus & Immunol Res, Dept Med, Comm Immunol & Dev Biol, Chicago, IL 60637 USA. NIAID, Clin Immunol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Reiner, SL (reprint author), Univ Penn, 421 Curie Blvd,4th Floor, Philadelphia, PA 19104 USA. NR 100 TC 60 Z9 60 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUL PY 1999 VL 11 IS 1 BP 1 EP 10 DI 10.1016/S1074-7613(00)80076-X PG 10 WC Immunology SC Immunology GA 220ND UT WOS:000081671300001 PM 10435574 ER PT J AU Ding, YH Baker, BM Garboczi, DN Biddison, WE Wiley, DC AF Ding, YH Baker, BM Garboczi, DN Biddison, WE Wiley, DC TI Four A6-TCR/peptide/HLA-A2 structures that generate very different T cell signals are nearly identical SO IMMUNITY LA English DT Article ID PEPTIDE-MHC COMPLEXES; ALPHA-BETA; LIGAND INTERACTIONS; MAXIMUM-LIKELIHOOD; VIRUS TYPE-1; RECEPTOR; ACTIVATION; ANTIGEN; PROTEIN; CRYSTALLIZATION AB The interactions of three singly substituted peptide variants of the HTLV-1 Tax peptide bound to HLA-A2 with the A6 T cell receptor have been studied using T cell assays, kinetic and thermodynamic measurements, and X-ray crystallography. The three peptide/MHC ligands include weak agonists and antagonists with different affinities for TCR. The three-dimensional structures of the three A6-TCR/peptide/HLA-A2 complexes are remarkably similar to each other and to the wild-type agonist complex, with minor adjustments at the interface to accommodate the peptide substitutions (P6A, V7R, and Y8A). The lack of correlation between structural changes and the type of T cell signals induced provides direct evidence that different signals are not generated by different ligand-induced conformational changes in the alpha beta TCR. C1 Harvard Univ, Dept Cellular & Mol Biol, Cambridge, MA 02138 USA. Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. NIAID, Struct Biol Sect, NIH, Rockville, MD 20852 USA. NINDS, Mol Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Wiley, DC (reprint author), Harvard Univ, Dept Cellular & Mol Biol, Cambridge, MA 02138 USA. RI Baker, Brian/B-4584-2009; Ain, Kenneth/A-5179-2012 OI Baker, Brian/0000-0002-0864-0964; Ain, Kenneth/0000-0002-2668-934X FU NIAID NIH HHS [AI39619] NR 46 TC 289 Z9 291 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUL PY 1999 VL 11 IS 1 BP 45 EP 56 DI 10.1016/S1074-7613(00)80080-1 PG 12 WC Immunology SC Immunology GA 220ND UT WOS:000081671300005 PM 10435578 ER PT J AU Gea-Banacloche, JC Lane, HC AF Gea-Banacloche, JC Lane, HC TI Lymphocyte turnover in the setting of HIV infection SO IMMUNOLOGIST LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL TURNOVER; ACTIVE ANTIRETROVIRAL THERAPY; IMMUNE ACTIVATION; INTENSIVE CHEMOTHERAPY; RHEUMATOID-ARTHRITIS; MONOCLONAL-ANTIBODY; TELOMERASE ACTIVITY; RAPID TURNOVER; NO EVIDENCE AB CD4 T cells decrease in number during HIV infection, suggesting an imbalance between production and destruction of these cells. In this review, Juan Gea-Banacloche and Clifford Lane summarize the knowledge to date relating to T-cell turnover in HIV infection, and show that this is increased. The possible driving forces for this and the effect of therapy ore discussed. C1 NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, Bethesda, MD 20892 USA. RP Gea-Banacloche, JC (reprint author), NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, 10 Ctr Dr,Room 11S231, Bethesda, MD 20892 USA. NR 52 TC 3 Z9 3 U1 0 U2 0 PU HOGREFE & HUBER PUBLISHERS PI KIRKLAND PA PO BOX 2487, KIRKLAND, WA 98083-2487 USA SN 1192-5612 J9 IMMUNOLOGIST JI Immunologist PD JUL-AUG PY 1999 VL 7 IS 4 BP 124 EP 131 PG 8 WC Immunology SC Immunology GA 241JJ UT WOS:000082879100005 ER PT J AU Sramkoski, RM Pretlow, TG Giaconia, JM Pretlow, TP Schwartz, S Sy, MS Marengo, SR Rhim, JS Zhang, DS Jacobberger, JW AF Sramkoski, RM Pretlow, TG Giaconia, JM Pretlow, TP Schwartz, S Sy, MS Marengo, SR Rhim, JS Zhang, DS Jacobberger, JW TI A new human prostate carcinoma cell line, 22R upsilon 1 SO IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL LA English DT Article DE cancer; epithelial cell; xenograft; androgen response; cell growth; EGF; TGF-beta ID IN-SITU-HYBRIDIZATION; ANDROGEN RECEPTOR; CANCER CELLS; DNA CONTENT; NUDE-MICE; ESTABLISHMENT; EXPRESSION; XENOGRAFT; MODEL; LNCAP AB A cell line has been derived from a human prostatic carcinoma xenograft, CWR22R. This represents one of, very few available cell lines representative of this disease. The cell line is derived from a xenograft that was serially propagated in mice after castration-induced regression and relapse of the parental, androgen-dependent CWR22 xenograft. Flow cytometric and cytogenetic analysis showed that this cell line represents one hyper DNA-diploid stem line with two clonal, evolved cytogenetic sublines. The basic karyotype is close to that of the grandparent xenograft, CWR22, and is relatively simple with 50 chromosomes. In nude mice, the line forms tumors with morphology similar to that of the xenografts, and like the parental CWR22 and CWR22R xenografts, this cell line expresses prostate specific antigen. Growth is weakly stimulated by dihydroxytestosterone and lysates are immunoreactive with androgen receptor antibody by Western blot analysis. Growth is stimulated by epidermal growth factor but is not inhibited by transforming growth factor-beta 1. C1 Case Western Reserve Univ, Ctr Canc Res, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Urol, Cleveland, OH 44106 USA. NCI, Lab Biochem Physiol, Frederick, MD 21702 USA. RP Jacobberger, JW (reprint author), Case Western Reserve Univ, Ctr Canc Res, 10900 Euclid Ave, Cleveland, OH 44106 USA. FU NCI NIH HHS [CA 43703] NR 37 TC 291 Z9 292 U1 0 U2 8 PU SOC IN VITRO BIOLOGY PI LARGO PA 9315 LARGO DR WEST, STE 25, LARGO, MD 20774 USA SN 1071-2690 J9 IN VITRO CELL DEV-AN JI In Vitro Cell. Dev. Biol.-Anim. PD JUL-AUG PY 1999 VL 35 IS 7 BP 403 EP 409 PG 7 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 224QG UT WOS:000081909300008 PM 10462204 ER PT J AU Carroll, JA Garon, CF Schwan, TG AF Carroll, JA Garon, CF Schwan, TG TI Effects of environmental pH on membrane proteins in Borrelia burgdorferi SO INFECTION AND IMMUNITY LA English DT Article ID LYME-DISEASE SPIROCHETE; VIBRIO-CHOLERAE; IXODES-DAMMINI; VIRULENCE GENES; IN-VITRO; COORDINATE REGULATION; EXPRESSION; INFECTION; TICKS; TRANSMISSION AB Borrelia burgdorferi, the causative agent of Lyme disease, alternates between the microenvironments of the tick vector, Ixodes scapularis, and a mammalian host. The environmental conditions the spirochete encounters during its infectious cycle are suspected to differ greatly in many aspects, including available nutrients, temperature, and pH. Here we identify alterations in the membrane protein profile, as determined by immunoblotting and two-dimensional nonequilibrium pH gradient gel electrophoresis (2D-NEPHGE), that occur in virulent B. burgdorferi B31 as the pH of the medium is altered. Initial comparisons of cultures incubated at pHs 6.0, 7.0, and 8.0 yielded alterations in the expression of seven membrane proteins as determined by probing with hyperimmune rabbit serum. Six of these membrane proteins (54, 45, 44, 43, 35, and 24 kDa) were either present in increased amounts in or solely expressed by cultures incubated at pHs 6.0 and 7.0. The 24-kDa protein that decreased in expression at pH 8.0 was identified as outer surface protein C (OspC). In addition, a 42-kDa membrane protein increased in amount in cultures incubated at pH 8.0. Similar changes were observed with serum from a mouse infected by tick bite, with the recognition of two additional bands (48 and 46 kDa) unique to pHs 6.0 and 7.0. When membrane fractions were analyzed by 2D-NEPHGE, at least 37 changes in the membrane protein profile between cells incubated at pHs 6.0, 7.0, and 8.0 were observed by immunoblotting and silver staining. Environmental cues such as pH may prove important in the regulation of virulence determinants and factors necessary for the adaptation of B. burgdorferi to the tick or mammalian microcosm. C1 NIAID, Rocky Mt Labs, Microscopy Branch, Hamilton, MT 59840 USA. NIAID, Rocky Mt Labs, Microbial Struct & Funct Lab, Hamilton, MT 59840 USA. RP Carroll, JA (reprint author), 903 S 4th St, Hamilton, MT 59840 USA. NR 51 TC 158 Z9 159 U1 0 U2 5 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 JUL PY 1999 VL 67 IS 7 BP 3181 EP 3187 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 209RZ UT WOS:000081063800001 PM 10377088 ER PT J AU Eberl, M Mountford, AP Jankovic, D Beck, E AF Eberl, M Mountford, AP Jankovic, D Beck, E TI Isolation of T-cell antigens by using a recombinant protein library and its application to the identification of novel vaccine candidates against schistosomiasis SO INFECTION AND IMMUNITY LA English DT Article ID PROTECTIVE IMMUNITY; EXPRESSION LIBRARIES; POSITIVE SELECTION; LEISHMANIA ANTIGEN; ESCHERICHIA-COLI; MANSONI; CLONING; GENE; MICE; LYMPHOCYTES AB We present here a novel approach to identify T-cell antigens from any infectious agent by use of a library of purified recombinant proteins. Essential features of this strategy include (i) a highly efficient cDNA cloning system which negatively selects against nonrecombinant transformants by making use of the bacterial EcoK restriction system, (ii) affinity staining of cDNA clones expressing recombinant proteins, and (iii) a procedure of simultaneous purification of recombinant proteins from large numbers of isolated clones (representing the protein library) in a single step from pools consisting of up to 24 individual clones. The feasibility of the screening system was confirmed by constructing a protein library of the human parasite Schistosoma mansoni. The recombinant antigens of this library were used to stimulate CD4(+) T cells derived from the axillary lymph nodes of mice vaccinated with irradiated cercariae. In initial screening experiments, we detected parasite-specific proliferation and gamma interferon (IFN-gamma) secretion in response to several pools of cDNA clones. Further analysis of one particular pool revealed that only one of its constituents stimulated considerable IFN-gamma secretion by CD4(+) T cells and that the expressed antigen is identical to a small fragment of myosin heavy chain. C1 Univ York, Dept Biol, York YO10 5YW, N Yorkshire, England. Univ Giessen, Inst Biochem, D-35392 Giessen, Germany. Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Eberl, M (reprint author), Univ York, Dept Biol, York YO10 5YW, N Yorkshire, England. RI Eberl, Matthias/A-5970-2009 OI Eberl, Matthias/0000-0002-9390-5348 FU Wellcome Trust NR 34 TC 12 Z9 13 U1 0 U2 1 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 JUL PY 1999 VL 67 IS 7 BP 3383 EP 3389 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 209RZ UT WOS:000081063800029 PM 10377116 ER PT J AU Hill, MR Clarke, S Rodgers, K Thornhill, B Peters, JM Gonzalez, FJ Gimble, JM AF Hill, MR Clarke, S Rodgers, K Thornhill, B Peters, JM Gonzalez, FJ Gimble, JM TI Effect of peroxisome proliferator-activated receptor alpha activators on tumor necrosis factor expression in mice during endotoxemia SO INFECTION AND IMMUNITY LA English DT Article ID PHOSPHOENOLPYRUVATE CARBOXYKINASE GENE; PPAR-ALPHA; LIPOPROTEIN METABOLISM; HYPOLIPIDEMIC DRUGS; KUPFFER CELLS; FATTY-ACIDS; KAPPA-B; GAMMA; TISSUE; IDENTIFICATION AB Inflammatory mediators orchestrate the host immune and metabolic response to acute bacterial infections and mediate the events leading to septic shock Tumor necrosis factor (TNF) has long been identified as one of the proximal mediators of endotoxin action. Recent studies have implicated peroxisome proliferator-activated receptor alpha (PPAR alpha) as a potential target to modulate regulation of the immune response. Since PPAR alpha activators, which are hypolipidemic drugs, are being prescribed for a significant population of older patients, it is important to determine the impact of these drugs on the host response to acute inflammation. Therefore, we examined the role of PPAR alpha activators on the regulation of TNF expression in a mouse model of endotoxemia. CD-1 mice treated with dietary fenofibrate or Wy-14,643 had fivefold-higher lipopolysaccharide (LPS)-induced TNF plasma levels than LPS-treated control-fed animals. Higher LPS-induced TNF levels in drug-fed animals were reflected physiologically in significantly lower glucose levels in plasma and a significantly lower 50% lethal dose than those in LPS-treated control-fed animals. Utilizing PPAR alpha wild type (WT) and knockout (KO) mice, we showed that the effect of fenofibrate on LPS-induced TNF expression was indeed mediated by PPAR alpha. PPAR alpha WT mice fed fenofibrate also had a fivefold increase in LPS-induced TNF levels in plasma compared to control-fed animals. However, LPS-induced TNF levels were significantly decreased and glucose levels in plasma were significantly increased in PPAR alpha KO mice fed fenofibrate compared to those in control-fed animals. Data from peritoneal macrophage studies indicate that Wy-14,643 modestly decreased TNF expression in vitro. Similarly, overexpression of PPAR alpha in 293T cells decreased activity of a human TNF promoter-luciferase construct. The results from these studies suggest that any anti-inflammatory activity of PPAR alpha in vivo can be masked by other systemic effects of PPAR alpha activators. C1 Univ Oklahoma, Hlth Sci Ctr, Dept Radiol Technol, OUHSC, Oklahoma City, OK 73190 USA. Univ Oklahoma, Hlth Sci Ctr, Dept Surg, Oklahoma City, OK 73190 USA. Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK 73190 USA. Univ Oklahoma, Dept Zool, Norman, OK 73019 USA. Oklahoma Christian Univ, Dept Biol Sci, Oklahoma City, OK 73136 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Univ Wisconsin, Dept Nutrit Sci, Madison, WI 53706 USA. RP Hill, MR (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Radiol Technol, OUHSC, POB 26901, Oklahoma City, OK 73190 USA. RI Peters, Jeffrey/D-8847-2011 FU HSRD VA [TPP 97-008]; NCI NIH HHS [CA 50898] NR 40 TC 60 Z9 66 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 JUL PY 1999 VL 67 IS 7 BP 3488 EP 3493 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 209RZ UT WOS:000081063800043 PM 10377130 ER PT J AU Perry, LL Hughes, S AF Perry, LL Hughes, S TI Chlamydial colonization of multiple mucosae following infection by any mucosal route SO INFECTION AND IMMUNITY LA English DT Article ID OUTER-MEMBRANE PROTEIN; LATE ACTIVATION ANTIGEN-4; MOUSE PNEUMONITIS BIOVAR; GENITAL-TRACT; ORAL IMMUNIZATION; TRACHOMATIS SALPINGITIS; IMMUNE-SYSTEM; T-CELLS; MICE; RESPONSES AB Chlamydia trachomatis inoculated by any mucosal route colonized multiple murine mucosae and, in most cases, the spleen, liver, and kidneys. Cell-to-cell transmission, systemic dissemination, and autoinoculation of infectious fluids may have contributed to chlamydial spread. Intermucosal trafficking of protective T cells cannot be accurately evaluated by using live chlamydial challenges. C1 NIAID, Rocky Mt Labs, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. RP Perry, LL (reprint author), NIAID, Rocky Mt Labs, Intracellular Parasites Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 35 TC 24 Z9 24 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 JUL PY 1999 VL 67 IS 7 BP 3686 EP 3689 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 209RZ UT WOS:000081063800074 PM 10377161 ER PT J AU Potter, M Wax, JS Hansen, CT Kenny, JJ AF Potter, M Wax, JS Hansen, CT Kenny, JJ TI BALB/c.CBA/N mice carrying the defective Btk(xid) gene are resistant to pristane-induced plasmacytomagenesis SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE B-1 lymphocytes; Bruton's tyrosine kinase; CBA/N; plasmacytoma; pristane; TI-2 antigens; xid ID X-LINKED AGAMMAGLOBULINEMIA; B-CELL DIFFERENTIATION; TYROSINE KINASE; XID MUTATION; EXPRESSION; SELECTION; MOUSE; IMMUNODEFICIENCY; INDOMETHACIN; LYMPHOCYTES AB The X-chromosome from the CBA/N mouse which carries the defective Bruton's tyrosine kinase (Btk) allele (X-xid) has been introgressively backcrossed onto the plasmacytoma (PCT) induction-susceptible BALB/cAN. Inbred BALB/c.CBA/N-xid/xid (C.CBA/N) mice raised and maintained in our conventional colony were given three 0.5 mi injections of pristane and were highly refractory to PCT induction. Only one PCT was found among 59 mice followed for greater than or equal to 300 days. Twenty mice were examined at day 200 for foci of plasma cells in the oil granuloma. Ten mice had small foci of plasma cells, most of which were plasmacytotic, embedded in the inflammatory oil granuloma. In one there were multiple foci, but most of the mice had only one or two foci. F-1 hybrid (XY)-Y-xid males derived from CBA/N females crossed to BALB/cAnPt were also resistant to PCT induction, while heterozygous and homozygous XY males were susceptible. C.CBA/N mice can develop extensive mucosal plasma cells as well as plasma cell accumulations in oil granuloma tissue, but the precursors of these plasma cells do not give rise to PCT in genetically susceptible hosts. The failure of C.CBA/N mice to develop PCT is probably due to the elimination of B cell clones that can be perpetuated by repeated exposure to thymus-independent type 2 antigens. C1 NCI, Genet Lab, NIH, Bethesda, MD 20892 USA. Perimmune Inc, Rockville, MD 20850 USA. NIH, Off Res Serv, Off Director, Bethesda, MD 20892 USA. NIA, NIH, Baltimore, MD 21224 USA. RP Potter, M (reprint author), NCI, Genet Lab, NIH, Bldg 37,Room 2B06,37 Convent Dr,MSC4255, Bethesda, MD 20892 USA. NR 47 TC 11 Z9 11 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD JUL PY 1999 VL 11 IS 7 BP 1059 EP 1064 DI 10.1093/intimm/11.7.1059 PG 6 WC Immunology SC Immunology GA 222JC UT WOS:000081780300007 PM 10383938 ER PT J AU Abbott, LC Jacobowitz, DM AF Abbott, LC Jacobowitz, DM TI Developmental expression of calretinin-immunoreactivity in the thalamic eminence of the fetal mouse SO INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE LA English DT Article DE diencephalon; thalamus; immunocytochemistry; fetal CNS development; in situ hybridization; histochemistry ID CALCIUM-BINDING PROTEIN; RAT NERVOUS-SYSTEM; IMMUNOHISTOCHEMICAL LOCALIZATION; DORSAL THALAMUS; BRAIN; DIENCEPHALON; PARVALBUMIN; CEREBELLUM; AFFERENT; ONTOGENY AB An investigation of the developmental expression of calretinin immunoreactivity and mRNA expression was carried out in the developing mouse diencephalon. Attention was focused on the thalamic eminence, which is a prominent structure previously described in the thalamus of the fetal mammalian diencephalon and adult lower vertebrates. Calretinin-positive staining was first observed in the thalamic eminence beginning at embryonic day 11. In situ hybridization histochemistry confirmed the presence of calretinin mRNA in the thalamic eminence. During subsequent embryonic development calretinin expression was very intense in neurons in the thalamic eminence though embryonic day 17, and thereafter, was increasingly difficult to distinguish. By postnatal day 0 the thalamic eminence was no longer discernable. Additional neurons within the murine diencephalon also expressed calretinin positive cell bodies and/or neuronal processes, including the stria medullaris, the habenular commissure and the paraventricular thalamic nucleus. It is possible that the thalamic eminence may form during development in order to act as an organizing center for the diencephalon. Published by Elsevier Science Ltd. C1 Texas A&M Univ, Coll Vet Med, Dept Vet Anat & Publ Hlth, College Stn, TX 77843 USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Jacobowitz, DM (reprint author), Texas A&M Univ, Coll Vet Med, Dept Vet Anat & Publ Hlth, College Stn, TX 77843 USA. FU NINDS NIH HHS [NS01681] NR 30 TC 25 Z9 25 U1 2 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0736-5748 J9 INT J DEV NEUROSCI JI Int. J. Dev. Neurosci. PD JUL PY 1999 VL 17 IS 4 BP 331 EP 345 DI 10.1016/S0736-5748(99)00037-4 PG 15 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 226HK UT WOS:000082014400006 PM 10479068 ER PT J AU Weyer, C Snitker, S Rising, R Bogardus, C Ravussin, E AF Weyer, C Snitker, S Rising, R Bogardus, C Ravussin, E TI Determinants of energy expenditure and fuel utilization in man: effects of body composition, age, sex, ethnicity and glucose tolerance in 916 subjects SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE energy metabolism; respiratory chamber; respiratory quotient; metabolic rate; Caucasians; Pima Indians ID METABOLIC-RATE; PIMA-INDIANS; RESPIRATORY QUOTIENT; WEIGHT GAIN; FAT; WOMEN; MEN; CARBOHYDRATE; PREDICTION; OXIDATION AB BACKGROUND: 24-h energy expenditure (24-EE) and 24-h respiratory quotient (24-RQ) are important measurements in obesity research, but their accurate assessment is limited to few specialized laboratories. OBJECTIVES: 1) To provide comprehensive prediction equations for 24-EE, sleeping metabolic rate (SMR) and 24-RQ, based on a large number of Caucasian and Pima Indian subjects, covering a wide range of body weight and composition, body fat distribution, and age and 2) to test whether Pima Indians have lower metabolic rate and/or higher 24-RQ than Caucasians. SUBJECTS AND METHODS: 916 non-diabetic subjects, aged 31.5+/-11.9y, body weight 90.5+/-26.1kg (mean+/-s.d.), (561 males, 355 females; 416 Caucasians, 500 Pima Indians; 720 with normal (NGT) and 196 with impaired (IGT) glucose tolerance) spent 24 h in a respiratory chamber for measurements of 24-EE, SMR and 24-RQ. Fat-free mass (FFM) and fat mass (FM) were assessed by either hydrodensitometry or DEXA. Waist circumference and waist-to-thigh ratio (WTR) were determined as measures of body fat distribution. RESULTS: In a stepwise multiple regression analysis, FFM, FM, sex, age, WTR, and ethnicity were significant independent determinants of 24-EE (2258 +/- 422 kcal/d), explaining 85% of its variability (24-EE (kcal/d)=696+18.9FFM (kg)+10.0FM (kg)+180 male - 1.9 age (y)+7.1 WTR (per decimal)+44 Pima Indian). SMR (1623+/-315kcal/d) was determined (78% of variability) by FFM, FM, sex, age, WTR, and glucose tolerance (SMR (kcal/d) = 443 + 14.6 FFM (kg) + 6.9 FM (kg) + 79 male - 1.0 age (y) + 5.8 WTR (per decimal) +38 IGT), but not by ethnicity. Adjustment for the respective variables reduced the variance in 24-EE from 422 to 162 kcal/d and in SMR from 315 to 146kcal/d. 24-RQ (0.854+/-0.026) was determined by waist circumference and energy balance (24-RQ= 0.88429-0.00175 waist circumference (cm) + 0.00004 energy balance (%)), but not by sex, ethnicity or glucose tolerance. With this equation only 13% of the variability in 24-RQ could be explained (residual variance 0.024). Compared to Caucasians, Pima Indians had higher 24-EE, but similar SMR and 24-RQ. CONCLUSIONS: This analysis provides comprehensive prediction equations for 24-EE, SMR and 24-RQ from their major known determinants. It confirms the previous findings that, even after adjustment for body composition, age, sex, ethnicity, and glucose tolerance, there is still considerable variability in energy expenditure and substrate oxidation that may, in part, be genetically determined. In adult Pima Indians, we found no evidence for lower metabolic rate or impaired fat oxidation that could explain the propensity towards obesity in this ethnic group. C1 NIDDK, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. RP Weyer, C (reprint author), NIDDK, Clin Diabet & Nutr Sect, NIH, 4212 N 16th St,Rm 5-14, Phoenix, AZ 85016 USA. NR 49 TC 86 Z9 92 U1 0 U2 6 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD JUL PY 1999 VL 23 IS 7 BP 715 EP 722 DI 10.1038/sj.ijo.0800910 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 214HR UT WOS:000081323000007 PM 10454105 ER PT J AU Lee, HR Chang, TH Tebalt, MJ Senderowicz, AM Szabo, E AF Lee, HR Chang, TH Tebalt, MJ Senderowicz, AM Szabo, E TI Induction of differentiation accompanies inhibition of Cdk2 in a non-small cell lung cancer cell line SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE Cdk2; differentiation; flavopiridol; antisense Cdk2; Cdk inhibitors ID DEPENDENT KINASE INHIBITOR; NEUROBLASTOMA-CELLS; CARCINOMA-CELLS; LEUKEMIA-CELLS; CYCLE ARREST; P21; FLAVOPIRIDOL; EXPRESSION; MUSCLE AB Induction of differentiation in a variety of model systems is accompanied by cell cycle exit and inhibition of Cdk2 kinase activity. We asked whether inhibition of Cdk2 activity is sufficient to allow differentiation to occur in a non-small cell lung cancer cell line. Treatment of NCI-H358 with flavopiridol, an inhibitor of multiple Cdk's, resulted in growth arrest and induction of mucinous differentiation. The onset of differentiation coincided temporally with loss of Cdk2 kinase activity. Western analysis revealed that flavopiridol treatment resulted in depletion of both cyclin E and D1, suggesting that loss of the regulatory subunits is at least partially responsible for the loss of Cdk2 kinase activity. Similarly, roscovitine, an inhibitor of Cdk's 1, 2, and 5, but not Cdk4, also induced differentiation in NCI-H358, although the resulting pattern of expression of cell cycle regulatory genes differed from the pattern obtained with flavopiridol. Furthermore, stable expression of an antisense Cdk2 construct in NCI-H358 also resulted in the appearance of a marker of mucinous differentiation. These results show that the inhibition of activity of cyclin dependent kinases, particularly Cdk2, by multiple different mechanisms is accompanied by differentiation. Thus, induction of differentiation is one potential mechanism of action for agents that down-regulate Cdk activity. C1 NCI, Div Clin Sci, Med Branch, Cell & Canc Biol Dept, Rockville, MD 20850 USA. NCI, DTP Clin Trials Unit, Rockville, MD 20850 USA. RP Szabo, E (reprint author), NCI, Div Clin Sci, Med Branch, Cell & Canc Biol Dept, 9610 Med Ctr Dr,Room 300, Rockville, MD 20850 USA. NR 20 TC 45 Z9 46 U1 0 U2 0 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 JUL PY 1999 VL 15 IS 1 BP 161 EP 166 PG 6 WC Oncology SC Oncology GA 210DG UT WOS:000081089400023 PM 10375610 ER PT J AU Herning, RI King, DE Cadet, JL AF Herning, RI King, DE Cadet, JL TI Cognitive ERP deficits in cocaine-dependent individuals SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 NIDA, Mol Neuropsychiat Sect, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD JUL PY 1999 VL 33 IS 1 MA 207 BP 97 EP 97 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 223AF UT WOS:000081817000214 ER PT J AU Kruger, EA Blagosklonny, MV Dixon, SC Figg, WD AF Kruger, EA Blagosklonny, MV Dixon, SC Figg, WD TI UCN-01, a protein kinase C inhibitor, inhibits endothelial cell proliferation and angiogenic hypoxic response SO INVASION & METASTASIS LA English DT Article DE 7-hydroxystaurosporine; cancer; angiogenesis; therapy; vascularization ID GROWTH-FACTOR EXPRESSION; OXIDE SYNTHASE PROMOTER; IN-VITRO; SELECTIVE INHIBITOR; TUMOR ANGIOGENESIS; PROSTATE-CANCER; GENE-EXPRESSION; PHORBOL ESTERS; SOLID TUMORS; ACTIVATION AB Angiogenesis is required for tumor formation and growth; inhibition of angiogenesis is a promising new approach in cancer therapy. UCN-01, a protein kinase C (PKC) inhibitor, induces growth arrest and apoptosis in cancer cells and was recently introduced in a phase I clinical trial. We demonstrate that UCN-01, at concentrations lower than those necessary to inhibit cancer cell growth, inhibit proliferation of human endothelial cells in vitro. Moreover, UCN-01, at concentrations as low as 32 nM prevent microvessel outgrowth from explant cultures of rat aortic rings. Since hypoxia activates hypoxia-inducible factor (HIF-1)-dependent transcription in cancer cells that, in a paracrine fashion, drive tumor angiogenesis, we investigated the effects of UCN-01 on HIF-1-responsive promoter constructs. We report that, in addition to direct inhibitory effects on endothelial cell growth, UCN-01 abrogates hypoxia-mediated transactivation of HIF-1-responsive promoters in a prostate cancer cell line. We conclude that UCN-01, at clinically relevant concentrations, exerts an anti-neovascularization effect by blocking two important steps in vessel formation: (1) the response of cancer cells to hypoxia, and (2) endothelial cell proliferation. Copyright (C) 2000 S. Karger AG, Basel. C1 NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Med Branch, Div Clin Sci, NIH, 10 Ctr Dr,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 44 TC 5 Z9 6 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0251-1789 J9 INVAS METAST JI Invasion Metastasis PD JUL-AUG PY 1999 VL 18 IS 4 BP 209 EP 218 PG 10 WC Oncology SC Oncology GA 279EE UT WOS:000085030800006 ER PT J AU Tumminia, S Epstein, DL Russell, P AF Tumminia, S Epstein, DL Russell, P TI TIGR and stretch in the trabecular meshwork - Response SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Letter C1 Duke Univ, Ctr Eye, Dept Ophthalmol, Durham, NC 27710 USA. NEI, NIH, Bethesda, MD 20892 USA. RP Tumminia, S (reprint author), Duke Univ, Ctr Eye, Dept Ophthalmol, Durham, NC 27710 USA. NR 7 TC 1 Z9 1 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 1999 VL 40 IS 8 BP 1889 EP 1889 PG 1 WC Ophthalmology SC Ophthalmology GA 210DR UT WOS:000081090300044 ER PT J AU Okabe, S Ochiai, Y Aida, M Park, K Kim, SJ Nomura, T Suganuma, M Fujiki, H AF Okabe, S Ochiai, Y Aida, M Park, K Kim, SJ Nomura, T Suganuma, M Fujiki, H TI Mechanistic aspects of green tea as a cancer preventive: Effect of components on human stomach cancer cell lines SO JAPANESE JOURNAL OF CANCER RESEARCH LA English DT Article DE stomach cancer; apoptosis; TNF-alpha; AP-1; NF-kappa B ID RAT GLANDULAR STOMACH; NF-KAPPA-B; (-)-EPIGALLOCATECHIN GALLATE; TUMOR PROMOTER; GROWTH-INHIBITION; MESSENGER-RNA; ALPHA GENE; POLYPHENOLS; ACTIVATION; TRANSFORMATION AB It is now well accepted that (-)-epigallocatechin gallate (EGCG) inhibits carcinogenesis in the digestive tract in rodents, To understand the mechanisms of anticarcinogenesis, we first studied growth inhibition by EGCG in human stomach cancer cell lines established at Seoul National University (SNU cell lines). Inhibition by EGCG of [H-3]thymidine incorporation into eight SNU cell lines was examined, in relation to transforming growth factor-beta (TGF-beta) responsiveness. Various tea polyphenols derived from green tea and black tea induced growth inhibition and apoptosis of human stomach cancer cell line KATO III, and inhibition of tumor necrosis factor-alpha (TNF-alpha) release from the cells, in the order of (-)-epicatechin gallate (ECG), EGCG, (-)-epigallocatechin (EGC), teaflavins (TF) and (-)-epicatechin (EC), In addition, me demonstrated that EGCG inhibited TNF-alpha gene expression in KATO III cells, as well as okadaic acid-induced AP-1 and NF-kappa B activation. The inhibitory potencies of EGCG for AP-1 and NF-kappa B binding to DNA were different between KATO III cells and mouse fibroblast cell line BALB/3T3. Thus, EGCG and other tea polyphenols may interact with various transcription factors, in addition to AP-1 and NF-kappa B, in nuclei of various cells, resulting in inhibition of TNF-alpha gene expression and TNF-alpha release. C1 Saitama Canc Ctr, Res Inst, Ina, Saitama 3620806, Japan. Toho Univ, Fac Pharmaceut Sci, Chiba 2740072, Japan. Natl Canc Inst, Lab Cell Regulat & Carcinogenesis, Bethesda, MD USA. RP Fujiki, H (reprint author), Saitama Canc Ctr, Res Inst, Ina, Saitama 3620806, Japan. NR 24 TC 103 Z9 110 U1 1 U2 5 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0910-5050 J9 JPN J CANCER RES JI Jpn. J. Cancer Res. PD JUL PY 1999 VL 90 IS 7 BP 733 EP 739 PG 7 WC Oncology SC Oncology GA 221HP UT WOS:000081721900005 PM 10470285 ER PT J AU Hirvensalo, M Lintunen, T Rantanen, T AF Hirvensalo, M Lintunen, T Rantanen, T TI The continuity of physical activity level - A retrospective and prospective study among older people SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Meeting Abstract C1 Univ Jyvaskyla, Dept Educ Phys, Jyvaskyla, Finland. Univ Jyvaskyla, Finnish Ctr Interdisciplinary Gerontol, Jyvaskyla, Finland. NIA, Epidemiol Demog & Biometry Program, NIH, Bethesda, MD 20892 USA. RI Lintunen, Taru/G-2838-2011 OI Lintunen, Taru/0000-0001-5191-2251 NR 0 TC 0 Z9 0 U1 0 U2 0 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1063-8652 J9 J AGING PHYS ACTIV JI J. Aging Phys. Act. PD JUL PY 1999 VL 7 IS 3 BP 272 EP 272 PG 1 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 218YV UT WOS:000081581300038 ER PT J AU Williams, AM Simon, I Landis, PK Moser, C Christens-Barry, W Carter, HB Metter, EJ Partin, AW AF Williams, AM Simon, I Landis, PK Moser, C Christens-Barry, W Carter, HB Metter, EJ Partin, AW TI Prostatic growth rate determined from MRI data: Age-related longitudinal changes SO JOURNAL OF ANDROLOGY LA English DT Article DE age; lower urinary tract symptoms (LUTS); benign prostatic hyperplasia; image analysis; volume reconstruction ID TRANSRECTAL ULTRASOUND; VOLUME DETERMINATION; HYPERPLASIA; COIL; POPULATION; CARCINOMA; SYMPTOMS AB Men with prostatic enlargement are at highest risk of developing symptomatic lower urinary tract symptoms (LUTS) and related outcomes, such as acute urinary retention. The study of prostatic growth rate can identify the age range at which prostate growth peaks. Evaluation of the natural course of prostate growth requires repeated intraindividual volume measurements at time intervals sufficient to document growth. Our objective was to examine age-stratified prostate growth rates from men taking part in a longitudinal study of aging using magnetic resonance imaging (MRI) of the prostate. Sixty-four men (ages 30-71 years) enrolled in the Baltimore Longitudinal Study of Aging (BLSA) who had T2 pelvic MRIs taken approximately every 2 years were studied. Men were age stratified into four groups: <45, 45-55, 56-65, and >65 years old. Whole prostate and central gland (anatomically referred to as the transition zone) volumes were determined from the MRI images by a semi-automated image analysis program. Peripheral gland volumes were calculated as the difference between whole prostate and central gland volumes. Growth rates (cc per year) were calculated as change in volume divided by the time interval. On the basis of measurements from the T2 images (n = 128), we observed a linear trend between prostate volume and age. The overall prostate growth rate was 2.36 +/- 3.52 cc per year. Age-stratified growth rates revealed that prostate growth increased with age, peaked at 4.15 +/- 4.98 cc/year for the 56-65-year-old age group and then declined rapidly for the older-aged men. The central gland growth rates followed a trend similar to total prostate volume. These data suggest that there is an age-related increase in prostate growth rate that peaks in men ages 56-55 and then declines. identification of this trend in prostate growth may aid physicians in targeting men for early diagnosis of LUTS and for possible early intervention. Future studies with a larger sample size are necessary to substantiate these findings. C1 Johns Hopkins Hosp, Dept Urol, James Buchanan Brady Urol Inst, Baltimore, MD 21287 USA. Johns Hopkins Appl Phys Lab, Laurel, MD USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Partin, AW (reprint author), Johns Hopkins Hosp, Dept Urol, James Buchanan Brady Urol Inst, 600 N Wolfe St, Baltimore, MD 21287 USA. FU NCI NIH HHS [CA 58236] NR 27 TC 21 Z9 23 U1 0 U2 0 PU AMER SOC ANDROLOGY, INC PI LAWRENCE PA C/O ALLEN PRESS, INC PO BOX 368, LAWRENCE, KS 66044 USA SN 0196-3635 J9 J ANDROL JI J. Androl. PD JUL-AUG PY 1999 VL 20 IS 4 BP 474 EP 480 PG 7 WC Andrology SC Endocrinology & Metabolism GA 222YQ UT WOS:000081813300007 PM 10452590 ER PT J AU Zeni, F Parent, C Correa, R Natanson, C Freeman, B Fontana, J Quezado, M Danner, RL Ritz, Y Richmond, S Gerstenberger, E Banks, SM Eichacker, PQ AF Zeni, F Parent, C Correa, R Natanson, C Freeman, B Fontana, J Quezado, M Danner, RL Ritz, Y Richmond, S Gerstenberger, E Banks, SM Eichacker, PQ TI ICAM-1 and CD11b inhibition worsen outcome in rats with E-coli pneumonia SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Thoracic-Society CY MAY 14, 1996 CL NEW ORLEANS, LOUISIANA SP Amer Thorac Soc DE adhesion molecule; neutrophil; sepsis; pneumonia; acute lung injury ID INTERCELLULAR-ADHESION MOLECULE-1; REDUCES ORGAN INJURY; INDUCED LUNG INJURY; MONOCLONAL-ANTIBODY; ESCHERICHIA-COLI; SEPTIC SHOCK; STAPHYLOCOCCUS-AUREUS; INFLAMMATORY INJURY; REPERFUSION INJURY; IMPROVES SURVIVAL AB ICAM-1 and CD11b inhibition worsen outcome in rats with E. coli pneumonia. J. Appl. Physiol. 87(1): 299-307, 1999.-We investigated whether inhibiting an endothelial adhesion molecule [intracellular adhesion molecule 1 (I:CAM-1)] would alter outcome and lung injury in a similar fashion to inhibition of a leukocyte adhesion molecule (integrin CD11b) in a rat model of gramnegative pneumonia. Inhibition of ICAM-1 with monoclonal antibody (MAb) 1A29 (1 mg/kg sc or 0.2 or 2 mg/kg iv, q 12 h x 3) or of CD11b with MAb 1B6 ii mg/kg sc, q 12 h x 3) were compared against similarly administered placebo proteins in rats challenged with intrabronchial Escherichia coli. After challenge, all animals were treated with antibiotics, ICAM-1 MAb (6 mg/kg, iv, total dose) increased mortality vs. control (P = 0.03). CD11b MAb (3 mg/kg, sc, total dose) did not significantly (P = 0.16) increase mortality rates, but this was not in a range of probability to exclude a harmful effect. All other doses of MAb had no significant effect on survival rates. ICAM-1 and CD11b MAbs had significantly different effects on the time course of lung injury, circulating white cells and lymphocytes, and lung lavage white cells and neutrophils (P = 0.04-0.003). CD11b MAb decreased, whereas ICAM-1 MAID increased these measures compared with control from 6 to 12 h after E. coli. However, from 144 to 168 h after E. coli both MAbs increased these measures compared with control rats but to a greater: level with CD11b MAb. Thus both ICAM-1 and CD11b appear to be necessary for survival during E. coli pneumonia. Although these adhesion molecules may participate differently in early lung injury, with CD11b increasing and ICAM-1 decreasing inflammation and injury, both are important for the resolution of later injury. During gram-negative pneumonia the protective roles of ICAM-1 and CD11b may make their therapeutic inhibition difficult. C1 NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Eichacker, PQ (reprint author), NIH, Dept Crit Care Med, Bldg 10,Rm 7D43,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 47 TC 21 Z9 21 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 JUL PY 1999 VL 87 IS 1 BP 299 EP 307 PG 9 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 215HN UT WOS:000081376200039 PM 10409588 ER PT J AU Yanowitz, TD Yao, AC Pettigrew, KD Werner, JC Oh, W Stonestreet, BS AF Yanowitz, TD Yao, AC Pettigrew, KD Werner, JC Oh, W Stonestreet, BS TI Postnatal hemodynamic changes in very-low-birthweight infants SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article; Proceedings Paper CT Academic Pediatrics Societies Annual Meeting CY MAY 02, 1997 CL WASHINGTON, D.C. SP Acad Pediat Soc DE Doppler blood flow velocity; brain; intestine; patent ductus arteriosus; antenatal steroid; enteral nutrition ID BLOOD-FLOW VELOCITY; RESPIRATORY-DISTRESS SYNDROME; BIRTH-WEIGHT INFANTS; PATENT DUCTUS-ARTERIOSUS; SUPERIOR MESENTERIC-ARTERY; LOW-DOSE INDOMETHACIN; HEALTHY TERM INFANTS; PRETERM INFANTS; PREMATURE-INFANTS; INTRAVENTRICULAR HEMORRHAGE AB The purpose of this study was to characterize postnatal changes in regional Doppler blood flow velocity (BFV) and cardiac function of very-low-birthweight infants and to examine factors that might influence these hemodynamic changes. Mean and end-diastolic BFV of the middle cerebral and superior mesenteric arteries, cardiac output, stroke volume, and fractional shortening were measured in 20 infants birthweight 1,002 +/- 173 g, gestational age 28 +/- 2 wk) at 6, 30, and 54 h after birth and before and after feedings on days 7 and 14. Postnatal increases in cerebral BFV, mesenteric BFV, and cardiac output were observed that were not associated with changes in blood pressure, hematocrit, pH, arterial PCO2, or oxygen saturation. The postnatal pattern of relative vascular resistance (RVR) differed between the cerebral and mesenteric vasculatures. RVR decreased in the middle cerebral but not the superior mesenteric artery. Physiological patency of the ductus arteriosus did not alter postnatal hemodynamic changes. In response to feeding, mesenteric BFV and stroke volume increased, and mesenteric RVR and heart rate decreased. Postprandial responses were not affected by postnatal age or the age at which feeding was initiated. However, the initiation of enteral nutrition before 3 days of life was associated with higher preprandial mesenteric BFV and lower mesenteric RVR than was later initiation of feeding. We conclude that in very-low-birthweight infants over the first week of life 1) systemic, cerebral, and mesenteric hemodynamics exhibit region-specific changes; 2) asymptomatic ductus arteriosus patency and early feedings do not significantly influence these postnatal hemodynamic changes; and 3) cardiac function adapts to increase local mesenteric BFV in response to feedings. C1 Brown Univ, Women & Infants Hosp, Sch Med, Dept Pediat, Providence, RI 02905 USA. Rhode Isl Hosp, Providence, RI 02905 USA. SUNY Hlth Sci Ctr, Dept Pediat, Childrens Med Ctr, Brooklyn, NY 11203 USA. NIMH, Div Sci & Intervent Res, Bethesda, MD 20892 USA. RP Stonestreet, BS (reprint author), Brown Univ, Women & Infants Hosp, Sch Med, Dept Pediat, 101 Dudley St, Providence, RI 02905 USA. FU NICHD NIH HHS [NIH1R01-HD34618] NR 49 TC 36 Z9 36 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD JUL PY 1999 VL 87 IS 1 BP 370 EP 380 PG 11 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 215HN UT WOS:000081376200048 PM 10409597 ER PT J AU Roum, JH Borok, Z McElvaney, NG Grimes, GJ Bokser, AD Buhl, R Crystal, RG AF Roum, JH Borok, Z McElvaney, NG Grimes, GJ Bokser, AD Buhl, R Crystal, RG TI Glutathione aerosol suppresses lung epithelial surface inflammatory cell-derived oxidants in cystic fibrosis SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE antioxidant; bronchoalveolar lavage; neutrophil; respiratory epithelium; superoxide anion ID IDIOPATHIC PULMONARY FIBROSIS; TRANSMEMBRANE CONDUCTANCE REGULATOR; RESPIRATORY-DISTRESS-SYNDROME; LINING FLUID; ALPHA-1-PROTEINASE INHIBITOR; PSEUDOMONAS-AERUGINOSA; BRONCHOALVEOLAR LAVAGE; NEUTROPHIL ELASTASE; HYDROGEN-PEROXIDE; CIGARETTE-SMOKE AB Cystic fibrosis (CF) is characterized by accumulation of activated neutrophils and macrophages on the respiratory epithelial surface (RES); these cells release toxic oxidants, which contribute to the marked epithelial derangements seen in CF. These deleterious consequences are magnified, since reduced glutathione (GSH), an antioxidant present in high concentrations in normal respiratory epithelial lining fluid (ELF), is deficient in CF ELF. To evaluate the feasibility of increasing ELF GSH levels and enhancing RES antioxidant protection, GSH aerosol was delivered (600 mg twice daily for 3 days) to seven patients with CF. ELF total, reduced, and oxidized GSH increased (P < 0.05, all compared with before GSH therapy), suggesting adequate RES delivery and utilization of GSH. Phorbol 12-myristate 13-acetate-stimulated superoxide anion (O-2(-).) release by ELF inflammatory cells decreased after GSH therapy (P < 0.002). This paralleled observations that GSH added in vitro to CF ELF inflammatory cells suppressed O-2(-). release (P < 0.001). No adverse effects were noted during treatment. Together, these observations demonstrate the feasibility of using GSH aerosol to restore RES oxidant-antioxidant balance in CF and support the rationale for further clinical evaluation. C1 Univ Calif Irvine, Irvine Med Ctr, Div Pulm & Crit Care Med, Orange, CA 92868 USA. NHLBI, Pulm Branch, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NIH, Dept Pharm, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. Univ So Calif, Dept Med, Div Pulm & Crit Care Med, Los Angeles, CA 90033 USA. New York Hosp, Cornell Med Ctr, Div Pulm Crit Care Med, New York, NY 10021 USA. RP Roum, JH (reprint author), Univ Calif Irvine, Irvine Med Ctr, Div Pulm & Crit Care Med, Bldg 53,Rm 119, Orange, CA 92868 USA. RI McElvaney, Noel/A-6809-2010 NR 45 TC 79 Z9 80 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD JUL PY 1999 VL 87 IS 1 BP 438 EP 443 PG 6 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 215HN UT WOS:000081376200056 PM 10409605 ER PT J AU Dressman, HK Drake, JW AF Dressman, HK Drake, JW TI Lysis and lysis inhibition in bacteriophage T4: rV mutations reside in the holin t gene SO JOURNAL OF BACTERIOLOGY LA English DT Article AB Upon infecting populations of susceptible host cells, T-even bacteriophages maximize their yield by switching from lysis at about 25 to 35 min at 37 degrees C after infection by a single phage particle to long-delayed lysis (lysis inhibition) under conditions of sequential infection occurring when free phages outnumber host cells. The timing of lysis depends upon gene t and upon one or more rapid-lysis (r) genes whose inactivation prevents lysis inhibition. t encodes a holin that mediates the movement of the T4 endolysin though the inner cell membrane to its target, the cell wall. The rI protein has been proposed to sense superinfection, Of the five reasonably well characterized r genes, only two, rI and rV, are clearly obligatory for lysis inhibition. We show here that rV mutations are alleles oft that probably render the t protein unable to respond to the lysis inhibition signal. The tr alleles cluster in the 5' third of t and produce a strong r phenotype, whereas conditional-lethal t alleles produce the classical t phenotype (inability to lyse) and other t alleles produce additional, still poorly understood phenotypes. tr mutations are dominant to t(+), a result that suggests specific ways to probe T4 holin function. C1 NIEHS, Genet Mol Lab, Res Triangle Pk, NC 27709 USA. RP Drake, JW (reprint author), NIEHS, Genet Mol Lab, E3-01,POB 12233, Res Triangle Pk, NC 27709 USA. NR 39 TC 23 Z9 26 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JUL PY 1999 VL 181 IS 14 BP 4391 EP 4396 PG 6 WC Microbiology SC Microbiology GA 215AQ UT WOS:000081360100031 PM 10400598 ER PT J AU Vathyam, S Byrd, RA Miller, AF AF Vathyam, S Byrd, RA Miller, AF TI Assignment of the backbone resonances of oxidized Fe-superoxide dismutase, a 42 kDa paramagnet-containing enzyme SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE iron; non-heme; oxidized; paramagnetic; superoxide dismutase ID ESCHERICHIA-COLI; NMR; PROTEINS; IRON; C-13; N-15 C1 Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. Univ Kentucky, Lexington, KY 40506 USA. NCI, FCRDC, ABL Basic Res Program, Frederick, MD 21702 USA. RP Miller, AF (reprint author), Johns Hopkins Univ, Dept Chem, Charles & 34th St, Baltimore, MD 21218 USA. RI Byrd, R. Andrew/F-8042-2015 OI Byrd, R. Andrew/0000-0003-3625-4232 FU NIGMS NIH HHS [GM55210] NR 8 TC 8 Z9 8 U1 0 U2 1 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 JUL PY 1999 VL 14 IS 3 BP 293 EP 294 DI 10.1023/A:1008348716066 PG 2 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 220XC UT WOS:000081692800015 PM 10481283 ER PT J AU Taymans, SE Pack, S Pak, E Orban, Z Barsony, J Zhuang, ZP Stratakis, CA AF Taymans, SE Pack, S Pak, E Orban, Z Barsony, J Zhuang, ZP Stratakis, CA TI The human vitamin D receptor gene (VDR) is localized to region 12cen-q12 by fluorescent in situ hybridization and radiation hybrid mapping: Genetic and physical VDR map SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article ID INSITU HYBRIDIZATION; BONE-DENSITY; HUMAN GENOME; CHROMOSOME-12; ORGANIZATION; RICKETS; LOCUS; BANDS; 12Q13; ARM AB The vitamin D receptor (VDR) is a member of the steroid hormone receptor superfamily of ligand-activated transcription factors. The VDR gene was previously mapped to human chromosome 12q13-12q14, but its precise physical and genetic localization are unknown. The present study reports the mapping of the human VDR gene by radiation hybrid (RH) analysis, the isolation of a bacterial artificial chromosome (BAC) containing this gene, and physical mapping of the VDR gene by fluorescent in situ hybridization (FISH). RH analysis placed the VDR gene locus at chromosome 12cen-q12, flanked by Stanford Human Genome Center (SHGC) 30216 and SHGC 9798 (D12S1892) markers. FISH analysis of a BAC containing the VDR gene confirmed its centromeric location. Thus, me have identified a BAC and genetic markers which can be used in the genetic analysis of the VDR gene and investigation of its involvement in osteoporosis and related disorders. We conclude that the VDR gene is centromeric to its previously reported locus on chromosome 12. C1 NICHHD, Unit Genet & Endocrinol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NCI, Dept Pathol, Bethesda, MD 20892 USA. NICHHD, Sect Pediat Endocrinol, Dev Endocrinol Branch, Bethesda, MD 20892 USA. NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHHD, Unit Genet & Endocrinol, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC 1862, Bethesda, MD 20892 USA. RI Pack, Svetlana/C-2020-2014 NR 27 TC 32 Z9 35 U1 0 U2 1 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUL PY 1999 VL 14 IS 7 BP 1163 EP 1166 DI 10.1359/jbmr.1999.14.7.1163 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 211JK UT WOS:000081157300012 PM 10404016 ER PT J AU Exner, DV Goodhart, DM Anderson, TJ Duff, HJ AF Exner, DV Goodhart, DM Anderson, TJ Duff, HJ TI Prolonged sinus node recovery time in humans after the intracoronary administration of a nitric oxide synthase inhibitor SO JOURNAL OF CARDIOVASCULAR PHARMACOLOGY LA English DT Article DE automaticity; intracoronary; L-NMMA; nitric oxide; sinoatrial node ID HEART-RATE; BLOOD-PRESSURE; ELECTROGRAMS; RESPONSES; DOGS AB In vitro studies indicate that nitric oxide synthase (NOS) inhibitors alter sinus node automaticity. Moreover, whereas the systemic delivery of N-G-monomethyl-L-arginine (L-NMMA), a NOS inhibitor, results in sinus bradycardia and arterial hypertension, its intracoronary administration has little effect on sinus heart rate. Therefore whether L-NMMA directly alters sinus node function in humans is not known. By using a crossover design, we evaluated the effect of intracoronary L-NMMA (20 mu mol/min x 10 min) on corrected sinus node recovery time (CSNRT), heart rate, mean arterial blood pressure, electrocardiographic intervals, and coronary artery blood flow in nine men and 13 women aged 48 +/- 12 years. All were in sinus rhythm and had normal baseline CSNRTs. Baseline measurements were made during a dextrose infusion, and then L-NMMA was administered, and these parameters remeasured. In 11 patients, the infusions were near the origin of the sinus node artery (Concordant), whereas in the remaining 11, they were into the opposite coronary circulation (Discordant). After L-NMMA, significant prolongations in CSNRT were seen in Concordant (p < 0.001) and Discordant patients (p < 0.05), but were most pronounced in the Concordant group (p < 0.05). Although a significant reduction in coronary artery blood flow and nonsignificant changes in blood pressure and heart rate were observed after L-NMMA, these changes were not related to changes in CSNRT (r(2) less than or equal to 0.2; p greater than or equal to 0.2). These data support the notion that NO is a modifier of human sinus node automaticity. C1 Univ Calgary, Dept Med, Div Cardiol, Calgary, AB, Canada. RP Exner, DV (reprint author), NHLBI 2, 6701 Rockledge Dr,Room 8146, Bethesda, MD 20892 USA. OI Duff, Henry/0000-0001-9292-5411 NR 32 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0160-2446 J9 J CARDIOVASC PHARM JI J. Cardiovasc. Pharmacol. PD JUL PY 1999 VL 34 IS 1 BP 1 EP 6 DI 10.1097/00005344-199907000-00001 PG 6 WC Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy SC Cardiovascular System & Cardiology; Pharmacology & Pharmacy GA 210CN UT WOS:000081087700001 PM 10413059 ER PT J AU Yu, SH Davis, AT Guo, CH Green, JE Ahmed, K AF Yu, SH Davis, AT Guo, CH Green, JE Ahmed, K TI Differential targeting of protein kinase CK2 to the nuclear matrix upon transient overexpression of its subunits SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE protein kinase CK2; nuclear matrix; overexpression; prostate; translocation ID CASEIN KINASE-2; CELLULAR-REGULATION; II-ALPHA; ASSOCIATION; PROSTATE; PHOSPHORYLATION; ORGANIZATION; GROWTH AB Modest dysregulation of CK2 has been shown to enhance the oncogenic potential in transgenic models of cancer. Since nuclear matrix serves as an anchor for CK2 and plays a key role in growth-related activities, we examined the effects of CK2 overexpression on its signaling to the nuclear matrix. Expression plasmids pCI-CK2 alpha, pCI-CK2 beta, and the bicistronic pCI-CK2 alpha beta containing full length cDNAs encoding the various subunits were employed to transiently transfect two cell lines, BPH-1 and COS-1. Cytosol from transfected BPH-1 cells containing alpha or beta or alpha + beta or alpha beta showed a modest increase in CK2 activity by 26%, 1%, 20%, and 17%, respectively, over that in the controls transfected with pCl vector. However, the corresponding increase in CK2 activity in the NM fraction was 156%, 8%, 147%, and 152%, respectively. Immunoblot analysis of the CK2 in the NM accorded with these data. Similar results were obtained with COS-1 cells or other expression vectors. The results suggest that moderate overexpression of CK2 in the cells evokes a differential several-fold enhancement in NM associated CK2 relative to that in the cytosol. This process may have a bearing on the functional signaling of this kinase in relation to its possible role in oncogenesis. J. Cell. Biochem. 74:12 7-134, 1999. (C) 1999 Wiley-Liss, Inc. C1 Dept Vet Affairs Med Ctr, Cellular & Mol Biochem Res Lab 151, Minneapolis, MN 55417 USA. Univ Minnesota, Dept Lab Med & Pathol, Cellular & Mol Biochem Res Lab, Minneapolis, MN 55417 USA. NCI, Transgen Oncogenesis Grp, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Dept Vet Affairs Med Ctr, Cellular & Mol Biochem Res Lab 151, 1 Vet Dr, Minneapolis, MN 55417 USA. EM ahmedk@tc.umn.edu FU NCI NIH HHS [CA-15062] NR 29 TC 14 Z9 14 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-2312 EI 1097-4644 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD JUL 1 PY 1999 VL 74 IS 1 BP 127 EP 134 DI 10.1002/(SICI)1097-4644(19990701)74:1<127::AID-JCB14>3.0.CO;2-3 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 201YQ UT WOS:000080625200014 PM 10381269 ER PT J AU Pendergrass, WR Lane, MA Bodkin, NL Hansen, BC Ingram, DK Roth, GS Yi, L Bin, H Wolf, NS AF Pendergrass, WR Lane, MA Bodkin, NL Hansen, BC Ingram, DK Roth, GS Yi, L Bin, H Wolf, NS TI Cellular proliferation potential during aging and caloric restriction in rhesus monkeys (Macaca mulatta) SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID LIFE-SPAN EXTENSION; DIETARY RESTRICTION; IN-VIVO; CLONAL ATTENUATION; CAPACITY; MICE; CELLS; CONSERVATION; FIBROBLASTS; BIOMARKER AB Caloric restriction (CR) is the most successful method of extending both median and maximal lifespans in rodents and other short-lived species. It is not yet clear whether this method of life extension will be successful in longer-lived species, possibly including humans; however, trials in rhesus monkeys are underway. We have examined the cellular proliferative potential of cells from CR and AL (ad libitum fed) monkey skin cells using two different bioassays: colony size analysis (CSA) of dermal fibroblasts isolated and cloned directly from the skin and betagalactosidase staining at PH 6.0 (BG-6.0) of epidermal cells in frozen sections of skin. Decreases in both proliferative markers occurred with ape, but no differences were observed between CR and AL animals. Skin biopsies were obtained from AL and CR rhesus monkeys from two different aging colonies, one at the National Institute on Aging (NIA) and one at the University of Maryland-Baltimore (UMB). These biopsies were used as a source of tissue sections and cells for two biomarkers of aging assays. The CR monkeys had been maintained for 9-12 years on approximately 70% of the caloric intake of control AL animals. In the CSA studies, the fraction of small clones increased significantly and the fraction of large clones decreased significantly with increasing age in AL monkeys. The frequency of epidermal BG-6.0 staining cells increased with age in older (>22 years) AL monkeys, but most predominately in those of the UMB colony, which were somewhat heavier than the NIH AL controls. Old monkeys on CR tended to have fewer BG-6.0-positive cells relative to old AL-derived epidermis, but this effect was not significant. These results indicate that cellular proliferative potential declined with age in Macaca mulatta, but was not significantly altered by CR under these conditions. Although these experiments are consistent with an absence of effect of CR on monkey skin cell proliferative potential, we have found in previous experiments with mice that a longer duration of CR (as a fraction of total lifespan) was needed to demonstrate CR-related improvement in clone size in mice. Further studies on the now mid-aged monkeys will be needed as their age exceeds 20 years to conclusively rule out an effect of CR on proliferative potential of skin cells from these primates. (C) 1999 Wiley-Liss, Inc. C1 Univ Washington, Dept Pathol, Seattle, WA 98195 USA. NIA, Gerontol Res Ctr, Intramural Res Program, Baltimore, MD 21224 USA. Univ Maryland, Dept Physiol, Obes & Diabet Res Ctr, Baltimore, MD 21201 USA. RP Wolf, NS (reprint author), Univ Washington, Dept Pathol, Box 357470, Seattle, WA 98195 USA. RI Hansen, Barbara/J-8723-2012 OI Hansen, Barbara/0000-0001-9646-3525 FU NIA NIH HHS [AG07724, AG42100] NR 31 TC 52 Z9 63 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD JUL PY 1999 VL 180 IS 1 BP 123 EP 130 DI 10.1002/(SICI)1097-4652(199907)180:1<123::AID-JCP14>3.0.CO;2-W PG 8 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 200ZX UT WOS:000080571100014 PM 10362025 ER PT J AU Arai, K Zachman, K Shibasaki, T Chrousos, GP AF Arai, K Zachman, K Shibasaki, T Chrousos, GP TI Polymorphisms of amiloride-sensitive sodium channel subunits in five sporadic cases of pseudohypoaldosteronism: Do they have pathologic potential? SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID MINERALOCORTICOID RECEPTOR GENE; EPITHELIAL NA+ CHANNEL; BETA-SUBUNIT; GAMMA-SUBUNIT; DOMINANT PSEUDOHYPOALDOSTERONISM; INHERITANCE; MUTATIONS; UNRESPONSIVENESS; DEFICIENCY; FAMILIES AB Pseudohypoaldosteronism (PHA) is characterized by congenital resistance of the kidney and/or other mineralocorticoid target tissues to aldosterone, resulting in excessive salt wasting. Mineralocorticoid receptor (MR) and postreceptor defects in the aldosterone-responsive amiloride-sensitive sodium channel (ENaC) subunits have been suggested as potential loci of the defect in this disease, whereas recently defects in MR and ENaC subunits were reported in familial PHA cases. Here we studied the ENaC subunit alpha, beta, and gamma complementary DNAs (cDNAs) in a series of five sporadic cases of PHA, whose MR cDNA contained nonconservative homozygous (C-944-->T-944, Ala(241)-->Val(241)) and/or a conservative heterozygous substitutions (A(760) --> G(760), Ileu(180) --> Val(180)), which, however, were also present at high frequencies in a control population with apparently normal salt conservation. We found a nonconservative substitution (A(2086) --> G(2086), Thr(663) --> Ala(663)) in the alpha ENaC in all five of our patients, two of whom were homozygous and three of whom were heterozygous for this alteration, which was also present in the homozygous and heterozygous form in 31% and 64% of control subjects, respectively. We also found nonconservative homozygous substitution (C-1006-->G(1006) Pro(336) --> Ara(336)) in the beta ENaC and three nonconservative and conservative homozygous substitutions (T-554-->A(554), Trp(178)-->Arg(178), C-1526-->G(1526), Pro(501) --> Ala(501); T-1862 --> G(1862), Ser(614) --> Ala(614)) in the gamma ENaC of all five of our patients and in a substantial proportion of control subjects. Interestingly, when the patient group was compared to controls, a significantly increased concurrence of the MR and alpha ENaC polymorphisms was found in the patients (P < 0.025). We conclude that the changes identified in the cDNA of the three ENaC subunits in the patients with sporadic PHA are polymorphisms, which on their own have no apparent pathophysiological significance. We hypothesize, however, that these polymorphisms might influence salt conservation negatively if they are present concurrently with other genetic defects of the MR or other proteins that participate in sodium homeostasis. The latter would be compatible with a sporadic presentation and digenic or multigenic expression and heredity in PHA. C1 Nippon Med Sch, Dept Physiol, Bunkyo Ku, Tokyo 1138602, Japan. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Arai, K (reprint author), Nippon Med Sch, Dept Physiol, Bunkyo Ku, 1-1-5 Sendagi, Tokyo 1138602, Japan. EM arai_keiko/phys2@nms.ac.jp NR 42 TC 33 Z9 37 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 JUL PY 1999 VL 84 IS 7 BP 2434 EP 2437 DI 10.1210/jc.84.7.2434 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 213EH UT WOS:000081259200032 PM 10404817 ER PT J AU Goldstein, DS Swoboda, KJ Miles, JM Coppack, SW Aneman, A Holmes, C Lamensdorf, I Eisenhofer, G AF Goldstein, DS Swoboda, KJ Miles, JM Coppack, SW Aneman, A Holmes, C Lamensdorf, I Eisenhofer, G TI Sources and physiological significance of plasma dopamine sulfate SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PERFORMANCE LIQUID-CHROMATOGRAPHY; CONJUGATED CATECHOLAMINES; PHENOL SULFOTRANSFERASE; 3,4-DIHYDROXYPHENYLACETIC ACID; ESSENTIAL-HYPERTENSION; EATING BANANAS; HUMANS; NOREPINEPHRINE; DIHYDROXYPHENYLALANINE; DISEASE AB Dopamine in the circulation occurs mainly as dopamine sulfate, the sources and physiological significance of which have been obscure. In this study, plasma concentrations of dopamine sulfate were measured after a meal, after fasting for 4 days, and during iv L-DOPA, nitro-prusside, or trimethaphan infusion in volunteers; after dopamine infusion in patients with L-aromatic-amino-acid decarboxylase deficiency; in arterial and portal venous plasma of gastrointestinal surgery patients; and in patients with sympathetic neurocirculatory failure. Meal ingestion increased plasma dopamine sulfate by more than 50-fold; however, prolonged fasting decreased plasma dopamine sulfate only slightly. L-DOPA infusion produced much larger increments in dopamine sulfate than in dopamine; the other drugs were without effect. Patients with L-aromatic amino acid decarboxylase deficiency had decreased dopamine sulfate levels, and patients with sympathetic neurocirculatory failure had normal levels. Decarboxylase-deficient patients undergoing dopamine infusion had a dopamine sulfate/dopamine ratio about 25 times less than that at baseline in volunteers. Surgery patients had large arterial-portal venous increments in plasma concentrations of dopamine sulfate, so that mesenteric dopamine sulfate production accounted for most of urinary dopamine sulfate excretion, a finding consistent with the localization of the dopamine sulfoconjugating enzyme to gastrointestinal tissues. The results indicate that plasma dopamine sulfate derives mainly from sulfoconjugation of dopamine synthesized from L-DOPA in the gastrointestinal tract. Both dietary and endogenous determinants affect plasma dopamine sulfate. The findings suggest an enzymatic gut-blood, barrier for detoxifying exogenous dopamine and delimiting autocrine/paracrine effects of endogenous dopamine generated in a "third catecholamine system." C1 NINDS, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Childrens Hosp, Div Genet, Boston, MA 02115 USA. St Lukes Hosp, Diabetes & Nutr Res Lab, Kansas City, MO 64111 USA. UCL, Sch Med, Whittington Hosp, London NI9 3UA, England. Gothenburg Univ, S-41390 Gothenburg, Sweden. RP Goldstein, DS (reprint author), NINDS, Clin Neurosci Branch, NIH, Bldg 10,Room 6N252, Bethesda, MD 20892 USA. EM daveg@box-d.nih.gov FU Wellcome Trust NR 58 TC 50 Z9 50 U1 1 U2 4 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 JUL PY 1999 VL 84 IS 7 BP 2523 EP 2531 DI 10.1210/jc.84.7.2523 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 213EH UT WOS:000081259200046 PM 10404831 ER PT J AU Linde, K Scholz, M Ramirez, G Clausius, N Melchart, D Jonas, WB AF Linde, K Scholz, M Ramirez, G Clausius, N Melchart, D Jonas, WB TI Impact of study quality on outcome in placebo-controlled trials of homeopathy SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE study quality; meta-analysis; homeopathy; randomized controlled trials; bias ID RANDOMIZED CONTROLLED TRIALS; CLINICAL-TRIALS; CRITICAL-LOOK; METAANALYSIS; SCORES AB We investigated the influence of indicators of methodological quality on study outcome in a set of 89 placebo-controlled clinical trials of homoeopathy in three different ways: (1) The results of studies meeting single criteria (explicit statement of random allocation, allocation concealment, double-blinding, completeness of follow-up) of methodological quality were compared with those of studies not meeting the criteria in univariate and multivariate analyses; (2) The results of studies scoring above and below predefined scores in two quality assessment scales were compared; (3) Primary studies were consecutively entered into a cumulative metaanalysis according to the summary scores derived from the quality assessment scales. All analyses were performed using meta-regression methods. Studies that were explicitly randomized and were double-blind as well as studies scoring above the cut-points yielded significantly less positive results than studies not meeting the criteria. In the cumulative meta-analyses, there was a trend for increasing effect sizes when more studies with lower-quality scores were added. However, there was no linear relationship between quality scores and study outcome. We conclude that in the study set investigated, there was clear evidence that studies with better methodological quality tended to yield less positive results. Because summarizing disparate study features into a single score is problematic, meta-regression methods simultaneously investigating the influence of single study features seem the best method for investigating the impact of study quality on outcome, (C) 1999 Elsevier Science Inc. C1 Tech Univ Munich, Dept Internal Med 2, Ctr Complementary Med Res, Munchener Modell, D-80801 Munich, Germany. Tech Univ Munich, Inst Med Stat & Epidemiol, D-80801 Munich, Germany. Univ N Texas, Dept Publ Hlth & Prevent Med, Hlth Sci Ctr, Ft Worth, TX USA. NIH, Off Alternat Med, Bethesda, MD 20892 USA. RP Linde, K (reprint author), Tech Univ Munich, Dept Internal Med 2, Ctr Complementary Med Res, Munchener Modell, Kaiserstr 9, D-80801 Munich, Germany. OI Linde, Klaus/0000-0002-2902-970X FU NIAMS NIH HHS [5 U24-AR-43346-02] NR 22 TC 97 Z9 100 U1 0 U2 9 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 JUL PY 1999 VL 52 IS 7 BP 631 EP 636 DI 10.1016/S0895-4356(99)00048-7 PG 6 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 210TR UT WOS:000081121200006 PM 10391656 ER PT J AU Suffredini, AF Fantuzzi, G Badolato, R Oppenheim, JJ O'Grady, NP AF Suffredini, AF Fantuzzi, G Badolato, R Oppenheim, JJ O'Grady, NP TI New insights into the biology of the acute phase response SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE acute phase response; acute phase proteins; serum amyloid A; human endotoxemia ID SERUM AMYLOID-A; TUMOR-NECROSIS-FACTOR; HIGH-DENSITY-LIPOPROTEIN; HUMAN INFLAMMATORY RESPONSES; COLONY-STIMULATING FACTOR; C-REACTIVE PROTEIN; INTRAVENOUS ENDOTOXIN; CYTOKINE RELEASE; INTERLEUKIN-1-BETA-DEFICIENT MICE; INTERLEUKIN-1 RECEPTOR AB Innate or natural immunity is a highly conserved defense mechanism against infection found in all multicellular organisms. The acute phase response is the set of immediate inflammatory responses initiated by pattern recognition molecules. These germ cell-encoded proteins recognize microbial pathogens based on shared molecular structures and induce host responses that localize the spread of infection and enhance systemic resistance to infection. Innate immunity also influences the initiation and type of adaptive immune response by regulating T cell costimulatory activity and antigen presentation by antigen presenting cells and by influencing mediator production, which affects lymphocyte function and trafficking. Acute phase protein concentrations rapidly increase after infection, and their production is controlled primarily by IL-6- and IL-l-type cytokines. The acute phase proteins provide enhanced protection against microorganisms and modify inflammatory responses by effects on cell trafficking and mediator release. For example, serum amyloid A has potent leukocyte activating functions including induction of chemotaxis, enhancement of leukocyte adhesion to endothelial cells, and increased phagocytosis. The constellation of inflammatory responses seen after endotoxin administration to humans represents an in vivo model of the acute phase response. Studies with inflammatory modifying agents, such as soluble dimeric TNF receptor and IL-10, show that these responses are not dependent on a single mediator but result from multiple overlapping inflammatory pathways. Understanding the factors that initiate and alter the magnitude and duration of the acute phase response represents an important step in the development of new therapies for infectious and inflammatory diseases. C1 NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. Univ Colorado, Hlth Sci Ctr, Div Infect Dis, Denver, CO USA. Univ Brescia, Dept Pediat, Brescia, Italy. NCI, Mol Immunoregulat Lab, Frederick Canc Res & Dev Ctr, Frederick, MD USA. RP Suffredini, AF (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bldg 10,Room 7D-43,10 Ctr Dr,MSC 1662, Bethesda, MD 20892 USA. RI Badolato, Raffaele/A-8081-2010; Fantuzzi, Giamila/A-1758-2009 OI Badolato, Raffaele/0000-0001-7375-5410; Fantuzzi, Giamila/0000-0001-5334-0082 NR 88 TC 260 Z9 270 U1 2 U2 13 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD JUL PY 1999 VL 19 IS 4 BP 203 EP 214 DI 10.1023/A:1020563913045 PG 12 WC Immunology SC Immunology GA 228GW UT WOS:000082129600002 PM 10471974 ER PT J AU Schuurman, R Demeter, L Reichelderfer, P Tijnagel, J de Groot, T Boucher, C AF Schuurman, R Demeter, L Reichelderfer, P Tijnagel, J de Groot, T Boucher, C TI Worldwide evaluation of DNA sequencing approaches for identification of drug resistance mutations in the human immunodeficiency virus type 1 reverse transcriptase SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID LAMIVUDINE 3TC; HIV-1; ASSAY; ZIDOVUDINE; EVOLUTION; THERAPY AB A panel (ENVA-1) of well-defined blinded samples containing wild-type and mutant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase was analyzed by automated DNA sequencing in 23 laboratories worldwide. Drug resistance mutations at codons 41, 215, and 183 were present in the panel samples at different ratios to the wild type. The presence of mutant genotypes was determined qualitatively and quantitatively, All laboratories reported the presence of sequence heterogeneities at codons 41, 215, and 184 in one or more of the panel samples, though not all reported the correct codon genotypes. Two laboratories reported a mutant genotype in samples containing only the wild type, whereas two and three laboratories failed to detect the mutant genotypes at codons 41 and 215, respectively, in a completely mutant DNA population, Mutations present at relative concentrations of 25% of the total DNA population were successfully identified by 13 of 23, 10 of 23, and 16 of 23 labs for codons 41, 215, and 184Val, respectively, For more than 80% of those laboratories that qualitatively detected the presence of a mutation correctly, the estimated wild type/mutant ratio was less than 25% different from the input ratio in those samples containing 25 to 50% or 75% mutant input. This first multicenter study on the quality of DNA sequencing approaches for identifying HIV-1 drug resistance mutations revealed large interlaboratory differences in the quality of the results, The application of these procedures in their current state would in several cases lead to inaccurate or even incorrect diagnostic results, Therefore, proper quality control and standardization are urgently needed. C1 Univ Utrecht Hosp, Dept Virol, NL-3584 CX Utrecht, Netherlands. Univ Rochester, Sch Med & Dent, Infect Dis Unit, Rochester, NY USA. NICHHD, Bethesda, MD USA. RP Schuurman, R (reprint author), Univ Utrecht Hosp, Dept Virol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands. NR 19 TC 142 Z9 143 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 JUL PY 1999 VL 37 IS 7 BP 2291 EP 2296 PG 6 WC Microbiology SC Microbiology GA 206FR UT WOS:000080867100027 PM 10364600 ER PT J AU Boccardo, F Rubagotti, A Borichello, M Battaglia, M Carmignani, G Comeri, G Conti, G Cruciani, G Dammino, S Delliponti, U Ditonno, P Ferraris, V Lilliu, S Montefiore, F Portoghese, F Spano, G AF Boccardo, F Rubagotti, A Borichello, M Battaglia, M Carmignani, G Comeri, G Conti, G Cruciani, G Dammino, S Delliponti, U Ditonno, P Ferraris, V Lilliu, S Montefiore, F Portoghese, F Spano, G CA Italian Prostate Cancer Project TI Bicalutamide monotherapy versus flutamide plus goserelin in prostate cancer patients: Results of an Italian Prostate Cancer Project study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 33rd Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 17-21, 1997 CL DENVER, COLORADO SP Amer Soc Clin Oncol ID QUALITY-OF-LIFE; UNTREATED PATIENTS; MG MONOTHERAPY; CARCINOMA; CASTRATION; CASODEX; ORCHIECTOMY; THERAPY; ANTIANDROGEN; NILUTAMIDE AB Purpose: To compare the efficacy of bicalutamide monotherapy to maximal androgen blockade (MAB) in the treatment of advanced prostatic cancer. Patients and Methods: Previously untreated patients with histologically proven stage C or D disease (American Urological Association Staging System) were randomly allocated to receive either bicalutamide or MAB. After disease progression, patients treated with bicalutamide were assigned to castration. The primary end point for this trial was overall survival. Secondary end points included response to treatment, disease progression, treatment safety, quality-of-life (QOL), and sexual function. Results: A total of 108 patients received bicalutamide and 112 received MAB. There was no difference in the percentage of patients whose prostate-specific antigen returned to normal levels. At the time of the present analysis (median follow-up time, 38 months; range, 1 to 60 months), 129 patients progressed and 89 died. There was no difference in the duration of either progression-free survival or overall survival. However, a survival trend favored bicalutamide in stage C disease but MAB in stage D disease. Overall and subgroup trends were confirmed by multivariate analysis. Serious adverse events and treatment discontinuations were more common in patients receiving MAB (P = .08 and P = .04, respectively). Fewer patients in the bicalutamide group complained of lass of libido (P = .01)and of erectile dysfunction (P = .002). Significant trends favored bicalutamide-treated patients also with respect to their QOL, namely relative to social functioning, vitality, emotional well-being, and physical capacity Conclusion: Bicalutamide monotherapy yielded comparable results relative to standard treatment with MAB, induced fewer ride effects, and produced a better QOL. (C) 1999 by American Society of Clinical Oncology. C1 Univ Genoa, Dept Med Oncol, I-16132 Genoa, Italy. Natl Canc Inst, I-16132 Genoa, Italy. Univ Genoa, Biostat Unit, I-16132 Genoa, Italy. Univ Genoa, Dept Urol, Genoa, Italy. Gen Hosp, Dept Urol, Venice, Italy. Univ Bari, Dept Urol R, Bari, Italy. S Anna Hosp, Dept Urol, Como, Italy. Osped Umberto 1, Dept Oncol, Lugo Di Romagna, Italy. Gen Hosp, Dept Urol, Caltagirone, Italy. Santo Spirito Hosp, Dept Urol, Casale Monferrato, Italy. S Michele Hosp, Dept Urol, Cagliari, Italy. Gen Hosp, Dept Urol, Alessandria, Italy. Univ Sassari, Dept Urol, I-07100 Sassari, Italy. RP Boccardo, F (reprint author), Univ Genoa, Dept Med Oncol, Largo R Benzi 10, I-16132 Genoa, Italy. RI ditonno, pasquale/C-5318-2011; Battaglia, Michele/C-7380-2011 NR 33 TC 103 Z9 105 U1 0 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL PY 1999 VL 17 IS 7 BP 2027 EP 2038 PG 12 WC Oncology SC Oncology GA 213GL UT WOS:000081264300011 PM 10561254 ER PT J AU Childs, RW Clave, E Tisdale, J Plante, M Hensel, N Barrett, J AF Childs, RW Clave, E Tisdale, J Plante, M Hensel, N Barrett, J TI Successful treatment of metastatic renal cell carcinoma with a nonmyeloablative allogeneic peripheral-blood progenitor-cell transplant: Evidence for a graft-versus-tumor effect SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MINOR HISTOCOMPATIBILITY ANTIGENS; BONE-MARROW TRANSPLANTATION; T-LYMPHOCYTES; INTERLEUKIN-2; CHEMOTHERAPY; LEUKEMIA; CLONES; CANCER AB Purpose: A 50-year-old man developed progressive pulmonary metastasis resistant to interferon alfa-2b treatment 7 months after he underwent left nephrectomy for stage III renal cell carcinoma. We performed a nonmyeloablative allogeneic peripheral-blood stem-cell transplant in this patient to exploit a possible graft-versus-tumor effect from allogeneic lymphocytes. Materials and Methods: The conditioning regimen consisted of fludarabine and cyclophosphamide followed by a T-cell replete, granulocyte-colony stimulating-factor-mobilized peripheral-blood stem-cell transplant from his HLA-identical brother. Cyclosporine was administered from days -4 to +45 to prevent graft rejection and acute graft-versus-host disease (GVHD). Results: Serial polymerase chain reaction analysis of hematopoietic lineage-specific minisatellites initially showed mixed chimerism in CD14(+) and CD15(+) myeloid cells, CD3(+) T cells, and CD34(+) progenitor cells, with rapid conversion to 100% donor T-cell chimerism by day +60 and 100% donor myeloid cells by day +100. Serial computed tomography scans of the chest showed stable disease at day +30, blight regression of pulmonary lesions at day +63, and complete disappearance of ail pulmonary metastatic disease by day +110, Mild transient acute GVHD disease of the skin occurred on day +60 and limited chronic GVHD of the skin occurred by day +200. Conclusion: The complete regression of metastatic disease, which has now been maintained for more than 1 year, is compatible with a graft-versus-tumor effect. (C) 1999 by American Society of Clinical Oncology. C1 NHLBI, Bone Marrow Transplant Unit, Hematol Branch, Bethesda, MD 20892 USA. RP Childs, RW (reprint author), NIH, Hematol Branch, Bldg 10,Room 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 22 TC 139 Z9 142 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 JUL PY 1999 VL 17 IS 7 BP 2044 EP 2049 PG 6 WC Oncology SC Oncology GA 213GL UT WOS:000081264300013 PM 10561256 ER PT J AU Atkins, MB Lotze, MT Dutcher, JP Fisher, RI Weiss, G Margolin, K Abrams, J Sznol, M Parkinson, D Hawkins, M Paradise, C Kunkel, L Rosenberg, SA AF Atkins, MB Lotze, MT Dutcher, JP Fisher, RI Weiss, G Margolin, K Abrams, J Sznol, M Parkinson, D Hawkins, M Paradise, C Kunkel, L Rosenberg, SA TI High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985 and 1993 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COOPERATIVE-ONCOLOGY-GROUP; RENAL-CELL CARCINOMA; ACTIVATED KILLER CELLS; MALIGNANT-MELANOMA; RANDOMIZED TRIAL; INTERFERON ALFA-2B; PROGNOSTIC FACTORS; PHASE-II; DACARBAZINE; COMBINATION AB Purpose: To determine the short- and long-term efficacy and toxicity of the high-dose intravenous bolus interleukin 2 (IL-2) regimen in patients with metastatic melanoma, Patients and Methods: Two hundred seventy assessable patients were entered onto eight clinical trials conducted between 1985 and 1993. IL-2 (Proleukin [aldesleukin]; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximum support, including pressors, A second identical treatment cycle was scheduled after 6 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients, Data were analyzed through fall 1996. Results: The overall objective response rate was 16% (95% confidence interval, 12% to 21%); there were 17 complete responses (CRs) (6%) and 26 partial responses (PRs) (10%), Responses occurred with ail sites of disease and in patients with large tumor burdens. The median response duration for patients who achieved a CR has not been reached and was 5.9 months for those who achieved a PR, Twelve (28%) of the responding patients, including 10 (59%) of the patients who achieved a CR, remain progression-free. Disease did not progress in any patient responding for more than 30 months. Baseline performance status and whether patients had received prior systemic therapy were the only predictive prognostic factors for response to IL-2 therapy. Toxicities, although severe, generally reversed rapidly after therapy was completed. Six patients (2%) died from adverse events, all related to sepsis, Conclusion: High-dose IL-2 treatment seems to benefit some patients with metastatic melanoma by producing durable CRs or PRs and should be considered for appropriately selected melanoma patients. (C) 1999 by American Society of Clinical Oncology. C1 NCI, Cytokine Working Grp, Bethesda, MD 20892 USA. NCI, Surg Branch, Bethesda, MD 20892 USA. Chiron Corp, Emeryville, CA 94608 USA. RP Atkins, MB (reprint author), Beth Israel Deaconess Med Ctr, Div Hematol & Oncol, 330 Brookline Ave,EKS-158, Boston, MA 02215 USA. FU NCI NIH HHS [N01-CM73702, N01-CM73703, N01-CM73704] NR 50 TC 998 Z9 1019 U1 2 U2 33 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 JUL PY 1999 VL 17 IS 7 BP 2105 EP 2116 PG 12 WC Oncology SC Oncology GA 213GL UT WOS:000081264300022 PM 10561265 ER PT J AU Herman, EH Zhang, J Lipshultz, SE Rifai, N Chadwick, D Takeda, K Yu, ZX Ferrans, VJ AF Herman, EH Zhang, J Lipshultz, SE Rifai, N Chadwick, D Takeda, K Yu, ZX Ferrans, VJ TI Correlation between serum levels of cardiac troponin-T and the severity of the chronic cardiomyopathy induced by doxorubicin SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; AMINO-ACID SEQUENCE; ADRIAMYCIN CARDIOTOXICITY; DIAGNOSTIC EFFICIENCY; HYPERTENSIVE RATS; RELEASE; ASSAY; MEMBRANES; DAMAGE; INJURY AB Purpose: To investigate, over a wide range of cumulative doxorubicin doses, the feasibility of using serum concentrations of cardiac troponin-T (cTnT) as a biomarker for doxorubicin-induced myocardial damage. Materials and Methods: Groups of spontaneously hypertensive rats (SHR) were given 1 mg/kg doxorubicin weekly for 2 to 12 weeks. Cardiomyopathy scores were assessed according to the method of Billingham and serum levels of cTnT were quantified by a noncompetitive immunoassay. Myocardial localization of cTnT was studied by immunohistochemical staining and confocal microscopy. Results: Increases in serum levels of cTnT (0.03 to 0.05 ng/mL) and myocardial lesions (cardiomyopathy scores of 1 or 1.5) were found in one out of five and two out of five SHR given 2 and 4 mg/kg doxorubicin, respectively. All animals given 6 mg/kg or more of doxorubicin had increases in serum cTnT and myocardial lesions. The average cTnT levels and the cardiomyopathy scores correlated with the cumulative dose of doxorubicin (0.13 v 0.4 ng/mL cTnT and scores of 1.4 v 3.0 in SHR given 6 and 12 mg/kg doxorubicin, respectively). Decreased staining for cTnT was observed in cardiac tissue from SHR receiving cumulative doses that caused only minimal histologic alterations (scores of 1 to 1.5), Staining for cTnT decreased simultaneously with increases in the severity of the cardiomyopathy scores. Conclusion: cTnT is released from doxorubicin-damaged myocytes. Measurements of serum levels of this protein seem to provide a sensitive means for assessing the early cardiotoxicity of doxorubicin. (C) 1999 by American Society of Clinical Oncology. C1 US FDA, Div Appl Pharmacol Res HFD910, Ctr Drug Evaluat & Res, Laurel, MD 20708 USA. Univ Rochester, Med Ctr, Div Pediat Cardiol, Rochester, NY 14642 USA. Boston Childrens Hosp, Dept Lab Med, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. RP Herman, EH (reprint author), US FDA, Div Appl Pharmacol Res HFD910, Ctr Drug Evaluat & Res, 8301 Muirkirk Rd, Laurel, MD 20708 USA. NR 33 TC 122 Z9 126 U1 0 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL PY 1999 VL 17 IS 7 BP 2237 EP 2243 PG 7 WC Oncology SC Oncology GA 213GL UT WOS:000081264300038 PM 10561281 ER PT J AU Altemus, M Greenberg, BD Keuler, D Jacobson, KR Murphy, DL AF Altemus, M Greenberg, BD Keuler, D Jacobson, KR Murphy, DL TI Open trial of flutamide for treatment of obsessive-compulsive disorder SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID MESSENGER-RNA LEVELS; SEX-DIFFERENCES; FLUOXETINE TREATMENT; STRIA TERMINALIS; TREATED PATIENTS; DOUBLE-BLIND; BED NUCLEUS; FEMALE RAT; VASOPRESSIN; ANTIANDROGEN AB Background: Several lines of evidence suggest that gonadal steroid hormones play a role in the onset and exacerbation of obsessive-compulsive disorder (OCD). In this study, we examined the effects of treatment with flutamide, a synthetic, nonsteroidal, competitive antagonist of the androgen receptor, on OCD symptoms. Method: Eight outpatients meeting DSM-III-R criteria for OCD participated in an 8-week open trial of flutamide. The dose was increased from 250 mg/day to 750 mg/day over the first 4 weeks and maintained at 750 mg/day for the final 4 weeks. The primary outcome measures for OCD symptoms were the Yale-Brown Obsessive compulsive Scale and the Maudsley Inventory and for anxiety symptoms, the Beck Anxiety Inventory and the Hamilton Rating Scale for Anxiety. Subjects also provided self-ratings of aggression and sexual interest and activity. Results: There were no reductions in measures of obsession and compulsions or measures of anxiety over the 8-week trial. However, self-ratings of feelings of aggression did fall significantly over the 8-week trial (p <.001). Conclusion: The lack of response to treatment with flutamide, an androgen receptor antagonist, suggests that any effects of gonadal steroids to exacerbate OCD symptoms are more likely to be mediated through estrogen receptors or through mechanisms that do not involve classical intracellular androgen receptors. Future treatment trials should examine agents that antagonize estrogen receptors or otherwise inhibit estrogen activity. C1 Cornell Univ, Weill Med Coll, Dept Psychiat, New York, NY 10021 USA. NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. RP Altemus, M (reprint author), Cornell Univ, Weill Med Coll, Dept Psychiat, Box 244,1300 York Ave, New York, NY 10021 USA. NR 42 TC 11 Z9 11 U1 0 U2 0 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JUL PY 1999 VL 60 IS 7 BP 442 EP 445 PG 4 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 225EJ UT WOS:000081945200004 PM 10453797 ER PT J AU Sharp, NJH Davis, BJ Guy, JS Cullen, JM Steingold, SF Kornegay, JN AF Sharp, NJH Davis, BJ Guy, JS Cullen, JM Steingold, SF Kornegay, JN TI Hydranencephaly and cerebellar hypoplasia in two kittens attributed to intrauterine parvovirus infection SO JOURNAL OF COMPARATIVE PATHOLOGY LA English DT Article ID FELINE PANLEUKOPENIA VIRUS; POLYMERASE CHAIN-REACTION; PARAFFIN-EMBEDDED TISSUES; CANINE PARVOVIRUS; RETINAL DYSPLASIA; DIARRHEA VIRUS; PREGNANT EWES; MALFORMATIONS; INOCULATION; FIXATION AB Six weeks after vaccination with modified live feline parvovirus vaccine, a cat gave birth to five kittens, three of which died soon afterwards. The remaining two kittens (A and B) survived, but at 8 weeks of age were unable to walk and showed abnormal behaviour, with lack of menace and oculovestibular responses, and severe dysmetria. These signs suggested multifocal disease associated with the cerebrum and cerebellum. Magnetic resonance imaging demonstrated severe bilateral (kitten A) or unilateral (kitten B) hydrocephalus or hydranencephaly, combined with cerebellar agenesis (kitten A) or severe hypoplasia (kitten B). Hydranencephaly was confirmed histopathologically in both kittens. Parvovirus was isolated from the kidney of one kitten. Parvoviral DNA was amplified by th polymerase chain reaction (PCR) from paraffin wax-embedded brain of both kittens. The severe malformations observed in these kittens presumably resulted from an in-utero parvovirus infection, possibly due to vaccination, that occurred late in the first, or early in the second, trimester of pregnancy. (C) 1999 W.B. Saunders Company Limited. C1 N Carolina State Univ, Coll Vet Med, Dept Compan Anim & Special Species Med, Raleigh, NC 27695 USA. N Carolina State Univ, Coll Vet Med, Dept Microbiol Pathol & Parasitol, Raleigh, NC 27606 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Missouri, Coll Vet Med, Columbia, MO 65201 USA. RP Sharp, NJH (reprint author), N Carolina State Univ, Coll Vet Med, Dept Compan Anim & Special Species Med, Raleigh, NC 27695 USA. NR 36 TC 29 Z9 29 U1 2 U2 9 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0021-9975 J9 J COMP PATHOL JI J. Comp. Pathol. PD JUL PY 1999 VL 121 IS 1 BP 39 EP 53 DI 10.1053/jcpa.1998.0298 PG 15 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 214CH UT WOS:000081309700004 PM 10373292 ER PT J AU Beiraghi, S Miller-Chisholm, A Kimberling, WJ Sun, CE Wang, YF Russell, LJ Khoshnevisan, M Storm, AL Long, RE Witt, PD Mazaheri, M Diehl, SR AF Beiraghi, S Miller-Chisholm, A Kimberling, WJ Sun, CE Wang, YF Russell, LJ Khoshnevisan, M Storm, AL Long, RE Witt, PD Mazaheri, M Diehl, SR TI Confirmation of linkage of Van der Woude syndrome to chromosome 1q32: Evidence of association with STR alleles suggests possible unique origin of the disease mutation SO JOURNAL OF CRANIOFACIAL GENETICS AND DEVELOPMENTAL BIOLOGY LA English DT Article DE short tandem repeat marker; gene mapping; linkage ID INHERITED LIP PITS; VANDERWOUDE SYNDROME; FAMILIES; CLEFTS; LOCUS AB Van der Woude syndrome (VWS) is an autosomal dominant craniofacial disorder with high penetrance and variable expression. Its clinical features are variably expressed, but include cleft lip and/or cleft palate, lip pits and hypodontia. All VWS families studied to date map the disease gene to a <2 cM region of chromosome 1q32, with no evidence of locus heterogeneity. The aim of this study is to refine the localization of the VWS gene and to further assess possible heterogeneity. We analyzed four multiplex VWS families. All available members were clinically assessed and genotyped for 19 short tandem repeat markers on chromosome 1 in the VWS candidate gene region. We performed two-point and multipoint limit of detection (LOD) score analyses using a high penetrance autosomal dominant model. All families showed positive LOD scores without any recombination in the candidate region. The largest two-point LOD score was 5.87. Our assay method for short tandem repeat (STR) markers provided highly accurate size estimation of marker allele fragment sizes, and therefore enabled us to determine the specific alleles segregating with the VWS gene in each of our four families. We observed a striking pattern of STR allele sharing at several closely linked loci among our four Caucasian VWS families recruited at three different locations in the US. These results suggest the possibility of a unique origin for a mutation responsible for many or most cases of VWS. C1 Natl Inst Dent & Craniofacial Res, Craniofacial Epidemiol & Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Nebraska, Med Ctr, Dept Pediat & Pathol, Omaha, NE USA. Boys Town Natl Res Hosp, Ctr Hereditary Commun Disorder, Omaha, NE 68131 USA. Univ Arizona, Hlth Sci Ctr, Dept Pediat, Tucson, AZ 85721 USA. Lancaster Cleft Palate Clin, Lancaster, PA USA. St Louis Childrens Hosp, St Louis, MO 63178 USA. RP Diehl, SR (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial Epidemiol & Genet Branch, NIH, 45 Ctr Dr,Natcher Bldg 45,Rm 4AS-43G, Bethesda, MD 20892 USA. FU NIDCR NIH HHS [ZO1 DE-00623, N01-DE-42603] NR 29 TC 6 Z9 6 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0270-4145 J9 J CRAN GENET DEV BIO JI J. Craniofac. Genet. Dev. Biol. PD JUL-SEP PY 1999 VL 19 IS 3 BP 128 EP 134 PG 7 WC Anatomy & Morphology; Developmental Biology; Genetics & Heredity SC Anatomy & Morphology; Developmental Biology; Genetics & Heredity GA 254YZ UT WOS:000083643100002 PM 10589394 ER PT J AU Saksida, LM AF Saksida, LM TI Effects of similarity and experience on discrimination learning: A nonassociative connectionist model of perceptual learning SO JOURNAL OF EXPERIMENTAL PSYCHOLOGY-ANIMAL BEHAVIOR PROCESSES LA English DT Article ID LATENT INHIBITION; PEAK SHIFT; STIMULUS; ASSOCIABILITY; PREEXPOSURE; ATTENTION; NETWORKS; MEMORY; TIME AB This article describes a novel connectionist model of perceptual learning (PL) that provides a mechanism for nonassociative differentiation (J. J. Gibson & E. J. Gibson, 1955). The model begins with the assumption that 2 processes-1 that decreases associability and 1 that increases discriminability-operate during preexposure (S. Champ & G. Hall, 1981). In contrast to other models (e.g., I. P. L. McLaren, H. Kaye, & N. J. Mackintosh, 1989), in the current model the mechanisms for these processes are compatible with a configural model of associative learning. A set of simulations demonstrates that the present model can account for critical PL phenomena such as exposure learning and effects of similarity on discrimination. It is also shown that the model can explain the paradoxical result that preexposure to stimuli can either facilitate or impair subsequent discrimination learning. Predictions made by the model are discussed in relation to extant theories of PL. C1 Carnegie Mellon Univ, Ctr Neural Basis Cognit, Pittsburgh, PA 15213 USA. RP Saksida, LM (reprint author), NIMH, Neuropsychol Lab, 49 Convent Rd,Bldg 49,Room 1B80, Bethesda, MD 20892 USA. RI Saksida, Lisa/M-2753-2016 OI Saksida, Lisa/0000-0002-8416-8171 NR 62 TC 32 Z9 32 U1 1 U2 4 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0097-7403 J9 J EXP PSYCHOL ANIM B JI J. Exp. Psychol.-Anim. Behav. Process. PD JUL PY 1999 VL 25 IS 3 BP 308 EP 323 DI 10.1037/0097-7403.25.3.308 PG 16 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental; Zoology SC Psychology; Behavioral Sciences; Zoology GA 216JL UT WOS:000081438900004 PM 10423855 ER PT J AU Harper, DM Hildesheim, A Cobb, JL Greenberg, M Vaught, J Lorincz, AT AF Harper, DM Hildesheim, A Cobb, JL Greenberg, M Vaught, J Lorincz, AT TI Collection devices for human papillomavirus SO JOURNAL OF FAMILY PRACTICE LA English DT Article DE vaginal smears; detection methods; human papillomavirus; hybrid capture [non-MESH] ID GENITAL HUMAN PAPILLOMAVIRUS; CERVICAL INTRAEPITHELIAL NEOPLASIA; CERVICOVAGINAL LAVAGE; INFECTION; DNA AB BACKGROUND. Human papillomavirus (HPV) testing has relied to date on samples collected by experienced health professionals. Self-administered testing devices could allow HPV testing to occur in large-scale epidemiologic studies of primary care screening populations. The purpose of this study is to determine whether a self-collection device for cervicovaginal HPV infection could be developed. METHODS. A prospective randomized trial of a consecutive sampling of 93 women, 18 years or older, receiving routine cervical cancer screening and colposcopy in the urban gynecologic clinics in Philadelphia, Pennsylvania, were randomized into 2 arms. Women in arm 1 used a self-administered tampon before the physician-directed swabs of the cervix; in arm 2, women underwent the physician-directed swab testing before using the self-administered tampon. The concordance of HPV DNA positivity between sampling methods detected by a Hybrid Capture HPV tube test for both low- and high-risk types of HPV was the main outcome measure. RESULTS. The concordance rate (ie, women whose cultures were classified as negative on both tests or positive on both tests) for arms 1 and 2 were similar: 78.3% and 80.9%, respectively. CONCLUSIONS. The tampon was equivalent to the physician-directed swab in HPV detection and suggests its feasibility in long-term primary care studies of screening populations. C1 Norris Cotton Canc Ctr, Dartmouth Med Sch, Lebanon, NH 03756 USA. Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. OMNIA, Philadelphia, PA USA. MA BioServ, Rockville, MD USA. Digene Diagnost Inc, Silver Spring, MD USA. RP Harper, DM (reprint author), Norris Cotton Canc Ctr, Dartmouth Med Sch, HB 7999,1 Med Ctr Dr, Lebanon, NH 03756 USA. NR 8 TC 34 Z9 34 U1 0 U2 0 PU DOWDEN PUBLISHING CORP PI MONTVALE PA 110 SUMMIT AVE, MONTVALE, NJ 07645-1712 USA SN 0094-3509 J9 J FAM PRACTICE JI J. Fam. Pract. PD JUL PY 1999 VL 48 IS 7 BP 531 EP 535 PG 5 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 314UX UT WOS:000087076900010 PM 10428251 ER PT J AU Spring, KR Kovbasnjuk, ON Gibson, CR Bungay, PM AF Spring, KR Kovbasnjuk, ON Gibson, CR Bungay, PM TI Application of a novel 8 x 8 PMT-array detector to light microscopy SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Meeting Abstract C1 Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUL PY 1999 VL 114 IS 1 MA 21 BP 6A EP 6A PG 1 WC Physiology SC Physiology GA 215HU UT WOS:000081376900028 ER PT J AU Rios, E Stern, MD Gonzalez, A Pizarro, G Shirokova, N AF Rios, E Stern, MD Gonzalez, A Pizarro, G Shirokova, N TI Calcium release flux underlying Ca2+ sparks of frog skeletal muscle SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article DE sarcoplasmic reticulum; excitation-contraction coupling; confocal microscopy; computer algorithm ID PERFUSED RABBIT HEART; SARCOPLASMIC-RETICULUM; CARDIAC MYOCYTES; TIME-COURSE; FIBERS; CELLS; EVENTS; MICROSCOPY; BINDING; MODEL AB An algorithm for the calculation of Ca2+ release flux underlying Ca2+ sparks (Blatter, L.A., j. Huser, and E. Rios. 1997. Proc. Natl. Acad. Sci. USA. 94:4176-4181) was modified and applied to sparks obtained by confocal microscopy in single frog skeletal muscle fibers, which were voltage clamped in a two-Vaseline gap chamber of permeabilized and immersed in fluro-3-containing internal solution. The performance of the algorithm was characterized on sparks obtained by simulation of fluorescence due to the release of Ca2+ from a spherical source, in a homogeneous three-dimensional space that contained components representing cytoplasmic molecules and Ca2+ removal processes. Total release flux of current, calculated by volume integration of the derived flux density, estimated quite closely the current used in the simulation, while full width at half magnitude of the derived release flux was a good monitor of source size only at diameters >0.7 mu m. On an average of 157 sparks of amplitude >2 U resting fluorescence, located automatically in a representative voltage clamp experiment, the algorithm reported a release current of 16.9 pA, coming from a source of 0.5 mu m, with an open time of 6.3 ms. Fewer sparks were obtained in permeabilized fibers. so that the algorithm had to be applied to individual sparks or averages of few events, which degraded its performance in comparable tests. The average current reported for 19 large sparks obtained in permeabilized fibers was 14.4 pA. A minimum estimate, derived from the rate of change of dye-bound Ca2+ concentration, was 8 pA. Such a current of the level recorded in bilayer experiments. Real sparks differ from simulated ones mainly in having greater width. Correspondingly, the algorithm reported greater spatial extent of the source for real sparks. This may again indicate a multichannel origin of sparks, of could reflect limitations in spatial resolution. C1 Rush Univ, Dept Physiol & Mol Biophys, Chicago, IL 60612 USA. NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. Univ Republ, Fac Med, Dept Biofis, Montevideo, Uruguay. RP Rios, E (reprint author), Rush Univ, Dept Physiol & Mol Biophys, 1750 W Harrison St, Chicago, IL 60612 USA. NR 44 TC 65 Z9 65 U1 0 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 JUL PY 1999 VL 114 IS 1 BP 31 EP 48 DI 10.1085/jgp.114.1.31 PG 18 WC Physiology SC Physiology GA 215HU UT WOS:000081376900003 PM 10398690 ER PT J AU Cereseto, A Kislyakova, T Parks, RW Nicot, C Franchini, G AF Cereseto, A Kislyakova, T Parks, RW Nicot, C Franchini, G TI Differential response to genotoxic stress in immortalized or transformed human T-lymphotropic virus type I-infected T-cells SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID LEUKEMIA-LYMPHOMA VIRUS; HTLV-1 TAX PROTEIN; CONSTITUTIVE ACTIVATION; INDUCED APOPTOSIS; LYMPHOCYTES-T; CYCLE ARREST; EXPRESSION; P53; INHIBITOR; RADIATION AB Several alterations in the mechanism of cell cycle control have been observed in human T-lymphotropic virus type I (HTLV-I)-infected cells. Here, it is reported that HTLV-I-infected cells both in their immortalized and transformed phase do not undergo apoptosis following ionizing radiation (IR) treatment. However, when IL-2 withdrawal is combined with genotoxic stress, HTLV-I-infected T-cells in their immortalized phase (IL-2-dependent) undergo apoptosis whereas their transformed counterparts (IL-2-independent) do not. These results suggest that, during the transformation process, the HTLV-I-infected T-cells become less sensitive to cell death signals through the acquisition of constitutive activation of the IL-2 receptor pathway. The expression of bcl-2 and bcl-XL proteins, which, are known to increase cell survival mediated by IL-2, as well as of p21(waf1) and p53, was not substantially different in immortalized and transformed cells following IR, All together, these findings suggest that activation of alternative anti-apoptotic pathways, regulated by IL-2, might be responsible for the differential cell death response observed in immortalized versus transformed HTLV-I-infected T-cells. C1 NCI, Basic Res Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Franchini, G (reprint author), NCI, Basic Res Lab, Div Basic Sci, NIH, 41 Lib Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. NR 38 TC 6 Z9 6 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 JUL PY 1999 VL 80 BP 1575 EP 1581 PN 7 PG 7 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 213ZV UT WOS:000081303900003 PM 10423124 ER PT J AU Arankalle, VA Paranjape, S Emerson, SU Purcell, RH Walimbe, AM AF Arankalle, VA Paranjape, S Emerson, SU Purcell, RH Walimbe, AM TI Phylogenetic analysis of hepatitis E virus isolates from India (1976-1993) SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID NON-B-HEPATITIS; DIFFERENT GEOGRAPHICAL REGIONS; WILD POLIOVIRUS TYPE-1; TRANSMITTED NON-A; GENOME SEQUENCE; MOLECULAR EPIDEMIOLOGY; VIRAL-HEPATITIS; UNITED-STATES; HEV; STRAINS AB Seventeen Indian hepatitis E virus (HEV) isolates, representing epidemic and sporadic hepatitis E cases during 1976-1991, were sequenced in the RNA polymerase (RNAP) region. Five isolates were also sequenced in the non-structural hypervariable region of open reading frame 1. Open reading frames 2 and 3 were sequenced only for the prototype isolate. On the basis of the comparison of all the available sequences of the conserved RNAP region, the HEV isolates were divided into three genotypes, differing from each other by > 15%. Genotype I included African and Asian isolates, whereas II and III were represented by Mexican and US isolates, respectively. Genotype I was further divided into four sub-genotypes. The majority of the Indian isolates (15/20), along with the Burmese and Nepali isolates, belonged to genotype IA, Genotype IB included HEV isolates from China, Pakistan and the former USSR and 2/20 Indian isolates, which represented the oldest (1976) HEV sequenced so far. Genotype IC included both the African isolates, whereas 3/20 Indian isolates formed genotype ID. Nucleotide sequence analysis of other regions of the HEV genome also placed isolates in the same genotypes. Both the Indian cities experiencing second HEV epidemics, after intervals of: 8 and 10 years, showed shifts in the sub-genotypes found; from IB (Ahm-76) to IA (Ahm-84) and from IA (Kol-81) to ID (Kol-91). However, no major shift in the genotypes was noted. Overall, HEV genotypes appear to be segregated geographically. C1 Indian Council Med Res, Natl Inst Virol, Poona 411001, Maharashtra, India. NIH, Bethesda, MD 20892 USA. RP Arankalle, VA (reprint author), Indian Council Med Res, Natl Inst Virol, 20-A Dr Ambedkar Rd, Poona 411001, Maharashtra, India. NR 40 TC 60 Z9 66 U1 0 U2 1 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 JUL PY 1999 VL 80 BP 1691 EP 1700 PN 7 PG 10 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 213ZV UT WOS:000081303900016 PM 10423137 ER PT J AU Chen, ZQ Lautenberger, JA Lyons, LA McKenzie, L O'Brien, SJ AF Chen, ZQ Lautenberger, JA Lyons, LA McKenzie, L O'Brien, SJ TI A human genome map of comparative anchor tagged sequences SO JOURNAL OF HEREDITY LA English DT Article ID RADIATION HYBRID MAP; GENETIC-LINKAGE MAP; PANEL; LOCI AB Effective comparative mapping inference utilizing developing gene maps of animal species requires the inclusion of anchored reference loci that are homologous to genes mapped in the more "gene-dense" mouse and human maps, Nominated anchor loci, termed comparative anchor tagged sequences (CATS), have been ordered in the mouse linkage map, but due to the dearth of common polymorphisms among human coding genes have not been well represented in human linkage maps. We present here an ordered framework map of 314 comparative anchor markers in humans based on mapping analysis in the Genebridge 4 panel of radiation hybrid cell lines, plus empirically optimized CATS PCR primers which detect these markers. The ordering of these homologous gene markers in human and mouse maps provides a framework for comparative gene mapping of representative mammalian species. C1 NCI, Lab Genom Divers, Frederick, MD USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. RP O'Brien, SJ (reprint author), NCI, Lab Genom Divers, Frederick, MD USA. NR 30 TC 9 Z9 9 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 J9 J HERED JI J. Hered. PD JUL-AUG PY 1999 VL 90 IS 4 BP 477 EP 484 DI 10.1093/jhered/90.4.477 PG 8 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 233UW UT WOS:000082446500007 PM 10485137 ER PT J AU Boykins, RA Mahieux, R Shankavaram, UT Gho, YS Lee, SF Hewlett, IK Wahl, LM Kleinman, HK Brady, JN Yamada, KM Dhawan, S AF Boykins, RA Mahieux, R Shankavaram, UT Gho, YS Lee, SF Hewlett, IK Wahl, LM Kleinman, HK Brady, JN Yamada, KM Dhawan, S TI Cutting edge: A short polypeptide domain of HIV-1-Tat protein mediates pathogenesis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TYPE-1 TAT PROTEIN; TUMOR-NECROSIS-FACTOR; ENDOTHELIAL-CELLS; T-CELLS; ACTIVATION; MONOCYTES; BINDING; KINASE; TRANSACTIVATION; TRANSCRIPTION AB HIV-1 encodes the transactivating protein Tat, which is essential for virus replication and progression of HIV disease. However, Tat has multiple domains, and consequently the molecular mechanisms by which it acts remain unclear. In this report, we provide evidence that cellular activation by Tat involves a short core domain, Tat(21-40), containing only 20 aa including seven cysteine residues highly conserved in most HIV-1 subtypes, Effective induction by Tat(21-40) of both NF-kappa B-mediated HIV replication and TAR-dependent transactivation of HIV-long terminal repeat indicates that this short sequence is sufficient to promote HIV infection, Moreover, Tat(21-40) possesses potent angiogenic activity, further underscoring its role in HIV pathogenesis. These data provide the first demonstration that a 20-residue core domain sequence of Tat is sufficient to transactivate, induce HIV replication, and trigger angiogenesis, This short peptide sequence provides a potential novel therapeutic target for disrupting the functions of Tat and inhibiting progression of HIV disease. C1 US FDA, Ctr Biol Evaluat & Res, Immunopathogenesis Sect, Mol Virol Lab, Rockville, MD 20852 USA. US FDA, Ctr Biol Evaluat & Res, Lab Parasit Biol & Biochem, Rockville, MD 20852 USA. NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. NIDCR, Immunopathol Sect, Bethesda, MD 20892 USA. NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP Dhawan, S (reprint author), US FDA, Ctr Biol Evaluat & Res, Immunopathogenesis Sect, Mol Virol Lab, 1401 Rockville Pike HFM-315, Rockville, MD 20852 USA. OI Yamada, Kenneth/0000-0003-1512-6805 NR 29 TC 34 Z9 37 U1 1 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 1999 VL 163 IS 1 BP 15 EP 20 PG 6 WC Immunology SC Immunology GA 208CY UT WOS:000080973700004 PM 10384093 ER PT J AU Koski, GK Schwartz, GN Weng, DE Czerniecki, BJ Carter, C Gress, RE Cohen, PA AF Koski, GK Schwartz, GN Weng, DE Czerniecki, BJ Carter, C Gress, RE Cohen, PA TI Calcium mobilization in human myeloid cells results in acquisition of individual dendritic cell-like characteristics through discrete signaling pathways SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; NF-KAPPA-B; CD34(+) HEMATOPOIETIC PROGENITORS; ACUTE PROMYELOCYTIC LEUKEMIA; PERIPHERAL-BLOOD MONOCYTES; COLONY-STIMULATING FACTOR; TUMOR-NECROSIS-FACTOR; HUMAN BONE-MARROW; JURKAT T-CELLS; TNF-ALPHA AB We have shown previously that calcium ionophore (CI) treatment of various myeloid origin cells results in rapid acquisition of properties associated with mature, activated dendritic cells. These properties include increased CD83 and costimulatory molecule expression, tendencies to form dendritic processes, loss of CD14 expression by monocytes, and typically an enhanced capacity to sensitize T lymphocytes to Ag, We here analyze the intracellular signaling pathways by which CI induces acquisition of such properties. Thapsigargin, which raises intracellular Ca2+ levels by antagonizing its sequestration, induced immunophenotypic and morphologic changes that paralleled CI treatment. CI-induced activation was broadly attenuated by the Ca2+ chelating compound EGTA and by calmodulin antagonists trifluoperazine dimaleate and W-7, However, antagonists of signaling pathways downstream to calmodulin displayed more selective inhibitory effects: Calcineurin antagonists cyclosporin A and the FK-506 analogue, ascomycin, diminished costimulatory molecule and CD83 expression, as well as formation of dendritic processes in CI-treated myeloid cells, and strongly attenuated the T cell allosensitizing capacity of CI-treated HL-60 cells. These calcineurin antagonists displayed minimal effect on CI-induced CD14 down-regulation in monocytes, In contrast, the calmodulin dependent protein kinase antagonists, K252a and KT5926, while displaying only modest effects on CI-induced costimulatory molecule and CD83 expression, strongly blocked CD14 down-regulation. These results are consistent with a Ca2+-dependent mechanism for CI-induced differentiation of myeloid cells, and indicate that multiple discrete signaling pathways downstream to calcium mobilization and calmodulin activation may be essential in regulating this process. C1 NCI, Med Branch, Bethesda, MD 20892 USA. Univ Penn, Med Ctr, Dept Surg, Philadelphia, PA 19104 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. RP Koski, GK (reprint author), NCI, Med Branch, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 58 TC 68 Z9 82 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 JUL 1 PY 1999 VL 163 IS 1 BP 82 EP 92 PG 11 WC Immunology SC Immunology GA 208CY UT WOS:000080973700014 PM 10384103 ER PT J AU Ragheb, JA Deen, M Schwartz, RH AF Ragheb, JA Deen, M Schwartz, RH TI CD28-mediated regulation of mRNA stability requires sequences within the coding region of the IL-2 mRNA SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MESSENGER-RNA DEGRADATION; INTERLEUKIN-2 GENE-EXPRESSION; ACCESSORY MOLECULE CD28; T-CELL ACTIVATION; TRANSCRIPTIONAL REGULATION; LYMPHOCYTES-T; BINDING; COSTIMULATION; PROTEINS; PATHWAY AB Using sequence-tagged genomic reporter constructs, we investigated the contribution of IL-2 sequences to CD28-mediated regulation of mRNA stability. We find that CD28 signaling acts transiently to stabilize the IL-2 mRNA following T cell activation. Such stabilization requires sequences within both exon 2 and the coding region of exon 4. Unexpectedly, CD28 signaling at later times enhances the decay of the IL-2 mRNA. This CD28-dependent decay of IL-2 mRNA requires sequences localized between exon 3 and the stop codon. Our findings demonstrate that the coding region of the IL-2 mRNA contains previously undefined CD28-responsive sequence elements that are critical for the regulation of mRNA stability. C1 NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Schwartz, RH (reprint author), NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. NR 48 TC 34 Z9 34 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 JUL 1 PY 1999 VL 163 IS 1 BP 120 EP 129 PG 10 WC Immunology SC Immunology GA 208CY UT WOS:000080973700018 PM 10384107 ER PT J AU Matsui, S Ahlers, JD Vortmeyer, AO Terabe, M Tsukui, T Carbone, DP Liotta, LA Berzofsky, JA AF Matsui, S Ahlers, JD Vortmeyer, AO Terabe, M Tsukui, T Carbone, DP Liotta, LA Berzofsky, JA TI A model for CD8(+) CTL tumor immunosurveillance and regulation of tumor escape by CD4 T cells through an effect on quality of CTL SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACTIVE SPECIFIC IMMUNOTHERAPY; RECOMBINANT VACCINIA VIRUS; ENDOTHELIAL GROWTH-FACTOR; PULSED DENDRITIC CELLS; CLASS-I; COLON-CARCINOMA; PEPTIDE VACCINE; LYMPHOCYTES-T; NEUTRALIZING ANTIBODY; METASTATIC MELANOMA AB Understanding immune mechanisms influencing cancer regression, recurrence, and metastasis may be critical to developing effective immunotherapy, Using a tumor expressing HIV gp160 as a model viral tumor Ag, we found a growth-regression-recurrence pattern, and used this to investigate mechanisms of immunosurveillance. Regression was dependent on CD8 T cells, and recurrent tumors were resistant to CTL, had substantially reduced expression of epitope mRNA, but retained the gp160 gene, MHC, and processing apparatus, Increasing CTL numbers by advance priming with vaccinia virus expressing gp160 prevented only the initial tumor growth but not the later appearance of escape variants. Unexpectedly, CD4 cell depletion protected mice from tumor recurrence, whereas IL-4 knockout mice, deficient in Th2 cells, did not show this protection, and IFN-gamma knockout mice were more susceptible, Purified CD8 T cells from CD4-depleted mice following tumor regression had more IFN-gamma mRNA and lysed tumor cells without stimulation ex vivo, in contrast to CD4-intact mice. Thus, the quality as well as quantity of CD8(+) CTL determines the completeness of immunosurveillance and is controlled by CD4 T cells but not solely Th2 cytokines, This model of immunosurveillance may indicate ways to enhance the efficacy of surveillance and improve immunotherapy. C1 NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Dept Med, Vanderbilt Canc Ctr, Sch Med, Nashville, TN 37232 USA. RP Berzofsky, JA (reprint author), NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bldg 10,Room 6B-12,MSC 1578, Bethesda, MD 20892 USA. NR 73 TC 65 Z9 69 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 1999 VL 163 IS 1 BP 184 EP 193 PG 10 WC Immunology SC Immunology GA 208CY UT WOS:000080973700026 PM 10384115 ER PT J AU Han, M Harrison, L Kehn, P Stevenson, K Currier, J Robinson, MA AF Han, M Harrison, L Kehn, P Stevenson, K Currier, J Robinson, MA TI Invariant or highly conserved TCR alpha are expressed on double-negative (CD3(+)CD4(-)CD8(-)) and CD8(+) T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTIGEN RECEPTOR; IN-VIVO; RECOGNITION; REPERTOIRE; PEPTIDE; INFECTION; GENES; OLIGOCLONALITY; REQUIREMENTS; ORGANIZATION AB TCR alpha (TCRA) expression was examined in RNA samples from PBMC and isolated populations of CD4(+), CD8(+), and DN T cells from 15 healthy individuals. The expressed TCR repertoire was surveyed using spectratype analysis, a technique that displays the distribution of complementarity determining region 3 (CDR3) lengths for each TCRAV gene family. The results revealed the presence of unusual populations of double-negative (DN; CD4(-)CD8(-)CD3(+)) T cells that express invariant or conserved TCRAV4A, AV7, AV19, and AV24 chains. Each of the conserved TCRA families was over-represented in >70% of the individuals studied, and all individuals expressed at least one of the over-represented TCRAV families, Over-represented conserved AV4A or AV7 sequences were also present in CD8(+) T cells from most donors. The extent of TCRA sequence conservation is unparalleled. TCRAV4A, AV19, and AV24 sequences were invariant, although AV4A and AV19 transcripts contained N region additions. TCRAV24 transcripts derived from the direct juxtaposition of V and J gene segments. TCRAV7 sequences showed some diversity in two amino acids encoded at junctions of V and J gene segments. Although derivation of DN T cells with conserved TCRA chains is puzzling, the nide-spread expression of these unusual cells suggests an important function. C1 NIAID, Immunogenet Lab, Twinbrook Facil 2, NIH, Rockville, MD 20852 USA. RP Robinson, MA (reprint author), NIAID, Immunogenet Lab, Twinbrook Facil 2, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. NR 43 TC 43 Z9 46 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 JUL 1 PY 1999 VL 163 IS 1 BP 301 EP 311 PG 11 WC Immunology SC Immunology GA 208CY UT WOS:000080973700040 PM 10384129 ER PT J AU Jankovic, D Kullberg, MC Noben-Trauth, N Caspar, P Ward, JM Cheever, AW Paul, WE Sher, A AF Jankovic, D Kullberg, MC Noben-Trauth, N Caspar, P Ward, JM Cheever, AW Paul, WE Sher, A TI Schistosome-infected IL-4 receptor knockout (KO) mice, in contrast to IL-4 KO mice, fail to develop granulomatous pathology while maintaining the same lymphokine expression profile SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELLS; DEPENDENT MECHANISM; DEFICIENT MICE; TH2 CYTOKINES; MANSONI; INTERLEUKIN-4; ANTIBODIES; MODULATION; INDUCTION; FIBROSIS AB Th2 lymphocytes have been postulated to play a major role in the immunopathology induced by Schistosoma mansoni-infection, Nevertheless, infected IL-4 knockout (KO) and wild-type (wt) mice develop egg granulomas comparable in size, To further investigate the function of the Th2 response in egg pathology we studied IL-4R alpha-deficient mice, which are nonresponsive to both IL-4 and IL-13, In striking contrast to IL-4 KO animals, infected IL-4R alpha KO mice developed only minimal hepatic granulomas and fibrosis despite the presence of CD3(+) T cells in the residual egg lesions. Moreover, liver lymphokine mRNA levels in these animals and IL-4 KO mice were equivalent. In addition, infected IL-4R alpha-deficient, IL-4-deficient, and wt animals developed similar egg Ag-specific IgG Ab titers, arguing that CD4-dependent Th activity is intact in KO mice, As expected, IFN-gamma secretion was strongly up-regulated in mesenteric lymph node cultures from both groups of deficient animals, a change reflected in increased serum IgG2a and IgG2b Ab levels; Surprisingly, Th2 cytokine production in infected IL-4Ra! KO mice was not abolished but was only reduced and resembled that previously documented in IL-4 KO animals. This residual Th2 response is likely to explain the ability of IL-4 KO mice to generate egg granulomas, which cannot be formed in IL-4R alpha-deficient animals because of their lack of responsiveness to the same cytokine ligands, Taken together, these findings argue that tissue pathology in schistosomiasis requires, in addition to egg-specific CD4(+) lymphocytes, a previously unrecognized IL-4R alpha(+) non-T cell effector population. C1 NIAID, Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. NCI, Anim Sci Branch, NIH, Frederick, MD 21702 USA. Biomed Res Inst, Rockville, MD 20852 USA. RP Jankovic, D (reprint author), NIAID, Immunol Sect, Parasit Dis Lab, NIH, Bldg 4,Room 126,9000 Rockville Pike, Rockville, MD 20892 USA. NR 39 TC 109 Z9 110 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 1999 VL 163 IS 1 BP 337 EP 342 PG 6 WC Immunology SC Immunology GA 208CY UT WOS:000080973700044 PM 10384133 ER PT J AU Cicala, C Arthos, J Ruiz, M Vaccarezza, M Rubbert, A Riva, A Wildt, K Cohen, O Fauci, AS AF Cicala, C Arthos, J Ruiz, M Vaccarezza, M Rubbert, A Riva, A Wildt, K Cohen, O Fauci, AS TI Induction of phosphorylation and intracellular association of CC chemokine receptor 5 and focal adhesion kinase in primary human CD4(+) T cells by macrophage-tropic HIV envelope SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SIGNAL-TRANSDUCTION; TYROSINE PHOSPHORYLATION; OLIGOMERIC STRUCTURE; GP120; GLYCOPROTEIN; TYPE-1; ACTIVATION; MECHANISM; INFECTION AB Binding of HIV-1 envelope glycoproteins to the surface of a CD4(+) cell transduces intracellular signals through the primary envelope receptor, CD4, and/or the envelope coreceptor, a seven-transmembrane chemokine receptor. Macrophage-tropic strains of HIV-1 preferentially use CCR5 as an entry coreceptor, whereas T cell-tropic strains use CXC chemokine receptor-4 for entry. Intracellular signals transduced by HIV-1 envelope may have immunopathogenic consequences, including anergy, syncytium formation, apoptosis, and inappropriate cell trafficking, We demonstrate here that a recombinant envelope protein derived from an M-tropic isolate of HIV-1 can transduce CD4-dependent as well as CCR5-dependent intracellular signals in primary human CD4(+) T cells. Novel HIV-induced intracellular signals that were identified include tyrosine phosphorylation of focal adhesion kinase (FAK) and CCR5, which are involved in cell adhesion and chemotaxis, respectively. HIV envelope-induced cellular association of FAK and CCR5 was also demonstrated, suggesting that ligation of CD4 and CCR5 leads to the formation of an activation complex composed of FAK and CCR5, Activation of this signaling pathway by HIV-1 envelope may be an important pathogenic mechanism of dysregulated cellular activation and trafficking during HIV infection. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Cicala, C (reprint author), 10 Ctr Dr,MSC 1876,Bldg 10,Room 11B13, Bethesda, MD 20892 USA. OI VACCAREZZA, Mauro/0000-0003-3060-318X NR 52 TC 80 Z9 82 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 JUL 1 PY 1999 VL 163 IS 1 BP 420 EP 426 PG 7 WC Immunology SC Immunology GA 208CY UT WOS:000080973700055 PM 10384144 ER PT J AU Clay, TM Custer, MC Sachs, J Hwu, P Rosenberg, SA Nishimura, MI AF Clay, TM Custer, MC Sachs, J Hwu, P Rosenberg, SA Nishimura, MI TI Efficient transfer of a tumor antigen-reactive TCR to human peripheral blood lymphocytes confers anti-tumor reactivity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN AUTOLOGOUS MELANOMA; CYTOTOXIC T-LYMPHOCYTES; APE LEUKEMIA-VIRUS; INFILTRATING LYMPHOCYTES; IN-VIVO; METASTATIC MELANOMA; GENE-TRANSFER; ALLOGENEIC MELANOMAS; CELL RECEPTOR; HLA-A2 AB The tumor-associated Ag MART-1 is expressed by most human melanomas. The genes encoding an alpha beta TCR from a MART-1-specific, HLA-A2-restricted, human T cell clone have been efficiently transferred and expressed in human PBL, These retrovirally transduced PBL cultures were MART-1 peptide reactive, and most cultures recognized HLA-A2(+) melanoma lines. Limiting dilution clones were generated from three bulk transduced PBL cultures to investigate the function of individual clones within the transduced cultures. Twenty-nine of 29 CD8(+) clones specifically secreted IFN-gamma in response to T2 cells pulsed with MART-1((27-35)) peptide, and 23 of 29 specifically secreted IFN-gamma in response to HLA-A2+ melanoma Lines. Additionally, 23 of 29 CD8+ clones lysed T2 cells pulsed with the MART-1((27-35)) peptide and 15 of 29 lysed the HLA-A2(+) melanoma line 888. CD4(+) clones specifically secreted IFN-gamma in response to T2 cells pulsed with the MART-1((27-35)) peptide. TCR gene transfer td patient PBL can produce CTL with anti-tumor reactivity in vitro and could potentially offer a treatment for patients with metastatic melanoma, This approach could also be applied to the treatment of other tumors and viral infections. Additionally, TCR gene transfer offers unique opportunities to study the fate of adoptively transferred T cells in vivo. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Nishimura, MI (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B06,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 51 TC 256 Z9 272 U1 1 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 1999 VL 163 IS 1 BP 507 EP 513 PG 7 WC Immunology SC Immunology GA 208CY UT WOS:000080973700066 PM 10384155 ER PT J AU Dudley, ME Nishimura, MI Holt, AKC Rosenberg, SA AF Dudley, ME Nishimura, MI Holt, AKC Rosenberg, SA TI Antitumor immunization with a minimal peptide epitope (G9-209-2M) leads to a functionally heterogeneous CTL response SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE immunotherapy; cytotoxic T lymphocyte; T cell receptor; melanoma; gp100 ID TUMOR-INFILTRATING LYMPHOCYTES; CYTOLYTIC T-LYMPHOCYTES; MELANOMA ANTIGEN GP100; MULTIPLE EPITOPES; IN-VITRO; IDENTIFICATION; GENE; RECOGNITION; CELLS; IMMUNOTHERAPY AB The goal of experimental clinical protocols using peptide antigen for active vaccination and treatment of patients with metastatic cancer is to induce a vigorous cytotoxic T lymphocyte (CTL) response against the immunizing antigen, and thereby against tumor cells expressing the antigen. However, the magnitude and breadth of human CTL responses induced by peptide immunization, and in particular against antigens expressed by normal tissues as well as tumors, is not well characterized. This issue was examined by characterizing CTL cloids derived from peripheral blood mononuclear cells of three patients who received peptide immunization as treatment for metastatic melanoma. All patients received G9-209-2M peptide, a modified epitope of the gp100 melanoma-associated antigen. The results indicated that the CTL response induced by this peptide antigen was highly heterogeneous both in terms of avidity toward the peptide antigen and recognition of tumor cell lines. Furthermore, avidity of each CTL cloid for the native peptide was highly predictive of tumor reactivity. These results are discussed in terms of their implications for peptide vaccination and adoptive tumor immunotherapy. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT USA. RP Dudley, ME (reprint author), NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 26 TC 54 Z9 56 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD JUL PY 1999 VL 22 IS 4 BP 288 EP 298 DI 10.1097/00002371-199907000-00002 PG 11 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 212NK UT WOS:000081222800002 PM 10404430 ER PT J AU Hurst, R White, DE Heiss, J Lee, DS Rosenberg, SA Schwartzentruber, DJ AF Hurst, R White, DE Heiss, J Lee, DS Rosenberg, SA Schwartzentruber, DJ TI Brain metastasis after immunotherapy in patients with metastatic melanoma or renal cell cancer: Is craniotomy indicated? SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE immunotherapy; brain; surgery; melanoma; renal cell ID MALIGNANT-MELANOMA; RANDOMIZED TRIAL; RESECTION; MANAGEMENT; SURGERY; INTERLEUKIN-2; RADIOTHERAPY; EXPERIENCE; RADIATION AB The purpose of this study was to evaluate the outcome of surgical treatment of brain metastasis in patients with metastatic melanoma or renal cell cancer after interleukin-2 (IL-2) therapy. A retrospective analysis was conducted at the Surgery Branch, National Cancer Institute. All patients with a diagnosis of metastatic melanoma or renal cell cancer who received IL-2 from January 1, 1985 to January 1, 1996 (n = 1385) were screened for the development of brain metastasis, Forty patients underwent surgical treatment of brain metastasis that developed after initiating IL-2 therapy. Thirty-six were rendered free of disease after resection of a single metastasis and were the focus of this study. Twenty-two of the 36 patients achieved a clinical response (10 complete responses and 12 partial responses) at extracranial sites of disease after IL-2-based immunotherapy and before the development of brain metastasis. The median disease-free interval in the brain after resection of a single metastasis was 21, 7, and 3 months for patients achieving a complete response, pal tial response, and no response (CR, PR, and NR) to IL-2 therapy, respectively. The median survival after craniotomy for these three groups of patients was 23, 17, and 7 months, respectively. The disease-free interval in the brain and the overall survival after craniotomy were significantly longer for patients achieving a CR to previous immunotherapy when compared with patients achieving a PR or NR. Of the 10 patients who had achieved a prior CR, 8 remained disease free in the brain at last follow-up, 6 remained alive beyond 1 year, and 3 >4 years. Twenty-five patients experienced neurologic symptoms before craniotomy and all had complete resolution of their symptoms after surgery. Surgical treatment of single brain metastasis in patients with metastatic melanoma or renal cell cancer is indicated in carefully selected patients. The benefits of resection include palliation of symptoms and the potential for a prolonged disease-free interval in the brain. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NCI, Div Clin Sci, Surg Neurol Sect, NIH, Bethesda, MD 20892 USA. RP Schwartzentruber, DJ (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B04, Bethesda, MD 20892 USA. NR 20 TC 11 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD JUL PY 1999 VL 22 IS 4 BP 356 EP 362 DI 10.1097/00002371-199907000-00009 PG 7 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 212NK UT WOS:000081222800009 PM 10404437 ER PT J AU Arno, A Ruiz, L Juan, M Jou, A Balague, M Zayat, MK Marfil, S Martinez-Picado, J Martinez, MA Romeu, J Pujol-Borrell, R Lane, C Clotet, B AF Arno, A Ruiz, L Juan, M Jou, A Balague, M Zayat, MK Marfil, S Martinez-Picado, J Martinez, MA Romeu, J Pujol-Borrell, R Lane, C Clotet, B TI Efficacy of low-dose subcutaneous interleukin-2 to treat advanced human immunodeficiency virus type 1 in persons with <= 250/mu L CD4 T cells and undetectable plasma virus load SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 5th Conference on Retroviruses and Opportunistic Infections CY FEB 01-05, 1998 CL CHICAGO, ILLINOIS ID ADVANCED HIV DISEASE; THERAPY; IMMUNE; INFECTION; LYMPHOCYTES; PHENOTYPE; INHIBITOR AB The immunologic efficacy of low;dose recombinant interleukin-2 (rIL-2) administered subcutaneously (sc) once a day in combination with highly active antiretroviral therapy (HAART) was assessed in a pilot study in patients with advanced human immunodeficiency virus HIV disease. Twenty-live persons with less than or equal to 250 CD4 cells/mu L and plasma HIV-1 RNA levels less than or equal to 500 copies/mL for >24 weeks were randomly assigned to receive sc rIL-2 (3 X 10(6) IU once a day) with their previous antiretroviral regimen (n = 13) or to continue with the same treatment (PE = 12), The level of CD4 T cells was significantly higher in the IL-2 group at week 24 (105 +/- 65/mu L; P<.05) but not in the control group (30 +/- 78/mu L), Memory T cells initially contributed to the CD4 T cell increase at week 4 (P<.05), Naive T cell increases (99 +/- 58/mu L) in the IL-2 group became statistically significant at week 24 compared with the control group (28 +/- 27/mu L; P<.05). Subcutaneous rIL-2 once a day in combination with HAART was well tolerated and improved immunologic surface markers in patients with advanced HIV infection. C1 Hosp Univ Germans Trias & Pujol, Retrovirol Lab Irsicaixa Fdn, Dept Immunol, HIV Dept, Barcelona 08916, Spain. NIH, Bethesda, MD USA. RP Ruiz, L (reprint author), Hosp Univ Germans Trias & Pujol, Retrovirol Lab Irsicaixa Fdn, Dept Immunol, HIV Dept, Barcelona 08916, Spain. RI Martinez-Picado, Javier/G-5507-2012; Martinez, Miguel Angel/K-6435-2014; Pujol Borrell, Ricardo/N-3415-2013 OI Martinez-Picado, Javier/0000-0002-4916-2129; Martinez, Miguel Angel/0000-0002-6681-4950; Pujol Borrell, Ricardo/0000-0001-7833-675X NR 27 TC 92 Z9 93 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUL PY 1999 VL 180 IS 1 BP 56 EP 60 DI 10.1086/314831 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 210YA UT WOS:000081132100008 PM 10353861 ER PT J AU Jacobson, JM Spritzler, J Fox, L Fahey, JL Jackson, JB Chernoff, M Wohl, DA Wu, AW Hooton, TM Sha, BE Shikuma, CM MacPhail, LA Simpson, DM Trapnell, CB Basgoz, N AF Jacobson, JM Spritzler, J Fox, L Fahey, JL Jackson, JB Chernoff, M Wohl, DA Wu, AW Hooton, TM Sha, BE Shikuma, CM MacPhail, LA Simpson, DM Trapnell, CB Basgoz, N CA Natl Inst Allergy Infect Dis AIDS Clin Trials G TI Thalidomide for the treatment of esophageal aphthous ulcers in patients with human immunodeficiency virus infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 25th AIDS Clinical Trail Group Meeting CY AUG 01-04, 1998 CL WASHINGTON, D.C. SP Aids Clin trial Grp, Natl Inst Allergy & Infect Dis, NIH, Gen Clin Res Ctr unit, Natl Ctr Res Resources ID HIV-INFECTION; ULCERATION; AIDS AB A multicenter, double-blind, randomized, placebo-controlled clinical trial was conducted to determine the safety and efficacy of thalidomide for treating esophageal aphthous ulceration in persons infected with human immunodeficiency virus (HIV), Twenty-four HIV-infected patients with biopsy-confirmed aphthous ulceration of the esophagus were randomly assigned to receive either oral thalidomide, 200 mg/day, or oral placebo daily for 4 weeks. Eight (73%) of 11 patients randomized to receive thalidomide had complete healing of aphthous ulcers at the 4-week endoscopic evaluation, compared with 3 (23%) of 13 placebo-randomized patients (odds ratio, 13.82; 95% confidence interval, 1.16-823.75; P=.033), Odynophagia and impaired eating ability caused by esophageal aphthae were improved markedly by thalidomide treatment. Adverse events among patients receiving thalidomide included somnolence (4 patients), rash (2 patients), and peripheral sensory neuropathy (3 patients). Thalidomide is effective in healing aphthous ulceration of the esophagus in patients infected with HIV. C1 Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. NIAID, Div Aids, Bethesda, MD USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. Univ Calif San Francisco, Dept Stomatol, San Francisco, CA 94143 USA. Univ N Carolina, Dept Med, Chapel Hill, NC 27515 USA. Univ Washington, Dept Med, Sch Med, Seattle, WA 98195 USA. Rush Med Coll, Dept Med, Chicago, IL 60612 USA. Univ Hawaii, Dept Med, Sch Med, Honolulu, HI 96822 USA. RP Jacobson, JM (reprint author), Mt Sinai Med Ctr, 1 Gustave L Levy Pl,Box 1009, New York, NY 10029 USA. FU NIAID NIH HHS [AI-38855] NR 17 TC 60 Z9 64 U1 2 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUL PY 1999 VL 180 IS 1 BP 61 EP 67 DI 10.1086/314834 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 210YA UT WOS:000081132100009 PM 10353862 ER PT J AU Semba, RD Kumwenda, N Hoover, DR Taha, TE Quinn, TC Mtimavalye, L Biggar, RJ Broadhead, R Miotti, PG Sokoll, LJ van der Hoeven, L Chiphangwi, JD AF Semba, RD Kumwenda, N Hoover, DR Taha, TE Quinn, TC Mtimavalye, L Biggar, RJ Broadhead, R Miotti, PG Sokoll, LJ van der Hoeven, L Chiphangwi, JD TI Human immunodeficiency virus load in breast milk, mastitis, and mother-to-child transmission of human immunodeficiency virus type 1 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 3th International Symposium on Global Strategies to Prevent Perinatal HIV Transmission CY NOV 10, 1998 CL VALENCIA, SPAIN SP NIH, Fogarty Int Ctr, US Agcy Int Dev ID PUERPERAL MASTITIS; HUMAN LACTATION; HIV-1; LACTOGENESIS; DELIVERY; SODIUM; COHORT; WOMEN AB Human immunodeficiency virus (HIV) type 1 load in breast milk and mastitis were examined as risk factors for vertical transmission of HIV-1, Six weeks after delivery, HIV-1 load and sodium (an indicator of mastitis) were measured in breast milk from 334 HIV-l-infected women in Malawi, Median breast milk HIV-1 load was 700 copies/mL among women with HIV-1-infected infants versus undetectable (<200 copies/mL) among those with uninfected infants, respectively (P<.0001). Elevated breast milk sodium levels consistent with mastitis occurred in 16.4% of HIV-1-infected women and were associated with increased vertical transmission of HIV-1 (P<.0001), Median breast milk HIV-1 load was 920 copies/mL among women with versus undetectable among those without elevated breast milk sodium levels, respectively (P<.0001), Mastitis and breast milk HIV-1 load may increase the risk of vertical transmission of HIV-1 through breast-feeding. C1 Johns Hopkins Univ, Dept Ophthalmol, Sch Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Epidemiol, Sch Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Med, Sch Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Pathol, Sch Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Baltimore, MD 21205 USA. NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Malawi, Coll Med, Dept Obstet & Gynaecol, Blantyre, Malawi. Univ Malawi, Coll Med, Dept Paediat & Child Hlth, Blantyre, Malawi. RP Semba, RD (reprint author), Johns Hopkins Univ, Dept Ophthalmol, Sch Med, Suite 700,550 N Broadway, Baltimore, MD 21205 USA. RI Quinn, Thomas/A-2494-2010 FU NIAID NIH HHS [AI-35173]; NICHD NIH HHS [HD-30042, HD-32247] NR 31 TC 276 Z9 281 U1 3 U2 10 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUL PY 1999 VL 180 IS 1 BP 93 EP 98 DI 10.1086/314854 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 210YA UT WOS:000081132100013 PM 10353866 ER PT J AU Roundtable, J Russell-Einhorn, M Vaitukaitis, J Synderman, R Rubenstein, A Abramson, R Hays, M Goodman, L AF Roundtable, J Russell-Einhorn, M Vaitukaitis, J Synderman, R Rubenstein, A Abramson, R Hays, M Goodman, L TI Far beyond informed consent SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Editorial Material AB A spate of suspensions by the Office for Protection from Research Risks (OPRR) has many federally funded US research institutions concerned about the sudden escalation in enforcement, OPRR's first suspension in recent years came in October 1998 when research was halted at Rush-Presbyterian St. Luke's Medical Center. In April, OPRR shut down the Veterans Administration hospital in West Los Angeles for similar reasons. In May, OPRR lifted Duke University Medical Center's authority to conduct federally funded research. Finally, OPRR recently visited Mt. Sinai School of Medicine and placed certain restrictions on their multiple project assurance (MPA). OPRR, a federal watchdog agency that is part of the National Institutes of Health in Bethesda, Maryland, has put every US research institution on notice that its right to conduct clinical research could be instantly removed. In an attempt to understand OPRR's latest suspensions, the Journal of Investigative Medicine has interviewed representatives of those institutions and the director of OPRR's Office of Regulatory Affairs. C1 NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. Duke Univ, Hlth Syst, Durham, NC 27706 USA. Mt Sinai Sch Med, New York, NY 10029 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. NR 0 TC 4 Z9 4 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 JUL PY 1999 VL 47 IS 6 BP 259 EP 266 PG 8 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 215HP UT WOS:000081376300001 PM 10431479 ER PT J AU Yau, WM Gawrisch, K AF Yau, WM Gawrisch, K TI Deuteration of indole and N-methylindole by Raney nickel catalysis SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Article DE deuterium; Raney nickel; deuteration; indole; N-methylindole; solid-state NMR ID CATION-PI INTERACTIONS; MEMBRANE-PROTEINS; DEUTERIUM-OXIDE; GRAMICIDIN; EXCHANGE; CHANNEL; ACIDS AB Indole and N-methylindole have been partially or fully deuterated by Raney nickel catalyzed H-1-H-2 exchange in a series of deuterated solvents. Perdeuterated indoles have been obtained in water and methanol while compounds that are preferentially deuterated at specific sites were obtained in chloroform, acetone, acetonitrile, ethanol, and isopropanol. The partially deuterated compounds are an important research tool for solid-state NMR studies on proteins. C1 NIAAA, LMBB, NIH, Rockville, MD 20852 USA. RP Yau, WM (reprint author), NIAAA, LMBB, NIH, 12420 Parklawn Dr,Rm 158, Rockville, MD 20852 USA. NR 23 TC 7 Z9 7 U1 1 U2 3 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0362-4803 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD JUL PY 1999 VL 42 IS 7 BP 709 EP 713 DI 10.1002/(SICI)1099-1344(199907)42:7<709::AID-JLCR235>3.0.CO;2-2 PG 5 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 222XQ UT WOS:000081811000010 ER PT J AU Gosselin, P Mason, LH Willette-Brown, J Ortaldo, JR McVicar, DW Anderson, SK AF Gosselin, P Mason, LH Willette-Brown, J Ortaldo, JR McVicar, DW Anderson, SK TI Induction of DAP12 phosphorylation, calcium mobilization, and cytokine secretion by Ly49H SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE natural killer cells; signal transduction; tumor necrosis factor alpha ID NATURAL-KILLER-CELLS; INTEGRAL MEMBRANE-PROTEINS; TYROSINE-PHOSPHATASE 1C; LY-49 MULTIGENE FAMILY; INHIBITORY RECEPTOR; SIGNAL-TRANSDUCTION; FC-RECEPTOR; NK CELLS; ACTIVATING RECEPTORS; GAMMA-CHAIN AB The ability of several Ly49 family members to inhibit natural killer (NK) cell functions through recruitment of SHP-1 phosphatase has been reported. In contrast, the mechanisms underlying the activating signal generated by Ly49D are poorly understood. A homodimeric phosphoprotein (pp16) that physically and functionally associates with Ly49D has been described. In this study, a rabbit anti-mouse pp16 antiserum,vas generated and used to demonstrate that pp16 corresponds to the recently described DAP12 molecule. In addition, we show chat a second Ly49 family member that lacks an immunoreceptor tyrosine-based inhibitory motif and contains a charged residue in the transmembrane domain, Ly49H, also associates with DAP12, Furthermore, we show that engagement of the Ly49H/DAP12 complex results in phosphorylation of DAP12, intracellular calcium mobilization, and tumor necrosis factor secretion in transfected cells. These results thus provide evidence that Ly49H is an activating receptor that associates with. DAP12, previously described as a pp16 component of the Ly49D receptor complex. C1 NCI, Intramural Res Support Program, SAIC Frederick, FCRDC, Frederick, MD 21702 USA. NCI, Expt Immunol Lab, Div Basic Sci, Frederick, MD 21702 USA. RP Anderson, SK (reprint author), NCI, Intramural Res Support Program, SAIC Frederick, FCRDC, Bldg 560,Rm 31-93, Frederick, MD 21702 USA. RI Anderson, Stephen/B-1727-2012; McVicar, Daniel/G-1970-2015 OI Anderson, Stephen/0000-0002-7856-4266; FU PHS HHS [N01-C0-56000] NR 43 TC 60 Z9 60 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUL PY 1999 VL 66 IS 1 BP 165 EP 171 PG 7 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 215YW UT WOS:000081413900022 PM 10411005 ER PT J AU Silva, ERDE Kong, M Han, ZH Starr, C Kass, EM Juo, SHH Foster, D Dansky, HM Merkel, M Cundey, K Brinton, EA Breslow, JL Smith, JD AF Silva, ERDE Kong, M Han, ZH Starr, C Kass, EM Juo, SHH Foster, D Dansky, HM Merkel, M Cundey, K Brinton, EA Breslow, JL Smith, JD TI Metabolic and genetic determinants of HDL metabolism and hepatic lipase activity in normolipidemic females SO JOURNAL OF LIPID RESEARCH LA English DT Article DE genetics; lipoproteins; metabolism; apoA-I; apoA-II; HDL turnover ID HIGH-DENSITY-LIPOPROTEIN; APOLIPOPROTEIN-A-I; FRACTIONAL CATABOLIC RATE; LOW-FAT DIET; CHOLESTEROL LEVELS; PLASMA-LIPIDS; PROMOTER; POLYMORPHISMS; DISEASE; REGION AB The metabolic and genetic determinants of HDL cholesterol (HDL-C) levels and HDL turnover were studied in 36 normolipidemic female subjects on a whole-food lowfat metabolic diet. Lipid, lipoprotein, and apolipoprotein levels, lipoprotein size, and apolipoprotein turnover parameters were determined, as were genetic variation at one site in the hepatic lipase promoter and six sites in the apolipoprotein AI/CIII/AIV gene cluster. Menopause had no significant effect on HDLC or turnover. Stepwise multiple regression analysis revealed that HDL-C was most strongly correlated with HDL size, apolipoprotein A-II (apoA-II), and apolipoprotein A-I (apoA-I) levels, which together could account for 90% of the variation in HDLC. HDL size was inversely correlated with triglycerides, body mass index, and hepatic lipase activity, which together accounted for 82% of the variation in HDL size. The hepatic lipase promoter genotype had a strong effect on hepatic lipase activity and could account for 38% of the variation in hepatic lipase activity. The apoA-I transport rate (AI-TR) was the major determinant of apoA-I levels, but AI-TR was not associated with six common genetic polymorphism in the apoAI/CIII/AIV gene cluster. A simplified model of HDL metabolism is proposed, in which A-I and apoA-II levels combined with triglycerides, and hepatic lipase activity could account for 80% of the variation in HDL-C. C1 Rockefeller Univ, Biochem Genet & Metab Lab, New York, NY 10021 USA. Rockefeller Univ, Stat Lab, New York, NY 10021 USA. NIH, Natl Human Genome Res Inst, Baltimore, MD 21225 USA. Univ Washington, Dept Bioengn, Seattle, WA 98195 USA. RP Smith, JD (reprint author), Rockefeller Univ, Biochem Genet & Metab Lab, New York, NY 10021 USA. RI Juo, Suh-Hang/A-1765-2010; Breslow, Jan/B-7544-2008; Juo, Suh-Hang/C-9545-2009 NR 38 TC 30 Z9 30 U1 0 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 JUL PY 1999 VL 40 IS 7 BP 1211 EP 1221 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 212CN UT WOS:000081198900005 ER PT J AU Duncan, T Osawa, Y Kutty, RK Kutty, G Wiggert, B AF Duncan, T Osawa, Y Kutty, RK Kutty, G Wiggert, B TI Heme-binding by Drosophila retinoid- and fatty acid-binding glycoprotein (RFABG), a member of the proapolipophorin gene family SO JOURNAL OF LIPID RESEARCH LA English DT Article DE heme; lipophorin; Drosophila; RFABG ID PURIFIED GUANYLATE-CYCLASE; LIPID TRANSPORT; AFFINITY-CHROMATOGRAPHY; RHODNIUS-PROLIXUS; CELLULAR FACTOR; NITRIC-OXIDE; LIPOPHORIN; PROTEINS; ACTIVATION; HEMOLYMPH AB We previously have cloned and characterized a retinoid- and fatty acid-binding glycoprotein (RFABG) isolated from the heads of Drosophila melanogaster. The protein is composed of two glycosylated subunits (M-r = >200,000 and 70,000) and is a member of the proapolipophorin gene family. Spectral analysis of purified RFABG revealed an absolute absorbance peak at 405 mn, which is typical for a heme-containing protein. The aim of the present study tvas to characterize the heme-binding properties of RFABG, Upon saturation of the protein solution with carbon monoxide followed by dithionite reduction, a red shift of the Soret peak to 424 mn and the characteristic alpha- and beta-bands at 567 and 539 nm were observed, Native RFABG contains approximately 0.175 moles of heme (mol/mol) indicating that purified RFABG is primarily the apoprotein, Hemin-agarose affinity chromatography of the native RFABG followed by Western blot analysis showed a single immunoreactive band at 70 kDa, indicating that the heme-binding domain resides in the 70 kDa subunit. Although retinoid and fatty acid also bind to the 70 kDa subunit, no competition tvas observed when an excess of heme was added to a solution of retinoid or fatty acid bound to RFABG. Heme added to a solution of purified RFABG bound in a saturable manner with an affinity of 3.8 x 10(-7) M. Thus, the current study clearly demonstrates that retinoid- and fatty acid-binding glycoprotein is a novel heme-binding protein, which may be involved in the transport and/or metabolism of heme in Drosophila. C1 NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. RP Wiggert, B (reprint author), NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 32 TC 7 Z9 8 U1 0 U2 0 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 JUL PY 1999 VL 40 IS 7 BP 1222 EP 1228 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 212CN UT WOS:000081198900006 PM 10393207 ER PT J AU Lambert, G Chase, MB Dugi, K Bensadoun, A Brewer, HB Santamarina-Fojo, S AF Lambert, G Chase, MB Dugi, K Bensadoun, A Brewer, HB Santamarina-Fojo, S TI Hepatic lipase promotes the selective uptake of high density lipoprotein-cholesteryl esters via the scavenger receptor B1 SO JOURNAL OF LIPID RESEARCH LA English DT Article DE SR-BI; HDL; cholesterol; HEK 293 cells ID APOLIPOPROTEIN-A-I; CELL-SURFACE PROTEOGLYCANS; SR-BI; RAT-LIVER; TRANSGENIC MICE; TRIGLYCERIDE LIPASE; HDL RECEPTOR; CHYLOMICRON REMNANTS; PLASMA-LIPOPROTEINS; RICH LIPOPROTEINS AB Hepatic lipase (HL) plays a major role in high-density lipoprotein (HDL) metabolism both as a lipolytic enzyme and as a ligand. To investigate whether HL enhances the uptake of HDL-cholesteryl ester (CE) via the newly described scavenger receptor BI (SR-BI), we measured the effects of expressing HL and SR-BI on HDL-cell association as well as uptake of I-125-labeled apoA-I and [H-3]CE-HDL, by embryonal kidney 293 cells. As expected, HDL cell association and CE selective uptake were increased in SR-BI transfected cells by 2- and 4-fold, respectively, compared to controls (P < 0.001). Cells transfected with HL alone or in combination with SR-BI expressed similar amounts of HL, 20% of which was bound to cell surface proteoglycans, HL alone increased HDL cell association by 2-fold but had no effect on HDL-CE uptake in 293 cells, However, in cells expressing SR-BI, HL further enhanced the selective uptake of CE from HDL by 3-fold (P < 0.001). To determine whether the lipolytic and/or ligand function of HL are required in this process, we generated a catalytically inactive form of HL (HL-145G). Cells co-transfected with HL-145G and SR-BI increased their HDL cell association and HDL-CE selective uptake by 1.4-fold compared to cells expressing SR-BI only (P < 0.03). Heparin abolished the effect of HH-145G on SR-BI-mediated HDL-CE selective uptake. Thus, the enhanced uptake of HDL-CE by HL is mediated by both its ligand role, which requires interaction with proteoglycans, and by Lipolysis with subsequent HDL particle remodeling. These results establish HL as a major modulator of SR-BI mediated selective uptake of HDL-CE. C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. Cornell Univ, Div Nutr Sci, Ithaca, NY 14852 USA. RP Lambert, G (reprint author), NHLBI, Mol Dis Branch, NIH, Bldg 10,Rm 7N115,10 Ctr Dr,MSC 1666, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [HL 14990] NR 77 TC 94 Z9 95 U1 0 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 JUL PY 1999 VL 40 IS 7 BP 1294 EP 1303 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 212CN UT WOS:000081198900013 PM 10393214 ER PT J AU Ando, H Funasaka, Y Oka, M Ohashi, A Furumura, M Matsunaga, J Matsunaga, N Hearing, VJ Ichihashi, M AF Ando, H Funasaka, Y Oka, M Ohashi, A Furumura, M Matsunaga, J Matsunaga, N Hearing, VJ Ichihashi, M TI Possible involvement of proteolytic degradation of tyrosinase in the regulatory effect of fatty acids on melanogenesis SO JOURNAL OF LIPID RESEARCH LA English DT Article DE free fatty acid; linoleic acid; melanin; melanoma; palmitic acid ID MESSENGER-RNA LEVELS; MELANOCYTE-STIMULATING HORMONE; MAMMALIAN TYROSINASE; CELLS; MELANIN; BIOSYNTHESIS; ENZYME AB The purpose of this study was to investigate the mechanism of fatty acid-induced regulation of melanogenesis, An apparent regulatory effect on melanogenesis was observed when cultured B16F10 melanoma cells were incubated with fatty acids, i.e., linoleic acid (unsaturated, C18:2) decreased melanin synthesis while palmitic acid (saturated, C16:0) increased it, However, mRNA levels of the melanogenic enzymes, tyrosinase, tyrosinase-related protein 1 (TRP1), and tyrosinase-related protein 2 (TRP2), were not altered, Regarding protein levels of these enzymes, the amount of tyrosinase was decreased by linoleic acid and increased by palmitic acid, whereas the amounts of TRP1 and TRP2 did not change after incubation with fatty acids, Pulse-chase assay by [S-35]methionine metabolic labeling revealed that neither linoleic acid nor palmitic acid altered the synthesis of tyrosinase. Further, it was shown that linoleic acid accelerated, while palmitic acid decelerated, the proteolytic degradation of tyrosinase. These results suggest that modification of proteolytic degradation of tyrosinase is involved in regulatory effects of fatty acids on melanogenesis in cultured melanoma cells. C1 Kobe Univ, Sch Med, Dept Dermatol, Kobe, Hyogo 650, Japan. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. SUNSTAR Inc, Cent Res Inst, Osaka, Japan. RP Ando, H (reprint author), Kobe Univ, Sch Med, Dept Dermatol, Kobe, Hyogo 650, Japan. NR 17 TC 80 Z9 85 U1 1 U2 4 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 JUL PY 1999 VL 40 IS 7 BP 1312 EP 1316 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 212CN UT WOS:000081198900015 PM 10393216 ER PT J AU Brunell, PA Ren, LC Cohen, JI Straus, SE AF Brunell, PA Ren, LC Cohen, JI Straus, SE TI Viral gene expression in rat trigeminal ganglia following neonatal infection with varicella-zoster virus SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE varicella-zoster; newborn rats; VZV DNA; VZV RNA; latency; ganglia ID POLYMERASE CHAIN-REACTION; VZV TRANSCRIPTION; LATENCY; DNA; PATHOGENESIS; INFANCY; MICE AB Newborn rats were injected intraperitoneally with uninfected human cells or cell infected with 56,000 pfu of varicella-zoster virus (VZV). Five to 6 weeks later, trigeminal ganglia were harvested and tested for VZV DNA and RNA by PCR. VZV gene 21 and 40 DNA were detected in most infected animals. Gene 21 RNA also was detected in ganglia from most infected animals, but not gene 40 RNA, paralleling previous observations in latently infected human ganglia. The neonatal rat may represent a useful new model for the study of VZV latency. Published 1999 Wiley-Liss, Inc.(dagger) C1 NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Cedars Sinai Med Ctr, Ahmanson Pediat Ctr, Los Angeles, CA 90048 USA. RP Brunell, PA (reprint author), NIAID, Clin Invest Lab, NIH, Bldg 10,Room 11N228,10 Ctr Dr, Bethesda, MD 20892 USA. NR 18 TC 15 Z9 16 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 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD JUL PY 1999 VL 58 IS 3 BP 286 EP 290 DI 10.1002/(SICI)1096-9071(199907)58:3<286::AID-JMV15>3.0.CO;2-E PG 5 WC Virology SC Virology GA 201YV UT WOS:000080625700015 PM 10447425 ER PT J AU Huq, MM Jabbar, A Rashid, MA Hasan, CM Ito, C Furukawa, H AF Huq, MM Jabbar, A Rashid, MA Hasan, CM Ito, C Furukawa, H TI Steroids from the roots of Nerium oleander SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID CARDIAC-GLYCOSIDES; CARDENOLIDE; ODORUM; C-13-NMR; LEAVES; NMR AB Two new cardenolides, 3 beta-hydroxy-5 alpha-carda-14(15),20(22)-dienolide (beta-anhydroepidigitoxigenin) (1) and 3 beta-O-(D-digitalosyl)-21-hydroxy-5 beta-carda-8,14,16,20,(22)-tetraenolide (neriumogenin-A-3 beta-D-digitaloside) (2), and two known compounds, proceragenin and neridienone A (3), have been isolated from the roots of Nerium oleander. The structures of 1 and 2 were elucidated on the basis of spectral data interpretation. C1 Univ Dhaka, Fac Pharm, Phytochem Res Lab, Dhaka 1000, Bangladesh. Meijo Univ, Fac Pharm, Tempa Ku, Nagoya, Aichi 468, Japan. RP Rashid, MA (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL, SAIC Frederick, Bldg 560,Rm 32-63B,Post Box B, Frederick, MD 21702 USA. NR 31 TC 18 Z9 19 U1 6 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD JUL PY 1999 VL 62 IS 7 BP 1065 EP 1067 DI 10.1021/np990031b PG 3 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 220DJ UT WOS:000081649000035 PM 10425146 ER PT J AU Grant, P Diggins, M Pant, HC AF Grant, P Diggins, M Pant, HC TI Topographic regulation of cytoskeletal protein phosphorylation by multimeric complexes in the squid giant fiber system SO JOURNAL OF NEUROBIOLOGY LA English DT Article DE squid; P13(suc1); multimeric complex; cytoskeleton; phosphorylation; axon; cell body ID CASEIN KINASE-II; MONOCLONAL-ANTIBODIES DISTINGUISH; NEURONAL INTERMEDIATE FILAMENTS; CALMODULIN-DEPENDENT KINASE; NEUROFILAMENT PROTEINS; CDC2-LIKE KINASE; STELLATE GANGLION; SPINAL-CORD; TAIL DOMAIN; ASSOCIATION AB In mammalian and squid nervous systems, the phosphorylation of neurofilament proteins (NFs) seems to be topographically regulated. Although NFs and relevant kinases are synthesized in cell bodies, phosphorylation of NFs, particularly in the lys-ser-pro (KSP) repeats in NF-M and NF-H tail domains, seem to be restricted to axons, To explore the factors regulating the cellular compartmentalization of NF phosphorylation, we separated cell bodies (GFL) from axons in the squid stellate ganglion and compared the kinase activity in the respective lysates, Although total kinase activity was similar in each lysate, the profile of endogenous phosphorylated substrates was strikingly different. Neurofilament protein 220 (NF220), high-molecular-weight NF protein (HMW), and tubulin were the principal phosphorylated substrates in axoplasm, while tubulin was the principal GFL phosphorylated substrate, in addition to highly phosphorylated low-molecular-weight proteins. Western blot analysis showed that whereas both lysates contained similar kinases and cytoskeletal proteins, phosphorylated NF220 and HMW were completely absent from the GFL lysate, These differences were highlighted by P13(suc1) affinity chromatography, which revealed in axoplasm an active multimeric phosphorylation complex(es), enriched in cytoskeletal proteins and kinases; the equivalent P13 GFL complex exhibited six to 20 times less endogenous and exogenous phosphorylation activity, respectively, contained fewer cytoskeletal proteins and kinases, and expressed a qualitatively different cdc2-like kinase epitope, 34 kDa rather than 49 kDa. Cell bodies and axons share a similar repertoire of molecular constitutents; however, the data suggest that the cytoskeletal/kinase phosphorylation complexes extracted from each cellular compartment by P13 are fundamentally different. (C) 1999 John Wiley & Sons, Inc. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. Marine Biol Lab, Woods Hole, MA 02543 USA. RP NINDS, Neurochem Lab, NIH, Bldg 36,Room 4D20, Bethesda, MD 20892 USA. NR 73 TC 17 Z9 17 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0022-3034 J9 J NEUROBIOL JI J. Neurobiol. PD JUL PY 1999 VL 40 IS 1 BP 89 EP 102 DI 10.1002/(SICI)1097-4695(199907)40:1<89::AID-NEU8>3.0.CO;2-R PG 14 WC Neurosciences SC Neurosciences & Neurology GA 212LB UT WOS:000081217200008 PM 10398074 ER PT J AU Sharma, M Sharma, P Pant, HC AF Sharma, M Sharma, P Pant, HC TI CDK-5-mediated neurofilament phosphorylation in SHSY5Y human neuroblastoma cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE cyclin-dependent kinase-5; human high molecular mass neurofilament; phosphorylation ID CYCLIN-DEPENDENT KINASE-5; MONOCLONAL-ANTIBODIES DISTINGUISH; DIRECTED PROTEIN-KINASE; NERVOUS-SYSTEM; CDC2-LIKE KINASE; BOVINE BRAIN; CDK5; EXPRESSION; SUBUNITS; GENE AB Cyclin-dependent kinase-5 (CDK-5) has been shown to play important roles in neuronal development and neurogenesis. In vitro studies indicate a role of CDK-5 in phosphorylation of neurofilaments (NFs), In this study, we have chosen the human neuroblastoma cell line SHSY5Y as a model system to study the in vivo phosphorylation of NF proteins by CDK-5. Upon differentiation of SHSY5Y cells with retinoic acid, we found that the phosphorylation of high molecular mass (NF-H) and medium molecular mass (NF-M) NFs increased, whereas the CDK-5 protein level and kinase activity were unaffected. The role of CDK-5 in the phosphorylation of cytoskeletal proteins was studied by using antisense oligonucleotides (ONs) to inhibit the expression of the CDK-5 gene. We found that inhibition of CDK-5 levels by antisense ON treatment resulted in a decrease in phosphorylation of NF-H that correlated with a decline in neurite outgrowth. These results demonstrate that CDK-5 is a major proline-directed kinase phosphorylating the human NF-H tail domain. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Pant, HC (reprint author), NINDS, Neurochem Lab, NIH, Rm 4D-28,Bldg 36, Bethesda, MD 20892 USA. NR 33 TC 49 Z9 53 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 JUL PY 1999 VL 73 IS 1 BP 79 EP 86 DI 10.1046/j.1471-4159.1999.0730079.x PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 207PV UT WOS:000080946000009 PM 10386957 ER PT J AU Kobierski, LA Wong, AE Srivastava, S Borsook, D Hyman, SE AF Kobierski, LA Wong, AE Srivastava, S Borsook, D Hyman, SE TI Cyclic AMP-dependent activation of the proenkephalin gene requires phosphorylation of CREB at serine-133 and a Src-related kinase SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE proenkephalin; Src kinase; cyclic AMP response element-binding protein; forskolin; gene regulation ID TRANSCRIPTION FACTOR CREB; C-FOS TRANSCRIPTION; PROTEIN-KINASE; BINDING-PROTEIN; GROWTH-FACTOR; RAT STRIATUM; TYROSINE PHOSPHORYLATION; ADENOSINE-MONOPHOSPHATE; MOLECULAR MECHANISMS; NUCLEAR FACTOR AB The transcription factor CREB [cyclic AMP response element (CRE)-binding protein] is activated by several kinase pathways on phosphorylation of serine-133. Phosphorylation of CREB at serine-133 is required for the induction of target gene expression. The proenkephalin gene is a target of cyclic AMP-dependent agonists like forskolin, and its expression is driven by the enhancer element CRE-2, It has been shown that CREB binds CRE-2 in extracts from striatum and hypothalamus, However, these studies did not show a functional requirement for CREB serine-133 phosphorylation in CRE-2 function. We demonstrate that CREB binds CRE-2 in primary astrocyte cultures and that transcriptional activation of CRE-2 requires CREB phosphorylation at serine-133. In addition, it has recently been shown that, at least in some contexts, CREB phosphorylation is not sufficient to activate target gene expression and that another intracellular signal seems to be required. Therefore, we also sought to determine if another signaling event, in addition to CREB phosphorylation, might be involved in cyclic AMP-mediated induction of the proenkephalin gene. We have found that the inhibition of src related nonreceptor tyrosine kinases blocks forskolin-induced proenkephalin gene expression without having any effect on serine-133-phosphorylated CREB revels and that constitutively activated src kinase can activate the proenkephalin promoter. C1 Massachusetts Gen Hosp E, Dept Anesthesia & Crit Care, Neural Plast Res Grp, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA USA. NIMH, Rockville, MD 20857 USA. RP Kobierski, LA (reprint author), Massachusetts Gen Hosp E, Dept Anesthesia & Crit Care, Neural Plast Res Grp, CNY-4,Room 4309,149 13th St, Charlestown, MA 02129 USA. FU NIA NIH HHS [AG05134]; NIDA NIH HHS [DA 10160] NR 60 TC 23 Z9 23 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 JUL PY 1999 VL 73 IS 1 BP 129 EP 138 DI 10.1046/j.1471-4159.1999.0730129.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 207PV UT WOS:000080946000015 PM 10386963 ER PT J AU Palkovits, M Baffi, JS Pacak, K AF Palkovits, M Baffi, JS Pacak, K TI The role of ascending neuronal pathways in stress-induced release of noradrenaline in the hypothalamic paraventricular nucleus of rats SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Article DE noradrenaline; stress; paraventricular nucleus; microdialysis; Fos expression; brainstem hemisections ID SUPERFICIAL DORSAL HORN; VENTROLATERAL RETICULAR-FORMATION; INDUCED NOREPINEPHRINE RELEASE; BRAIN-STEM; MESSENGER-RNA; SPINAL-CORD; C-FOS; NORADRENERGIC INNERVATION; NOXIOUS-STIMULATION; SUPRAOPTIC NUCLEI AB Central catecholaminergic pathways carrying pain-related signals to the hypothalamic paraventricular nucleus (PVN) were investigated in laboratory rats. Four per cent formalin injected subcutaneously was employed as a stressful stimulus. Neuronal activity in brainstem catecholaminergic and paraventricular neurones was assessed by Fos immunohistochemistry. Stress-induced noradrenaline (NE) release from nerve terminals in the PVN was measured in extracellular fluid by in-vivo microdialysis. Within 30 min, formalin elicited a four- to sixfold increase in plasma ACTH and corticosterone concentrations and intense Fos-like activity was seen in the superficial zones of the lumbar spinal cord ipsilateral to the side of the formalin injection. In brainstem catecholaminergic neurones, the PVN, and midline thalamic nuclei, formalin-induced Fos-immunopositivity was equally present in the ipsi- and contralateral sides of the injection. An immediate elevation (4-5 times higher than baseline levels) of NE levels was measured in both the right and left PVN after a formalin injection into the right paw. Unilateral surgical transections at the medulla-spinal cord junction failed to affect formalin-induced elevations in NE levels in the PVN independently of the side of the formalin injection or the knife cut. Thus, this observation clearly shows that fibres carrying pain-evoked signals ascend bilaterally from the spinal cord to the brainstem and forebrain. Hemisections of the medulla oblongata between the level of A1-A2 NE cell groups and the locus coeruleus reduced but did not eliminate formalin-induced NE release from the PVN ipsilateral to the knife cut. This effect was independent of the side of the formalin injection. In the contralateral PVN, high and similar NE levels were measured in response to a formalin injection into the right or the left leg. The present study indicates that formalin-induced pain signals are carried by sensory fibres to the ipsilateral spinal cord. From there, axons of different dorsal horn neurones reach noradrenergic cells on both sides of the medulla oblongata, The majority of noradrenergic fibers ascend on the same side and innervate the ipsilateral PVN. Since formalin administration resulted in a moderate elevation of NE levels in the PVN on the operated side, the role of other ascending noradrenergic (from the locus coeruleus) or noncatecholaminergic fibres that could modulate NE release from the PVN should be considered. C1 NIMH, Genet Lab, NIH, Bethesda, MD 20892 USA. Semmelweis Univ Med, Sch Med, Neuromorphol Lab, Budapest, Hungary. NINDS, Clin Neurosci Branch, Bethesda, MD 20892 USA. NICHHD, Dev Endocrinol Branch, Bethesda, MD 20892 USA. RP Palkovits, M (reprint author), NIMH, Genet Lab, NIH, Bldg 36,Room 3D06, Bethesda, MD 20892 USA. RI Palkovits, Miklos/F-2707-2013 NR 49 TC 68 Z9 68 U1 0 U2 11 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 JUL PY 1999 VL 11 IS 7 BP 529 EP 539 PG 11 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 219FY UT WOS:000081598300006 PM 10444310 ER PT J AU Bourdette, D Antel, J McFarland, H Montgomery, E AF Bourdette, D Antel, J McFarland, H Montgomery, E TI Monitoring relapsing remitting MS patients SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE multiple sclerosis; treatment; immunomodulation; magnetic resonance imaging ID PLACEBO-CONTROLLED TRIAL; GADOLINIUM-ENHANCED MRI; MYELIN BASIC-PROTEIN; MULTIPLE-SCLEROSIS; INTERFERON BETA-1B; DOUBLE-BLIND; COPOLYMER-1; MULTICENTER AB The availability of safe and partially effective disease modifying therapies necessitates changes in how neurologists monitor patients with relapsing remitting multiple sclerosis (RRMS). Neurologists need to make the diagnosis of MS as soon as possible to be able to initiate therapy-early in the course of disease. In deciding whom to treat, neurologists should consider information on disease activity and burden acquired from the neurologic history and examination and magnetic resonance imaging (MRT). Patients not on a disease modifying therapy should undergo yearly clinical assessments and periodic cerebral MRT to monitor for changes in disease activity. Patients on disease modifying therapy should undergo regular clinical assessments. to monitor for side-effects and disease activity. Cerebral. MRT scanning may also be useful in assessing patients on therapy, particularly when considering changes in therapy. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Oregon Hlth Sci Univ, Dept Neurol, Multiple Sclerosis Ctr Oregon, Portland, OR 97201 USA. Dept Vet Affairs Med Ctr, Neurol Serv, Portland, OR 97201 USA. Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada. NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. Cleveland Clin Fdn, Dept Neurol, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Dept Neurosci, Cleveland, OH 44195 USA. RP Bourdette, D (reprint author), Oregon Hlth Sci Univ, Dept Neurol, Multiple Sclerosis Ctr Oregon, Portland, OR 97201 USA. NR 24 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD JUL 1 PY 1999 VL 98 IS 1 BP 16 EP 21 DI 10.1016/S0165-5728(99)00076-4 PG 6 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 216VU UT WOS:000081465800004 PM 10426357 ER PT J AU Sommer, M Grafman, J Clark, K Hallett, M AF Sommer, M Grafman, J Clark, K Hallett, M TI Learning in Parkinson's disease: eyeblink conditioning, declarative learning, and procedural learning SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article DE eyeblink classical conditioning; Parkinson's disease; implicit and explicit memory ID CEREBELLAR DEGENERATION; BASAL GANGLIA; HUMANS; ACQUISITION; DEMENTIA; PARADIGM; DEFICIT; DELAY AB Objective-To assess the degree of learning ability in Parkinson's disease. Methods-Three different learning tasks: eyeblink classical conditioning with delay and trace paradigms, the California verbal learning test (CVLT), and a serial reaction time task (SRTT) were studied in patients with Parkinson's disease and normal (control) subjects. Results-In the eyeblink conditioning tasks, both patients and normal subjects showed significant learning effects without between group differences. In the CVLT, patients remembered significantly fewer words than normal subjects in both short term and long term cued recall tasks. In the SRTT, normal subjects had significantly reduced response time and error rates across blocks of repeated sequence trials, whereas patients had significantly reduced error, but not response time rates. Conclusion-Impairment of nigrostriatal pathways selectively affects performance in complex learning tasks that are competitive and require alertness such as the SRTT, but not in simple learning procedures such as eyeblink conditioning. C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. RI Sommer, Martin/F-1503-2015; OI Grafman, Jordan H./0000-0001-8645-4457 NR 27 TC 69 Z9 71 U1 2 U2 7 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD JUL PY 1999 VL 67 IS 1 BP 27 EP 34 DI 10.1136/jnnp.67.1.27 PG 8 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 207FL UT WOS:000080925400008 PM 10369818 ER PT J AU Abel, A Bone, LJ Messing, A Scherer, SS Fischbeck, KH AF Abel, A Bone, LJ Messing, A Scherer, SS Fischbeck, KH TI Studies in transgenic mice indicate a loss of connexin32 function in X-linked Charcot-Marie-tooth disease SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE connexin32; mutation; myelin; neuropathy; transgenic mouse model ID HEREDITARY MOTOR; SENSORY NEUROPATHY; MUTATIONS; MYELIN; GENE; EXPRESSION; PROTEIN; LOCALIZATION; EFFICIENCY; INTRONS AB X-linked Charcot-Marie-Tooth disease (CMTX) is an inherited demyelinating neuropathy caused by mutations in the gene encoding the gap junction protein connexin32 (Cx32). Despite the identification of over 160 different mutations in the Cx32 coding sequence, it is not known whether the mutations cause the disease manifestations through a loss of Cx32 function or through toxic effects on peripheral nerve. We created transgenic mice with a frameshift mutation at codon 175 (175fs), identified in a large CMTX pedigree. Light microscopic examination of the peripheral nerves from adult transgenic animals showed no pathological features. Western blotting did not show transgenic Cx32 protein in any of the 26 lines, although expression of transgenic messenger RNA was detected by reverse-transcriptase polymerase chain reaction and by ribonuclease protection assay. Our findings indicate that the 175fs mutation results in a loss of Cx32 function, without additional toxic effects. C1 NINDS, Neurogenet Branch, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA. Univ Wisconsin, Dept Pathobiol Sci, Madison, WI 53705 USA. RP Abel, A (reprint author), NINDS, Neurogenet Branch, Bldg 10 Rm,3B14,10 Ctr Dr, Bethesda, MD 20892 USA. FU NINDS NIH HHS [NS08075] NR 35 TC 27 Z9 27 U1 0 U2 0 PU AMER ASSN NEUROPATHOLOGISTS INC PI LAWRENCE PA 1041 NEW HAMPSHIRE ST, LAWRENCE, KS 66044 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUL PY 1999 VL 58 IS 7 BP 702 EP 710 DI 10.1097/00005072-199907000-00004 PG 9 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 217PR UT WOS:000081508600004 PM 10411340 ER PT J AU Butera, RJ Rinzel, J Smith, JC AF Butera, RJ Rinzel, J Smith, JC TI Models of respiratory rhythm generation in the pre-Botzinger complex. I. Bursting pacemaker neurons SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID PANCREATIC BETA-CELLS; PERSISTENT SODIUM CURRENT; ELECTRICAL-ACTIVITY; ELECTROPHYSIOLOGICAL PROPERTIES; NEOCORTICAL NEURONS; HIPPOCAMPAL-NEURONS; SLOW INACTIVATION; PATTERN GENERATOR; MEDULLARY SLICES; APLYSIA NEURON AB A network of oscillatory bursting neurons with excitatory coupling is hypothesized to define the primary kernel for respiratory rhythm generation in the pre-Botzinger complex (pre-BotC) in mammals. Two minimal models of these neurons are proposed. In model 1, bursting arises via fast activation and slow inactivation of a persistent Na+ current INaP-h. In model 2, bursting arises via a fast-activating persistent Na+ current I-NaP and slow activation of a K+ current I-KS. In both models, action potentials are generated via fast Na+ and K+ currents. The two models have few differences in parameters to facilitate a rigorous comparison of the two different burst-generating mechanisms. Both models are consistent with many of the dynamic features of electrophysiological recordings from pre-BotC oscillatory bursting neurons in vitro, including voltage-dependent activity modes (silence, bursting, and beating), a voltage-dependent burst frequency that can vary from 0.05 to >1 Hz, and a decaying spike frequency during bursting. These results are robust and persist across a wide range of parameter values for both models. However, the dynamics of model 1 are more consistent with experimental data in that the burst duration decreases as the baseline membrane potential is depolarized and the model has a relatively flat membrane potential trajectory during the interburst interval. We propose several experimental tests to demonstrate the validity of either model and to differentiate between the two mechanisms. C1 NINDS, Cellular & Syst Neurobiol Sect, Neural Control Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Math Res Branch, NIH, Bethesda, MD 20892 USA. NYU, Ctr Neural Sci, New York, NY 10013 USA. NYU, Courant Inst Math Sci, New York, NY 10013 USA. RP NINDS, Cellular & Syst Neurobiol Sect, Neural Control Lab, NIH, Bldg 49,Room 3A50,49 Convent Dr, Bethesda, MD 20892 USA. OI Butera, Robert/0000-0002-1806-0621 NR 78 TC 277 Z9 278 U1 3 U2 10 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUL PY 1999 VL 82 IS 1 BP 382 EP 397 PG 16 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 218NM UT WOS:000081558700039 PM 10400966 ER PT J AU Butera, RJ Rinzel, J Smith, JC AF Butera, RJ Rinzel, J Smith, JC TI Models of respiratory rhythm generation in the pre-Botzinger complex. II. Populations of coupled pacemaker neurons SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID NEURAL MECHANISMS; MEDULLARY SLICES; NEONATAL RAT; NETWORK; PATTERN; TRANSMISSION; MOTONEURONS; OSCILLATOR; GENESIS; INVITRO AB We have proposed models for the ionic basis of oscillatory bursting of respiratory pacemaker neurons in the pre-Botzinger complex. In this paper, we investigate the frequency control and synchronization of these model neurons when coupled by excitatory amino-acid-mediated synapses and controlled by convergent synaptic inputs modeled as tonic excitation. Simulations of pairs of identical cells reveal that increasing tonic excitation increases the frequency of synchronous bursting while increasing thp strength of excitatory coupling between the neurons decreases the frequency of synchronous bursting Low levels of coupling extend the range of values of tonic excitation where synchronous bursting is found. Simulations of a heterogeneous population of 50-500 bursting neurons reveal coupling effects similar tn those found experimentally in vitro: coupling increases the mean burst duration and decreases the mean burst frequency. Burst synchronization occurred over a wide range of intrinsic frequencies (0.1-1 Hz) and even in populations where as few as 10% of the cells were intrinsically bursting. Weak coupling, extreme parameter heterogeneity, and low levels of depolarizing input could contribute to the desynchronization of the population and give rise to quasiperiodic states. The introduction of sparse coupling did not affect the burst synchrony, although it did make the interburst intervals more irregular from cycle to cycle. At a population level, both parameter heterogeneity, and excitatory coupling synergistically combine to increase the dynamic input range: robust synchronous bursting persisted across a much greater range of parameter space (in terms of mean depolarizing input) than that of a single model cell. This extended dynamic range for rhp bursting cell population indicates that cellular heterogeneity is functionally advantageous. Our modeled system accounts for the range of intrinsic frequencies and spiking patterns of inspiratory (I) bursting cells found in the pre-Botzinger complex in neonatal rat brain stem slices in vitro. There is a temporal dispersion in the spiking onset times of neurons in the population, predicted to be due to heterogeneity in intrinsic neuronal properties, with neurons starting to spike before (pre-I), with (I), or after (late-I) the onset of the population burst. Experimental tests for a number of the model's predictions are proposed. C1 NIH, Neural Control Lab, NINDS, Cellular & Syst Neurobiol Sect, Bethesda, MD 20892 USA. NIH, Math Res Branch, Natl Inst Diabetes & Digest & Kidney Dis, Bethesda, MD 20892 USA. NYU, Ctr Neural Sci, New York, NY 10013 USA. NYU, Courant Inst Math Sci, New York, NY 10013 USA. RP NIH, Neural Control Lab, NINDS, Cellular & Syst Neurobiol Sect, Bldg 49,Room 3A50,49 Convent Dr, Bethesda, MD 20892 USA. OI Butera, Robert/0000-0002-1806-0621 NR 37 TC 210 Z9 211 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUL PY 1999 VL 82 IS 1 BP 398 EP 415 PG 18 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 218NM UT WOS:000081558700040 PM 10400967 ER PT J AU Petit, L Haxby, JV AF Petit, L Haxby, JV TI Functional anatomy of pursuit eye movements in humans as revealed by fMRI SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID POSITRON EMISSION TOMOGRAPHY; CEREBRAL HEMISPHERIC LESIONS; PARIETAL ASSOCIATION CORTEX; DORSOMEDIAL FRONTAL-CORTEX; CORTICAL AREAS MT; CINGULATE CORTEX; MONKEY CORTEX; RHESUS-MONKEY; CEBUS MONKEYS; HUMAN BRAIN AB We have investigated the functional anatomy of pursuit eye movements in humans with functional magnetic imaging. The performance of pursuit eye movements induced activations in the cortical eye fields also activated during the execution of visually guided saccadic eye movements, namely in the precentral cortex [frontal eye field (FEF)], the medial superior frontal cortex (supplementary eye field), the intraparietal cortex (parietal eye field), and the precuneus, and at the junction of occipital and temporal cortex (MT/MST) cortex. Pursuit-related areas could be distinguished from saccade-related areas both in terms of spatial extent and location. Pursuit-related areas were smaller than their saccade-related counterparts, three of eight significantly so. The pursuit-related FEF was usually inferior to saccade-related FEF. Other pursuit-related areas were consistently posterior to their saccade-related counterparts. The current findings provide the first functional imaging evidence for a distinction between two parallel cortical systems that subserve pursuit and saccadic eye movements in humans. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Petit, L (reprint author), NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RI GINSPAN, All/B-8714-2008; Petit, Laurent/D-6583-2011 OI Petit, Laurent/0000-0003-2499-5367 NR 70 TC 187 Z9 187 U1 1 U2 13 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUL PY 1999 VL 82 IS 1 BP 463 EP 471 PG 9 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 218NM UT WOS:000081558700045 PM 10400972 ER PT J AU Weeks, RA Gerloff, C Honda, M Dalakas, MC Hallett, M AF Weeks, RA Gerloff, C Honda, M Dalakas, MC Hallett, M TI Movement-related cerebellar activation in the absence of sensory input SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID POSITRON EMISSION TOMOGRAPHY; MOTOR; PROPRIOCEPTION; NEUROPATHY; ARM AB Movement-related cerebellar activation may be due to sensory or motor processing. Ordinarily, sensory and motor processing are obligatorily linked, but in patients who have severe pansensory neuropathies with normal muscle strength, motor activity occurs in isolation. In the present study, positron emission tomography and functional magnetic resonance imaging in such patients showed no cerebellar activation with passive movement, whereas there was prominent movement-related cerebellar activation despite absence of proprioceptive or visual input. The results indicate that motor processing occurs within the cerebellum and do not support the recently advanced view that the cerebellum is primarily a sensory organ. C1 NINDS, NIH, Human Motor Control Sect, Bethesda, MD 20892 USA. NINDS, Neuromuscular Dis Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, NIH, Human Motor Control Sect, Bldg 10,Room 5N226,10 Ctr Dr MSC-1428, Bethesda, MD 20892 USA. NR 25 TC 7 Z9 7 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUL PY 1999 VL 82 IS 1 BP 484 EP 488 PG 5 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 218NM UT WOS:000081558700048 PM 10400975 ER PT J AU Ghiani, CA Yuan, XQ Eisen, AM Knutson, PL DePinho, RA McBain, CJ Gallo, V AF Ghiani, CA Yuan, XQ Eisen, AM Knutson, PL DePinho, RA McBain, CJ Gallo, V TI Voltage-activated K+ channels and membrane depolarization regulate accumulation of the cyclin-dependent kinase inhibitors p277(Kip1) and p21(CIP1) in glial progenitor cells SO JOURNAL OF NEUROSCIENCE LA English DT Article DE oligodendrocyte development; cell cycle; ion channels; G1 arrest; cell proliferation; cyclin D ID CENTRAL NERVOUS-SYSTEM; GLUTAMATE RECEPTORS; POTASSIUM CHANNELS; ION CHANNELS; OPTIC-NERVE; IN-VITRO; OLIGODENDROCYTE DIFFERENTIATION; NEURAL DIFFERENTIATION; PRECURSOR CELLS; SCHWANN-CELLS AB Neural cell development is regulated by membrane ion channel activity. We have previously demonstrated that cell membrane depolarization with veratridine or blockage of K+ channels with tetraethylammonium (TEA) inhibit oligodendrocyte progenitor (OP) proliferation and differentiation (Knutson et al., 1997); however the molecular events involved are largely unknown. Here we show that forskolin (FSK) and its derivative dideoxyforskolin (DFSK) block K+ channels in OPs and inhibit cell proliferation. The antiproliferative effects of TEA, FSK, DFSK, and veratridine were attributable to OP cell cycle arrest in G1 phase. In fact, (1) cyclin D accumulation in synchronized OP cells was not affected by K+ channel blockers or veratridine; (2) these agents prevented OP cell proliferation only if present during G1 phase; and (3) G1 blockers, such as rapamycin and deferoxamine, mimicked the anti-proliferative effects of K+ channel blockers. DFSK also prevented OP differentiation, whereas FSK had no effect. Blockage of K+ channels and membrane depolarization also caused accumulation of the cyclin-dependent kinase inhibitors p27(Kip1) and p21 (CIP1) in OP cells. The antiproliferative effects of K+ channel blockers and veratridine were still present in OP cells isolated from INK4a(-/-) mice, lacking the cyclin-dependent kinase inhibitors p16(INK4a) and p19(ARF). Our results demonstrate that blockage of K+ channels and cell depolarization induce G1 arrest in the OP cell cycle through a mechanism that may involve p27(Kip1) and p21(CIP1) and further support the conclusion that OP cell cycle arrest and differentiation are two uncoupled events. C1 NICHHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Gallo, V (reprint author), NICHHD, Lab Cellular & Mol Neurophysiol, NIH, Bldg 49,Room 5A-78,49 Convent Dr, Bethesda, MD 20892 USA. OI Ghiani, Cristina/0000-0002-9867-6185 NR 84 TC 101 Z9 101 U1 1 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 1 PY 1999 VL 19 IS 13 BP 5380 EP 5392 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 209PL UT WOS:000081056900021 PM 10377348 ER PT J AU Rubio, ME Wenthold, RJ AF Rubio, ME Wenthold, RJ TI Differential distribution of intracellular glutamate receptors in dendrites SO JOURNAL OF NEUROSCIENCE LA English DT Article DE glutamate receptor; immunocytochemistry; dendrite; postembedding; targeting; cochlear nucleus ID CULTURED HIPPOCAMPAL-NEURONS; CEREBELLAR PURKINJE NEURONS; DORSAL COCHLEAR NUCLEUS; RAT-BRAIN; ENDOPLASMIC-RETICULUM; POSTSYNAPTIC DENSITY; AMPA RECEPTORS; ANTIBODY SHOWS; SUBUNITS; LOCALIZATION AB Glutamate receptors are synthesized in the cell body and transported in intracellular compartments to the target synapse. The objective of the present study was to analyze the intracellular pool of glutamate receptors and determine whether the intracellular pool was related to the synaptic distribution of the receptors. As a model system, we chose the fusiform cell of the dorsal cochlear nucleus for which we have previously demonstrated that receptors are selectively targeted to synapses on apical and basal dendrites. A combination of retrograde tracing and postembedding immunogold labeling was used to quantify intracellular receptors in segments of apical and basal dendrites. Immunolabeling for GluR4 and mGluR1 alpha is present at synapses on basal dendrites but not on apical dendrites, whereas immunolabeling for GluR2/3 is present at both populations of synapses. In the analysis of intracellular pools, we find that GluR2/3 is equally distributed in apical and basal dendrites, whereas GluR4 and mGluR1 alpha are more concentrated in basal dendrites than in apical dendrites. These findings indicate that the distribution of intracellular receptors is related to that of synaptic receptors and suggest that a mechanism exists in neurons to target proteins to dendritic domains soon after synthesis. We found no evidence for the existence of a pool of intracellular receptors, which could represent a receptor reserve, near the postsynaptic density. Receptors were often found in clusters associated with tubulovesicular membranes of the endoplasmic reticulum, identified with immunoglobulin binding protein (BIP) or calnexin, suggesting that this organelle is involved in receptor transport in dendrites. C1 Natl Inst Deafnes & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Rubio, ME (reprint author), Natl Inst Deafnes & Other Commun Disorders, Neurochem Lab, NIH, Bldg 36,Room 5D08,36 Convent Dr, Bethesda, MD 20892 USA. NR 58 TC 61 Z9 62 U1 0 U2 2 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 JUL 1 PY 1999 VL 19 IS 13 BP 5549 EP 5562 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 209PL UT WOS:000081056900035 PM 10377362 ER PT J AU Silverman, WF Alfahel-Kakunda, A Dori, A Barker, JL AF Silverman, WF Alfahel-Kakunda, A Dori, A Barker, JL TI Separation of dorsal and ventral dopaminergic neurons from embryonic rat mesencephalon by buoyant density fractionation: disassembling pattern in the ventral midbrain SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE development; cell separation; cell culture; substantia nigra; dopamine; Percoll; pattern ID TYROSINE-HYDROXYLASE; SUBSTANTIA-NIGRA; NEUROTROPHIC FACTOR; TEGMENTAL AREA; BRAIN; COLOCALIZATION; PROLIFERATION; PEROXIDASE; CALRETININ; SYSTEMS AB The dopaminergic neurons of the ventral mesencephalon, though physically mixed with non-dopamine neurons, are organized into dorsal and ventral 'tiers' with regard to their ontogeny, efferent projections and their relative position in the various mesencephalic sub-nuclei. We have employed buoyant density fractionation to separate the dopaminergic neurons of the two compartments and compare their subsequent phenotype development with respect to their expression of the gene encoding tyrosine hydroxylase, the rate-limiting enzyme in the catecholamine biosynthetic pathway. Using immunocytochemistry, separately and combined with in situ hybridization, we demonstrate here that sedimentation of cell suspensions from E19 rat ventral mesencephalon on fi-step Percoll gradients produces cell fractions enriched in ventral and dorsal tier DA neurons, respectively. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Ben Gurion Univ Negev, Zlotowski Ctr Neurosci, Dept Morphol, IL-84105 Beer Sheva, Israel. NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Silverman, WF (reprint author), Ben Gurion Univ Negev, Zlotowski Ctr Neurosci, Dept Morphol, IL-84105 Beer Sheva, Israel. NR 26 TC 17 Z9 17 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD JUL 1 PY 1999 VL 89 IS 1 BP 1 EP 8 DI 10.1016/S0165-0270(99)00029-1 PG 8 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 226EH UT WOS:000082007000001 PM 10476677 ER PT J AU Sallinen, SL Sallinen, PK Kononen, JT Syrjakoski, KM Nupponen, NN Rantala, IS Helen, PT Helin, HJ Haapasalo, HK AF Sallinen, SL Sallinen, PK Kononen, JT Syrjakoski, KM Nupponen, NN Rantala, IS Helen, PT Helin, HJ Haapasalo, HK TI Cyclin D1 expression in astrocytomas is associated with cell proliferation activity and patient prognosis SO JOURNAL OF PATHOLOGY LA English DT Article DE astrocytoma; brain tumours; cyclin D1; prognosis; proliferation ID S-PHASE; GLIOBLASTOMA-MULTIFORME; BRAIN-TUMORS; AMPLIFICATION; GENE; OVEREXPRESSION; PROTEIN; PROGRESSION; CARCINOMA; BREAST AB An important positive regulator of the cell cycle, cyclin D1, is often amplified and overexpressed in malignancies. CS clin D1 aberrations were analysed in grade II-IV astrocytomas by fluorescence in situ hybridization (FISH), mRNA in situ hybridization and immunohistochemistry. Proliferation activity was determined by Ki-67(MIB-1) immunolabelling and mitotic counting. High cyclin D1 expression was observed in grade IV astrocytomas (grades II-III versus grade IV; mRNA expression: p<0.001; immunoexpression: p=0.013), and correlated with poor patient survival (p<0.001, n=46). Upregulated cyclin D1 expression was also closely associated with poor patient prognosis in grade Ii-III astrocytomas (p<0.001, n=30). Cyclin D1 gene was not found to be amplified (n=7). Cell proliferation activity was significantly increased in rumours exhibiting high cyclin D1 mRNA levels (Ki-67(MIB-1): p<0.002; mitotic count: p<0.001) and high cyclin D1 protein expression (Ki-67(MIB-1): p=0.002; mitotic count: p=0.012). These results indicate that increased production of cyclin D1 is closely associated with high cell proliferation activity and aggressive behaviour in diffusely infiltrating astrocytomas. Copyright (C) 1999 John Wiley & Sons, Ltd. C1 Univ Tampere, Inst Med Technol, Canc Genet Lab, FIN-33101 Tampere, Finland. Tampere Univ Hosp, Dept Pathol, Tampere, Finland. Tampere Univ Hosp, Dept Neurosurg, Tampere, Finland. Natl Human Genome Res Inst, Canc Genet Branch, NIH, Bethesda, MD USA. RP Sallinen, SL (reprint author), Univ Tampere, Inst Med Technol, Canc Genet Lab, POB 607, FIN-33101 Tampere, Finland. NR 34 TC 30 Z9 34 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0022-3417 J9 J PATHOL JI J. Pathol. PD JUL PY 1999 VL 188 IS 3 BP 289 EP 293 PG 5 WC Oncology; Pathology SC Oncology; Pathology GA 214DQ UT WOS:000081312700012 PM 10419598 ER PT J AU Accili, D Nakae, J Kim, JJ Park, BC Rother, KI AF Accili, D Nakae, J Kim, JJ Park, BC Rother, KI TI Targeted gene mutations define the roles of insulin and IGF-I receptors in mouse embryonic development SO JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM LA English DT Review DE insulin-like growth factor-I (IGF-I); insulin-like growth factor-II (IGF-II); insulin receptor; IGF-I receptor; IGF-II receptor; mutations; knockout mice ID HOMOZYGOUS NONSENSE MUTATION; GROWTH-FACTOR-I; IRS-SIGNALING SYSTEM; PHOSPHOTYROSINE PROTEIN; GLUCOSE-TOLERANCE; SUBSTRATE FAMILY; CYTOKINE ACTION; ADIPOSE-TISSUE; KNOCKOUT MICE; NULL ALLELE AB Insulin-like growth factors (IGFs) and their receptors regulate embryonic and post-natal growth. Genetic evidence derived from targeted mouse mutants indicates that both the insulin receptor (IR) and IGF-I receptors (IGF-IRs) are required for mouse embryonic growth. However, the roles of IRs and IGF-IRs are functionally distinct, with IGF-IRs mediating both IGF-I and IGF-II actions, and IRs mediating IGF-II, rather than insulin, action. The combined interactions of IGF-IRs and IRs with IGF-I and IGF-II account for the entirety of the growth effects of these two ligands, and provide the molecular basis for IGFs-mediated intrauterine growth and differentiation. Genetic ablation experiments of insulin receptor substrate-1 (IRS-1) and -2 (IRS-2), two important molecules in the IR and IGF-IR signaling pathways, are also beginning to shed light onto the mechanisms accounting for the specificity of IR and IGF-IR signaling, IRS-1-deficient mice are growth retarded, while IRS-2-deficient mice develop diabetes, indicating that the two molecules play a more specific role than previously recognized in IGF-IR and IR signaling. C1 NICHHD, Dev Endocrinol Branch, Unit Genet & Hormone Act, NIH, Bethesda, MD 20892 USA. RP Accili, D (reprint author), Bldg 10,Room 10D18, Bethesda, MD 20892 USA. NR 62 TC 24 Z9 24 U1 1 U2 3 PU FREUND PUBLISHING HOUSE LTD PI LONDON PA STE 500, CHESHAM HOUSE, 150 REGENT ST, LONDON W1R 5FA, ENGLAND SN 0334-018X J9 J PEDIATR ENDOCR MET JI J. Pediatr. Endocrinol. Metab. PD JUL-AUG PY 1999 VL 12 IS 4 BP 475 EP 485 PG 11 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 214TP UT WOS:000081343900001 PM 10417963 ER PT J AU Serwint, JR Damokosh, AI Berger, OG Chisolm, JJ Gunter, EW Jones, RL Rhoads, GG Rogan, W AF Serwint, JR Damokosh, AI Berger, OG Chisolm, JJ Gunter, EW Jones, RL Rhoads, GG Rogan, W CA Treatment Lead-Exposed Children Trial TI No difference in iron status between children with low and moderate lead exposure SO JOURNAL OF PEDIATRICS LA English DT Article; Proceedings Paper CT National American-Pediatric-Society/Society-for-Pediatric-Research/Ambulatory-Ped iatric-Association Meeting CY MAY 03-04, 1997 CL WASHINGTON, D.C. SP Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc ID DEFICIENCY AB We compared the iron status between children 11 to 33 months old with confirmed blood lead levels of 20 to 44 mu g/dL and demographically similar children with blood lead levels of <10 mu g/dL. There were no differences. Laboratory investigation or empirical treatment for iron deficiency is not justified on the basis of moderately elevated blood lead levels alone. C1 Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA. Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. Kennedy Krieger Inst, Baltimore, MD USA. Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. Environm & Occupat Hlth Sci Inst, Piscataway, NJ USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Serwint, JR (reprint author), Johns Hopkins Hosp, 600 N Wolfe St CMSC 143, Baltimore, MD 21287 USA. RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 12 TC 28 Z9 31 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JUL PY 1999 VL 135 IS 1 BP 108 EP 110 DI 10.1016/S0022-3476(99)70338-0 PG 3 WC Pediatrics SC Pediatrics GA 215JQ UT WOS:000081378900023 PM 10393615 ER PT J AU Machelska, H Pfluger, M Weber, W Piranvisseh-Volk, M Daubert, JD Dehaven, R Stein, C AF Machelska, H Pfluger, M Weber, W Piranvisseh-Volk, M Daubert, JD Dehaven, R Stein, C TI Peripheral effects of the kappa-opioid agonist EMD 61753 on pain and inflammation in rats and humans SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NMDA RECEPTOR ANTAGONIST; ADJUVANT ARTHRITIS; MORPHINE; OPIATE; INVOLVEMENT; MODULATION; MECHANISMS; ANALGESIA; PEPTIDES; MODEL AB The objective of the present study was to evaluate the effects of EMD 61753 (asimadoline), a K-opioid receptor agonist with restricted access to the central nervous system, on postoperative pain in patients who underwent knee surgery and on nociceptive thresholds and inflammation in rats treated with Freund's complete adjuvant. Patients treated with EMD 61753 (10 mg p.o.) tended to report an increase in pain, as evaluated by a visual analog scale and by the time to the first request for and the total amount of supplemental analgesic medication. The global tolerability of EMD 61753 was assessed as significantly inferior to that of a placebo by the investigator. In rats, the bilateral intraplantar (i.pl.) injection of EMD 61753 (0.1-3.2 mg) resulted in dose-dependent antinociception in both inflamed and noninflamed paws, with a peak at 5 min after injection, as evaluated by the paw pressure method. However, at later time points (1 h-4 days), a significant decrease in the paw pressure threshold was observed, confirming its tendency toward a hyperalgesic action in humans. This was accompanied by an increase in paw volume and paw temperature, with a peak at 6 h after injection. EMD 61753 (1.6 mg)-induced analgesia was blocked by the peripheral opioid receptor antagonist naloxone methiodide (2.5-10 mg/kg s.c.) and by the kappa-receptor antagonist nor-binaltorphimine (0.1 mg; i.pl.). In contrast, EMD 61753 (1.6 mg)-induced hyperalgesia and increases in paw volume and paw temperature were blocked neither by naloxone methiodide (10-40 mg/kg s.c.) nor by dizocilpine maleate (0.003-0.009 mg i,pl.), a N-methyl-D-aspartic acid receptor antagonist. These data show differentially mediated peripheral actions of EMD 61753: K-opioid receptor-induced analgesia and nonopioid, non-N-methyl-D-aspartic acid hyperalgesic and proinflammatory effects. C1 Free Univ Berlin, Klinikum Benjamin Franklin, Klin Anaesthesiol & Operative Intensivmed, D-12200 Berlin, Germany. Johns Hopkins Univ, Dept Anesthesiol & Crit Care Med, Baltimore, MD USA. NIDA, Preclin Pharmacol Lab, Intramural Res Program, NIH, Baltimore, MD USA. Univ Munich, Dept Anesthesiol, Munich, Germany. Adolor Corp, Malvern, PA USA. RP Machelska, H (reprint author), Free Univ Berlin, Klinikum Benjamin Franklin, Klin Anaesthesiol & Operative Intensivmed, Hindenburgdamm 30, D-12200 Berlin, Germany. NR 31 TC 66 Z9 66 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUL PY 1999 VL 290 IS 1 BP 354 EP 361 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 209GM UT WOS:000081039900048 PM 10381799 ER PT J AU Rizzo, P Tinello, C Pearlstein, RA Taniuchi, H AF Rizzo, P Tinello, C Pearlstein, RA Taniuchi, H TI Antibody immunodiversity: A study on the marked specificity difference between two anti-yeast iso-1 cytochrome c monoclonal antibodies whose epitopes are closely related SO JOURNAL OF PROTEIN CHEMISTRY LA English DT Article DE antibody immunodiversity; anti-yeast iso-1 cytochromes c; antigen-combining site model; expression of a Fab gene; flexibility of combining site ID 3-DIMENSIONAL STRUCTURE; CRYSTAL-STRUCTURES; VARIABLE DOMAINS; COMPLEX; BINDING; PACKING; CONFORMATIONS; RESOLUTION; PROTEINS; REGIONS AB Anti-yeast iso-1 cytochrome c (cyt. c) monoclonal antibodies 2-96-12 and 4-74-6 have closely related epitopes (antigenic determinants). However, while the specificity of 4-74-6 is stringent, 2-96-12 cross-reacts with many evolutionarily related cytochromes c. Such a marked difference in specificity of antibodies with overlapping epitopes may represent unique antibody immuno-diversity. Thus, we constructed Fv fragment models consisting of the variable domains of the heavy and light chains of 2-96-12 and 4-74-6 and that of another anti-iso-1 cyt. c as a control to gain insight into the origin of this difference in specificity. Our models show that 4-74-6 and 2-96-12 contain five and two aromatic side chains, respectively, in or near the central area of the antigen-combining site. The side chains of Arg95H (heavy chain) in 2-96-12 and Arg91L (light chain) in 4-74-6 project toward the central area of the combining site in our model. Antigen docking to our Fv models, combined with previous immunological studies, suggests that iso-1 cyt. c Asp60 may interact with Arg95H in 2-96-12 and Arg91L in 4-74-6 and that both epitopes of 2-96-12 and 4-74-7 may include iso-1 cyt. c Leu58, Asp60, Asn62, and Asn63. The effect of the Arg95H to Lys mutation on the antigen binding is also in accord with our model. The difference in specificity may be partly explained by a greater degree of conformational flexibility in and around the central area of the: combining site in 2-96-12 compared to 4-74-6 due to differences in aromatic side chain packing. C1 NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. NIH, Ctr Biol Modeling, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Taniuchi, H (reprint author), NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. NR 43 TC 0 Z9 0 U1 0 U2 1 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0277-8033 J9 J PROTEIN CHEM JI J. Protein Chem. PD JUL PY 1999 VL 18 IS 5 BP 523 EP 532 DI 10.1023/A:1020695031952 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 245NB UT WOS:000083114100003 PM 10524770 ER PT J AU Boyer, GS Templin, DW Bowler, A Lawrence, RC Heyse, SP Everett, DF Cornoni-Huntley, JC AF Boyer, GS Templin, DW Bowler, A Lawrence, RC Heyse, SP Everett, DF Cornoni-Huntley, JC TI Spondyloarthropathy in the community: Clinical syndromes and disease manifestations in Alaskan Eskimo populations SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE clinical spectrum; community based study; ankylosing spondylitis; reactive arthritis; undifferentiated spondyloarthropathy ID ANKYLOSING-SPONDYLITIS; RHEUMATOID-ARTHRITIS; PREVALENCE; CRITERIA AB Objective. To define the clinical spectrum and disease manifestations of spondyloarthropathy (SpA) as seen in a community, rather than a referral setting. Methods. Eighty percent (83/104) of all individuals identified as having SpA in a community wide epidemiologic study of Alaskan Eskimos and 83 age and sex matched controls from the same regions participated in a 5 year clinical study. The study included baseline and followup interviews, physical, radiographic, and electrocardiographic examinations, record reviews, and functional assessment. The medical records of an additional 83 age and sex matched controls were reviewed and followed over the same 5 year period. Results. The spectrum of disease varied from very mild undifferentiated SpA (USpA) to incapacitating ankylosing spondylitis (AS). Most cases were mild. Overlapping clinical features were common in the different syndromes; 10% of the cases met more than 1 set of disease criteria. Axial signs and symptoms were more frequent in patients with AS, but occurred in over half of the patients with USpA and reactive arthritis (ReA) also. Peripheral joint involvement was noted in 85% of the AS cases, usually early in the course of disease. The patterns of joint involvement and enthesopathy were similar in SpA subjects with different syndromes and significantly different from those in control subjects, Patients with AS had a higher frequency of uveitis and of aortic root disease than patients with other syndromes. Conclusion. The results illustrate the extent of shared clinical features in the different SpA syndromes, and describe the frequency of different features associated with SpA in patients and matched controls in a community setting. ReA and USpA were more prevalent and less severe than AS in these populations. C1 Alaska Area Native Hlth Serv, Anchorage, AK USA. NIAID, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Durham, NC USA. NIAMSD, Bethesda, MD 20892 USA. NEI, Bethesda, MD 20892 USA. RP Boyer, GS (reprint author), 500 E Rudasill Rd, Tucson, AZ 85704 USA. FU NIAMS NIH HHS [YO2-AR-00005-02] NR 20 TC 22 Z9 22 U1 0 U2 0 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD JUL PY 1999 VL 26 IS 7 BP 1537 EP 1544 PG 8 WC Rheumatology SC Rheumatology GA 212QF UT WOS:000081227200019 PM 10405942 ER PT J AU Kino, T Nordeen, SK Chrousos, GP AF Kino, T Nordeen, SK Chrousos, GP TI Conditional modulation of glucocorticoid receptor activities by CREB-binding protein (CBP) and p300 SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE coactivator; SRC-1; p300; mouse mammary tumor virus (MMTV); CREB ID NUCLEAR-RECEPTOR; TRANSCRIPTIONAL COACTIVATOR; HISTONE ACETYLTRANSFERASE; ACTIVATION; CBP/P300; COMPLEX; DETERMINANTS; RESISTANCE; PROMOTER; ALPHA AB Coactivators of nuclear receptors are integral components of the signal transduction pathways of steroid hormones. Here, we show that one of the major coactivators of the glucocorticoid receptor (GF:), CREB-binding protein (CBP), can also function conditionally as a negative regulator of its activities. Indeed, CBP suppressed the responsiveness of the mouse mammary tumor virus (MMTV) promoter to dexamethasone in a dose-dependent fashion in HeLa and A204 cells. Similarly, this protein suppressed the responsiveness of several glucocorticoid-responsive element (GRE)-containing synthetic promoters. Using deletion mutants of CBP, we localized the repressor effect of this protein to its N-terminal domain and showed that it was independent of the histone acetyltransferase and coactivator-binding domains but dependent upon its GR-binding domain. We also demonstrated functional differentiation between CBP and other coactivators, including SRC-1 and the CBP-related protein p300, both of which influenced GR signaling in a positive fashion. In fact, p300 completely antagonized the suppressive effects of CBP in a dose-dependent fashion, probably by competing with this protein at the level of the transcription complex. These findings suggest that CBP and p300 may function additively or antagonistically to each other depending on their relative concentrations and type of target tissue, to influence the sensitivity of tissues to glucocorticoids. (C) 1999 Published by Elsevier Science Ltd. All rights reserved. C1 NICHHD, Dev Endocrinol Branch, Sect Pediat Endocrinol, Bethesda, MD 20892 USA. Univ Colorado, Hlth Sci Ctr, Dept Pathol, Denver, CO USA. Univ Colorado, Hlth Sci Ctr, Program Mol Biol, Denver, CO USA. RP Kino, T (reprint author), NICHHD, Dev Endocrinol Branch, Sect Pediat Endocrinol, 10 Ctr Dr MSC 1862, Bethesda, MD 20892 USA. NR 41 TC 40 Z9 44 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD JUL-AUG PY 1999 VL 70 IS 1-3 BP 15 EP 25 DI 10.1016/S0960-0760(99)00100-4 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 240FM UT WOS:000082815300002 PM 10528999 ER PT J AU Jensen, PS Kettle, L Roper, MT Sloan, MT Dulcan, MK Hoven, C Bird, HR Bauermeister, JJ Payne, JD AF Jensen, PS Kettle, L Roper, MT Sloan, MT Dulcan, MK Hoven, C Bird, HR Bauermeister, JJ Payne, JD TI Are stimulants overprescribed? Treatment of ADHD in four US Communities SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE attention-deficit hyperactivity disorder; attention deficit; hyperactivity; stimulants; misdiagnosis; services; treatment ID DIAGNOSTIC INTERVIEW SCHEDULE; ATTENTION-DEFICIT DISORDER; HYPERACTIVE INATTENTIVE STUDENTS; MULTIMODAL TREATMENT; NATIONAL-INSTITUTE; CHILDREN DISC-2.1; HEALTH; METHYLPHENIDATE; EPIDEMIOLOGY; RELIABILITY AB Objective: To address rising concerns about the possible overdiagnosis of attention-deficit hyperactivity disorder (ADHD) and overtreatment with stimulants, To date, almost no studies have examined ADHD in unbiased community-based studies, ascertaining both the prevalence of the diagnosis within nonreferred populations and the extent to which various treatments (i.e., stimulant medication, mental health treatments, and educational interventions) are used. Method: As a part of the Methods for the Epidemiology of Child and Adolescent Mental Disorders (MECA) Study, the authors examined epidemiological survey data obtained from 1,285 children and their parents across 4 U.S. communities. Analyses examined the frequency of children's ADHD diagnosis, the extent to which medications were prescribed, as well as the provision of other services (e.g., psychosocial treatments, school-based educational interventions). Results: Findings indicated that 5.1% of children met full DSM-III-R ADHD criteria across the pooled sample. Only 12.5% of children meeting ADHD criteria had been treated with stimulants during the previous 12 months. Some children who had been prescribed stimulants did not meet full ADHD diagnostic criteria, but these children manifested high levels of ADHD symptoms, suggesting that the medication had been appropriately prescribed, Children with ADHD were generally more likely to receive mental health counseling and/or school-based interventions than medication. Conclusions: Medication treatments are often not used in treating ADHD children identified in the community, suggesting the need for better education of parents, physicians, and mental health professionals about the effectiveness of these treatments. On the basis of these data it cannot be concluded that substantial "overtreatment" with stimulants is occurring across communities in general. C1 NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. Brigham Young Univ, Provo, UT 84602 USA. Univ Maryland, College Pk, MD 20742 USA. Northwestern Univ, Sch Med, Div Child & Adolescent Psychiat, Chicago, IL USA. New York State Psychiat Inst, Dept Child Psychiat, New York, NY 10032 USA. Univ Puerto Rico, Dept Psychiat, San Juan, PR 00936 USA. Stanford Univ, Stanford, CA 94305 USA. RP Jensen, PS (reprint author), NIMH, Div Serv & Intervent Res, 6001 Execut Blvd,Room 8223 MSC 9669, Bethesda, MD 20892 USA. OI Jensen, Peter/0000-0003-2387-0650 FU NIMH NIH HHS [UO1 MH46717, UO1 MH46718, UO1 MH46725] NR 33 TC 198 Z9 198 U1 7 U2 36 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUL PY 1999 VL 38 IS 7 BP 797 EP 804 DI 10.1097/00004583-199907000-00008 PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 212NQ UT WOS:000081223400008 PM 10405496 ER PT J AU Slavkin, HC AF Slavkin, HC TI Visual illusions, science and esthetic dentistry SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Editorial Material C1 Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. RP Slavkin, HC (reprint author), Natl Inst Dent & Craniofacial Res, 31 Ctr Dr,MSC 2290,Bldg 31,Room 2C39, Bethesda, MD 20892 USA. NR 7 TC 2 Z9 2 U1 1 U2 2 PU AMER DENTAL ASSN PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD JUL PY 1999 VL 130 IS 7 BP 1115 EP 1119 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 216YV UT WOS:000081472800028 PM 10422408 ER PT J AU Roth, GS Ingram, DK Lane, MA AF Roth, GS Ingram, DK Lane, MA TI Calorie restriction in primates: Will it work and how will we know? SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE aging; caloric restriction; humans; primates ID MALE RHESUS-MONKEYS; DIETARY RESTRICTION; DEHYDROEPIANDROSTERONE-SULFATE; BLOOD-CHEMISTRY; BIOMARKERS; HEMATOLOGY; MODEL AB Dietary caloric restriction is the most robust and reproducible means of slowing aging and extending lifespan and healthspan in short-lived mammals and lower organisms. Numerous aspects of this paradigm have been investigated in laboratories around the world since its inception more than 60 years ago. However, two questions about calorie restriction remain unanswered to this day: (1) By what mechanism does it work? and (2) Will it work in humans? This review will focus on the latter with particular emphasis on evaluation criteria, current studies in primate models,available data, and plans for actual human caloric restriction interventions. C1 Johns Hopkins Univ, Gerontol Res Ctr, NIH, NIA,Bayview Med Ctr, Baltimore, MD 21224 USA. RP Roth, GS (reprint author), Johns Hopkins Univ, Gerontol Res Ctr, NIH, NIA,Bayview Med Ctr, Box 11,Rm 4E02,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 41 TC 143 Z9 146 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 1999 VL 47 IS 7 BP 896 EP 903 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 214HW UT WOS:000081323400020 PM 10404938 ER PT J AU Handler, JS AF Handler, JS TI The similarity of effects of vasopressin, adenosine-3 ',5 '-phosphate (cyclic AMP) and theophylline on the toad bladder - Author commentary SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material C1 Natl Heart Inst, Lab Kidney & Electrolyte Metab, Bethesda, MD USA. RP Handler, JS (reprint author), Natl Heart Inst, Lab Kidney & Electrolyte Metab, Bethesda, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 1999 VL 10 IS 7 BP 1623 EP + PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 211DD UT WOS:000081143900029 ER PT J AU Orloff, J Handler, JS AF Orloff, J Handler, JS TI The similarity of effects of vasopressin, adenosine-3 ',5 '-phosphate (cyclic AMP) and theophylline on the toad bladder (Reprinted from J. Clin. Invest. vol 41, pg 702-709, 1962) SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Reprint C1 Natl Heart Inst, Lab Kidney & Electrolyte Metab, Bethesda, MD USA. RP Orloff, J (reprint author), Natl Heart Inst, Lab Kidney & Electrolyte Metab, Bethesda, MD USA. NR 26 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 1999 VL 10 IS 7 BP 1623 EP 1630 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 211DD UT WOS:000081143900028 PM 10405220 ER PT J AU Teigen, PM AF Teigen, PM TI "A kindly, useful mentor": Applying the history of medicine to public policy SO JOURNAL OF THE HISTORY OF MEDICINE AND ALLIED SCIENCES LA English DT Editorial Material C1 Natl Lib Med, Hist Med Div, Bethesda, MD 20894 USA. RP Teigen, PM (reprint author), Natl Lib Med, Hist Med Div, Bethesda, MD 20894 USA. NR 25 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-5045 J9 J HIST MED ALL SCI JI J. Hist. Med. Allied Sci. PD JUL PY 1999 VL 54 IS 3 BP 353 EP 363 DI 10.1093/jhmas/54.3.353 PG 11 WC Health Care Sciences & Services; History & Philosophy Of Science SC Health Care Sciences & Services; History & Philosophy of Science GA 234CZ UT WOS:000082468100001 PM 10533357 ER PT J AU Wagner, JR Walther, MM Linehan, WM White, DE Rosenberg, SA Yang, JC AF Wagner, JR Walther, MM Linehan, WM White, DE Rosenberg, SA Yang, JC TI Interleukin-2 based immunotherapy for metastatic renal cell carcinoma with the kidney in place SO JOURNAL OF UROLOGY LA English DT Article DE kidney; carcinoma, renal cell; interleukin-2; neoplasm metastasis; kidney neoplasms ID HIGH-DOSE INTERLEUKIN-2; CYTOREDUCTIVE SURGERY; ALPHA-INTERFERON; ADVANCED CANCER; THERAPY; NEPHRECTOMY; COMBINATION; MELANOMA; REGIMENS AB Purpose: We assessed morbidity, response and survival in patients with metastatic renal carcinoma treated with high dose intravenous interleukin-2 (IL-2) based immunotherapy with the primary renal tumor in place. Materials and Methods: We retrospectively analyzed the records of patients with metastatic renal carcinoma and the primary kidney tumor in situ who were treated at the surgery branch of the National Cancer Insititute. Of the patients 607 were treated with IL-2 based therapy. Patient age, sex, sites of extrarenal disease, morbidity, and response and survival rates were examined. Results: From 1986 to 1996, 51 patients with the majority of disease at extrarenal sites were treated with the primary tumor in place. Treatment involved IL-2 based regimens, reflecting the evolution of immunotherapy at the National Institutes of Health. When evaluating only extrarenal sites, response was complete in 1 and partial in 2 of the 51 cases (6%). No responses were noted in the primary renal tumor. Three patients with responses at extrarenal sites underwent nephrectomy. The duration of response in these 3 cases was greater than 88, 11 and 4 months, respectively. Median survival in all 51 patients was 13 months (range 1 to 86). Conclusions: Select patients may be treated with IL-2 based immunotherapy with the primary renal tumors in place with morbidity. A randomized study is needed to assess the role of cytoreductive nephrectomy for treating metastatic renal cell carcinoma. C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20205 USA. NCI, Surg Branch, NIH, Bethesda, MD USA. RP Wagner, JR (reprint author), NCI, Urol Oncol Branch, NIH, Bethesda, MD 20205 USA. NR 24 TC 72 Z9 72 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUL PY 1999 VL 162 IS 1 BP 43 EP 45 DI 10.1097/00005392-199907000-00011 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 204FP UT WOS:000080753700010 PM 10379736 ER PT J AU Gamelin, E Mertins, SD Regis, JT Mickley, L Abati, A Worrell, RA Linehan, WM Bates, SE AF Gamelin, E Mertins, SD Regis, JT Mickley, L Abati, A Worrell, RA Linehan, WM Bates, SE TI Intrinsic drug resistance in primary and metastatic renal cell carcinoma SO JOURNAL OF UROLOGY LA English DT Article DE renal carcinoma; metastases; multi-drug resistance ID GROWTH-FACTOR RECEPTOR; POLYMERASE CHAIN-REACTION; TUMOR-SUPPRESSOR GENE; HUMAN COLON-CARCINOMA; ADULT HUMAN KIDNEY; MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; MESSENGER-RNA; ABERRANT EXPRESSION; REFRACTORY LYMPHOMA AB Much remains to be learned about drug resistance in the biology of RCC and its metastases. We measured MDR-1/P-glycoprotein expression in 19 tumor samples from patients with metastatic RCC by RNase protection and quantitative PCR assays. The median level of the 16 tumor metastases was 4.9 (range: 0.10 to 156.2) relative to the level of 10 assigned to a reference cell line, SW620, which has been characterized as expressing a minimum level of MDR-1. Since these levels were lower than expected for RCC, we asked whether the metastases possessed a phenotype different from primary RCC and examined MDR-1 expression in 5 paired cell lines derived from primary and metastatic RCC. In 8/10 lines, MDR-1 expression was >10. Relative to the level in the primary line, MDR-I expression was decreased (3 to 50-fold) in 3 metastatic lines, was increased in 1, and unchanged in 1. MRP mRNA expression was lower in the metastatic Lines while EGFR expression was variable. IC50 values for 6 compounds (including 4 standard agents and one new Phase 1 agent) were determined for the paired lines. Rhodamine and calcein efflux assays were performed as measures of P-glycoprotein and MRP function. Rhodamine efflux correlated with MDR-1 mRNA expression (r = 0.87) and with the IC(50)s (r = 0.60) for paclitaxel in the paired cell Lines. In contrast, calcein efflux did not correlate with MRP expression. Lastly, MDR-1 expression correlated with cytokeratin 8 (CK8) protein levels, a measure of cellular differentiation. In sum, these data suggest renal cell carcinoma (RCC) metastases have altered MDR-1 expression potentially due to altered differentiation relative to the primary tumor. Thus, the drug resistance phenotype of primary RCC tumors may not reflect that of their metastases. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 12N226, Bethesda, MD 20892 USA. NR 36 TC 22 Z9 22 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUL PY 1999 VL 162 IS 1 BP 217 EP 224 DI 10.1097/00005392-199907000-00071 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 204FP UT WOS:000080753700069 PM 10379790 ER PT J AU Rehermann, B AF Rehermann, B TI Cellular immune response to the hepatitis C virus SO JOURNAL OF VIRAL HEPATITIS LA English DT Article; Proceedings Paper CT 2nd Flaviviridae Symposium CY SEP 06, 1998 CL VIENNA, AUSTRIA DE hepatitis C; immune response; cytotoxic T cell ID CYTOTOXIC T-LYMPHOCYTES; NONSTRUCTURAL PROTEIN-3; INFECTED PATIENTS; CELLS; INDUCTION; HELPER; CORE; ANTIGENS; EPITOPES; KILLER AB Hepatitis C virus (HCV) infection is most often clinically inapparent and rarely associated with symptoms of acute hepatitis. Most patients, however, fail to resolve the acute infection and proceed to develop chronic hepatitis with the risk of liver cirrhosis and hepatocellular carcinoma later in life, Since the kinetics of the earliest events of virus-host interaction are likely to determine the outcome of infection, research has focused on the characterization of the strength and kinetics of the antiviral immune response in different stages of disease. The identification of the immunological correlates of viral clearance is pivotal for the development of vaccines and efficient therapies. C1 NIDDK, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. RP Rehermann, B (reprint author), NIDDK, Liver Dis Sect, NIH, 10 Ctr Dr,Bldg 10,Rm 9B16, Bethesda, MD 20892 USA. NR 33 TC 28 Z9 28 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1352-0504 J9 J VIRAL HEPATITIS JI J. Viral Hepatitis PD JUL PY 1999 VL 6 SU 1 BP 31 EP 35 DI 10.1046/j.1365-2893.1999.00008.x PG 5 WC Gastroenterology & Hepatology; Infectious Diseases; Virology SC Gastroenterology & Hepatology; Infectious Diseases; Virology GA 225BT UT WOS:000081936700006 PM 10760032 ER PT J AU Kosalaraksa, P Kavlick, MF Maroun, V Le, R Mitsuya, H AF Kosalaraksa, P Kavlick, MF Maroun, V Le, R Mitsuya, H TI Comparative fitness of multi-dideoxynucleoside-resistant human immunodeficiency virus type 1 (HIV-1) in an in vitro competitive HIV-1 replication assay SO JOURNAL OF VIROLOGY LA English DT Article ID REVERSE-TRANSCRIPTASE INHIBITORS; POL GENE-MUTATIONS; DRUG-RESISTANCE; ANTIRETROVIRAL THERAPY; ZIDOVUDINE RESISTANCE; DISEASE PROGRESSION; COMBINATION THERAPY; NUCLEOSIDE ANALOGS; INFECTED PATIENTS; DNA AB We examined whether human immunodeficiency virus type 1 (HIV-1) fitness was altered upon the acquisition of a set or subset of five mutations (A62V, V75I, F77L, F116Y, and Q151M) in the pol gene, which confers resistance to multiple dideoxynucleosides (MDR), as well as the zidovudine resistance-associated mutation T215Y, using a competitive HIV-1 replication assay in a setting of an HXB2D genetic background. Target H9 cells were exposed to a 50:50 mixture of paired infectious molecular clones, and HIV-1 in the culture supernatant was transmitted to new cultures every 7 to 10 days. The polymerase-encoding region of the virus was sequenced at various time points, and the relative proportion of the two viral populations was determined. In the absence of drugs, the comparative order for replicative fitness was HIV-1(62/75/77/116/151) > HIV-1(77/116/151) > HIV-1(151) > wild-type HIV-1 (HIV-1(wt)) > HIV-1(75/77/116/151) > HIV-1(151/215) > HIV-1(215). In the presence of zidovudine or didanosine, the order was HIV-1(62/75/77/116/151) > HIV-1(77/116/151) > HIV-1(75/77/116/151) > HIV-1(151) > HIV-1(215). HIV-1(215S(TCC)), a putative intermediate infectious clone for HIV-1(151) replicated comparably to HIV-1(wt), while two putative intermediates for HIV-1(151) [HIV-1(151L(CTG)) and HIV-1(151K(AAG))] replicated much less efficiently than HIV-1(wt), and HIV-1(151) suggesting that for HIV-1(151) to develop, two base substitutions are likely to occur concurrently or within a short interval. These data may illustrate the molecular basis by which HIV-1(151) emerges much less frequently than HIV-1(215). The present data also demonstrate that several MDR HIV-1 variants are more fit than HIV-1(wt), in the absence of drugs and that resistance-associated mutations and drug pressure are critical variates for HIV-1 fitness. C1 NCI, Med Branch, Expt Retrovirol Sect,Dept Dev Therapeut, Div Clin Sci,NIH, Bethesda, MD 20892 USA. Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 860, Japan. RP Mitsuya, H (reprint author), NCI, Med Branch, Expt Retrovirol Sect,Dept Dev Therapeut, Div Clin Sci,NIH, Bldg 10,Room 5A11, Bethesda, MD 20892 USA. NR 31 TC 101 Z9 105 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 1999 VL 73 IS 7 BP 5356 EP 5363 PG 8 WC Virology SC Virology GA 205GT UT WOS:000080813500013 PM 10364282 ER PT J AU Lewis, AF Stacy, T Green, WR Taddesse-Heath, L Hartley, JW Speck, NA AF Lewis, AF Stacy, T Green, WR Taddesse-Heath, L Hartley, JW Speck, NA TI Core-binding factor influences the disease specificity of Moloney murine leukemia virus SO JOURNAL OF VIROLOGY LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; FETAL LIVER HEMATOPOIESIS; LONG TERMINAL REPEAT; TRANSCRIPTION FACTOR; NONDEFECTIVE FRIEND; ENHANCER CORE; RUNT DOMAIN; AML1 GENE; IN-VIVO AB The core site in the Moloney murine leukemia virus (Moloney MLV) enhancer was previously shown to be an important determinant of the T-cell disease specificity of the virus. Mutation of the core site resulted in a significant shift in disease specificity of the Moloney virus from: T-cell leukemia to erythroleukemia. We and others have since determined that a protein that binds the core site, one of the core-binding factors (CBF) is highly expressed in thymus and is essential for hematopoiesis. Here we test the hypothesis that CBF plays a critical role in mediating pathogenesis of Moloney MLV in vivo. We measured the affinity of CBE for most core sites found in MLV enhancers, introduced sites with different affinities for CBF into the Moloney MLV genome, and determined the effects of these sites on viral pathogenesis. We found a correlation between CBF affinity and the latent period of disease onset, in that Moloney MLVs with high-affinity CBF binding sites induced leukemia following a shorter latent period than viruses with lower-affinity sites. The T-cell disease specificity of Moloney MLV also appeared to correlate with the affinity of CBF for its binding site. The data support a role for CBF in determining the pathogenic properties of Moloney MLV. C1 Dartmouth Med Sch, Dept Biochem, Hanover, NH 03755 USA. Dartmouth Med Sch, Dept Microbiol, Hanover, NH 03755 USA. NIAID, Viral Dis Lab, Bethesda, MD 20205 USA. RP Speck, NA (reprint author), Dartmouth Med Sch, Dept Biochem, Hanover, NH 03755 USA. FU NCI NIH HHS [R01CA58343, CA75611, R01 CA058343, R01 CA075611, T32 CA009658]; NIAID NIH HHS [N01-AI-45203] NR 86 TC 21 Z9 21 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 1999 VL 73 IS 7 BP 5535 EP 5547 PG 13 WC Virology SC Virology GA 205GT UT WOS:000080813500033 PM 10364302 ER PT J AU Lander, JK Chesebro, B Fan, H AF Lander, JK Chesebro, B Fan, H TI Appearance of mink cell focus-inducing recombinants during in vivo infection by moloney murine leukemia virus (M-MuLV) or the Mo+PyF101 M-MuLV enhancer variant: Implications for sites of generation and roles in leukemogenesis SO JOURNAL OF VIROLOGY LA English DT Article ID LONG TERMINAL REPEAT; ENZYMATIC AMPLIFICATION; MULTISTEP PROCESS; FORMING VIRUSES; FRIEND; SEQUENCES; MICE; DNA; INTERFERENCE; INOCULATION AB One hallmark of murine leukemia virus (MuLV) leukemogenesis in mice is the appearance of env gene recombinants known as mink cell focus-inducing (MCF) viruses. The site(s) of MCF recombinant generation in the animal during Moloney MuLV (M-MuLV) infection is unknown, and the exact roles of MCF viruses in disease induction remain unclear. Previous comparative studies between M-MuLV and an enhancer variant, Mo+PyF101 MuLV, suggested that MCF generation or early propagation might take place in the bone marrow under conditions of efficient leukemogenesis. Moreover, M-MuLV induces disease efficiently following both intraperitoneal (i.p.) and subcutaneous (s.c.) inoculation but leukemogenicity by Mo+PyF101 M-MuLV is efficient following i.p. inoculation but attenuated upon s.c. inoculation. Time course studies of MCF recombinant appearance in the bone marrow, spleen, and thymus of wild-type and Mo+PyF101 M-MuLV i.p.- and s.c.-inoculated mice were carried out by performing focal immunofluorescence assays. Both the route of inoculation and the presence of the PyF101 enhancer sequences affected the patterns of MCF generation or early propagation. The bone marrow was a likely site of MCF recombinant generation and/or early propagation following i.p. inoculation of M-MuLV. On the other hand, when the same virus was inoculated s.c., the primary site of MCF generation appeared to be the thymus. Also, when Mo+PyF101 M-MuLV was inoculated i.p., MCF generation appeared to occur primarily in the thymus. The time course studies indicated that MCF recombinants are not involved in preleukemic changes such as splenic hyperplasia. On the other hand, MCFs were detected in tumors from Mo+PyF101 M-MuLV s.c.-inoculated mice even though they were largely undetectable at preleukemic times. These results support a role for MCF recombinants late in disease induction. C1 Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. Univ Calif Irvine, Inst Canc Res, Irvine, CA 92697 USA. NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Fan, H (reprint author), Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. FU NCI NIH HHS [R01 CA-32455, R01 CA032455, T32 CA 09054, T32 CA009054]; NIGMS NIH HHS [T32 GM 07134] NR 32 TC 10 Z9 10 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 1999 VL 73 IS 7 BP 5671 EP 5680 PG 10 WC Virology SC Virology GA 205GT UT WOS:000080813500048 PM 10364317 ER PT J AU Fearns, R Collins, PL AF Fearns, R Collins, PL TI Role of the M2-1 transcription antitermination protein of respiratory syncytial virus in sequential transcription SO JOURNAL OF VIROLOGY LA English DT Article ID VESICULAR STOMATITIS-VIRUS; MESSENGER-RNA; NUCLEOTIDE-SEQUENCES; ELONGATION-FACTOR; GENE-EXPRESSION; GENOME; CELLS; IDENTIFICATION; REPLICATION; POLYMERASE AB M2-1 protein of human respiratory syncytial virus (RSV) is a transcription antitermination factor that is important fur the efficient synthesis of full-length mRNAs as well as for the synthesis of polycistronic readthrough mRNAs, which are characteristic of nonsegmented negative-strand RNA viruses. The contributions of these effects to RSV sequential transcription were investigated with minigenomes which contained one to five genes which were either foreign marker genes or authentic RSV genes. When evaluated on a promoter-proximal gene, the effect of M2-1 on the synthesis of full-length mRNA was much greater for a long (1,212- or 1,780-nucleotide) gene (up to a 615-fold increase) than for a short (274-nucleotide) gene (less than a 2-fold increase). This was independent of whether the gene contained non-RSV or RSV-specific sequence. Once the polymerase had terminated prematurely, it was unable to reinitiate at a downstream gene. These studies also confirmed that M2-1 enhances the synthesis of polycistronic mRNAs; and that the magnitude of this effect varied greatly among different naturally occurring gene junctions, The synthesis of polycistronic mRNAs, which presumably involves antitermination at the gene-end signal, required a higher level of M2-1 than did the synthesis of the corresponding monocistronic mRNAs. M2-1 did not have a comparable antitermination effect at the junction between the leader region and the first gene, In a minigenome containing the NS1 and NS2 genes in their authentic sequence context, synthesis of full-length NS1 and NS2 mRNAs in the absence of M2-1 was remarkably high (36 and 57%, respectively, of the maximum levels observed in the presence of M2-1), In contrast, synthesis of mRNA from additional downstream genes was highly dependent on M2-1. Thus, RSV has the potential for two transcription programs: one in the absence of M2-1, in which only the NS1 and NS2 genes are transcribed, and one in the presence of M2-1, in which sequential transcription of the complete genome occurs, The dependence on M2-1 for transcription was greater for a gene in the fifth position from the promoter than for one in the third position. This indicates that under conditions where M2-1 is limiting its concentration affects the gradient of transcription. Although M2-1 was found to have profound effects on transcription, it had no effect on replication of any minigenome tested, suggesting that it is not an active participant in RNA replication or regulation of RNA replication. Finally, since a permissive RSV infection is marked by a gradual increase in the intracellular accumulation of viral proteins including M2-1, we examined the relative abundances of various mRNAs during RSV infection for evidence of temporal regulation of transcription. None was found, implying that the availability of M2-1 during a permissive infection is sufficient at all times such that its concentration does not mediate temporal regulation of gene transcription. C1 NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Collins, PL (reprint author), NIAID, Infect Dis Lab, 7 Ctr Dr,MSC 0720, Bethesda, MD 20892 USA. NR 35 TC 115 Z9 121 U1 1 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 1999 VL 73 IS 7 BP 5852 EP 5864 PG 13 WC Virology SC Virology GA 205GT UT WOS:000080813500068 PM 10364337 ER PT J AU Zoeteweij, JP Eyes, ST Orenstein, JM Kawamura, T Wu, LJ Chandran, B Forghani, B Blauvelt, A AF Zoeteweij, JP Eyes, ST Orenstein, JM Kawamura, T Wu, LJ Chandran, B Forghani, B Blauvelt, A TI Identification and rapid quantification of early- and late-lytic human herpesvirus 8 infection in single cells by flow cytometric analysis: Characterization of antiherpesvirus agents SO JOURNAL OF VIROLOGY LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; BLOOD MONONUCLEAR-CELLS; KAPOSIS-SARCOMA; DNA-SEQUENCES; PERIPHERAL-BLOOD; IN-VITRO; HIV-INFECTION; HUMAN-HERPESVIRUS-8; PROTEIN; POLYMERASE AB Human herpesvirus 8 (HHV-8) infection is associated with Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. In this study, me used monoclonal antibodies (MAbs) directed against HHV-8 lytic cycle-associated proteins encoded by open reading frame (ORF) 59 (nuclear PF-8 protein) and ORF K8.1 (viral envelope glycoprotein K8.1 [gpK8.1]) to investigate HHV-8 lytic infection in single cells. Lytically infected cells were labeled with MAbs, stained with fluorescently conjugated secondary Abs, and analyzed by Bow cytometry. A 3-day stimulation of HHV-8-positive PEL cell lines (BCBL-1 and BC-3) with 12-O-tetradecanoylphorbol-13-acetate (30 nM) or n-butyric acid (0.3 mM) maximized the expression of lytic-phase viral proteins and minimized cell toxicity. The absolute number of expressing cells was inducer and cell line dependent. Expression of PF-8 occurred earlier and more frequently tin up to 20% of cells) than did expression of gpK8.1. A subset of PF-8 positive cells (25%) co-expressed,gpK8.1., representing the majority of gpK8.1 expressing cells. Acyclovir, foscarnet, cidofovir, and PMEA reduced the number of cells expressing gpK8.1, but not the number expressing the nonstructural early lytic gene product PF-8. By contrast, alpha interferon (IFN-alpha) and IFN-beta reduced expression of both PF-8 and gpK8.1, implying an overall inhibitory effect on viral gene transcription or translation. In summary, we have characterized and quantified HHV-8 lytic infection in single cells by dual measurement of early- and late-lytic-cycle HHV-8 protein expression. This technique should prove useful for screening of possible antiherpesvirus agents and for detailed phenotypic characterization of HHV-8-infected cells in vitro and in patients with HHV-8-associated diseases. C1 NCI, Dermatol Branch, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Bethesda, MD 20892 USA. George Washington Univ, Dept Pathol, Washington, DC 20037 USA. Calif Dept Hlth Serv, Div Communicable Dis Control, Viral & Rickettsial Dis Lab Branch, Berkeley, CA 94704 USA. Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Kansas City, KS 66160 USA. RP Blauvelt, A (reprint author), NCI, Dermatol Branch, Bldg 10,Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA82056, CA75911, R01 CA075911] NR 41 TC 49 Z9 54 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 1999 VL 73 IS 7 BP 5894 EP 5902 PG 9 WC Virology SC Virology GA 205GT UT WOS:000080813500072 PM 10364341 ER PT J AU Graff, J Richards, OC Swiderek, KM Davis, MT Rusnak, F Harmon, SA Jia, XY Summers, DF Ehrenfeld, E AF Graff, J Richards, OC Swiderek, KM Davis, MT Rusnak, F Harmon, SA Jia, XY Summers, DF Ehrenfeld, E TI Hepatitis A virus capsid protein VP1 has a heterogeneous C terminus SO JOURNAL OF VIROLOGY LA English DT Article ID RECOMBINANT VACCINIA VIRUS; TANDEM MASS-SPECTROMETRY; A VIRUS; 3C PROTEINASE; SUBSTRATE-SPECIFICITY; SUBVIRAL PARTICLES; RNA TRANSCRIPTS; BS-C-1 CELLS; POLYPROTEIN; IDENTIFICATION AB Hepatitis A virus (HAV) encodes a single polyprotein which is posttranslationally processed into the functional structural and nonstructural proteins. Only one protease, viral protease 3C, has been implicated in the nine protein scissions. Processing of the capsid protein precursor region generates a unique intermediate, PX (VP1-2A), which accumulates in infected cells and is assumed to serve as precursor to VP1 found in virions, although the details of this reaction have not been determined. Coexpression in transfected cells of a variety of P1 precursor proteins with viral protease 3C demonstrated efficient production of PX, as well as VP0 and VP3; however, no mature VP1 protein was detected. To identify the C-terminal amino acid residue of HAV VPI, we performed peptide sequence analysis by protease-catalyzed [O-18]H2O incorporation followed by liquid chromatography ion-trap microspray tandem mass spectrometry of HAV VP1 isolated from purified virions. Two different cell culture-adapted isolates of HAV, strains HM175pE and HM175p35, were used for these analyses. VP1 preparations from both virus isolates contained heterogeneous C termini. The predominant C-terminal amino acid in both virus preparations was VP1-Ser274, which is located N terminal to a methionine residue in VP1-2A. In addition, the analysis of HM175pE recovered smaller amounts of amino acids VP1-Glu273 and VP1-Thr272. In the case of HM175p35, which contains valine at amino acid position VP1-273, VP1-Thr272 was found in addition to VP1-Ser274. The data suggest that HAV 3C is not the protease responsible for generation of the VP1 C terminus. We propose the involvement of host cell protease(s) in the production of HAV VP1. C1 Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92697 USA. Inst City Hope, Beckman Res Inst, Duarte, CA 91010 USA. RP Graff, J (reprint author), NIAID, NIH, LID, Mol Hepatol Sect, Bldg 7,Room 200,7 Ctr Dr, Bethesda, MD 20892 USA. FU NCI NIH HHS [P30 CA033572, CA33572]; NCRR NIH HHS [R01 RR006217]; NIAID NIH HHS [AI17386, AI26350] NR 47 TC 33 Z9 34 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 1999 VL 73 IS 7 BP 6015 EP 6023 PG 9 WC Virology SC Virology GA 205GT UT WOS:000080813500084 PM 10364353 ER PT J AU Munoz-Barroso, I Salzwedel, K Hunter, E Blumenthal, R AF Munoz-Barroso, I Salzwedel, K Hunter, E Blumenthal, R TI Role of the membrane-proximal domain in the initial stages of human immunodeficiency virus type 1 envelope glycoprotein-mediated membrane fusion SO JOURNAL OF VIROLOGY LA English DT Article ID INFLUENZA HEMAGGLUTININ; ATOMIC-STRUCTURE; CELL-FUSION; HIV-1 GP41; PEPTIDE; DILATION; GENE AB We have examined mutations in the ectodomain of the human immunodeficiency virus type 1 transmembrane glycoprotein gp41 within a region immediately adjacent to the membrane-spanning domain for their effect on the outcome of the fusion cascade. Using the recently developed three-color assay (I, Munoz-Barroso, S. Durell, K, Sakaguchi, E. Appella, and R, Blumenthal, J. Cell Biol, 140:315-323, 1998), we have assessed the ability of the mutant gp41s to transfer lipid and small solutes from susceptible target cells to the gp120-gp41-expressing cells. The results were compared with the syncytium-inducing capabilities of these gp41 mutants. Two mutant proteins were incapable of mediating both dye transfer and syncytium formation. Two mutant proteins mediated dye transfer but were less effective at inducing syncytium formation than was wild-type gp41. The most interesting mutant proteins were those that were not capable of inducing syncytium formation but still mediated dye transfer, indicating that the fusion cascade was blocked beyond the stage of small fusion pore formation. Fusion mediated by the mutant gp41s was inhibited by the peptides DP178 and C34. C1 NCI, Lab Expt & Computat Biol, Div Basic Sci, NIH, Frederick, MD 21701 USA. Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. RP Blumenthal, R (reprint author), NCI, Frederick Canc Res & Dev Ctr, Miller Dr,POB B,Bldg 469,Rm 213, Frederick, MD 21702 USA. NR 15 TC 164 Z9 166 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 1999 VL 73 IS 7 BP 6089 EP 6092 PG 4 WC Virology SC Virology GA 205GT UT WOS:000080813500094 PM 10364363 ER PT J AU von Gegerfelt, AS Liska, V Ray, NB McClure, HM Ruprecht, RM Felber, BK AF von Gegerfelt, AS Liska, V Ray, NB McClure, HM Ruprecht, RM Felber, BK TI Persistent infection of rhesus macaques by the Rev-independent Nef(-) simian immunodeficiency virus SIVmac239: Replication kinetics and genomic stability SO JOURNAL OF VIROLOGY LA English DT Article ID CONSTITUTIVE TRANSPORT ELEMENT; POLYMERASE CHAIN-REACTION; MESSENGER-RNA EXPORT; POSTTRANSCRIPTIONAL REGULATION; RETROVIRUS TYPE-1; VIRAL LOAD; MONKEYS; DISEASE; SIV; PATHOGENICITY AB We generated previously a Nef(-), replication-competent clone of SIVmac239 in which the Rev protein and the Rev-responsive element were replaced by the constitutive transport element (CTE) of simian retrovirus type 1 (A. S. von Gegerfelt and B. K. Feliber, Virology 232:291-299, 1997). In the present report, we show that this virus was able to infect and replicate in rhesus macaques. The Rev-independent Nef(-) simian immunodeficiency virus induced a persistent humoral immune response in all monkeys, although viral loads were very low. Upon propagation in the monkeys, the genotype remained stable and the virus retained its in vitro growth characteristics. The infected monkeys showed normal hematological values and no signs of disease at more than 18 months post-virus exposure. Therefore, replacement of the essential Rev regulation by the CTE generated a virus variant that retained its replicative capacity both in vitro and in vivo, albeit at low levels. C1 NCI, ABL Basic Res Program, FCRDC, Human Retrovirus Pathogenesis Grp, Frederick, MD 21702 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Emory Univ, Yerkes Reg Primate Res Ctr, Atlanta, GA 30322 USA. RP Felber, BK (reprint author), NCI, ABL Basic Res Program, FCRDC, Human Retrovirus Pathogenesis Grp, Bldg 535,Rm 110, Frederick, MD 21702 USA. FU NCRR NIH HHS [RR-00165, P51 RR000165]; PHS HHS [R01 A135533-S1] NR 30 TC 13 Z9 13 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 1999 VL 73 IS 7 BP 6159 EP 6165 PG 7 WC Virology SC Virology GA 205GT UT WOS:000080813500107 PM 10364376 ER PT J AU Garnett, N DeHaven, WR AF Garnett, N DeHaven, WR TI A word from OPBR and USDA SO LAB ANIMAL LA English DT Editorial Material C1 NIH, OPRR, Div Anim Welf, Bethesda, MD 20892 USA. USDA, APHIS, Washington, DC USA. RP Garnett, N (reprint author), NIH, OPRR, Div Anim Welf, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD JUL-AUG PY 1999 VL 28 IS 7 BP 21 EP 21 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 215FN UT WOS:000081371400008 ER PT J AU Blagosklonny, MV Chuman, Y Bergan, RC Fojo, T AF Blagosklonny, MV Chuman, Y Bergan, RC Fojo, T TI Mitogen-activated protein kinase pathway is dispensable for microtubule-active drug-induced Raf-1/Bcl-2 phosphorylation and apoptosis in leukemia cells SO LEUKEMIA LA English DT Article DE leukemia; apoptosis; Raf-1; Bcl-2; MAPK; paclitaxel ID TAXOL-INDUCED APOPTOSIS; SIGNAL-TRANSDUCTION; TYROSINE KINASE; GROWTH ARREST; BCL-2 PROTEIN; PHORBOL ESTER; MITOTIC CELLS; CANCER-CELLS; CYCLE ARREST; RAF-1 AB Raf-1 activation and Bcl-2 hyperphosphorylation following treatment with paclitaxel (Taxol) or other microtubule-active drugs is associated with mitotic arrest. Here we show that microtubule-active drugs do not activate the mitogen-activated protein kinase (MAPK) pathway in leukemia cells. PD98059, a MEK inhibitor, and SB202190, a p38 MAP kinase inhibitor, do not abrogate Bcl-2 phosphorylation nor apoptosis. Simultaneously with PARP cleavage, paclitaxel induces cleavage of Bcl-2 protein yielding a potentially pro-apoptotic 22 kDa product. In comparison, the stimulation of Raf-1 by phorbol ester (TPA) activates the MAPK pathway, causes MAPK-dependent p21(WAF1/CIP1) induction, Rb dephosphorylation and growth arrest without Bcl-2 phosphorylation or apoptosis. Like TPA, cAMP induces p21(WAF1/CIP1) but does not cause Bcl-2 phosphorylation. MEKK1 and Ras, upstream activators of JNK and ERK MAPK, also fail to induce Bcl-2 hyperphosphorylation. Although Lck tyrosine kinase has been recently implicated in Raf-1 activation during mitotic arrest, microtubule-active drugs induce Raf-1/Bcl-2 hyperphosphorylation and apoptosis in a Lck-deficient Jurkat cells. Therefore, microtubule-active drugs induce apoptosis which is associated with Raf-1 and Bcl-2 phosphorylation and Bcl-2 cleavage but is independent of the MAPK pathway. In contrast, TPA-activated MAPK pathway causes p21(WAF1/CIP1)-dependent growth arrest without apoptosis. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Blagosklonny, MV (reprint author), NCI, Med Branch, NIH, Bldg 10,R 12N226, Bethesda, MD 20892 USA. NR 62 TC 74 Z9 76 U1 0 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD JUL PY 1999 VL 13 IS 7 BP 1028 EP 1036 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 220GA UT WOS:000081655300007 PM 10400418 ER PT J AU Charlton, M Seaberg, E AF Charlton, M Seaberg, E TI Impact of immunosuppression and acute rejection on recurrence of hepatitis C: Results of the National Institute of Diabetes and Digestive and Kidney Diseases liver transplantation database SO LIVER TRANSPLANTATION AND SURGERY LA English DT Article; Proceedings Paper CT Symposium on Hepatic Allograft Rejection and Evolving Immunosuppression Strategies, at the AASLD/ILTS Transplant Course CY NOV 08, 1998 CL CHICAGO, ILLINOIS ID VIRUS-RNA LEVELS; AFFECTS AMINOTRANSFERASE ACTIVITY; PREDNISONE THERAPY; VIRAL-INFECTION; RECIPIENTS; CYCLOSPORINE; INTERFERON; TACROLIMUS; INJURY AB Whereas the impact of early (first 6 postoperative weeks) acute cellular rejection on patient survival among liver transplant recipients as a whole has been reported to be favorable, we hypothesized treatment for acute cellular rejection may have differing impacts on patient and graft survival in hepatitis C virus (HCV)-infected and HCV-negative transplant recipients. We studied the impact of immunosuppression and rejection on patient and graft survival among the 166 HCV-infected and 602 HCV-negative transplant recipients enrolled onto the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. All data were collected prospectively. The association of early acute cellular rejection with mortality was determined using a Cox proportional hazards model with a time-dependent covariate. Median follow-up was 5.0 years for HCV-infected and 5.2 years for HCV-negative transplant recipients. HCV-infected transplant recipients experienced similar frequencies of acute cellular and steroid-resistant rejection as patients undergoing liver transplantation for most other indications. The mortality risk was significantly increased (relative risk = 2.4; P = .03) for HCV-infected transplant recipients who developed early acute cellular rejection compared with HCV-negative transplant recipients. None of the HCV-infected transplant recipients developed allograft failure secondary to chronic rejection. The choice of calcineurin inhibitor did not affect posttransplantation outcomes. Early acute cellular rejection occurs at similar frequencies in HCV-infected and HCV-negative transplant recipients. Although an episode of early acute cellular rejection is associated with a lower cumulative mortality among HCV-negative transplant recipients, the opposite is; true for HCV-infected transplant recipients, who experience an increased risk for mortality after an episode of early acute cellular rejection. The adverse impact of early acute cellular rejection on patient survival should be considered in developing primary immunosuppression and acute cellular rejection treatment protocols for HCV-infected transplant recipients, Copyright (C) 1999 by the American Association for the Study of Liver Diseases. C1 NIDDKD, Bethesda, MD 20892 USA. RP Charlton, M (reprint author), Mayo Clin, Div Gastroenterol & Hepatol, 200 1st St,SW, Rochester, MN 55905 USA. FU NCRR NIH HHS [RR00585]; NIDDK NIH HHS [R01 DK 434238] NR 28 TC 122 Z9 122 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 1074-3022 J9 LIVER TRANSPLANT SUR JI Liver Transplant. Surg. PD JUL PY 1999 VL 5 IS 4 SU 1 BP S107 EP S114 PG 8 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA 218GN UT WOS:000081545000012 PM 10431024 ER PT J AU Corn, M AF Corn, M TI Show me the money: Funding informatics research SO M D COMPUTING 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 2 Z9 2 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0724-6811 J9 M D COMPUT JI M D Comput. PD JUL-AUG PY 1999 VL 16 IS 4 BP 17 EP + PG 3 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 236AU UT WOS:000082576700013 PM 10507230 ER PT J AU Arai, AE Gaither, CC Epstein, FH Balaban, RS Wolff, SD AF Arai, AE Gaither, CC Epstein, FH Balaban, RS Wolff, SD TI Myocardial velocity gradient imaging by phase contrast MRI with application to regional function in myocardial ischemia SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE magnetic resonance imaging; systole; diastole; mechanics; myocardial contraction; myocardial ischemia; ventricles ID LEFT-VENTRICULAR FUNCTION; MAGNETIC-RESONANCE; OPTICAL-FLOW; MOTION ANALYSIS; CARDIAC MOTION; HUMAN-HEART; IMAGES; VALIDATION; TRACKING; REST AB Velocity-encoded phase contrast magnetic resonance imaging (MRI) has the potential to quantify regional myocardial contractile function with a sensitivity to motion comparable to implanted ultrasonic crystals. An MRI sequence and postprocessing algorithm were developed to measure myocardial velocity gradients on a 1.5 T MRI scanner. These methods were validated on a rotating phantom and applied to dogs before (n = 11) and during prolonged coronary occlusion (n = 5). In phantom validation studies, the average absolute error corresponded to motion equivalent to 0.03 +/- 0.04 mm (mean +/- SD) during the repetition time of the experiment. Rigid body corrections during post-processing significantly simplified the interpretation of myocardial velocity vectors. In vivo, rigid body motion contributes substantially to the recorded myocardial velocities in systole and diastole and can give the false impression of regional wall motion abnormalities. After rigid body correction, normal systolic and diastolic velocity vectors in short-axis views of the left ventricle were primarily directed toward the center of the left ventricle. Transmural radial strain rate was 2.0 +/- 0.6 sec(-1) during systole and -3.6 +/- 1.1 sec(-1) during early diastole in normal canine hearts. Ischemic myocardium was easily discriminated from normal left ventricle by velocity-encoded phase contrast MRI both qualitatively and quantitatively (P < 0.01 in systole and P < 0.05 in early diastole). Although the myocardial velocity images have a spatial resolution on the order of a millimeter, the velocity encoding describes the mechanical consequences of focal myocardial ischemia with sensitivity to submillimeter displacement of the pixels. The three-dimensional nature of velocity-encoded MRI is particularly well suited to the study of the complex motion of the heart in vivo. Magn Reson Med 42:98-109, 1999. (C) 1999 Wiley-Liss, Inc. C1 NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Div Cardiol, Portland, OR 97201 USA. GE, Med Syst, Appl Sci Lab, Milwaukee, WI 53201 USA. RP Arai, AE (reprint author), NHLBI, Cardiac Energet Lab, NIH, Bldg 10,Room B1D161,MSC 1061,10 Ctr Dr, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [K08-HL03135] NR 42 TC 60 Z9 60 U1 1 U2 4 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUL PY 1999 VL 42 IS 1 BP 98 EP 109 DI 10.1002/(SICI)1522-2594(199907)42:1<98::AID-MRM14>3.0.CO;2-H PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 216GV UT WOS:000081433800014 PM 10398955 ER PT J AU Finelli, P Stanyon, R Plesker, R Ferguson-Smith, MA O'Brien, PCM Wienberg, J AF Finelli, P Stanyon, R Plesker, R Ferguson-Smith, MA O'Brien, PCM Wienberg, J TI Reciprocal chromosome painting shows that the great difference in diploid number between human and African green monkey is mostly due to non-Robertsonian fissions SO MAMMALIAN GENOME LA English DT Article ID IN-SITU HYBRIDIZATION; INSITU SUPPRESSION HYBRIDIZATION; CERCOPITHECUS-AETHIOPS; GENOMIC REORGANIZATION; DNA LIBRARIES; REARRANGEMENTS; TRANSLOCATIONS; EVOLUTION; PHYLOGENY; METAPHASE AB We used reciprocal chromosome painting with both African green monkey (C. aethiops) and human chromosome specific DNA probes to delineate homologous regions in the two species. Probes were derived by fluorescence-activated chromosome flow sorting and then were reciprocally hybridized to metaphase spreads of each species. Segments in the size range of a single chromosome band were identified, demonstrating the sensitivity of the approach when comparing species that diverged more than 20 million years ago. Outgroup analysis shows that the great difference in diploid numbers between the African green monkey (2n = 60) and humans (2n = 46) is mainly owing to fissions, and the direction of change is towards increasing diploid numbers. However, most break points apparently lie outside of the centromere regions, suggesting that the changes were not solely Robertsonian as has been previously assumed. No reciprocal translocations have occurred in the phylogenetic lines leading to humans or African green monkeys. The primate paints established here are a valuable tool to establish interspecies homology, to define rearrangements, and to determine the mechanisms of chromosomal evolution in primate species. C1 NCI, Lab Genom Divers, Frederick Canc Res & Dev Ctr, NIH, Frederick, MD 21702 USA. Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. Paul Ehrlich Inst, Frankfurt, Germany. RP Wienberg, J (reprint author), NCI, Lab Genom Divers, Frederick Canc Res & Dev Ctr, NIH, Bldg 560, Frederick, MD 21702 USA. RI Finelli, Palma/A-3578-2016; OI Finelli, Palma/0000-0001-8464-6906; Stanyon, Roscoe/0000-0002-7229-1092 NR 32 TC 41 Z9 41 U1 1 U2 2 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD JUL PY 1999 VL 10 IS 7 BP 713 EP 718 DI 10.1007/s003359901077 PG 6 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 211FL UT WOS:000081149800011 PM 10384046 ER PT J AU Southard-Smith, EM Collins, JE Ellison, JS Smith, KJ Baxevanis, AD Touchman, JW Green, ED Dunham, I Pavan, WJ AF Southard-Smith, EM Collins, JE Ellison, JS Smith, KJ Baxevanis, AD Touchman, JW Green, ED Dunham, I Pavan, WJ TI Comparative analyses of the Dominant megacolon-SOX10 genomic interval in mouse and human SO MAMMALIAN GENOME LA English DT Article ID COMPREHENSIVE GENETIC-MAP; SEQUENCE; DOM; CHROMOSOME-15; CONSERVATION; LOCUS; CELLS C1 Natl Human Genome Res Inst, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. Sanger Ctr, Cambridge CB10 1SA, England. Natl Human Genome Res Inst, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Pavan, WJ (reprint author), Natl Human Genome Res Inst, Genet Dis Res Branch, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. RI Southard-Smith, Michelle/C-3488-2012 FU Wellcome Trust NR 22 TC 10 Z9 10 U1 1 U2 3 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD JUL PY 1999 VL 10 IS 7 BP 744 EP 749 DI 10.1007/s003359901083 PG 6 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 211FL UT WOS:000081149800017 PM 10384052 ER PT J AU Thomas, JW Lee-Lin, SQ Green, ED AF Thomas, JW Lee-Lin, SQ Green, ED TI Human-mouse comparative mapping of the genomic region containing CDK6: localization of an evolutionary breakpoint SO MAMMALIAN GENOME LA English DT Article ID CDC2-RELATED PROTEIN-KINASES; YAC CONTIG; MAP; DNA C1 Natl Human Genome Res Inst, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Green, ED (reprint author), Natl Human Genome Res Inst, Genome Technol Branch, NIH, Bldg 49,Room 2A08, Bethesda, MD 20892 USA. NR 16 TC 13 Z9 15 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD JUL PY 1999 VL 10 IS 7 BP 764 EP 767 DI 10.1007/s003359901088 PG 4 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 211FL UT WOS:000081149800022 PM 10384057 ER PT J AU Vogel, AM Gerster, T AF Vogel, AM Gerster, T TI Promoter activity of the zebrafish bhikhari retroelement requires an intact activin signaling pathway SO MECHANISMS OF DEVELOPMENT LA English DT Article DE mesoderm induction; bhikhari; activin signaling pathway; retrotransposon; fibroblast growth factor ID TGF-BETA; MESODERM INDUCTION; NO TAIL; XENOPUS-EMBRYOS; DNA-BINDING; WILD-TYPE; EXPRESSION; GENE; SPADETAIL; TRANSCRIPTION AB We have investigated mesoderm induction in zebrafish employing the zebrafish LTR-retroelement bhikhari (bik). bik elements are transcribed in all early mesendodermal cells. This expression pattern is generated by a promoter located in the U3 region of the LTR. We show that bik is activated through the activin/Vg1 signaling pathway in an immediate early fashion. This activation critically depends on a sequence motif that occurs among others also in the Xenopus Mix2 activin response element (ARE). It has been shown that the Mix2 ARE binds FAST-1, which complexes with Smad proteins to form a multi-protein complex. We confirm that also the bik ARE can be bound by FAST-1 in vitro. In animal cap experiments we demonstrate that this binding site is required for activin-induced transcriptional activation mediated by FAST and Smad-type proteins. (C) 1999 Elsevier Science ireland Ltd. All rights reserved. C1 Univ Basel, Bioctr, CH-4056 Basel, Switzerland. NICHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Gerster, T (reprint author), Univ Basel, Bioctr, Klingelbergstr 70, CH-4056 Basel, Switzerland. NR 50 TC 21 Z9 21 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD JUL PY 1999 VL 85 IS 1-2 BP 133 EP 146 DI 10.1016/S0925-4773(99)00104-5 PG 14 WC Developmental Biology SC Developmental Biology GA 223AW UT WOS:000081818400013 PM 10415354 ER PT J AU Bertuzzi, S Porter, FD Pitts, A Kumara, M Agulnik, A Wassif, C Westphal, H AF Bertuzzi, S Porter, FD Pitts, A Kumara, M Agulnik, A Wassif, C Westphal, H TI Characterization of Lhx9, a novel LIM/homeobox gene expressed by the pioneer neurons in the mouse cerebral cortex (vol 81, pg 193, 1999) SO MECHANISMS OF DEVELOPMENT LA English DT Correction C1 NICHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD USA. NICHD, Unit Mol Dysmorphol, NIH, Hereditable Disorders Branch, Bethesda, MD USA. RP Bertuzzi, S (reprint author), Salk Inst Biol Studies, Mol Nuerobiol Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. NR 1 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD JUL PY 1999 VL 85 IS 1-2 BP 219 EP 219 PG 1 WC Developmental Biology SC Developmental Biology GA 223AW UT WOS:000081818400026 ER PT J AU Swaminathan, N Lopez-Berestein, G Rudikoff, S AF Swaminathan, N Lopez-Berestein, G Rudikoff, S TI Assessment of all-trans retinoic acid (ATRA) efficacy as a single agent in primary lymphoid neoplasia SO MEDICAL ONCOLOGY LA English DT Article DE all-trans retinoic acid; plasma cell tumors; multiple myeloma ID ACUTE PROMYELOCYTIC LEUKEMIA; HUMAN MYELOMA CELLS; ADVANCED MULTIPLE-MYELOMA; PLASMA-CELL; MURINE PLASMACYTOMAGENESIS; MYELODYSPLASTIC SYNDROMES; DIFFERENTIATION THERAPY; INTERFERON-ALPHA; IN-VITRO; V-MYC AB All-trans retinoic acid (ATRA) is currently widely used in the therapy of acute promyelocytic leukemia and is being tested in vitro and in vivo on several other malignancies. Previously ATRA has been shown to inhibit the growth in vitro, of established human myeloma cell lines as well as cultured primary myeloma cells from patients. ATRA acts by down-regulating IL-6-receptor-alpha or gp130 on the surface of the myeloma cells. However, despite its in vitro effects on myeloma cells, ATRA therapy on advanced stage multiple myeloma (MM) patients has so far largely been ineffective. In current studies, we have assessed the efficacy of ATRA therapy against primary murine plasma cell tumors, which are an animal model for human MM, These tumors are induced at about 50% incidence in pristane-primed BALB/c mice by injection of v-raf/v-myc- containing retroviruses and are IL-6 dependent. Using this animal model, we assessed the effect of ATRA as a therapeutic agent against primary tumors at two early time points in disease development. ATRA was administered in liposomal vesicles (ATRAGEN(R)), since liposomal-ATRA has been shown to circumvent clearance mechanisms by hepatic microsomes, which normally occur with free ATRA. In addition, ATRAGEN(R) was previously shown to be less toxic in mice than free ATRA, ATRAGEN(R) was administered beginning on day 25 or day 45 after virus injection and continued twice weekly for 8-11 weeks. ATRAGEN(R) administration begun at either time point did not alter the incidence or the latency of plasma cell tumors compared with control animals. These results suggest that ATRA may not be an effective sole therapy against early MM. C1 NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Div Med, Houston, TX 77030 USA. RP Rudikoff, S (reprint author), NCI, Cellular & Mol Biol Lab, NIH, Bldg 37,Room ID08, Bethesda, MD 20892 USA. NR 50 TC 6 Z9 6 U1 1 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0736-0118 J9 MED ONCOL JI Med. Oncol. PD JUL PY 1999 VL 16 IS 2 BP 119 EP 128 DI 10.1007/BF02785845 PG 10 WC Oncology SC Oncology GA 217TH UT WOS:000081514700007 PM 10456660 ER PT J AU Hoque, ATMS Panyutin, IG Baum, BJ AF Hoque, ATMS Panyutin, IG Baum, BJ TI Use of tripler-forming oligonucleotides and adenoviral constructs for studying the regulation of gene expression SO METHODS-A COMPANION TO METHODS IN ENZYMOLOGY LA English DT Article ID POLYLYSINE-DNA COMPLEXES; PLASMID DNA; IN-VITRO; EPITHELIAL-CELLS; DELIVERY; EFFICIENCY; POLYETHYLENIMINE; VIVO; AQUAPORIN-5; INHIBITION AB Short synthetic homopyrimidine- or homopurine-rich oligonucleotides can form sequence-specific triplexes with corresponding homopurine- homopyrimidine sites on duplex DNA and block transcription of a target gene in vitro. Such tripler-forming oligonucleotides (TFOs) can be rationally designed to target homopurine/homopyrimidine sequences that are often found in eukaryotic genes and thus used to modulate the expression of these genes. The antigene strategy using TFOs has been successfully applied to a number of genes in vitro. In this article we describe methods used in applying this antigene approach to the rat aquaporin 5 (rAQP5) gene. We specifically focus on the selection of TFOs based on the sequence of the target gene and on a novel method employing adenoviruses for delivery of TFOs to cells in vitro. C1 Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Nucl Med, Bethesda, MD 20892 USA. RP Hoque, ATMS (reprint author), Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, Bethesda, MD 20892 USA. NR 36 TC 2 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD JUL PY 1999 VL 18 IS 3 BP 266 EP 272 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 221XF UT WOS:000081752300004 ER PT J AU Holcomb, WF AF Holcomb, WF TI Humanity and radiation: The good, the bad, and the unusual SO MILITARY MEDICINE LA English DT Article AB Radiation has permeated the universe since time began, People disagree widely about the merits and dangers of nuclear technology. Radiation is often associated in the minds of people with bombs, fallout, destruction, and death rather than with the many benefits of nuclear technology that are present in our daily lives. Rarely do individuals focus on the medical applications of radiation and the fact that nuclear technology saves lives. Over the years, accidents have happened in the nuclear industry; some have produced fatalities, but most proved to be a major source of concern only to the local populace. Since the discovery of naturally occurring radium and uranium and the advent of synthetic radionuclides, a number of consumer products have used radiation, some of which were beneficial and some which were of no benefit at all. C1 NIH, Radiat Safety Branch, Radiat Safety Training Unit, Bethesda, MD 20892 USA. RP Holcomb, WF (reprint author), NIH, Radiat Safety Branch, Radiat Safety Training Unit, Bldg 10, Bethesda, MD 20892 USA. NR 37 TC 0 Z9 0 U1 0 U2 1 PU ASSN MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 J9 MIL MED JI Milit. Med. PD JUL PY 1999 VL 164 IS 7 BP 520 EP 525 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 215LV UT WOS:000081383900019 PM 10414069 ER PT J AU Anborgh, PH Qian, XL Papageorge, AG Vass, WC DeClue, JE Lowy, DR AF Anborgh, PH Qian, XL Papageorge, AG Vass, WC DeClue, JE Lowy, DR TI Ras-specific exchange factor GRF: Oligomerization through its Dbl homology domain and calcium-dependent activation of Raf SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NUCLEOTIDE-RELEASING FACTOR; SACCHAROMYCES-CEREVISIAE; SEVENLESS PROTEIN; KINASE CASCADE; IMPRINTED GENE; IDENTIFICATION; PHOSPHORYLATION; DIMERIZATION; PLECKSTRIN; EXPRESSION AB The full-length versions of the Ras-specific exchange factors Ras-GRF1 (GRF1) and Ras-GRF2 (GRF2), which are expressed in brain and a restricted number of other organs, possess an ionomycin-dependent activation of Erk mitogen-activated protein kinase activity in 293T cells (C. L. Farnsworth et al., Nature 376:524-527, 1995; N. P. Fam et al., Mel. Cell. Biol. 17:1396-1406, 1996). Each GRF protein contains a Dbl homology (DH) domain. A yeast two hybrid screen was used to identify polypeptides that associate with the DH domain of GRF1. In this screen, a positive cDNA clone from a human brain cDNA library was isolated which consisted of the GRF2 DH domain and its adjacent ilimaquinone domain. Deletion analysis verified that the two-hybrid interaction required only the DH domains, and mutation of Leu-263 to Gln (L263Q) in the N terminus of the GRF1 DH domain abolished the two-hybrid interaction, while a cluster of more C-terminally located mutations in the DH domain did not eliminate the interaction. Oligomers between GRF1 and GRF2 were detected in a rat brain extract, and forced expression of GRF1 and GRF2 in cultured mammalian cells formed homo- and hetero-oligomers. Introduction of the L263Q mutation in GRF1 led to a protein that was deficient in oligomer formation, while GRF1 containing the DH cluster mutations formed homo-oligomers with an efficiency similar to that of wild type. Compared to wild-type GRF1, the focus forming activity on NIH 3T3 cells of the GRF1 DH cluster mutant was reduced, while the L263Q mutant was inactive. Both mutants were impaired in their ability to mediate ionomycin-dependent Erk activity in 293T cells. In the absence of ionomycin, 293T cells expressing,wild-type GRF1 contained much higher levels of Ras-GTP than control cells; the increase in Erk activity induced by ionomycin in the GRF1-expressing cells also induced a concomitant increase in Raf kinase activity, but without a further increase in the level Ras-GTP. We conclude that GRF1 and GRF2 can form homo- and hetero-oligomers via their DH domains, that mutational inactivation of oligomer formation by GRF1 is associated with impaired biological and signaling activities, and that in 293T cells GRF1 mediates at least two pathways for Raf activation: one a constitutive signal that is mainly Ras-dependent, and one an ionomycin-induced signal that cooperates with the constitutive signal without further augmenting the level of GTP-Ras. C1 NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Lowy, DR (reprint author), NCI, Cellular Oncol Lab, Bldg 36,Rm 1D-32, Bethesda, MD 20892 USA. NR 55 TC 60 Z9 68 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 1999 VL 19 IS 7 BP 4611 EP 4622 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 207TR UT WOS:000080952300008 PM 10373510 ER PT J AU Howcroft, TK Murphy, C Weissman, JD Huber, SJ Sawadogo, M Singer, DS AF Howcroft, TK Murphy, C Weissman, JD Huber, SJ Sawadogo, M Singer, DS TI Upstream stimulatory factor regulates major histocompatibility complex class I gene expression: the U2 Delta E4 splice variant abrogates E-box activity SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANSCRIPTION FACTOR USF; LOOP-HELIX PROTEINS; SINGLE AMINO-ACID; DNA-BINDING; LATE PROMOTER; TRANSGENIC MICE; ELEMENTS; FAMILY; IDENTIFICATION; SEQUENCE AB The tissue-specific expression of major histocompatibility complex class I genes is determined by a series of upstream regulatory elements, many of which remain ill defined. We now report that a distal E-box element, located between bp -309 and -314 upstream of transcription initiation, acts as a cell type-specific enhancer of class I promoter activity. The class I E box is very active in a neuroblastoma cell line, CHP-126, but is relatively inactive in the HeLa epithelial cell line. The basic helix-loop-helix leucine zipper proteins upstream stimulatory factor 1 (USF1) and USF2 were shown to specifically recognize the class I E box, resulting in the activation of the downstream promoter. Fine mapping of USF1 and USF2 amino-terminal functional domains revealed differences in their abilities to activate the class I E box. Whereas USF1 contained only an extended activation domain, USF2 contained both an activation domain and a negative regulatory region. Surprisingly, the naturally occurring splice variant of USF2 lacking the exon 4 domain, U2 Delta E4, acted as a dominant-negative regulator of USF-mediated activation of the class I promoter. This latter activity is in sharp contrast to the known ability of U2 Delta E4 to activate the adenovirus major late promoter. Class I E-box function is correlated with the relative amount of U2 Delta E4 in a cell, leading to the proposal that U2 Delta E4 modulates class I E-box activity and may represent one mechanism to fine-tune class I expression in various tissues. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. RP Howcroft, TK (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B-17,10 Ctr Dr MSC 1360, Bethesda, MD 20892 USA. NR 43 TC 28 Z9 28 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 1999 VL 19 IS 7 BP 4788 EP 4797 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 207TR UT WOS:000080952300026 PM 10373528 ER PT J AU Borde, V Wu, TC Lichten, M AF Borde, V Wu, TC Lichten, M TI Use of a recombination reporter insert to define meiotic recombination domains on chromosome III of Saccharomyces cerevisiae SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID DOUBLE-STRAND BREAKS; NUCLEASE-HYPERSENSITIVE SITES; CHROMATIN STRUCTURE; TOPOISOMERASE-II; HOT-SPOT; GENE CONVERSION; DNA-REPLICATION; YEAST; MEIOSIS; NONDISJUNCTION AB In Saccharomyces cerevisiae, meiotic recombination is initiated by DNA double-strand breaks (DSBs). DSBs usually occur in intergenic regions that display nuclease hypersensitivity in digests of chromatin. DSBs are distributed nonuniformly across chromosomes; on chromosome III, DSBs are concentrated in two "hot" regions, one in each chromosome arm. DSBs occur rarely in regions within about 40 kb of each telomere and in an 80-kb region in the center of the chromosome, just to the right of the centromere. We used recombination reporter inserts containing arg4 mutant alleles to show that the "cold" properties of the central DSB-deficient region are imposed on DNA inserted in the region. Cold region inserts display DSB and recombination frequencies that are substantially less than those seen with similar inserts in flanking hot regions. This occurs without apparent change in chromatin structure, as the same pattern and level of DNase I hypersensitivity is seen in chromatin of hot and cold region inserts. These data are consistent with the suggestion that features of higher-order chromosome structure or chromosome dynamics act in a target sequence-independent manner to control where recombination events initiate during meiosis. C1 NCI, Biochem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP NCI, Biochem Lab, Div Basic Sci, NIH, Bldg 37 Room 4C03,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. EM lichten@helix.nih.gov RI Borde, Valerie/G-5228-2012; Lichten, Michael/C-5795-2013 OI Lichten, Michael/0000-0001-9707-2956 NR 72 TC 73 Z9 74 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 1999 VL 19 IS 7 BP 4832 EP 4842 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 207TR UT WOS:000080952300031 PM 10373533 ER PT J AU Cooper, MP Balajee, AS Bohr, VA AF Cooper, MP Balajee, AS Bohr, VA TI The C-terminal domain of p21 inhibits nucleotide excision repair in vitro and in vivo SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID DEPENDENT KINASE INHIBITOR; CELL NUCLEAR ANTIGEN; DNA-REPLICATION; STRAND SYNTHESIS; BINDING DOMAINS; PCNA; PROTEIN; CDK; DAMAGE; SITES AB The protein p21(Cip1,) (Waf1,) (Sdi1) is a potent inhibitor of cyclin-dependent kinases (CDKs). p21 can also block DNA replication through its interaction with the proliferating cell nuclear antigen (PCNA), which is an auxiliary factor for polymerase delta. PCNA is also implicated in the repair resynthesis step of nucleotide excision repair (NER). Previous studies have yielded contradictory results on whether p21 regulates NER through its interaction with PCNA. Resolution of this controversy is of interest because it would help understand how DNA repair and replication are regulated. Hence, we have investigated the effect of p21 on NER both in vitro and in vivo using purified fragments of p21 containing either the CDK-binding domain (N terminus) or the PCNA binding domain (C terminus) of the protein. In the in vitro studies, DNA repair synthesis was measured in extracts from normal human fibroblasts using plasmids damaged by UV irradiation. In the in vivo studies, we used intact and permeabilized cells. The results show that the C terminus of the p21 protein inhibits NER both in vitro and in vivo. These are the first in vivo studies in which this question has been examined, and we demonstrate that inhibition of NER by p21 is not merely an artificial in vitro effect. A 50% inhibition of in vitro NER occurred at a 50:1 molar ratio of p21 C-terminus fragment to PCNA monomer. p21 differentially regulates DNA repair and replication, with repair being much less sensitive to inhibition than replication. Our in vivo results suggest that the inhibition occurs at the resynthesis step of the repair process. It also appears that preassembly of PCNA at repair sites mitigates the inhibitory effect of p21. We further demonstrate that the inhibition of DNA repair is mediated via binding of p21 to PCNA. The N terminus of p21 had no effect on DNA repair, and the inhibition of DNA repair by the C terminus of p21 was relieved by the addition of purified PCNA protein. C1 NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. NR 36 TC 63 Z9 63 U1 0 U2 5 PU AMER SOC CELL BIOLOGY PI BETHESDA PA PUBL OFFICE, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL PY 1999 VL 10 IS 7 BP 2119 EP 2129 PG 11 WC Cell Biology SC Cell Biology GA 217TQ UT WOS:000081515400003 PM 10397753 ER PT J AU Bianco, P Robey, PG AF Bianco, P Robey, PG TI An animal model of fibrous dysplasia SO MOLECULAR MEDICINE TODAY LA English DT Article ID MCCUNE-ALBRIGHT SYNDROME; BONE-FORMATION; CELLS C1 Univ Aquila, Dipartimento Med Sperimentale, I-67100 Laquila, Italy. Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Bianco, P (reprint author), Univ Aquila, Dipartimento Med Sperimentale, I-67100 Laquila, Italy. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Telethon [E.0519] NR 5 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1357-4310 J9 MOL MED TODAY JI Mol. Med. Today PD JUL PY 1999 VL 5 IS 7 BP 322 EP 323 DI 10.1016/S1357-4310(99)01485-9 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 215AB UT WOS:000081358800013 PM 10498438 ER PT J AU Guano, F Pourquier, P Tinelli, S Binaschi, M Bigioni, M Animati, F Manzini, S Zunino, F Kohlhagen, G Pommier, Y Capranico, G AF Guano, F Pourquier, P Tinelli, S Binaschi, M Bigioni, M Animati, F Manzini, S Zunino, F Kohlhagen, G Pommier, Y Capranico, G TI Topoisomerase poisoning activity of novel disaccharide anthracyclines SO MOLECULAR PHARMACOLOGY LA English DT Article ID II DNA CLEAVAGE; SEQUENCE SPECIFICITY; SACCHAROMYCES-CEREVISIAE; MULTIDRUG-RESISTANCE; COVALENT COMPLEXES; ANTITUMOR AGENT; ACTINOMYCIN-D; CAMPTOTHECIN; BINDING; YEAST AB Doxorubicin and idarubicin are very effective anticancer drugs in the treatment of human hematological malignancies and solid tumors. These agents are well known topoisomerase II poisons; however, some anthracycline analogs recently have been shown to poison topoisomerase I. In the present work, we assayed novel disaccharide analogs and the parent drug, idarubicin, for their poisoning effects of human topoisomerase I and topoisomerases II alpha and II beta Drugs were evaluated with a DNA cleavage assay in vitro and with a yeast system to test whether the agents were able to poison the enzymes in vivo. We have found that the test agents are potent poisons of both topoisomerases II alpha and II beta The axial orientation of the second sugar relative to the first one of the novel disaccharide analogs was shown to be required for poisoning activity and cytotoxicity. Interestingly, idarubicin and the new analogs stimulated topoisomerase I-mediated DNA cleavage at low levels in vitro. As expected, the cytotoxic level of the drug was highly affected by the content of topoisomerase II; nevertheless, the test agents had a yeast cell-killing activity that also was weakly dependent on cellular topoisomerase I content. The results are relevant for the full understanding of the molecular mechanism of topoisomerase poisoning by anticancer drugs, and they define structural determinants of anthracyclines that may help in the rational design of new compounds directed against topoisomerase I. C1 Ist Nazl Studio & Cura Tumori, Dept Expt Oncol, I-20133 Milan, Italy. NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Menarini Ric Sud, Pomezia, Italy. RP Capranico, G (reprint author), Univ Bologna, Dept Biochem, Via Irnerio 48, I-40126 Bologna, Italy. RI Capranico, Giovanni/K-1678-2014 OI Capranico, Giovanni/0000-0002-8708-6454 NR 42 TC 56 Z9 57 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 JUL PY 1999 VL 56 IS 1 BP 77 EP 84 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 212WL UT WOS:000081240600009 PM 10385686 ER PT J AU Anouar, Y Lee, HW Eiden, LE AF Anouar, Y Lee, HW Eiden, LE TI Both inducible and constitutive activator protein-1-like transcription factors are used for transcriptional activation of the galanin gene by different first and second messenger pathways SO MOLECULAR PHARMACOLOGY LA English DT Article ID ADRENAL CHROMAFFIN CELLS; CYCLIC-AMP; CATECHOLAMINE SECRETION; SIGNALING PATHWAYS; SOMATOSTATIN GENE; RESPONSE-ELEMENT; MEDULLARY CELLS; RNA LEVELS; KINASE-C; PROENKEPHALIN AB We investigated trans-acting factors mediating galanin (GAL) gene activation by protein kinase-dependent signal transduction pathways in chromaffin cells. GAL mRNA up-regulation via the protein kinase A (PKA) pathway (25 mu M forskolin) required new protein synthesis. Stimulation via protein kinase C (0.1 mu M phorbol myristate acetate) did not. The involvement of activator protein-1(AP-1) and cAMP response element-binding protein (CREB) in serine/threonine protein kinase activation of GAL gene transcription was assessed. Cotransfection of a GAL reporter gene along with expression plasmids encoding c-Jun plus c-Fos, or the catalytic subunit of PKA (PKA beta), resulted in a 4- to 8-fold enhancement of GAL reporter gene transcription. Transcriptional activation required the galanin 12-O-tetradecanoylphorbol-13-acetate (phorbol-12-myristate-13-acetate) response element (GTRE) octamer sequence (TGACGCGG) in the proximal enhancer of the GAL gene, previously shown to confer phorbol ester responsiveness in chromaffin cells. CREB coexpression did not stimulate GAL gene transcription or increase transcriptional activation by PKA beta. The GTRE preferentially bound in vitro synthesized Jun and Fos-Jun, compared with CREB, in electrophoretic mobility shift assays. The GTRE preference for binding AP-1-immunoreactive protein compared with CREB was even more pronounced in chromaffin cell nuclear extracts, in which the majority of GTRE-bound protein in electrophoretic mobility shift assays was supershifted with anti-Fos and anti-Jun antibodies. Thus, GAL gene regulation mediated by protein kinase activation appears to involve both constitutively expressed and inducible AP-1-related proteins. Elevated potassium stimulation of GAL mRNA was completely blocked, but pituitary adenylyl cyclase-activating polypeptide and histamine stimulations were only partially blocked,by cycloheximide. Both inducible and constitutive pathways are therefore used by physiologically relevant first messengers that stimulate GAL biosynthesis in vivo. C1 NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Eiden, LE (reprint author), NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, NIH, Bldg 36,Room 2A-11,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Eiden, Lee/0000-0001-7524-944X NR 40 TC 23 Z9 23 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 JUL PY 1999 VL 56 IS 1 BP 162 EP 169 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 212WL UT WOS:000081240600020 PM 10385697 ER PT J AU Sher, L AF Sher, L TI Phenotype definition and association studies in behavioral genetics SO MOLECULAR PSYCHIATRY LA English DT Editorial Material ID CANDIDATE-GENE; PERSONALITY C1 NIMH, Sect Biol Rhythms, Bethesda, MD 20892 USA. RP Sher, L (reprint author), NIMH, Sect Biol Rhythms, Bldg 10,Rm 3S-231,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 7 TC 1 Z9 1 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 JUL PY 1999 VL 4 IS 4 BP 316 EP 316 DI 10.1038/sj.mp.4000553 PG 1 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 235PH UT WOS:000082550900006 PM 10483046 ER PT J AU Licinio, J Wong, ML AF Licinio, J Wong, ML TI The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection SO MOLECULAR PSYCHIATRY LA English DT Article DE cytokines; depression; neurotoxicity; neuroprotection; interleukins ID INTERLEUKIN-1 RECEPTOR ANTAGONIST; CORTICOTROPIN-RELEASING-FACTOR; TUMOR-NECROSIS-FACTOR; FOCAL CEREBRAL-ISCHEMIA; RAT-BRAIN VASCULATURE; MESSENGER-RNA; GENE-EXPRESSION; IL-1 RECEPTOR; FACTOR-ALPHA; PATHOPHYSIOLOGICAL IMPLICATIONS AB Depression represents a major public health problem. It is estimated that 13-20% of the population has some depressive symptoms at any given time and about 5% of the population is assumed to suffer from major depression. Known pathological processes include ischemia, neoplasia, necrosis, apoptosis, infection, and inflammation. Of those, inflammation is the most compatible with the waxing and waning course of depression, and could explain the biology of this disorder that has a fluctuating course with severe episodes that can be followed by partial or complete remission. Over the years a body of evidence has been accumulated suggesting that major depression is associated with dysfunction of inflammatory mediators. Major depression commonly co-occurs with ischemic heart disease and decreased bone mineral density. Depressive symptoms are known to have a negative impact on cardiovascular prognosis, increasing the mortality rate of coronary artery disease. Several lines of evidence indicate that brain cytokines, principally interleukin-1 beta (IL-I beta) and IL-l receptor antagonist may have a role in the biology of major depression, and that they might additionally be involved in the pathophysiology and somatic consequences of depression as well as in the effects of antidepressant treatment. A particularly unique and novel aspect of the studies and views discussed here is their potential to lead to interventions which may reduce the morbidity and mortality risks for osteoporosis, cardiovascular disease, and behavioral symptoms in patients with major depression. We also discuss the emerging concept of peripheral and central cytokine compartments: their integration and differential regulation is a key element for the optimal functioning of the immune and nervous systems. C1 NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Licinio, J (reprint author), NIMH, Clin Neuroendocrinol Branch, NIH, Bldg 10-2D46,10 Ctr Dr,MSC 1284, Bethesda, MD 20892 USA. RI Wong, Ma-Li/D-7903-2011; Licinio, Julio/L-4244-2013 OI Licinio, Julio/0000-0001-6905-5884 NR 92 TC 251 Z9 260 U1 4 U2 12 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUL PY 1999 VL 4 IS 4 BP 317 EP 327 DI 10.1038/sj.mp.4000586 PG 11 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 235PH UT WOS:000082550900007 PM 10483047 ER PT J AU Rotondo, A Schuebel, KE Bergen, AW Aragon, R Virkkunen, M Linnoila, M Goldman, D Nielsen, DA AF Rotondo, A Schuebel, KE Bergen, AW Aragon, R Virkkunen, M Linnoila, M Goldman, D Nielsen, DA TI Identification of four variants in the tryptophan hydroxylase promoter and association to behavior SO MOLECULAR PSYCHIATRY LA English DT Article DE tryptophan hydroxylase; serotonin; promoter; genetic polymorphisms; suicidality; aggression; variant ID SUICIDAL-BEHAVIOR; GENE; POLYMORPHISM; CSF; CHROMOSOME-11; METABOLITES; POPULATION; VICTIMS; FAMILY; BRAIN AB One of the most replicated findings in biological psychiatry is the observation of lower 5-hydroxyindoleacetic acid concentrations, the major metabolite of serotonin, in the brain and cerebrospinal fluid of subjects with impulsive aggression. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin, however functional variants have not been reported from the coding sequence of this gene. Therefore, we screened the human TPH promoter (TPH-P) for genetic variants which could modulate TPH gene transcription. The TPH-P (2093 nucleotides) was screened for sequence variation by SSCP analysis of 260 individuals from Finnish, Italian, American Caucasian, and American Indian populations. Four common polymorphisms were identified: -7180T>G, -7065C>T, -6526A>G, and -5806G>T (designated as nucleotides upstream of the translation start site). In the Finns, the four polymorphisms had a minor allele frequency of 0.40 and in this population linkage disequilibrium between the four loci was complete. In the other populations the minor allele frequencies ranged from 0.40 to 0.45. TPH -6526A>G genotype was determined in 167 unrelated Finnish offenders and 153 controls previously studied for the TPH IVS7+779C>A polymorphism. A significant association was observed between -6526A>G and suicidality in the offenders. TPH -6526A>G and the previously reported intron seven polymorphism, TPH IVS7+779C>A, exhibited a normalised linkage disequilibrium of 0.89 in Finns. Normalized linkage disequilibrium was reduced in other populations, being 0.49 and 0.21 in Italians and American Indians, respectively. In conclusion, four TPH-P variants were identified which can be used for haplotype-based analysis to localize functional TPH alleles influencing behavior. C1 Univ Pisa, Dept Psychiat Neurobiol Pharmacol & Biotechnol, I-56100 Pisa, Italy. NIAAA, Mol Genet Sect, NIH, Rockville, MD 20852 USA. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. Johns Hopkins Oncol Ctr, Baltimore, MD 21231 USA. NCI, Genet Epidemiol Branch, Rockville, MD 20852 USA. Univ Helsinki, Dept Psychiat, SF-00180 Helsinki, Finland. RP Rotondo, A (reprint author), Univ Pisa, Dept Psychiat Neurobiol Pharmacol & Biotechnol, Via Roma 67, I-56100 Pisa, Italy. RI Nielsen, David/B-4655-2009; Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Bergen, Andrew/0000-0002-1237-7644 NR 27 TC 72 Z9 76 U1 0 U2 3 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUL PY 1999 VL 4 IS 4 BP 360 EP 368 DI 10.1038/sj.mp.4000578 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 235PH UT WOS:000082550900013 PM 10483053 ER PT J AU Karp, BI Goldstein, SR Chen, R Samii, A Bara-Jimenez, W Hallett, M AF Karp, BI Goldstein, SR Chen, R Samii, A Bara-Jimenez, W Hallett, M TI An open trial of clozapine for dystonia SO MOVEMENT DISORDERS LA English DT Article DE dystonia; torticollis; clozapine; dopamine; basal ganglia ID TARDIVE DYSTONIA; PHARMACOLOGY; HALOPERIDOL; CLONAZEPAM; AFFINITY AB Pharmacologic treatment of seven dystonia is often unsatisfactory. The atypical antipsychotic medication clozapine appears to improve tardive dystonia associated with conventional neuroleptic use. We studied the efficacy of clozapine for severe dystonia in five patients in an open trial. The patient cohort included four with generalized dystonia and one with Meige syndrome. All patients were evaluated at baseline and at least weekly while on medication with subjective assessment of response by the patient and physician rating using the Burke-Fahn-Marsden Evaluation Scale for Dystonia. All five subjects had significant improvement detected by the Burke-Fahn-Marsden Evaluation Scale as well as subjective improvement while on clozapine. Side effects, such as sedation and orthostatic hypotension, developed in all patients but was only treatment-limiting in one subject who developed persistent symptomatic orthostatic hypotension and tachycardia. Two of the four remaining patients continued clozapine after completion of the study; an additional patient was uncertain if the benefit outweighed the side effects, One patient discontinued treatment because of difficulty obtaining the FDA-required weekly white blood cell counts for patients on clozapine. We conclude that clozapine appears to be effective for generalized and refractory focal dystonia although its use may be limited by the side effects and need for hematologic monitoring. C1 NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Toronto, Toronto Hosp, Toronto, ON, Canada. Univ Washington, Dept Neurol, Seattle, WA 98195 USA. RP Karp, BI (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 5S209,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Chen, Robert/B-3899-2009 OI Chen, Robert/0000-0002-8371-8629 NR 34 TC 32 Z9 33 U1 0 U2 4 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 JUL PY 1999 VL 14 IS 4 BP 652 EP 657 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 243LT UT WOS:000082999700015 PM 10435503 ER PT J AU Quarles, RH Weiss, MD AF Quarles, RH Weiss, MD TI Autoantibodies associated with peripheral neuropathy SO MUSCLE & NERVE LA English DT Review DE antibody; ganglioside; glycolipid; myelin-associated glycoprotein; neuropathy ID MYELIN-ASSOCIATED GLYCOPROTEIN; GUILLAIN-BARRE-SYNDROME; INFLAMMATORY DEMYELINATING POLYNEUROPATHY; ANTI-GM1 GANGLIOSIDE ANTIBODIES; MULTIFOCAL MOTOR NEUROPATHY; CELL LUNG-CANCER; MONOCLONAL IMMUNOGLOBULIN-M; SULFATED GLUCURONIC-ACID; MILLER-FISHER SYNDROME; PARANEOPLASTIC ENCEPHALOMYELITIS ANTIGEN AB High titers of serum antibodies to neural antigens occur in several forms of neuropathy, These include neuropathies associated with monoclonal gammopathy, inflammatory polyneuropathies, and paraneoplastic neuropathies. The antibodies frequently react with glycosylated cell surface molecules, including glycolipids, glycoproteins, and glycosaminoglycans, but antibodies to intracellular proteins have also been described. There are several correlations between antibody specificity and clinical symptoms, such as anti-MAG antibodies with demyelinating sensory dr sensorimotor neuropathy, anti-GM1 ganglioside antibodies with motor nerve disorders, antibodies to gangliosides containing disialosyl moieties with sensory ataxic neuropathy and Miller-Fisher syndrome, and antibodies to the neuronal nuclear Hu antigens with paraneoplastic sensory neuronopathy, These correlations suggest that the neuropathies may be caused by the antibodies, but evidence for a causal relationship is stronger in some examples than others, In this review, we discuss the origins of the antibodies, evidence for and against their involvement in pathogenic mechanisms, and the implications of these findings for therapy. (C) 1999 John Wiley & Sons, Inc. C1 NINDS, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Quarles, RH (reprint author), NINDS, Mol & Cellular Neurobiol Lab, NIH, 49 Convent Dr,Bldg 49,Room 2A28, Bethesda, MD 20892 USA. NR 197 TC 100 Z9 101 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0148-639X EI 1097-4598 J9 MUSCLE NERVE JI Muscle Nerve PD JUL PY 1999 VL 22 IS 7 BP 800 EP 822 DI 10.1002/(SICI)1097-4598(199907)22:7<800::AID-MUS2>3.0.CO;2-F PG 23 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 214FU UT WOS:000081318600002 PM 10398197 ER PT J AU Jimenez, GS Bryntesson, F Torres-Arzayus, MI Priestley, A Beeche, M Saito, S Sakaguchi, K Appella, E Jeggo, PA Taccioli, GE Wahl, GM Hubank, M AF Jimenez, GS Bryntesson, F Torres-Arzayus, MI Priestley, A Beeche, M Saito, S Sakaguchi, K Appella, E Jeggo, PA Taccioli, GE Wahl, GM Hubank, M TI DNA-dependent protein kinase is not required for the p53-dependent response to DNA damage SO NATURE LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; CELL-CYCLE ARREST; V(D)J RECOMBINATION; P53; GROWTH; MICE; GENE; PK AB Damage to DNA in the cell activates the tumour-suppressor protein p53 (ref. 1), and failure of this activation leads to genetic instability and a predisposition to cancer, It is therefore crucial to understand the signal transduction mechanisms that connect DNA damage with p53 activation. The enzyme known as DNA-dependent protein kinase (DNA-PK) has been proposed to be an essential activator of p53 (refs 2, 3), but the evidence for its involvement in this pathway is controversial(3,4). We now show that the p53 response is fully functional in primary mouse embryonic fibroblasts lacking DNA-PK: irradiation-induced DNA damage in these defective fibroblasts induces a normal response of p53 accumulation, phosphorylation of a p53 serine residue at position 15, nuclear localization and binding to DNA of p53. The upregulation of p53-target genes and cell-cycle arrest also occur normally. The DNA-PR-deficient cell line SCGR11 contains a homozygous mutation in the DNA-binding domain of p53, which may explain the defective response by p53 reported in this line(3), Our results indicate that DNA-PK activity is not required for cells to mount a p53-dependent response to DNA damage. C1 Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA. Univ Sussex, Trafford Ctr, Brighton BN1 9RY, E Sussex, England. Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. Univ Sussex, MRC, Cell Mutat Unit, Brighton BN1 9RR, E Sussex, England. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wahl, GM (reprint author), Salk Inst Biol Studies, Gene Express Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. RI Hubank, Michael/C-1837-2008 OI Hubank, Michael/0000-0002-2901-0742 FU Wellcome Trust NR 19 TC 108 Z9 111 U1 0 U2 4 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 1 PY 1999 VL 400 IS 6739 BP 81 EP 83 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 213DA UT WOS:000081255700055 PM 10403253 ER PT J AU Bittner, M Meltzer, P Trent, J AF Bittner, M Meltzer, P Trent, J TI Data analysis and integration: of steps and arrows SO NATURE GENETICS LA English DT Editorial Material C1 Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. RP Bittner, M (reprint author), Natl Human Genome Res Inst, NIH, 49 Convent Dr,Bldg 49, Bethesda, MD 20892 USA. NR 10 TC 60 Z9 61 U1 0 U2 3 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUL PY 1999 VL 22 IS 3 BP 213 EP 215 DI 10.1038/10265 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 210VT UT WOS:000081125900002 PM 10391202 ER PT J AU Wolffe, AP AF Wolffe, AP TI Architectural regulations and Hmg1 SO NATURE GENETICS LA English DT Editorial Material ID HISTONE H1; TRANSCRIPTION; PROTEIN; XENOPUS C1 NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RP Wolffe, AP (reprint author), NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. NR 17 TC 25 Z9 25 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUL PY 1999 VL 22 IS 3 BP 215 EP 217 DI 10.1038/10267 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 210VT UT WOS:000081125900003 PM 10391203 ER PT J AU Duesbery, NS Webb, CP Woude, GFV AF Duesbery, NS Webb, CP Woude, GFV TI MEK Wars, a new front in the battle against cancer SO NATURE MEDICINE LA English DT Editorial Material ID MAP-KINASE-KINASE; ACTIVATED PROTEIN-KINASE; TRANSFORMATION; CELLS C1 NCI, Div Basic Sci, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. Van Andel Rsch Inst, Grand Rapids, MI 49503 USA. RP Woude, GFV (reprint author), NCI, Div Basic Sci, Bethesda, MD 20892 USA. RI Webb, Craig/I-8123-2012; OI DUESBERY, NICK/0000-0002-4258-5655 NR 14 TC 32 Z9 33 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 JUL PY 1999 VL 5 IS 7 BP 736 EP 737 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 224YB UT WOS:000081926600024 PM 10395314 ER PT J AU Husain, SR Kreitman, RJ Pastan, I Puri, RK AF Husain, SR Kreitman, RJ Pastan, I Puri, RK TI Interleukin-4 receptor-directed cytotoxin therapy of AIDS-associated Kaposi's sarcoma tumors in xenograft- model SO NATURE MEDICINE LA English DT Article ID CIRCULARLY PERMUTED INTERLEUKIN-4; HUMAN CHORIONIC-GONADOTROPIN; HUMAN-IMMUNODEFICIENCY-VIRUS; ENDOTHELIAL GROWTH-FACTOR; PSEUDOMONAS EXOTOXIN; CELL-LINE; CARCINOMA-CELLS; EXPRESSION; TOXIN; INFECTION AB The elusive and enigmatic origin of AIDS-associated Kaposi's sarcoma (AIDS-KS) makes it a complex tumor and therefore difficult to treat. Here we demonstrate that AIDS-KS cells express surface interleukin-4 (IL-4) receptors, and that IL-4 toxin (IL-4(38-37)-PE38KDEL) is specifically cytotoxic to these cells. Intratumoral, intraperitoneal and intravenous administration of IL-4 toxin in nude mice with established subcutaneous AIDS-KS tumors caused considerable antitumor activity in a dose-dependent manner, with highest dose producing durable complete responses. Metabolic changes, including cachexia and lymphopenia, induced by KS tumors were prevented by IL-4 toxin treatment. This report establishes IL-4(38-37)-PE38KDEL as an experimental therapeutic agent for the treatment of AIDS-KS. C1 US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Lab Mol Tumor Biol, Bethesda, MD 20892 USA. NCI, Div Basic Sci, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Lab Mol Tumor Biol, Bethesda, MD 20892 USA. NR 48 TC 47 Z9 49 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 JUL PY 1999 VL 5 IS 7 BP 817 EP 822 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 224YB UT WOS:000081926600038 PM 10395328 ER PT J AU Ying, H Zaks, TZ Wang, RF Irvine, KR Kammula, US Marincola, FM Leitner, WW Restifo, NP AF Ying, H Zaks, TZ Wang, RF Irvine, KR Kammula, US Marincola, FM Leitner, WW Restifo, NP TI Cancer therapy using a self-replicating RNA vaccine SO NATURE MEDICINE LA English DT Article ID ESTABLISHED PULMONARY METASTASES; IMMUNE-RESPONSES; DNA IMMUNIZATION; VIRUS; ANTIGEN; MODEL; ENHANCEMENT; MELANOMA; CELLS AB 'Naked' nucleic acid Vaccines are potentially useful candidates for the treatment of patients with cancer(1-3), but their clinical efficacy has yet to be demonstrated. We sought to enhance the immunogenicity of a nucleic acid Vaccine by making it 'self-replicating'. We accomplished this by using a gene encoding an RNA replicase polyprotein derived from the Semliki forest virus, in combination with a model antigen. A single intramuscular injection of a self-replicating RNA immunogen elicited antigen-specific antibody and CD8(+) T-cell responses at doses as low as 0.1 mu g. Pre-immunization with a self-replicating RNA vector protected mice from tumor challenge, and therapeutic immunization prolonged the survival of mice with established tumors. The self-replicating RNA vectors did not mediate the production of substantially more model antigen than a conventional DNA vaccine did in vitro. However, the enhanced efficacy in vivo correlated with a caspase-dependent apoptotic death in transfected cells. This death facilitated the uptake of apoptotic cells by dendritic cells, providing a potential mechanism for enhanced immunogenicity. Naked, non-infectious, self-replicating RNA may be an excellent candidate for the development of new cancer vaccines. C1 NCI, Surg Branch, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), NCI, Surg Branch, Bldg 10,Room 2B42,10 Ctr Dr, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; Leitner, Wolfgang/F-5741-2011; OI Leitner, Wolfgang/0000-0003-3125-5922; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 23 TC 214 Z9 225 U1 1 U2 9 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 JUL PY 1999 VL 5 IS 7 BP 823 EP 827 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 224YB UT WOS:000081926600039 PM 10395329 ER PT J AU Contreras, MA Chang, MCJ Kirkby, D Bell, JM Rapoport, SI AF Contreras, MA Chang, MCJ Kirkby, D Bell, JM Rapoport, SI TI Reduced palmitate turnover in brain phospholipids of pentobarbital-anesthetized rats SO NEUROCHEMICAL RESEARCH LA English DT Article DE anesthesia; phospholipids; recycling; remodeling; fatty acids; brain ID FATTY-ACID INCORPORATION; ACYL-COA ESTERS; IN-VIVO; ARACHIDONIC-ACID; BOVINE BRAIN; SIGNAL-TRANSDUCTION; MAMMALIAN-CELLS; BINDING PROTEIN; FRACTIONS; AWAKE AB Our laboratory has reported that pentobarbital-induced anesthesia reduced the incorporation of intravenously injected radiolabeled palmitic acid into brain phospholipids. To determine if this decrease reflected a pentobarbital-induced decrease in palmitate turnover in phospholipids, we applied our method and model to study net flux and turnover of palmitate in brain phospholipids (1). Awake, light and deep pentobarbital (25-70 mg/kg, iv) anesthetized rats were infused with [9,10-H-3]palmitate over a 5 min period. Brain electrical activity was monitored by electroencephalography. An isoelectric electroencephalogram characterized deep pentobarbital anesthesia. Net incorporation rates (J(FA,i)) and turnover rates (F-i) of palmitate were calculated. J(FA,i) for palmitate incorporated into phospholipids was dramatically reduced by pentobarbital treatment in a dose-dependent manner, by 70% and 90% respectively for lightly and deeply anesthetized animals, compared with awake controls. Turnover rates for palmitate in total phospholipid and individual phospholipid classes were decreased by nearly 70% and 90% for lightly and deeply anesthetized animals, respectively. Thus, pentobarbital decreases, in a dose-dependent manner, the turnover of palmitate in brain phospholipids. This suggests that palmitate turnover is closely coupled to brain functional activity. C1 NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. NINDS, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. RP Contreras, MA (reprint author), NIA, Neurosci Lab, NIH, Bldg 10,6-C-103,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 67 TC 13 Z9 13 U1 0 U2 0 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 JUL PY 1999 VL 24 IS 7 BP 833 EP 841 DI 10.1023/A:1020997728511 PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 210YN UT WOS:000081133300004 PM 10403622 ER PT J AU Kamel, F Umbach, DM Munsat, TL Shefner, JM Sandler, DP AF Kamel, F Umbach, DM Munsat, TL Shefner, JM Sandler, DP TI Association of cigarette smoking with amyotrophic lateral sclerosis SO NEUROEPIDEMIOLOGY LA English DT Article DE amyotrophic lateral sclerosis; cigarette smoking; alcohol use; family history ID MOTOR-NEURON-DISEASE; IDIOPATHIC PARKINSONS-DISEASE; ANTECEDENT EVENTS; RISK-FACTORS; DISORDERS; DEMENTIA AB We explored the relationship between amyotrophic lateral sclerosis (ALS) and cigarette smoking in a case-control study conducted in New England from 1993 to 1996. Recently diagnosed ALS cases (n = 109) were recruited from two major referral centers. Population controls (n = 256) were identified by random telephone screening. Data were analyzed by logistic regression. After adjusting for age, sex, region and education, ever having smoked cigarettes was associated with an increase in risk for ALS (odds ratio 1.7; 95% confidence interval 1.0-2.8). Average cigarettes smoked per day, years smoked and pack-years were all greater in cases than controls, but dose-response trends were not observed. Similar numbers of cases and controls had ever used alcohol, and only a small, nonsignificant association of drinks per month with ALS was observed. The association of cigarette smoking with ALS was not affected by adjusting for alcohol use. In contrast, the weak relationship of ALS with alcohol use was apparently due to confounding by smoking. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. New England Med Ctr, Boston, MA 02111 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Kamel, F (reprint author), NIEHS, Epidemiol Branch, MD A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. OI Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 NR 29 TC 60 Z9 60 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0251-5350 J9 NEUROEPIDEMIOLOGY JI Neuroepidemiology PD JUL-AUG PY 1999 VL 18 IS 4 BP 194 EP 202 DI 10.1159/000026211 PG 9 WC Public, Environmental & Occupational Health; Clinical Neurology SC Public, Environmental & Occupational Health; Neurosciences & Neurology GA 209XP UT WOS:000081075300004 PM 10364720 ER PT J AU Hahm, S Mizuno, TM Wu, TJ Wisor, JP Priest, CA Kozak, CA Boozer, CN Peng, B McEvoy, RC Good, P Kelley, KA Takahashi, JS Pintar, JE Roberts, JL Mobbs, CV Salton, SRJ AF Hahm, S Mizuno, TM Wu, TJ Wisor, JP Priest, CA Kozak, CA Boozer, CN Peng, B McEvoy, RC Good, P Kelley, KA Takahashi, JS Pintar, JE Roberts, JL Mobbs, CV Salton, SRJ TI Targeted deletion of the Vgf gene indicates that the encoded secretory peptide precursor plays a novel role in the regulation of energy balance SO NEURON LA English DT Article ID NERVE GROWTH-FACTOR; MESSENGER-RNA; HYPOTHALAMIC EXPRESSION; CARBOXYPEPTIDASE-E; MOLECULAR-CLONING; SECRETOGRANIN-II; PROTEIN VGF; MICE; OBESITY; RAT AB To determine the function of VGF, a secreted polypeptide that is synthesized by neurons, is abundant in the hypothalamus, and is regulated in the brain by electrical activity, injury, and the circadian clock, we generated knockout mice lacking Vgf. Homozygous mutants are small, hypermetabolic, hyperactive, and infertile, with markedly reduced leptin levels and fat stores and altered hypothalamic proopiomelanocortin (POMC), neuropeptide Y (NPY), and agouti-related peptide (AGRP) expression. Furthermore, VGF mRNA synthesis is induced in the hypothalamic arcuate nuclei of fasted normal mice. VGF therefore plays a critical role in the regulation of energy homeostasis, suggesting that the study of lean VGF mutant mice may provide insight into wasting disorders and, moreover, that pharmacological antagonism of VGF action(s) might constitute the basis for treatment of obesity. C1 Mt Sinai Sch Med, Fishberg Res Ctr Neurobiol, New York, NY 10029 USA. Mt Sinai Sch Med, Dept Geriatr, New York, NY 10029 USA. Mt Sinai Sch Med, Dept Pathol, New York, NY 10029 USA. Mt Sinai Sch Med, Div Pediat Endocrinol & Diabet, New York, NY 10029 USA. Northwestern Univ, Howard Hughes Med Inst, Evanston, IL 60208 USA. Northwestern Univ, Natl Sci Fdn Ctr Biol Timing, Dept Physiol & Neurobiol, Evanston, IL 60208 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Columbia Univ, Coll Phys & Surg, Obes Res Ctr, St Lukes Roosevelt Hosp, New York, NY 10025 USA. RP Salton, SRJ (reprint author), Mt Sinai Sch Med, Fishberg Res Ctr Neurobiol, New York, NY 10029 USA. RI Takahashi, Joseph/E-8482-2012; OI Takahashi, Joseph/0000-0003-0384-8878; Mizuno, Tooru/0000-0002-0836-3506 NR 57 TC 138 Z9 140 U1 3 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL PY 1999 VL 23 IS 3 BP 537 EP 548 DI 10.1016/S0896-6273(00)80806-5 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 221AA UT WOS:000081701000017 PM 10433265 ER PT J AU Tu, JC Xiao, B Naisbitt, S Yuan, JP Petralia, RS Brakeman, P Doan, A Aakalu, VK Lanahan, AA Sheng, M Worley, PF AF Tu, JC Xiao, B Naisbitt, S Yuan, JP Petralia, RS Brakeman, P Doan, A Aakalu, VK Lanahan, AA Sheng, M Worley, PF TI Coupling of mGluR/Homer and PSD-95 complexes by the shank family of postsynaptic density proteins SO NEURON LA English DT Article ID METABOTROPIC GLUTAMATE RECEPTORS; LONG-TERM POTENTIATION; CEREBELLAR PURKINJE-CELLS; ALDRICH-SYNDROME PROTEIN; DENDRITIC SPINES; ENDOPLASMIC-RETICULUM; SYNAPTIC ACTIVATION; RAT HIPPOCAMPUS; LEUCINE-ZIPPER; INDUCTION AB Shank is a recently described family of postsynaptic proteins that function as part of the NMDA receptor-associated PSD-95 complex (Naisbitt et al., 1999 [this issue of Neuron]). Here, we report that Shank proteins also bind to Homer. Homer proteins form multivalent complexes that bind proline-rich motifs in group 1 metabotropic glutamate receptors and inositol trisphosphate receptors, thereby coupling these receptors in a signaling complex. A single Homer-binding site is identified in Shank, and Shank and Homer coimmunoprecipitate from brain and colocalize at postsynaptic densities. Moreover, Shank clusters mGluR5 in heterologous cells in the presence of Homer and mediates the coclustering of Homer with PSD-95/GKAP. Thus, Shank may cross-link Homer and PSD-95 complexes in the PSD and play a role in the signaling mechanisms of both mGluRs and NMDA receptors. C1 Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. Massachusetts Gen Hosp, Dept Neurobiol, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA 02114 USA. Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Worley, PF (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. FU NIDA NIH HHS [DA10309, DA11742]; NIMH NIH HHS [KO2 MH01152] NR 45 TC 620 Z9 637 U1 0 U2 21 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL PY 1999 VL 23 IS 3 BP 583 EP 592 DI 10.1016/S0896-6273(00)80810-7 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 221AA UT WOS:000081701000021 PM 10433269 ER PT J AU Herning, RI King, DE Better, WE Cadet, JL AF Herning, RI King, DE Better, WE Cadet, JL TI Neurovascular deficits in cocaine abusers SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE cocaine abuse; blood flow velocity; pulsatility; cerebrovascular resistance ID TRANSCRANIAL DOPPLER SONOGRAPHY; CEREBRAL BLOOD-FLOW; MULTIINFARCT DEMENTIA; ALZHEIMERS-DISEASE; DEPENDENCE; BRAIN; WITHDRAWAL; PERFUSION; EEG; TECHNETIUM-99M-HMPAO AB The nature of the neurological and cerebrovascular deficits in cocaine abusers and whether they persist in abstinence is unclear. Blood flow velocity of the anterior and middle cerebral arteries was measured within 3 days and again after about 28 days after being admitted to an inpatient research ward to determine whether blood flow velocity improved during monitored abstinence conditions. The mean, systolic, and diastolic velocities as well as the pulsatility index in middle and anterior cerebral arteries significantly differed between controls and cocaine abusers (p < .05). Cerebrovascular resistance is increased in cocaine abusers and the increase persists for over a month of abstinence. Further research is needed to determine whether cerebrovascular resistance can be improved by pharmacological manipulations and whether improved blood flow relates to improved treatment outcome. C1 NIDA, Mol Neuropsychiat Sect, Div Intramural Res, Mol Neuropsychiat Sect, Baltimore, MD 21224 USA. RP Herning, RI (reprint author), NIDA, Mol Neuropsychiat Sect, Div Intramural Res, Mol Neuropsychiat Sect, POB 5180, Baltimore, MD 21224 USA. NR 56 TC 27 Z9 27 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUL PY 1999 VL 21 IS 1 BP 110 EP 118 DI 10.1016/S0893-133X(98)00141-9 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 205ZH UT WOS:000080850800012 PM 10379525 ER PT J AU Shoaf, SE Hommer, D Williams, W Higley, JD Carson, R Herscovitch, P Eckelman, W AF Shoaf, SE Hommer, D Williams, W Higley, JD Carson, R Herscovitch, P Eckelman, W TI The validity of the PET/alpha-[C-11]methyl-L-tryptophan method for measuring rates of serotonin synthesis in the human brain - Reply SO NEUROPSYCHOPHARMACOLOGY LA English DT Letter ID DEPRESSION C1 NIH, Ctr Clin, PET Dept, Bethesda, MD 20892 USA. NIAAA, DICBR, Clin Studies Lab, Bethesda, MD 20892 USA. RP Shoaf, SE (reprint author), NIH, Ctr Clin, PET Dept, Bethesda, MD 20892 USA. RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 NR 11 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 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUL PY 1999 VL 21 IS 1 BP 156 EP 157 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 205ZH UT WOS:000080850800018 ER PT J AU Roca, CA Schmidt, PJ Rubinow, DR AF Roca, CA Schmidt, PJ Rubinow, DR TI Gonadal steroids and affective illness SO NEUROSCIENTIST LA English DT Review DE estrogen; progesterone; androgens; depression ID PITUITARY-ADRENAL AXIS; HUMAN ESTROGEN-RECEPTOR; FEMALE RATS; SEX-DIFFERENCES; PREMENSTRUAL-SYNDROME; 5-HYDROXYTRYPTAMINE(2A) RECEPTORS; CORTICOSTERONE SECRETION; PROGESTIN RECEPTORS; GENE-TRANSCRIPTION; HORMONE RECEPTORS AB Gonadal steroids seem to regulate affective state in some people (but not all), despite the absence of abnormal steroid hormone levels or dysfunction of the reproductive endocrine axis. In this article, we attempt to explain this paradox 1) by describing the molecular mechanisms by which gonadal steroids can regulate neuronal function; 2) by describing the specific regulatory impact of gonadal steroids on two systems implicated in the pathophysiology of mood disorders; and 3) by defining the role of gonadal steroids in several mood disorders linked to periods of reproductive change. We suggest that the context in which the neuroregulatory actions of gonadal steroids occur determines the impact of steroid signaling on the regulation of affective state. C1 NIMH, Behav Endocrinol Branch, Bethesda, MD 20892 USA. NR 93 TC 5 Z9 6 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1073-8584 J9 NEUROSCIENTIST JI Neuroscientist PD JUL PY 1999 VL 5 IS 4 BP 227 EP 237 DI 10.1177/107385849900500412 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 216PU UT WOS:000081451700012 ER PT J AU Freed, LA Levy, D Levine, RA Larson, MG Evans, JC Fuller, DL Lehman, B Benjamin, EJ AF Freed, LA Levy, D Levine, RA Larson, MG Evans, JC Fuller, DL Lehman, B Benjamin, EJ TI Prevalence and clinical outcome of mitral-valve prolapse SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GENERAL-POPULATION; FOLLOW-UP; REGURGITATION; FEATURES; IDENTIFICATION; ASSOCIATION; DIAGNOSIS; WOMEN; RISK; MEN AB Background Mitral-valve prolapse has been described as a common disease with frequent complications. To determine the prevalence of mitral-valve prolapse in the general population, as diagnosed with the use of current two-dimensional echocardiographic criteria, we examined the echocardiograms of 1845 women and 1646 men (mean [+/-SD] age, 54.7+/-10.0 years) who participated in the fifth examination of the offspring cohort of the Framingham Heart Study. Methods Classic mitral-valve prolapse was defined as superior displacement of the mitral leaf lets of more than 2 mm during systole and as a maximal leaflet thickness of at least 5 mm during diastasis, and nonclassic prolapse was defined as displacement of more than 2 mm, with a maximal thickness of less than 5 mm. Results A total of 84 subjects (2.4 percent) had mitral-valve prolapse: 47 (1.3 percent) had classic prolapse, and 37 (1.1 percent) had nonclassic prolapse. Their age and sex distributions were similar to those of the subjects without prolapse. None of the subjects with prolapse had a history of heart failure, one (1.2 percent) had atrial fibrillation, one (1.2 percent) had cerebrovascular disease, and three (3.6 percent) had syncope, as compared with unadjusted prevalences of these findings in the subjects without prolapse of 0.7, 1.7, 1.5, and 3.0 percent, respectively. The frequencies of chest pain, dyspnea, and electrocardiographic abnormalities were similar among subjects with prolapse and those without prolapse. The subjects with prolapse were leaner (P<0.001) and had a greater degree of mitral regurgitation than those without prolapse, but on average the regurgitation was classified as trace or mild. Conclusions In a community-based sample of the population, the prevalence of mitral-valve prolapse was lower than previously reported. The prevalence of adverse sequelae commonly associated with mitral-valve prolapse in studies of patients referred for that diagnosis was also low. (N Engl J Med 1999;341:1-7.) (C)1999, Massachusetts Medical Society. C1 NHLBI, Framingham Heart Study, Framingham, MA USA. Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA USA. Beth Israel Deaconess Med Ctr, Div Clin Epidemiol, Boston, MA USA. Boston Univ, Sch Med, Div Cardiol, Boston, MA 02118 USA. Boston Univ, Sch Med, Div Epidemiol & Prevent Med, Boston, MA 02118 USA. RP Benjamin, EJ (reprint author), Boston Univ, Sch Med, Framingham Heart Study, 5 Thurber St, Framingham, MA 01702 USA. OI Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [2-R01-HL-38176-06, N01-HC-38038]; NINDS NIH HHS [5-R01-NS-17950-16] NR 40 TC 411 Z9 424 U1 1 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 1 PY 1999 VL 341 IS 1 BP 1 EP 7 DI 10.1056/NEJM199907013410101 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 212BC UT WOS:000081195600001 PM 10387935 ER PT J AU Collins, FS AF Collins, FS TI Shattuck lecture - Medical and societal consequences of the human genome project SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article; Proceedings Paper CT 109th Shattuck Lecture to Annual Meeting of the Massachusetts-Medical-Society CY MAY 08, 1999 CL BOSTON, MASSACHUSETTS ID DENSITY OLIGONUCLEOTIDE ARRAYS; PARKINSONS-DISEASE; HEREDITARY HEMOCHROMATOSIS; POSITIONAL CLONING; ALZHEIMER-DISEASE; GENE; MUTATIONS; SEQUENCE; CANCER; HOMOLOG C1 Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), Natl Human Genome Res Inst, NIH, 31 Ctr Dr,MSC 2152,Bldg 31,Rm 4B09, Bethesda, MD 20892 USA. NR 46 TC 434 Z9 448 U1 0 U2 13 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 JUL 1 PY 1999 VL 341 IS 1 BP 28 EP 37 DI 10.1056/NEJM199907013410106 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 212BC UT WOS:000081195600006 PM 10387940 ER PT J AU Davis, IA Glowienka, KA Boll, RA Deal, KA Brechbiel, MW Stabin, M Bochsler, PN Mirzadeh, S Kennel, SJ AF Davis, IA Glowienka, KA Boll, RA Deal, KA Brechbiel, MW Stabin, M Bochsler, PN Mirzadeh, S Kennel, SJ TI Comparison of (225) actinium chelates: Tissue distribution and radiotoxicity SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE a-particle; biodistribution; radiotoxicity; tissue toxicity; biologic effective dose; chelators ID RADIOIMMUNOTHERAPY; BI-213; COMPLEXES; AC-225 AB The biodistribution and tissue toxicity of intravenously administered 225-actinium ((225)Ac) complexed with acetate, ethylene diamine tetraacetic acid (EDTA), 1, 4, 7, 10, 13-pentaazacyclopentadecane-N, N', N ", N''', N''''-pentaacetic acid (PEPA), or the "a" isomer of cyclohexyl diethylenetriamine pentaacetic acid (CHX-DTPA), were examined. The percent of injected dose per organ and per gram of tissue for each chelate complex was determined. (225)Ac-CHX-DTPA was evaluated further for radiotoxic effects. Mice receiving greater than or equal to 185 kBq (225)Ac-CHX-DTPA suffered 100% morbidity by 5 days and 100% mortality by 8 days postinjection, and all animals evaluated had significant organ damage. The in vivo instability of the (225)Ac-CHX-DTPA complex likely allowed accumulation of free (225)Ac in organs, which resulted in tissue (C) 1999 Elsevier Science Inc. All rights reserved. pathology. C1 Oak Ridge Natl Lab, Div Life Sci, Oak Ridge, TN 37831 USA. NCI, Radioimmune & Inorgan Chem Sect, ROB, DCS,NIH, Bethesda, MD 20892 USA. IPEN CNEN SP, CN ENSP, Sao Paulo, Brazil. Univ Tennessee, Coll Vet Med, Dept Pathol, Knoxville, TN USA. RP Kennel, SJ (reprint author), Oak Ridge Natl Lab, Div Life Sci, Bldg 4500S,MS-6101, Oak Ridge, TN 37831 USA. EM SJ9@ornl.gov RI Boll, Rose/C-4138-2016 OI Boll, Rose/0000-0003-2507-4834 FU NHLBI NIH HHS [HL09718] NR 25 TC 28 Z9 28 U1 4 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD JUL PY 1999 VL 26 IS 5 BP 581 EP 589 DI 10.1016/S0969-8051(99)00024-4 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 219BA UT WOS:000081586800013 PM 10473198 ER PT J AU Andres, R AF Andres, R TI Beautiful hypotheses and ugly facts: The BMI-Mortality Association SO OBESITY RESEARCH LA English DT Editorial Material ID BODY-WEIGHT C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Andres, R (reprint author), NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. NR 11 TC 7 Z9 7 U1 0 U2 1 PU NORTH AMER ASSOC STUDY OBESITY PI ROCHESTER PA C/O DR MICHAEL JENSEN, MAYO MEDICAL CENTER, MAYO CLIN 200 FIRST ST, SW, ROCHESTER, MN 55905 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD JUL PY 1999 VL 7 IS 4 BP 417 EP 419 PG 3 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 217UC UT WOS:000081516500014 PM 10440600 ER PT J AU Smith, R Wickerham, DL Wieand, HS Colangelo, L Mamounas, EP AF Smith, R Wickerham, DL Wieand, HS Colangelo, L Mamounas, EP TI UFT plus calcium folinate vs 5-FU plus calcium folinate in colon cancer SO ONCOLOGY-NEW YORK LA English DT Article ID ORAL REGIMEN; URACIL; LEUCOVORIN; 5-FLUOROURACIL; FTORAFUR AB Adjuvant chemotherapy has been shown to alter the natural history of resected colon cancer. Two regimens (5-fluorouracil [5-FU] pbs calcium folinate and 5-FU plus levamisole [Ergamisol]) have been found to prolong disease-free survival and overall survival in affected patients, Previous comparisons of these two regimens indicate that 5-FU plus calcium foliate may offer a small disease-free survival and overall survival advantage, The demonstration that UFT (uracil and tegafur) plus oral calcium folinate (Orzel) offers significant antitumor activity and an acceptable toxicity profile makes this a logical formulation for the adjuvant treatment of colon cancer, The National Surgical Adjuvant Breast and Bowel Project Protocol C-06 is a randomized comparison of the relative efficacies of 5-FU/calcium folinate vs UFT plus oral calcium folinate. Preliminary analysis of toxicity findings among 473 evaluable patients indicates that both regimens are well tolerated and have similar toxicity profiles, If, in the final survival analysis, UFT plus oral calcium folinate treatment yields the same or better disease-free survival and/or overall survival as the 5-FU/calcium folinate treatment and the toxicity profiles remain similar, it is likely that UFT plus oral calcium folinate will be accepted as a new standard for adjuvant treatment of colon cancer. C1 Allegheny Univ Hlth Sci, Natl Surg Adjuvant Breast & Bowel Project Operat, Pittsburgh, PA 15212 USA. Ctr Biostat, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Mt Sinai Med Ctr, Cleveland, OH 44106 USA. RP Smith, R (reprint author), Allegheny Univ Hlth Sci, Natl Surg Adjuvant Breast & Bowel Project Operat, E Commons Profess Bldg,4 Allegheny Ctr,5th Floor, Pittsburgh, PA 15212 USA. NR 13 TC 12 Z9 12 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 JUL PY 1999 VL 13 IS 7 SU 3 BP 44 EP 47 PG 4 WC Oncology SC Oncology GA 371KN UT WOS:000165178300008 PM 10442360 ER PT J AU Liesenfeld, O Kang, H Park, D Nguyen, TA Parkhe, CV Watanabe, H Abo, T Sher, A Remington, JS Suzuki, Y AF Liesenfeld, O Kang, H Park, D Nguyen, TA Parkhe, CV Watanabe, H Abo, T Sher, A Remington, JS Suzuki, Y TI TNF-alpha, nitric oxide and IFN-gamma are all critical for development of necrosis in the small intestine and early mortality in genetically susceptible mice infected perorally with Toxoplasma gondii SO PARASITE IMMUNOLOGY LA English DT Article DE Toxoplasma gondii; genetic susceptibility; intestine; necrosis; interferon-gamma; tumour necrosis factor-alpha; nitric oxide ID CD4(+) T-CELLS; INTERFERON-GAMMA; L-ARGININE; PERITONEAL-MACROPHAGES; ACTIVATED MACROPHAGES; IN-VIVO; SYNTHASE; ENCEPHALITIS; RESPONSES; RESISTANCE AB We previously reported that genetic susceptibility of mice to peroral infection with T. gondii is associated with CD4(+) T cell-dependent, interferon (IFN)-gamma-mediated necrosis of their small intestine. We examined the role of tumour necrosis factor (TNF)-alpha and nitric oxide (NO), in addition to IFN-gamma. At 7 days after infection, a marked increase in CD4(+) T cells was observed in lamina propria mononuclear cells (LPC) of the small intestine as compared with normal mice, and significantly greater amounts of mRNA for IFN-gamma, TNF-alpha, and inducible NO synthase (iNOS) were detected in LPC of the small intestine of infected than uninfected animals. Treatment of infected mice with anti-TNF-alpha monoclonal antibody (mAb) or the iNOS inhibitor aminoguanidine, prevented necrosis and prolonged time to death. Infected iNOS-targeted mutant mice did not develop the disease whereas infected, control mice did. Treatment with anti-TNF-alpha mAb did not affect the expression of IFN-gamma in the LPC but inhibited expression of iNOS in the infected mice, indicating the role of TNF-alpha in the induction of iNOS. These results suggest that NO induced by a combination of IFN-gamma and TNF-alpha through activation of iNOS is a critical mediator of intestinal pathology and contributes to early mortality in genetically susceptible mice. C1 Palo Alto Med Fdn, Res Inst, Dept Immunol & Infect Dis, Palo Alto, CA 94301 USA. Stanford Univ, Sch Med, Dept Med, Div Infect Dis & Geog Med, Stanford, CA 94305 USA. Niigata Univ, Sch Med, Dept Immunol, Niigata 951, Japan. NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Suzuki, Y (reprint author), Palo Alto Med Fdn, Res Inst, Dept Immunol & Infect Dis, 860 Bryant St, Palo Alto, CA 94301 USA. FU NIAID NIH HHS [AI04717, AI 38260, AI30230] NR 48 TC 100 Z9 103 U1 0 U2 2 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0141-9838 J9 PARASITE IMMUNOL JI Parasite Immunol. PD JUL PY 1999 VL 21 IS 7 BP 365 EP 376 DI 10.1046/j.1365-3024.1999.00237.x PG 12 WC Immunology; Parasitology SC Immunology; Parasitology GA 223EJ UT WOS:000081827500005 PM 10417671 ER PT J AU Schlegel, J Piontek, G Kersting, M Schuermann, M Kappler, R Scherthan, H Weghorst, C Buzard, G Mennel, HD AF Schlegel, J Piontek, G Kersting, M Schuermann, M Kappler, R Scherthan, H Weghorst, C Buzard, G Mennel, HD TI The p16/Cdkn2a/Ink4a gene is frequently deleted in nitrosourea-induced rat glial tumors SO PATHOBIOLOGY LA English DT Article DE glioma; cell cycle; comparative genomic hybridization; chemical carcinogenesis; rat ID WILD-TYPE P53; GLIOBLASTOMA-MULTIFORME; NERVOUS-SYSTEM; THERAPY; HYBRIDIZATION; ASSOCIATION; MUTATIONS; GLIOMAS; MODEL AB The present study investigates nitrosourea-induced rat (Rattus norvegicus) glioma cell lines for the functional status of the p16/Cdkn2a/Ink4a gene, which encodes the p16 cdk4 inhibitor and the alternative reading frame protein, p19ARF. We detected homozygous deletions of the p16/Cdkn2a/Ink4a gene locus in 4 of 5 glioma cell lines (C6, F98, RG2, and RGL.3), but not in the 9L gliosarcoma cell line or in a rat primary fibroblast cell line. RT-PCR demonstrated expression of the p16 and p19ARF mRNAs only in 9L cells and in rat fibroblasts. Comparative genomic in situ hybridization showed that the copy number of rat chromosome RNO5 was not altered in any of the glioma cell lines investigated, indicating that the deletions result from a discrete loss in the region of the p16/Cdkn2a/Ink4a locus. This is the first report of p16/Cdkn2a/Ink4a deletions present in nitrosourea-induced rat glioma cell lines. Since this genetic alteration is also commonly observed in human malignant glial tumors, our results validate the use of chemically induced rat glioma cell lines as an experimental model in the development of gene therapy strategies. Copyright (C) 2000 S. Karger AG, Basel. C1 Univ Med Ctr, Dept Neuropathol, Mol Neurobiol Lab, Marburg, Germany. Univ Med Ctr, Dept Hematol & Oncol, Marburg, Germany. Univ Kaiserslautern, Dept Human Biol & Human Genet, D-67663 Kaiserslautern, Germany. Ohio State Univ, Coll Med & Publ Hlth, Sch Publ Hlth, Div Environm Hlth Sci, Columbus, OH 43210 USA. NCI, Intramural Res Support Program, SAIC Frederick, FCRDC, Frederick, MD 21701 USA. RP Schlegel, J (reprint author), Inst Pathol, Neuropathol Lab, Ismaninger Str 22, D-81675 Munich, Germany. FU NCI NIH HHS [N01-CO-56000] NR 24 TC 21 Z9 22 U1 1 U2 2 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1015-2008 J9 PATHOBIOLOGY JI Pathobiology PD JUL-AUG PY 1999 VL 67 IS 4 BP 202 EP 206 DI 10.1159/000028073 PG 5 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 280QC UT WOS:000085112600007 PM 10738182 ER PT J AU Chen, MF Gray, KD Prentice, MA Mariano, JM Jakowlew, SB AF Chen, MF Gray, KD Prentice, MA Mariano, JM Jakowlew, SB TI Human pulmonary acinar aplasia: Reduction of transforming growth factor-beta ligands and receptors SO PEDIATRIC RESEARCH LA English DT Article ID LUNG BRANCHING MORPHOGENESIS; EMBRYONIC MOUSE LUNG; EPITHELIAL-MESENCHYMAL INTERACTION; CYSTIC ADENOMATOID MALFORMATION; N-MYC; IMMUNOHISTOCHEMICAL LOCALIZATION; DIFFERENTIAL EXPRESSION; EXTRACELLULAR-MATRIX; CELL-PROLIFERATION; GENE-EXPRESSION AB Pulmonary hypoplasia has been found in the human neonatal autopsy population and has been attributed to an alteration in epithelial-mesenchymal interactions during development of the lung. Pulmonary acinar aplasia is a very rare and severe form of pulmonary hypoplasia. The transforming growth factor-betas (TGF-beta) are multifunctional regulatory peptides that are secreted by a variety of normal and malignant cells and are expressed in developing organs including the lung; their tissue distribution patterns have possible significance for signaling roles in many epithelial-mesenchymal interactions. Here, we report our examination of TGF-beta in the lungs of a term female infant diagnosed with pulmonary acinar aplasia whose autopsy revealed extremely hypoplastic lungs with complete absence of alveolar ducts and alveoli. Immunohistochemical and in situ hybridization analyses were used to localize and measure the proteins and mRNA, respectively, for TGF-beta 1, TGF-beta 2, TGF-beta 3, and TGF-beta type I and type II receptors (TGF-beta RI and RII) in formalin-fixed and paraffin-embedded sections of these hypoplastic lungs and normal lungs. Immunostaining for TGF-beta 1,TGF-beta 2, and TGF-beta RI and RII was significantly lower in the bronchial epithelium and muscle of the hypoplastic lungs than in normal lungs, whereas no difference was detected in staining for other proteins including Clara cell 10-kD protein, adrenomedullin, hepatocyte growth factor/scatter factor, and hepatocyte growth factor receptor/Met in the hypoplastic and normal lungs or in the liver and kidneys of this infant compared with normal liver and kidney. In addition, in situ hybridization showed that TGF-beta 1 and TGF-beta RI transcripts were considerably reduced in the bronchial epithelium of the hypoplastic lung compared with normal lung. These results show that there is a selective reduction of TGF-beta in pulmonary acinar aplasia and suggest that the signaling action of TGF-beta in epithelial-mesenchymal interactions in the lungs of this developmental condition may be compromised. C1 NCI, Med Branch, Dept Cell & Canc Biol, Rockville, MD 20850 USA. McGill Univ, Dept Pathol, Montreal, PQ H3A 2B4, Canada. Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. RP Jakowlew, SB (reprint author), NCI, Med Branch, Dept Cell & Canc Biol, 9610 Med Ctr Dr,Suite 300, Rockville, MD 20850 USA. NR 64 TC 9 Z9 9 U1 0 U2 1 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 JUL PY 1999 VL 46 IS 1 BP 61 EP 70 DI 10.1203/00006450-199907000-00011 PG 10 WC Pediatrics SC Pediatrics GA 209QZ UT WOS:000081061100011 PM 10400136 ER PT J AU Clemens, J Abu Elyazeed, R Rao, M Savarino, S Morsy, BZ Kim, Y Wierzba, T Naficy, A Lee, YJ AF Clemens, J Abu Elyazeed, R Rao, M Savarino, S Morsy, BZ Kim, Y Wierzba, T Naficy, A Lee, YJ TI Early initiation of breastfeeding and the risk of infant diarrhea in rural Egypt SO PEDIATRICS LA English DT Article DE breastfeeding; colostrum; diarrhea; Egypt ID PERSISTENT DIARRHEA; GUINEA-BISSAU; CHILDREN AB Background. Initiation of breastfeeding shortly after delivery may enhance breastfeeding's protective effect against diarrhea because of the protective properties of human colostrum contained in early breast milk. Objective. To evaluate whether initiation of breast-feeding within the first 3 days of life, when breast milk contains colostrum, was associated with a lower rate of diarrhea in rural Egyptian infants during the first 6 months of life. Methods. Infants initially breastfed (n = 198) were monitored prospectively with twice-weekly home visits to ascertain dietary practices and diarrheal illnesses. Results. The burden of diarrhea during the first 6 months of life in the cohort was high: seven episodes per child-year of follow-up. Only 151 (76%) infants initiated breastfeeding during the first 3 days of life ("early initiation"). Infants in whom breastfeeding was initiated early had a 26% (95% CI: 2%,44%) lower rate of diarrhea than those initiated late. The protective association between early initiation and diarrhea was independent of the pattern of postinitiation dietary practices and was evident throughout the first 6 months of life. Conclusions. Early initiation of breastfeeding was associated with a marked reduction of the rate of diarrhea throughout the first 6 months of life, possibly because of the salutary effects of human colostrum. These data highlight the need for interventions to encourage early initiation of breastfeeding in less developed settings. C1 NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. USN, Med Res Unit 3, Cairo, Egypt. Minist Hlth & Populat, Abu Homos, Egypt. RP Clemens, J (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, Bldg 6100,Rm 7B03, Bethesda, MD 20892 USA. RI Savarino, Stephen/A-8030-2011 FU NICHD NIH HHS [Y1-HD-0026-01] NR 17 TC 31 Z9 32 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 1999 VL 104 IS 1 BP art. no. EP e3 DI 10.1542/peds.104.1.e3 PG 5 WC Pediatrics SC Pediatrics GA 213EC UT WOS:000081258700018 PM 10390289 ER PT J AU Russian, DA Andrawis-Sorial, V Goheen, MP Edman, JC Vogel, P Turner, RE Klivington, DL Angus, CW Kovacs, JA AF Russian, DA Andrawis-Sorial, V Goheen, MP Edman, JC Vogel, P Turner, RE Klivington, DL Angus, CW Kovacs, JA TI Characterization of a multicopy family of genes encoding a surface-expressed serine endoprotease in rat Pneumocystis carinii SO PROCEEDINGS OF THE ASSOCIATION OF AMERICAN PHYSICIANS LA English DT Article DE AIDS; antigenic variation; kexin; pneumonia; serine proteases; SPRT ID PRO-PROTEIN CONVERTASES; GLYCOPROTEIN GENES; PROHORMONE; ALIGNMENT; PROTEASES; VARIANTS AB A unique family of genes encoding serine endoproteases related to the Saccharomyces cerevisiae serine endoprotease kexin was identified in Pneumocystis carinii. Unlike previously described serine endoprotease genes that are single copies, multiple copies of the P. carinii serine endoprotease are distributed throughout the genome. The proteins predicted by these variant genes demonstrate sequence variability, but they retain the conserved active sites associated with endoprotease activity. The serine endoprotease was localized to the organism surface by immunohistochemical and immunofluorescence studies and to the electron lucent layer of the cyst wall by immunoelectron microscopy. The findings of multiple copies of the serine endoprotease gene in the P. carinii genome, and its localization to the cell surface, suggest that this protease plays an important role in the biology of P. carinii and that antigenic variation of the surface-expressed serine endoprotease may be a strategy for immune evasion. P. carinii serine endoprotease provides a novel target for chemotherapeutic and immune-based approaches to the treatment of P. carinii pneumonia. C1 NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. Indiana Univ, Med Ctr, Dept Pathol, Indianapolis, IN USA. Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. USA, Med Res Inst Infect Dis, Div Pathol, Frederick, MD USA. RP Kovacs, JA (reprint author), NIH, Dept Crit Care Med, Bldg 10,Room 7D43,MSC 1662, Bethesda, MD 20892 USA. NR 22 TC 18 Z9 18 U1 0 U2 0 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 JUL-AUG PY 1999 VL 111 IS 4 BP 347 EP 356 DI 10.1046/j.1525-1381.1999.99118.x PG 10 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 216MT UT WOS:000081447000012 PM 10417743 ER PT J AU McClure, RK AF McClure, RK TI The visual backward masking deficit in schizoaffective disorder SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE backward masking; cognitive deficits; schizoaffective disorder; visual channels; visual perception ID SCHIZOPHRENIA; CHANNELS; MANIA AB 1. Subjects with schizoaffective disorder have an impairment in early visual information processing known as backward masking. 2. Backward masking studies in schizoaffective disorder have not established if the deficit: is state- or trait-related; is associated with negative symptoms or neuroleptic treatment; or is partially attributable to lithium treatment. 3. Integration and interruption are mechanisms of backward masking in schizoaffective disorder, but experiments maximizing interruption only, have not been performed. 4. Studies isolating the transient visual channels have not been performed in patients with schizoaffective disorder. C1 NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP McClure, RK (reprint author), 20405 Shadow Oak Court, Gaithersburg, MD 20886 USA. NR 10 TC 1 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD JUL PY 1999 VL 23 IS 5 BP 785 EP 790 DI 10.1016/S0278-5846(99)00040-8 PG 6 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 228MH UT WOS:000082139900002 PM 10509374 ER PT J AU Oriji, GK AF Oriji, GK TI Nitric oxide in cyclosporine A-induced hypertension: endothelin receptors gene expression SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article ID RENAL-TRANSPLANT RECIPIENTS; TREATED RATS; CELLS; DYSFUNCTION; RESPONSES; RELEASE; ET(A) AB Cyclosporine A (CsA) is an immunosuppressive agent, which also causes hypertension. The effect of CsA on vascular responses was determined in spontaneously hypertensive rats and isolated rat aortic rings. Male rats weighing 250-300 g were given either CsA (25 mg/kg/day) in olive oil or vehicle by i.p. injection for 7 days. CsA administration produced a 27% increase (P < 0.001) in mean arterial pressure (MAP) which reached a plateau after 3 days. Conversely, the level of nitrate/nitrite, metabolites of nitric oxide (NO), decreased by 44% (P < 0.001) in the urine. In the presence of endothelin (ET) 10(-9) M, thoracic aortic rings from rats treated with olive oil, L-Arginine (L-Arg) or L-Arg+CsA showed a 100% increase (P < 0.001) in tension compared to the aortic rings from rats treated with CsA alone; aortic rings from rats treated with CsA alone did not respond to ET. The effects of CsA were reversed in both in vivo and in vitro by pretreatment with L-Arg (10 mg/kg/day ip), the precursor of NO. There were no changes in MAP and tension in rats treated with L-Arg alone. Possible explanation for lack of response to ET of aortic rings from CsA treated rats may be that CsA affected ET signalling pathway; ET receptors mRNA (messenger ribonucleic acid) gene expression was inhibited in aortic rings of rats treated with CsA. In summary, CsA inhibits endothelial NO formation, with resulting increases in MAP, and this inhibition can be overcome by parenteral administration of L-Arg. C1 William Paterson Univ, Dept Biol, Coll Sci & Hlth, Wayne, NJ 07470 USA. NHLBI, Hypertens Endocrine Branch, NIH, Bethesda, MD 20892 USA. RP Oriji, GK (reprint author), William Paterson Univ, Dept Biol, Coll Sci & Hlth, Wayne, NJ 07470 USA. NR 20 TC 2 Z9 2 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD JUL PY 1999 VL 61 IS 1 BP 41 EP 44 DI 10.1054/plef.1999.0071 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 227ZP UT WOS:000082110300008 PM 10477041 ER PT J AU Oriji, GK AF Oriji, GK TI Endothelin-induced prostacyclin production in rat aortic endothelial cells: role of calcium SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article ID PROTEIN-KINASE-C; VASCULAR SMOOTH-MUSCLE; CAT IRIS SPHINCTER; MESANGIAL CELLS; RABBIT AORTA; RECEPTOR; INVOLVEMENT; EXPRESSION; CHANNELS; CLONING AB Endothelin (ET) is a potent vasoconstrictor peptide, released from endothelial cells, which is associated with prostaglandin (PG) release. The mechanism by which ET causes the release of PG is not clearly understood. We used rat aortic endothelial cells to investigate the role of calcium (Ca2+) in ET-1-induced prostacyclin (PGI(2)) release. ET-1 (10(-9) M) produced a significant increase in PGI(2) release. Pretreatment of rat aortic endothelial cells with different doses (10(-9) M and 10(-6) M) of diltiazem (voltage-sensitive L-type calcium channel blocker) produced significant inhibition of ET-1- and PDBu-induced PGI(2) release. Inhibition was first noted at 10(-9) M and was complete at 10(-6) M. Conversely, pretreatment of rat aortic endothelial cells with different doses (10(-9) M and 10(-6) M) of calcium channel blockers (thapsigargin, an intracellular calcium channel blocker or conotoxin, a voltage-sensitive N-type calcium channel blocker) produced no changes on ET-1- or PDBu-induced PGI(2) release. These results provide further support for the concept that PKC mediates ET-induced PGI(2) release in rat aortic endothelial cells via an increase in intracellular calcium and this increase is due to the influx of extracellular calcium and not to the release of calcium from the sarcoplasmic reticulum. C1 William Paterson Univ, Coll Sci & Hlth, Dept Biol, Wayne, NJ 07470 USA. NHLBI, Hypertens Endocrine Branch, NIH, Bethesda, MD 20892 USA. RP Oriji, GK (reprint author), William Paterson Univ, Coll Sci & Hlth, Dept Biol, Wayne, NJ 07470 USA. NR 30 TC 5 Z9 5 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD JUL PY 1999 VL 61 IS 1 BP 45 EP 49 DI 10.1054/plef.1999.0072 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 227ZP UT WOS:000082110300009 PM 10477042 ER PT J AU Geetha, V Di Francesco, V Garnier, J Munson, PJ AF Geetha, V Di Francesco, V Garnier, J Munson, PJ TI Comparing protein sequence-based and predicted secondary structure-based methods for identification of remote homologs SO PROTEIN ENGINEERING LA English DT Article DE hidden Markov models; motifs; remote homologs; secondary structures ID HIDDEN MARKOV-MODELS; ALIGNMENT; RECOGNITION; SEARCH; FOLDS; ACCURACY; DATABASE; CLASSIFICATION; FEATURES; SUCCESS AB We have compared a novel sequence-structure matching technique, FORESST, for detecting remote homologs to three existing sequence based methods, including local amino acid sequence similarity by BLASTP, hidden Markov models (HMMs) of sequences of protein families using SAM, HMMs based on sequence motifs identified using meta-MEME. FORESST compares predicted secondary structures to a library of structural families of proteins, using HMMs, Altogether 45 proteins from nine structural families in the database CATH were used in a cross-validated test of the fold assignment accuracy of each method. Local sequence similarity of a query sequence to a protein family is measured by the highest segment pair (HSP) score, Each of the HMM-based approaches (FORESST, MEME, amino acid sequence-based HMM) yielded log-odds score for the query sequence. In order to make a fair comparison among these methods, the scores for each method were converted to Z-scores in a uniform way by comparing the raw scores of a query protein with the corresponding scores for a set of unrelated proteins, Z-Scores were analyzed as a function of the maximum pairwise sequence identity (MPSID) of the query sequence to sequences used in training the model. For MPSID above 20%, the Z-scores increase linearly with MPSID for the sequence-based methods but remain roughly constant for FORESST. Below 15%, average Z-scores are close to zero for the sequence-based methods, whereas the FORESST method yielded average Z-scores of 1.8 and 1.1, using observed and predicted secondary structures, respectively. This demonstrates the advantage of the sequence-structure method for detecting remote homologs. C1 NIH, ABS, MSCL, CIT, Bethesda, MD 20892 USA. Inst Genom Res, Rockville, MD 20850 USA. INRA, Biol Cellulaire & Mol Lab, F-78352 Jouy En Josas, France. RP Geetha, V (reprint author), NIH, ABS, MSCL, CIT, Bldg 10, Bethesda, MD 20892 USA. NR 44 TC 11 Z9 11 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0269-2139 J9 PROTEIN ENG JI Protein Eng. PD JUL PY 1999 VL 12 IS 7 BP 527 EP 534 DI 10.1093/protein/12.7.527 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 226JW UT WOS:000082017700002 PM 10436078 ER PT J AU Li, DW Allen, DL Harvey, S Perrino, FW Schaaper, RM London, RE AF Li, DW Allen, DL Harvey, S Perrino, FW Schaaper, RM London, RE TI A preliminary CD and NMR study of the Escherichia coli DNA polymerase III Theta subunit SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE DNA polymerase; Theta subunit; nuclear magnetic resonance; circular dichroism ID PROTEIN SECONDARY STRUCTURE; EPSILON-SUBUNIT; SENSITIVITY; RELAXATION; HOLOENZYME; SPECTROSCOPY; EXONUCLEASE; DYNAMICS; DOMAIN; HOLE AB The theta subunit of DNA polymerase III, the main replicative polymerase of Escherichia coli, has been examined by circular dichroism and by NMR spectroscopy, The polymerase core consists of three subunits: alpha, epsilon, and theta, with alpha possessing the polymerase activity, epsilon functioning as a proofreading exonuclease, and theta, a small subunit of 8.9 kD, of undetermined function. The theta subunit has been expressed in E. coli, and a CD analysis of theta indicates the presence of a significant amount of secondary structure: similar to 52% alpha helix, 9% beta sheet, 21% turns, and 18% random coil, However, at higher concentrations, theta yields a poorly-resolved 1D proton NMR spectrum in which both the amide protons and the methyl protons show poor chemical shift dispersion. Subsequent H-1,N-15 HSQC analysis of uniformly-N-15-labeled theta supports the conclusion that approximately half of the protein is reasonably well-structured. Another quarter of the protein, probably including some of the N-terminal region, is highly mobile, exhibiting a chemical shift pattern indicative of random coil structure. The remaining amide resonances exhibit significant broadening, indicative of intermolecular and/or intramolecular exchange processes. Improved chemical shift dispersion and greater uniformity of resonance intensities in the H-1-N-15 HSQC spectra resulted when [U-N-15]-theta was examined in the presence of epsilon 186-the N-terminal domain of the epsilon-subunit, Further work is currently in progress to define the solution structure of theta and the theta-epsilon 186 complex. Proteins 1999; 36:111-116. Published 1999 Wiley-Liss, Inc.dagger C1 NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Wake Forest Univ, Med Ctr, Dept Biochem, Winston Salem, NC 27103 USA. NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP London, RE (reprint author), NIEHS, Struct Biol Lab, MR-01,Box 12233, Res Triangle Pk, NC 27709 USA. NR 21 TC 7 Z9 7 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 0887-3585 J9 PROTEINS JI Proteins PD JUL 1 PY 1999 VL 36 IS 1 BP 111 EP 116 DI 10.1002/(SICI)1097-0134(19990701)36:1<111::AID-PROT9>3.0.CO;2-1 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 200UK UT WOS:000080558300009 PM 10373010 ER PT J AU Somerfield, MR Stefanek, ME Smith, TJ Padberg, JJ AF Somerfield, MR Stefanek, ME Smith, TJ Padberg, JJ TI A systems model for adaptation to somatic distress among cancer survivors SO PSYCHO-ONCOLOGY LA English DT Article ID BONE-MARROW TRANSPLANTATION; BREAST-CANCER; 5-FACTOR MODEL; PERSONALITY; NEUROTICISM; HEALTH; COMPLAINTS; STRESS; COGNITION; CHECKLIST AB Applied coping research has generally failed to fulfill its goal of providing an empirical basis for clinical interventions, and research on coping with cancer is no exception. This can be attributed in large measure to the wide gap between coping theory and coping research. Theories of stress and adaptation are complex systems formulations that present conceptual and methodological challenges and thus make testing comprehensive models difficult. The present paper reviews arguments for a microanalytic strategy through which researchers can increase coverage of relevant variables from broad systems models of stress and coping by concentrating their resources on selected, high-frequency, high-stress problems. The utility of this approach for formulating problem-specific systems models is illustrated using the example of coping with somatic distress among cancer survivors. Copyright (C) 1999 John Wiley & Sons, Ltd. C1 Amer Soc Clin Oncol, Hlth Serv Res, Alexandria, VA 22314 USA. NCI, Biobehav Res Branch, Div Canc Control & Populat Sci, NIH, Bethesda, MD USA. Virginia Commonwealth Univ, Med Coll Virginia, Massey Canc Ctr, Richmond, VA 23298 USA. RP Somerfield, MR (reprint author), Amer Soc Clin Oncol, Hlth Serv Res, 225 Reinekers Lane,Suite 650, Alexandria, VA 22314 USA. NR 64 TC 15 Z9 15 U1 1 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD JUL-AUG PY 1999 VL 8 IS 4 BP 334 EP 343 DI 10.1002/(SICI)1099-1611(199907/08)8:4<334::AID-PON392>3.0.CO;2-E PG 10 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 229CL UT WOS:000082175900006 PM 10474851 ER PT J AU Gurguis, GNM Turkka, J Laruelle, M Kleinman, J Linnoila, M AF Gurguis, GNM Turkka, J Laruelle, M Kleinman, J Linnoila, M TI Coupling efficiency of brain beta-adrenergic receptors to G(s) protein in suicide, alcoholism and control subjects SO PSYCHOPHARMACOLOGY LA English DT Article DE brain; beta-adrenergic receptor; alcoholism; suicide; G(s) protein; coupling ID ADRENOCEPTOR BINDING-SITES; RAT-BRAIN; ADENYLATE-CYCLASE; MONONUCLEAR LEUKOCYTES; I125 IODOCYANOPINDOLOL; ENDOGENOUS-DEPRESSION; QUANTITATIVE-ANALYSIS; CEREBRAL-CORTEX; FRONTAL-CORTEX; VICTIMS AB Abnormal beta-adrenergic receptor (beta AR) density in the brains of suicide victims has been reported, although results of studies are inconsistent. Ethanol modifies beta AR-mediated signal transduction. Moreover abnormal beta AR function has been implicated in alcoholism. beta AR antagonists, which were used as ligands in previous beta AR binding studies, also bind to 5-HT1B/1D beta receptors; hence, their estimates of beta AR density are confounded by binding to 5-HT1B/1D beta receptors. More importantly, previous studies did not examine beta AR agonist affinity or coupling efficiency to G(s) protein. We investigated agonist affinity and coupling efficiency of beta AR to G(s) protein in the brains of ten suicide victims, six subjects with alcoholism, and eight controls. There were no differences in beta AR density in either the frontal cortex or hippocampus of suicide victims or alcoholic subjects compared to controls, Preliminary results indicate beta AR supercoupling in suicide victims in both brain regions and uncoupling in alcoholic subjects in the frontal cortex. These results are discussed in view of the existing literature on the role of beta AR in suicide and alcoholism and the mechanism of action of antidepressants. C1 Dept Vet Affairs Med Ctr, Lab Clin Neurosci, Dallas, TX 75216 USA. NIAAA, DICBR, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. Oulu Univ, Dept Neurol, Oulu, Finland. Columbia Univ, Dept Psychiat, New York, NY 10029 USA. NIMH, St Elizabeths Hosp, Ctr Neurosci, Washington, DC 20032 USA. RP Gurguis, GNM (reprint author), Dept Vet Affairs Med Ctr, Lab Clin Neurosci, 4500 S Lancaster Rd,Mental Hlth 116A, Dallas, TX 75216 USA. NR 65 TC 10 Z9 10 U1 1 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 1999 VL 145 IS 1 BP 31 EP 38 DI 10.1007/s002130051029 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 219MM UT WOS:000081611100003 PM 10445370 ER PT J AU Sher, L AF Sher, L TI The possible role of seasonal mood changes in the seasonal distribution of acute myocardial infarction SO PSYCHOSOMATICS LA English DT Letter C1 NIMH, Sect Biol Rhythms, Bethesda, MD 20892 USA. RP Sher, L (reprint author), NIMH, Sect Biol Rhythms, Bethesda, MD 20892 USA. NR 5 TC 3 Z9 3 U1 0 U2 0 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD JUL-AUG PY 1999 VL 40 IS 4 BP 364 EP 364 PG 1 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 212VJ UT WOS:000081238100015 PM 10402885 ER PT J AU Avila, NA Dwyer, AJ Dale, JK Lopatin, UA Sneller, MC Jaffe, ES Puck, JM Straus, SE AF Avila, NA Dwyer, AJ Dale, JK Lopatin, UA Sneller, MC Jaffe, ES Puck, JM Straus, SE TI Autoimmune lymphoproliferative syndrome: A syndrome associated with inherited genetic defects that impair lymphocytic apoptosis-CT and US features SO RADIOLOGY LA English DT Article DE autoimmune lymphoproliferative syndrome; familial conditions; lymphatic system, CT; lymphatic system, diseases; lymphatic system, US ID MUTATIONS AB PURPOSE: To describe the imaging findings in patients with autoimmune lymphoproliferative syndrome (ALPS) and to relate the findings to the clinical and genetic features of this recently recognized syndrome. MATERIALS AND METHODS: Retrospective or prospective reviews of the computed tomographic (CT) and ultrasonographic (US) studies and the clinical features in 19 consecutive patients with ALPS were performed. RESULTS: Most patients presented in the 1st year of life with symptoms of adenopathy and hepatosplenomegaly. At the time of presentation to the institution, 12 patients had already undergone splenectomy, and 14 patients had developed autoimmune disorders. All patients had multifocal adenopathy, which war massive in some patients; 14 of 15 patients who underwent CT of the chest had an enlarged thymus, and all six patients who retained their spleens and who underwent imaging had splenomegaly. Ten of 18 patients who underwent liver imaging had hepatomegaly. The adenopathy at US was hyper- and/or isoechoic relative to the liver and thyroid and was enhanced at CT in some patients. All patients had defective lymphocytic apoptosis, or programmed cell death, which was due to specific Fas (APT1 [TNFRSF6]) mutations in 15 patients. CONCLUSION: Patients with ALPS demonstrate nonspecific but often dramatic imaging findings of lymphoproliferative disorders, such as adenopathy, splenomegaly, thymic enlargement, and hepatomegaly. The stability of the clinical findings over months to years and the pattern of lymph node echogenicity may suggest the diagnosis of ALPS. C1 NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIAID, Clin Invest Lab, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Bethesda, MD USA. RP Avila, NA (reprint author), NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bldg 10,Rm 1C660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. NR 15 TC 15 Z9 15 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 JUL PY 1999 VL 212 IS 1 BP 257 EP 263 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 210CE UT WOS:000081086900039 PM 10405750 ER PT J AU Hyman, SE AF Hyman, SE TI Mind and body SO SCIENCES-NEW YORK LA English DT Letter C1 NIMH, Bethesda, MD 20892 USA. RP Hyman, SE (reprint author), NIMH, Bethesda, MD 20892 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 JUL-AUG PY 1999 VL 39 IS 4 BP 47 EP 48 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 210PE UT WOS:000081113200021 ER PT J AU Leshner, AI AF Leshner, AI TI Mind and body SO SCIENCES-NEW YORK LA English DT Letter C1 NIMH, Bethesda, MD 20892 USA. RP Leshner, AI (reprint author), NIMH, Bethesda, MD 20892 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 JUL-AUG PY 1999 VL 39 IS 4 BP 47 EP 47 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 210PE UT WOS:000081113200022 ER PT J AU Jaffe, ES AF Jaffe, ES TI Introduction: Hodgkin's lymphoma - Pathology, pathogenesis, and treatment SO SEMINARS IN HEMATOLOGY LA English DT Editorial Material ID DISEASE; COMPOSITE C1 NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. NR 16 TC 4 Z9 4 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JUL PY 1999 VL 36 IS 3 BP 217 EP 219 PG 3 WC Hematology SC Hematology GA 222FY UT WOS:000081774400001 PM 10462321 ER PT J AU Austin, H Macaluso, M Nahmias, A Lee, FK Kelaghan, J Fleenor, M Hook, EW AF Austin, H Macaluso, M Nahmias, A Lee, FK Kelaghan, J Fleenor, M Hook, EW TI Correlates of herpes simplex virus seroprevalence among women attending a sexually transmitted disease clinic SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID GENITAL HERPES; UNITED-STATES; INFECTION; TYPE-2; RISK; EPIDEMIOLOGY; GLYCOPROTEIN; ACQUISITION AB Background: Infections by herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are common in the United States. Herpes simplex virus type 2 is transmitted sexually, and the prevalence of antibodies to HSV-2 has increased in recent years. Goals of this Study: The objective of the present study was to estimate the seroprevalence of HSV-1 and HSV-2 antibodies among women attending a sexually transmitted disease (STD) clinic and to evaluate factors associated with HSV-1 and HSV-2 seropositivity. Study Design: The report describes a cross-sectional study conducted at an STD clinic. This study included 1,103 women between the ages of 18 and 35, Eighty-nine percent of the subjects were African Americans. The remaining subjects were white. Results: The overall prevalence of HSV-1 and HSV-2 antibodies among study subjects was 72% and 64%, respectively. Both HSV-1 and HSV-2 seropositivity were related directly to age and were higher among African Americans than whites. The prevalence of HSV-2 antibodies also increased with the number of lifetime sexual partners, an early age at first coitus, a history of syphilis, and the absence of HSV-1 antibodies. Drug use and recent use of barrier contraception were unrelated to either HSV-1 or HSV-2. Comment: Despite efforts by the public health community to prevent AIDS by promoting safe sexual practices, the prevalence of HSV-2 seropositivity has increased in recent years. Increased numbers of partners and an early age at first coitus are important correlates of HSV-2 infection. Public health interventions to prevent HSV-2 infection should target teenagers. Women of reproductive age attending STD clinics may also comprise an important target for interventions to prevent perinatal herpes. C1 Emory Univ, Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA. NICHHD, Contracept & Reprod Hlth Branch, Bethesda, MD 20892 USA. Univ Alabama, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. Univ Alabama, Sch Med, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. Jefferson Cty Dept Hlth, Birmingham, AL USA. RP Austin, H (reprint author), Emory Univ, Sch Publ Hlth, Dept Epidemiol, 1518 Clifton Rd NE, Atlanta, GA 30322 USA. RI Macaluso, Maurizio/J-2076-2015 OI Macaluso, Maurizio/0000-0002-2977-9690 FU NICHD NIH HHS [N01-HD-1-3135] NR 19 TC 44 Z9 45 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 JUL PY 1999 VL 26 IS 6 BP 329 EP 334 DI 10.1097/00007435-199907000-00004 PG 6 WC Infectious Diseases SC Infectious Diseases GA 211BA UT WOS:000081139000004 PM 10417020 ER PT J AU Zhong, Z Enomoto, N Connor, HD Moss, N Mason, RP Thurman, RG AF Zhong, Z Enomoto, N Connor, HD Moss, N Mason, RP Thurman, RG TI Glycine improves survival after hemorrhagic shock in the rat SO SHOCK LA English DT Article DE amino acid; hypovolemic shock; tumor necrosis factor-alpha; free radicals; Kupffer cells ID MULTIPLE-ORGAN-FAILURE; NECROSIS-FACTOR-ALPHA; LEUKOCYTE ADHESION; KUPFFER CELLS; INCREASES; LIVER; MACROPHAGES; GENERATION; INHIBITION; STRYCHNINE AB This study investigated the effect of glycine on hemorrhagic shock in the rat. Rats were bled to maintain mean arterial pressure at 30-35 mm Hg for 1 h and subsequently resuscitated with 60% shed blood and lactated Ringer's solution. Only 20% of rats receiving saline just prior to resuscitation survived 72 h after shock. Survival was increased by glycine (11.2-90.0 mg/kg, i.v.) in a dose;dependent manner (half-maximal effect = 25 mg/kg) and reached maximal values of 78% at 45 mg/kg. Eighteen hours after resuscitation, creatinine phosphokinase increased 23-fold, transaminases increased 33-fold, and creatinine was elevated 2.4-fold, indicating injury to the heart, liver, and kidney, respectively. Pulmonary edema, leukocyte infiltration, and hemorrhage were also observed. In the kidney, proximal tubular necrosis, leukocyte infiltration, and severe hemorrhage in the outer medullary area occurred in rats receiving saline. Glycine reduced these pathological alterations significantly. It has been reported that oxidative stress and tumor necrosis factor(TNF)-alpha-production are involved in the pathophysiology of multiple-organ injury after shock. In this study, free radical production was increased 4-fold during shock, an effect blocked largely by glycine. Increases in intracellular calcium and production of TNF-alpha by isolated Kupffer cells stimulated by endotoxin were elevated significantly by hemorrhagic shock, alterations which were totally prevented by glycine. Taken together, it is concluded that glycine reduces organ injury and mortality caused by hemorrhagic shock by preventing free radical production and TNF-alpha formation. C1 Univ N Carolina, Dept Pharmacol, Hepatobiol & Toxicol Lab, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Thurman, RG (reprint author), Univ N Carolina, Dept Pharmacol, Hepatobiol & Toxicol Lab, CB 7365,Mary Ellen Jones Bldg, Chapel Hill, NC 27599 USA. NR 33 TC 47 Z9 50 U1 0 U2 1 PU BIOMEDICAL PRESS PI AUGUSTA PA 1021 15TH ST, BIOTECH PARK STE 9,, AUGUSTA, GA 30901 USA SN 1073-2322 J9 SHOCK JI Shock PD JUL PY 1999 VL 12 IS 1 BP 54 EP 62 DI 10.1097/00024382-199907000-00008 PG 9 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 216BQ UT WOS:000081421000008 PM 10468052 ER PT J AU Leonard, JC Toji, LH Bender, PK Beiswanger, CM Beck, JC Johnson, RT AF Leonard, JC Toji, LH Bender, PK Beiswanger, CM Beck, JC Johnson, RT TI Regional mapping panels for human chromosomes 1, 2, and 7 SO SOMATIC CELL AND MOLECULAR GENETICS LA English DT Article ID SOMATIC-CELL HYBRIDS; HUMAN X-CHROMOSOME; TRANSLOCATION BREAKPOINTS; GENITOURINARY DYSPLASIA; DNA PROBES; GENE; LOCALIZATION; ASSIGNMENT; MARKERS; MAPS AB The NIGMS Human Genetic Cell Repository has assembled regional mapping panels for human chromosomes 1, 2, and 7 from human rodent somatic cell hybrids submitted to the collection by researchers from 14 different laboratories. All hybrids were characterized initially by the submitters and verified by the Repository. Each hybrid carries a stable defined human segment as a derivative or deletion chromosome. These panels define 8-10 intervals for each chromosome. The panel for chromosome 2 is a new resource. The panels for chromosomes 1 and 7 complement previously published panels. The Repository distributes these regional mapping panels as cell cultures or as DNA. Information about these panels as well as for panels for chromosomes 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 21, 22, and X may be viewed in the NIGMS Repository electronic catalog (http://locus.umdnj.edu/nigms). C1 NIGMS, Human Genet Cell Repository, Coriell Inst Med Res, Camden, NJ 08103 USA. RP Leonard, JC (reprint author), NIGMS, Human Genet Cell Repository, Coriell Inst Med Res, Camden, NJ 08103 USA. FU NIGMS NIH HHS [N01-GM-9-2102] NR 39 TC 0 Z9 0 U1 0 U2 1 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 JUL PY 1999 VL 25 IS 4 BP 247 EP 251 DI 10.1023/A:1019236027475 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity GA 477WP UT WOS:000171307500005 PM 11586791 ER PT J AU Venkatesh, B Ramasamy, S Mylrajan, M Asokan, R Manoharan, PT Rifkind, JM AF Venkatesh, B Ramasamy, S Mylrajan, M Asokan, R Manoharan, PT Rifkind, JM TI Fourier transform Raman approach to structural correlation in hemoglobin derivatives SO SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY LA English DT Article DE hemeproteins; hemoglobin; reconstituted hemoglobins; FT-Raman; derivatives; structure ID HYBRID HEMOGLOBINS; HEME-PROTEINS; SPIN STATE; SPECTRA; SPECTROSCOPY; OXYHEMOGLOBIN; MYOGLOBIN; DEOXY; HEMOPROTEINS; SCATTERING AB In order to obtain information on the structural aspects of hemoglobin (Hb), Fourier transform Raman (FT-R) measurements on various ferrous, ferric derivatives and nickel reconstituted Kb (NiHb) has been made. FT-R spectra for these derivatives were obtained by laser excitation in the near infrared region (NIR) (1064 nm) whereby the wave-number region (600-1700 cm(-1)) related to both porphyrin ring modes and some globin modes were monitored. Comparison of various modes was made based on previous resonance Raman (RR) results. The wave-number shifts with respect to changes in oxidation state and spin state are very similar to those observed by RR. Additional bands at 1654, 1459, and 1003 cm(-1) for deoxyHb and at 1656, 1454, and 1004 cm(-1) for oxy Hb can be correlated to globin modes. The shift in the position of these bands for the binding of oxygen can be related to changes in conformation during the transformation. The presence of two distinct sites in NiHb could be monitored by the use of FT-R technique. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Indian Inst Technol, Dept Chem, Reg Sophisticated Instrumentat Ctr, Madras 600036, Tamil Nadu, India. NIA, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Manoharan, PT (reprint author), Indian Inst Technol, Dept Chem, Reg Sophisticated Instrumentat Ctr, Madras 600036, Tamil Nadu, India. NR 34 TC 30 Z9 32 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1386-1425 J9 SPECTROCHIM ACTA A JI Spectroc. Acta Pt. A-Molec. Biomolec. Spectr. PD JUL PY 1999 VL 55 IS 7-8 BP 1691 EP 1697 DI 10.1016/S1386-1425(99)00008-6 PG 7 WC Spectroscopy SC Spectroscopy GA 209AY UT WOS:000081025900034 PM 10439514 ER PT J AU Whitcup, SM AF Whitcup, SM TI Uveitis: Insight into the immune response - Introduction SO SPRINGER SEMINARS IN IMMUNOPATHOLOGY LA English DT Editorial Material C1 NEI, Bethesda, MD 20892 USA. RP Whitcup, SM (reprint author), NEI, 10 Ctr Dr, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-4325 J9 SPRINGER SEMIN IMMUN JI Springer Semin. Immunopathol. PD JUL PY 1999 VL 21 IS 2 BP 91 EP 94 DI 10.1007/BF00810242 PG 4 WC Immunology; Pathology SC Immunology; Pathology GA 224HP UT WOS:000081892200001 ER PT J AU Caspi, RR AF Caspi, RR TI Immune mechanisms in uveitis SO SPRINGER SEMINARS IN IMMUNOPATHOLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; ORAL TOLERANCE; S-ANTIGEN; GENETIC SUSCEPTIBILITY; INFLAMMATORY RESPONSE; MOLECULAR MIMICRY; RETINAL ANTIGENS; TH2 CELLS; INDUCTION; DISEASE C1 NEI, Sect Immunoregulat, Immunol Lab, Bethesda, MD 20892 USA. RP Caspi, RR (reprint author), NEI, Sect Immunoregulat, Immunol Lab, NIH Bg 10,Rm 10N222,10 Ctr Dr MSC 1857, Bethesda, MD 20892 USA. NR 61 TC 55 Z9 56 U1 1 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-4325 J9 SPRINGER SEMIN IMMUN JI Springer Semin. Immunopathol. PD JUL PY 1999 VL 21 IS 2 BP 113 EP 124 DI 10.1007/BF00810244 PG 12 WC Immunology; Pathology SC Immunology; Pathology GA 224HP UT WOS:000081892200003 PM 10457585 ER PT J AU Chan, CC Mochizuki, M AF Chan, CC Mochizuki, M TI Sympathetic ophthalmia: an autoimmune ocular inflammatory disease SO SPRINGER SEMINARS IN IMMUNOPATHOLOGY LA English DT Article ID KOYANAGI-HARADA DISEASE; DALEN-FUCHS NODULES; POSTERIOR UVEITIS; ANTERIOR UVEITIS; YAG CYCLOTHERAPY; RETINAL ANTIGENS; S-ANTIGEN; UVEORETINITIS; IMMUNOHISTOCHEMISTRY; INDUCTION C1 NEI, NIH, Bethesda, MD 20892 USA. Tokyo Med & Dent Univ, Sch Med, Dept Ophthalmol, Tokyo 113, Japan. RP Chan, CC (reprint author), NEI, NIH, Bldg 10,Rm 10N103,10 Ctr DR MSC 1857, Bethesda, MD 20892 USA. NR 58 TC 13 Z9 13 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-4325 J9 SPRINGER SEMIN IMMUN JI Springer Semin. Immunopathol. PD JUL PY 1999 VL 21 IS 2 BP 125 EP 134 DI 10.1007/BF00810245 PG 10 WC Immunology; Pathology SC Immunology; Pathology GA 224HP UT WOS:000081892200004 PM 10457586 ER PT J AU Csaky, K Nussenblatt, R AF Csaky, K Nussenblatt, R TI Gene therapy in the treatment of ocular inflammation SO SPRINGER SEMINARS IN IMMUNOPATHOLOGY LA English DT Article ID ENDOTOXIN-INDUCED UVEITIS; NF-KAPPA-B; IN-VIVO; TRANSFORMING GROWTH-FACTOR-BETA-1; PIGMENT EPITHELIUM; IMMUNE PRIVILEGE; RAT RETINA; T-CELLS; EXPRESSION; DELIVERY AB Gene therapy may become a powerful therapeutic modality in the treatment of both ocular inflammatory disease and as a means of preventing rejection following tissue transplantation. By directly introducing into ocular cells genes that encode proteins capable of down-regulating the immune response, gene therapy has potential for both therapy and as a method for studying mechanisms of disease. While marked and rapid advances in the study of gene therapy have been realized, technical questions regarding the appropriate vector or the choice of efficacious immunomodulatory protein still remain. C1 NEI, Bethesda, MD 20892 USA. RP Csaky, K (reprint author), NEI, 10 Ctr Dr,MSC-1858,Bldg 10 Room 10N-202, Bethesda, MD 20892 USA. NR 36 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-4325 J9 SPRINGER SEMIN IMMUN JI Springer Semin. Immunopathol. PD JUL PY 1999 VL 21 IS 2 BP 191 EP 197 DI 10.1007/BF00810250 PG 7 WC Immunology; Pathology SC Immunology; Pathology GA 224HP UT WOS:000081892200009 PM 10457591 ER PT J AU Buggage, RR Spraul, CW Wojno, TH Grossniklaus, HE AF Buggage, RR Spraul, CW Wojno, TH Grossniklaus, HE TI Kimura disease of the orbit and ocular adnexa SO SURVEY OF OPHTHALMOLOGY LA English DT Review DE angiolymphoid hyperplasia with eosinophilia; eosinophilia; eyelid; Kimura disease; lacrimal gland; orbit tumor; proptosis ID ANGIOLYMPHOID HYPERPLASIA; SOFT-TISSUE; EOSINOPHILIA; SKIN; DISTINCTION; HEMANGIOMA; GRANULOMA; ENTITIES AB Kimura disease (KD) is a distinct clinicopathologic entity that has been the subject of considerable confusion and debate. Although common in Asia, KD rarely occurs in non-Asian patients. Kimura disease shares both clinical and histopathologic features with angiolymphoid hyperplasia with eosinophilia (ALHE). Because of this overlap and the rarity of KD in Europe and the United States, KD and ALHE have been used synonymously in the Western medical literature, as they were thought to represent variations of the same disease. Some pathologic reports have called for distinguishing KD and ALHE as two separate entities, based on their histologic features. Kimura disease occurs most commonly in the head and neck region and has been described in the orbit, eyelids, and lacrimal gland more frequently than ALHE. Because both diseases can cause proptosis, lid swelling, ocular dysmotility, or a palpable mass, they should be considered in the differential diagnosis of orbital lesions occurring in adults. We report two cases of KD involving the orbit and ocular adnexa, and review additional cases reported in the literature. The ophthalmic literature does not clearly reflect the current understanding that KD and ALHE are best considered two separate clinicopathologic entities. (C) 1999 by Elsevier Science Inc. All rights reserved. C1 Emory Univ, Sch Med, Dept Ophthalmol, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. RP Buggage, RR (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10,Rm 10N112, Bethesda, MD 20892 USA. FU NEI NIH HHS [EY06030] NR 41 TC 30 Z9 34 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0039-6257 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD JUL-AUG PY 1999 VL 44 IS 1 BP 79 EP 91 DI 10.1016/S0039-6257(99)00064-8 PG 13 WC Ophthalmology SC Ophthalmology GA 226XU UT WOS:000082049100007 PM 10466591 ER PT J AU Hall, FS DeVries, AC Fong, GW Huang, S Pert, A AF Hall, FS DeVries, AC Fong, GW Huang, S Pert, A TI Effects of 5,7-dihydroxytryptamine depletion of tissue serotonin levels on extracellular serotonin in the striatum assessed with in vivo microdialysis: Relationship to behavior SO SYNAPSE LA English DT Article DE serotonin; microdialysis; anxiety; recovery ID MEDIAN RAPHE NUCLEI; ELEVATED PLUS-MAZE; 5-HYDROXYINDOLEACETIC ACID; LOCOMOTOR-ACTIVITY; BRAIN-SEROTONIN; 6-OHDA LESION; MDMA ECSTASY; RAT; 5-HYDROXYTRYPTAMINE; DOPAMINE AB Effects of i.c.v. administration of 5,7-dihydroxytryptamine (5,7-DHT) on biochemistry and behavior were studied in awake Sprague-Dawley rats. It was found that 5,7-DHT depletion of striatal tissue levels of serotonin (5-HT) does not diminish extracellular levels until substantial depletions occur. This finding is similar to those observed after 6-hydroxydopamine lesions of the brain dopamine systems. Although varying amounts of 5,7-DHT produced serotonin depletions in striatal tissue, decreases in extracellular levels were only observed at tissue depletions greater than 60% compared to saline-injected control subjects. Thus, the effects of serotonin lesions which produce only moderate depletions may not be the result of decreased extracellular serotonin, but instead may be the result of compensatory changes in remaining neurons which maintain normal extracellular serotonin concentrations. Different degrees of striatal serotonin depletion were associated with opposite behavioral effects. Moderate levels of serotonin depletion (50-75%) produced evidence of increased anxiety, while these effects were no longer seen in rats with more severe 5-HT depletions (>75%). Synapse 33:16-25, 1999. (C) 1999 Wiley-Liss, Inc. C1 NIAAA, DICBR, Clin Studies Lab, Bethesda, MD 20892 USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. RP Hall, FS (reprint author), NIDA, IRP, Mol Neurobiol Branch, POB 5180, Baltimore, MD 21224 USA. RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 NR 48 TC 43 Z9 43 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 JUL PY 1999 VL 33 IS 1 BP 16 EP 25 DI 10.1002/(SICI)1098-2396(199907)33:1<16::AID-SYN2>3.3.CO;2-# PG 10 WC Neurosciences SC Neurosciences & Neurology GA 203GW UT WOS:000080700800002 PM 10380847 ER PT J AU Langford, CA Hoffman, GS AF Langford, CA Hoffman, GS TI Wegener's granulomatosis SO THORAX LA English DT Review ID ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES; HUMAN ENDOTHELIAL-CELLS; SYSTEMIC VASCULITIS; C-ANCA; PULSE CYCLOPHOSPHAMIDE; IN-VITRO; DISEASE; PROTEINASE-3; NEUTROPHILS; THERAPY C1 NIAID, Immunol Dis Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Cleveland Clin Fdn, Dept Rheumat & Immunol Dis, Cleveland, OH 44195 USA. RP Langford, CA (reprint author), NIAID, Immunol Dis Sect, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 68 TC 64 Z9 75 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD JUL PY 1999 VL 54 IS 7 BP 629 EP 637 PG 9 WC Respiratory System SC Respiratory System GA 212JC UT WOS:000081212700015 PM 10377211 ER PT J AU Shimada, H Achanzar, W Waalkes, MP Hochadel, JF AF Shimada, H Achanzar, W Waalkes, MP Hochadel, JF TI Testosterone pretreatment enhances cadmium-induced increases in c-myc and c-jun transcript levels in L6 myoblasts SO TOXIC SUBSTANCE MECHANISMS LA English DT Article DE cadmium; testosterone; aberrant gene expression; c-myc; c-jun; myoblasts ID METAL CARCINOGENESIS; METALLOTHIONEIN; EXPRESSION; GENE; TRANSFORMATION; ONCOGENE; CELLS AB Cadmium is a known carcinogen that often targets male reproductive tissues. In many cells cadmium induces expression of the proto-oncogenes c-myc and c-jun. Several steroid hormones can. modify the effects of cadmium, including testosterone. Thus, we studied the effects of testosterone on, cadmium toxicity or c-myc and c-jun expression in L6 cells. Testosterone at non-toxic doses (0-10 mu M) did not modify either cadmium-induced cytotoxicity or expression of metallothionein, a protein involved in acquired cadmium tolerance. Cadmium (5 mu M) increased c-myc and c-jun mRNA levels by 3.1-fold and 2.8-fold of control, respectively. Testosterone alone (10 mu M) decreased basal levels of c-myc transcript but did not affect c-jun. Despite reducing transcript levels by itself testosterone pretreatment increased cadmium-induced c-myc transcript accumulation to 5-fold over control. Testosterone pretreatment also enhanced cadmium induction of c-jun mRNA accumulation. Thus it appears that testosterone increases cadmium-induced increases of proto-oncogene transcripts, an. observation that may have implications in cadmium carcinogenesis. C1 NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. NCI, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. NR 28 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI LONDON PA ONE GUNPOWDER SQUARE, LONDON EC4A 3DE, ENGLAND SN 1076-9188 J9 TOX SUBST MECH JI Tox. Subst. Mech. PD JUL-SEP PY 1999 VL 18 IS 3 BP 129 EP 137 DI 10.1080/107691899229098 PG 9 WC Biochemistry & Molecular Biology; Toxicology SC Biochemistry & Molecular Biology; Toxicology GA 231LA UT WOS:000082309400002 ER PT J AU Nyska, A Haseman, JK Hailey, JR Smetana, S Maronpot, RR AF Nyska, A Haseman, JK Hailey, JR Smetana, S Maronpot, RR TI The association between severe nephropathy and pheochromocytoma in the male F344 rat - The National Toxicology Program experience SO TOXICOLOGIC PATHOLOGY LA English DT Article DE rat adrenal medullary tumors; glomerulonephropathy; calcium; nongenotoxic; carcinogenicity ID CELL-PROLIFERATION; B6C3F(1) MICE; CARCINOGENICITY; CALCIUM AB The possible correlation between the severity of chronic progressive glomerulonephropathy (CPN) and the incidence of adrenal pheochromocytoma was examined in selected studies of male Fischer 344 (F344) rats at the National Toxicology Program (NTP). The NTP historical control database was first examined in order to determine whether there was association between the severity of CPN and the occurrence of adrenal pheochromocytoma in unexposed animals. Following this analysis, the 125 most recent NTP studies conducted in F344 rats were examined in order to determine how frequently chemicals that cause increased severity of CPN show-ed an increased incidence of pheochromocytoma. Finally, we examined the association between the incidence of pheochromocytoma and the severity of CPN in those NTP studies with chemically related increased rates of pheochromocytoma. In control male F344 rats surviving beyond 21 mo, the incidence of adrenal pheochromocytoma was consistently higher in animals with more severe CPN. This association was significant (p ( 0.05) both for 900 NTP inhalation study controls and 900 NTP feeding study controls. An association was not consistently observed when dosed groups were considered. Although 22% (28/125) of NTP studies reported a chemically related increased severity of CPN, only 3 of these reported a corresponding significant increase in the incidence of pheochromocytoma. Of 6 NTP studies that reported increased incidence of pheochromocytoma, animals with pheochromocytoma from 5 of those studies had some degree of increased severity of CPN. However, the estimated strength of the correlation with the severity of CPN varied from study to study and was often quite different from that indicated by an analysis of the more extensive NTP control databases. The possible correlation between the severity of CPN and the incidence of pheochromocytoma may influence interpretation of carcinogenic effects observed at this site. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Nyska, A (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 27 TC 19 Z9 19 U1 0 U2 0 PU SOC TOXICOLOGIC PATHOLOGISTS PI MT ROYAL PA 19 MANTUA RD, MT ROYAL, NJ 08061 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL-AUG PY 1999 VL 27 IS 4 BP 456 EP 462 DI 10.1177/019262339902700410 PG 7 WC Pathology; Toxicology SC Pathology; Toxicology GA 222AD UT WOS:000081759300010 PM 10485827 ER PT J AU Peters, JM Morishima, H Ward, JH Coakley, CJ Kimura, S Gonzalez, FJ AF Peters, JM Morishima, H Ward, JH Coakley, CJ Kimura, S Gonzalez, FJ TI Role of CYP1A2 in the toxicity of long-term phenacetin feeding in mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE cytochrome P-450 (CYP); CYP1A2; phenacetin; toxicity; carcinogenicity ID N-HYDROXYPHENACETIN; METABOLITES; ANALGESICS; ABUSE; CARCINOGENICITY; NEOPLASIA; MORBIDITY; MORTALITY; RAT AB The mechanisms underlying phenacetin-induced toxicity and carcinogenicity are not clear. In particular, it is not known whether these effects are mediated by metabolic activation of the drug. CYP1A2 is known to metabolize phenacetin in vitro. To determine the role of this enzyme in vivo, the toxicity and carcinogenicity of phenacetin was examined in Cyp1a2-null mice (that lack CYP1A2), Six- to 8-week-old wild type (+/+) or null (-/-) mice were fed either a control diet, or one containing 1.25% phenacetin, ad libitum for up to 67 weeks. Representative groups of mice were examined for phenacetin-induced toxicity and carcinogenicity after 36, 48, 58, or 67 weeks of feeding. Consistent with the known role of CYP1A2 in phenacetin metabolism, plasma levels of phenacetin were higher and acetaminophen levels lower in the (-/-) mice fed phenacetin compared to phenacetin-fed (+/+) controls. Weight gain was significantly depressed in both groups of phenacetin-fed mice after 4 weeks of feeding, and continued to be lower for the remainder of the experiment, compared to controls. Hepatomegaly and splenomegaly were more severe in (-/-) mice but present in both genotypes fed phenacetin at all time points assessed. Histological analysis of liver, kidney, spleen, and urogenital tract also revealed a differential response in the (-/-) mice fed phenacetin compared to (+/+) mice fed the same diet. further, mortality was the most severe in the (-/-) mice fed phenacetin than in all other groups. Despite significant toxicity in (-/-) mice fed phenacetin, only one renal carcinoma was found among them. Results from this work demonstrate that, in the absence of CYP1A2, phenacetin is more toxic than in controls. This provides evidence that metabolism of phenacetin by CYP1A2, alters toxicity in vivo, and suggests that alternate CYP1A2-independent metabolic pathways contribute to its toxicity. C1 NCI, Lab Metab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Vet & Tumor Pathol Sect, Anim Sci Branch, Off Lab Anim Resources,Div Basic Sci, Frederick, MD 21702 USA. RP Peters, JM (reprint author), NCI, Lab Metab, Div Basic Sci, NIH, Bldg 37,Room 3E-24, Bethesda, MD 20892 USA. RI Peters, Jeffrey/D-8847-2011 NR 19 TC 21 Z9 21 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUL PY 1999 VL 50 IS 1 BP 82 EP 89 DI 10.1093/toxsci/50.1.82 PG 8 WC Toxicology SC Toxicology GA 251PZ UT WOS:000083455200010 PM 10445756 ER PT J AU Kirchner, DL Mercieca, MD Crowell, JA Levine, BS AF Kirchner, DL Mercieca, MD Crowell, JA Levine, BS TI Developmental toxicity studies of 2-(difluoromethyl)-dl-ornithine (DFMO) in rats and rabbits SO TOXICOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT 36th Annual Meeting of the Society-of-Toxicology CY MAR 09-13, 1997 CL CINCINNATI, OHIO SP Soc Toxicol DE difluoromethylornithine; ornithine decarboxylase; polyamine; cancer chemopreventive; maternal toxicity; developmental toxicity; teratology; fetotoxicity; embryotoxicity; skeletal; rat; rabbit ID ORNITHINE DECARBOXYLASE ACTIVITY; ALPHA-DIFLUOROMETHYLORNITHINE; IRREVERSIBLE INHIBITOR; CELL-PROLIFERATION; MATERNAL TOXICITY; FETAL DEVELOPMENT; MOUSE SKIN; CARCINOGENESIS; POLYAMINES; MALFORMATIONS AB DFMO, an irreversible inhibitor of ornithine decarboxylase (ODC), is under development as a chemopreventive drug against cancers with pronounced proliferative phases. In support of human clinical trials, preclinical developmental toxicity studies were conducted in pregnant rats and rabbits. Rats were treated during GD 6-17, and fetuses were obtained by C-section on GD 20. Rabbits were treated during GD 7-20, and fetuses were obtained by C-section on GD 29. The dose range-finding study in rats (5/group at 0, 50, 125, 300, 800, or 1000 mg/kg/day) revealed maternal toxicity at doses greater than or equal to 800 mg/kg/day (decreased body weights and food consumption) and developmental toxicity at doses greater than or equal to 300 mg/kg/day (increased early resorptions and reduced fetal body weights). In the main study, rats (25/group) received 0, 30, 80, or 200 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 200 mg/kg/day as significantly decreased fetal weights and increased incidence of litters with skeletal variations of 14th rudimentary rib, 14th full rib, and/or 27th presacral vertebrae. There were no treatment-related fetal skeletal malformations or external or visceral anomalies at any dose level. The dose range-finding study in rabbits (5/group at 0, 30, 60, 120, 240, or 500 mg/kg/day) revealed developmental toxicity at doses greater than or equal to 60 mg/kg/day (increased resorptions and reduced fetal body weights) in the absence of maternal toxicity. In the main study, rabbits (20/group) received 0, 15, 45, or 135 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 135 mg/kg/day as nonsignificantly increased early resorptions, decreased implantation sites, decreased viable fetuses, and reduced fetal weights. There were no external, visceral, or skeletal anomalies at any dose level. Thus, in the main developmental toxicity studies, DFMO produced developmental but not maternal toxicity at 200 and 135 mg/kg/day in rats and rabbits, respectively. Accordingly, in rats, the maternal no-observable-effect level (NOEL) was 200 mg/kg/day and the fetal NOEL was 80 mg/kg/day; while in rabbits the maternal NOEL was 135 mg/kg/day and the fetal NOEL was 45 mg/kg/day. These fetal NOELs are several-fold higher than the dose level currently used in Phase II and III clinical trials (similar to 13 mg/kg). C1 Univ Illinois, Toxicol Res Lab MC 868, Chicago, IL 60612 USA. Pathol Associates Int, Frederick, MD 21701 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP Levine, BS (reprint author), Univ Illinois, Toxicol Res Lab MC 868, 1940 W Taylor St, Chicago, IL 60612 USA. FU NCI NIH HHS [N01-CN55110-MAO] NR 46 TC 6 Z9 6 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 JUL PY 1999 VL 50 IS 1 BP 127 EP 135 DI 10.1093/toxsci/50.1.127 PG 9 WC Toxicology SC Toxicology GA 251PZ UT WOS:000083455200015 PM 10445761 ER PT J AU Murthy, KK Henrard, DR Eichberg, JW Cobb, KE Busch, MP Allain, JP Alter, HJ AF Murthy, KK Henrard, DR Eichberg, JW Cobb, KE Busch, MP Allain, JP Alter, HJ TI Redefining the HIV-infectious window period in the chimpanzee model: evidence to suggest that viral nucleic acid testing can prevent blood-borne transmission SO TRANSFUSION LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; PLASMA; ANTIBODY; SEROCONVERSION; LYMPHOCYTES; TIME; RISK AB BACKGROUND: Although it is rare, blood-transmitted HIV infection can occur when a donor presents in the window period between HIV-1 exposure and the first appearance of detectable p24 antigen. STUDY DESIGN AND METHODS: To study this seronegative window period, a chimpanzee (X034) was inoculated with 38 median tissue culture infective doses of HIV-1 IIIB; serum and peripheral blood mononuclear cells were obtained one to two times per week for 12 weeks and then biweekly for 12 weeks. Infectivity was monitored by the detection of serum HIV RNA, cell-associated HIV DNA, p24 antigen, and anti-HIV and by coculture methods. RESULTS: No HIV markers were noted until 5 weeks after inoculation, at which time virus was isolated and HIV RNA and DNA were detected in plasma and cells, respectively. Anti-HIV and HIV p24 antigen were not present until 8 weeks after inoculation. Plasma and cells obtained from Chimpanzee X034 3 or 4 weeks after exposure were then sequentially inoculated into a second chimpanzee (X176); no HIV infection was observed in this animal during serial follow-up for 24 weeks after each inoculation. In contrast, when the fifth-week HIV-1 RNA- and DNA-positive sample was inoculated, Chimpanzee X176 was unequivocally infected with HIV-1. CONCLUSIONS: Nucleic acid testing narrowed the seronegative window by 3 weeks (37%). More important, there was no demonstrable infectivity in either plasma or peripheral blood mononuclear cells obtained before molecular markers were detectable. This suggests that the infectious window may be considerably shorter than the total window as measured from exposure and that nucleic acid testing might not only shorten the seronegative window, but totally prevent transfusion-transmitted HIV infection. C1 SW Fdn Biomed Res, Dept Virol & Immunol, San Antonio, TX 78227 USA. Irwin Mem Blood Ctr, Sci Serv Res, San Francisco, CA USA. MRC Ctr, Dept Hematol Blood Transfus, Cambridge, England. NIH, Infect Dis Sect, Dept Transfus Med, Bethesda, MD 20892 USA. RP Murthy, KK (reprint author), SW Fdn Biomed Res, Dept Virol & Immunol, 7620 NW Loop 410, San Antonio, TX 78227 USA. FU NHLBI NIH HHS [N01-HB-27091] NR 20 TC 47 Z9 50 U1 0 U2 1 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUL PY 1999 VL 39 IS 7 BP 688 EP 693 DI 10.1046/j.1537-2995.1999.39070688.x PG 6 WC Hematology SC Hematology GA 216EK UT WOS:000081428100005 PM 10413275 ER PT J AU Bussey, TJ Murray, EA AF Bussey, TJ Murray, EA TI What does semantic dementia reveal about the functional role of the perirhinal cortex? Reply SO TRENDS IN COGNITIVE SCIENCES LA English DT Letter ID MEMORY C1 NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Bussey, TJ (reprint author), NIMH, Neuropsychol Lab, Bldg 49,Room 1B80, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 U1 0 U2 1 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 JUL PY 1999 VL 3 IS 7 BP 249 EP 250 DI 10.1016/S1364-6613(99)01335-2 PG 2 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 216QJ UT WOS:000081453100002 ER PT J AU Wise, SP AF Wise, SP TI The prefrontal cortex: Executive and cognitive functions SO TRENDS IN COGNITIVE SCIENCES LA English DT Book Review C1 NIMH, Poolesville, MD 20837 USA. RP Wise, SP (reprint author), NIMH, Poolesville, MD 20837 USA. NR 8 TC 0 Z9 0 U1 0 U2 2 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 JUL PY 1999 VL 3 IS 7 BP 280 EP 281 DI 10.1016/S1364-6613(99)01348-0 PG 2 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 216QJ UT WOS:000081453100008 ER PT J AU Jang, WH Chen, HC Sicotte, H Schuler, GD AF Jang, WH Chen, HC Sicotte, H Schuler, GD TI Making effective use of human genomic sequence data SO TRENDS IN GENETICS LA English DT Article ID QUALITY; PROJECT C1 NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Jang, WH (reprint author), NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. NR 9 TC 22 Z9 22 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD JUL PY 1999 VL 15 IS 7 BP 284 EP 286 DI 10.1016/S0168-9525(99)01762-X PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 214YA UT WOS:000081354100011 PM 10390628 ER PT J AU Wen, H AF Wen, H TI Volumetric Hall effect tomography - A feasibility study SO ULTRASONIC IMAGING LA English DT Article DE biological; conductivity; dielectric constant; Wall effect; imaging; three-dimensional ultrasound; tomography ID 2-DIMENSIONAL ARRAYS; MEDICAL ULTRASOUND; IMAGING-SYSTEM AB Wall effect imaging is an ultrasound-based method of mapping spatial variations in the dielectric constants of an acoustically-uniform sample. This paper presents three-dimensional Wail effect images of phantoms obtained by scanning a single transducer across a two-dimensional grid, effectively simulating two-dimensional phased-array signal reception. The experiments demonstrate the feasibility of volumetric Hall effect tomography and show the advantage of volumetric scans over planar scans. The images reflect several limitations of the current scanning method and point to directions for further hardware development. The inherent limitations of Mall effect imaging are also discussed in light of these results. C1 NIH, Cardiac Energet Lab, NHLBI, Bethesda, MD 20892 USA. RP Wen, H (reprint author), NIH, Cardiac Energet Lab, NHLBI, Bldg 10,Room BID-161, Bethesda, MD 20892 USA. RI Wen, Han/G-3081-2010 OI Wen, Han/0000-0001-6844-2997 FU Intramural NIH HHS [Z01 HL004606-12] NR 15 TC 21 Z9 21 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0161-7346 J9 ULTRASONIC IMAGING JI Ultrason. Imaging PD JUL PY 1999 VL 21 IS 3 BP 186 EP 200 PG 15 WC Acoustics; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 264HQ UT WOS:000084175100003 PM 10604800 ER PT J AU Engel, JD Kundu, SD Yang, T Yang, S Goodwin, S Janulis, L Cho, JS Chang, J Kim, SJ Lee, C AF Engel, JD Kundu, SD Yang, T Yang, S Goodwin, S Janulis, L Cho, JS Chang, J Kim, SJ Lee, C TI Transforming growth factor-beta type II receptor confers tumor suppressor activity in murine renal carcinoma (RENCA) cells SO UROLOGY LA English DT Article ID GASTRIC-CANCER CELLS; TGF-BETA; MICROSATELLITE INSTABILITY; DIFFERENTIAL SENSITIVITY; PROSTATE-CANCER; EXPRESSION; COLON; TUMORIGENICITY; INHIBITION; LINE AB Objectives. To demonstrate that the introduction of the transforming growth factor-beta (TGF-beta) type II receptor (T beta R-II) decreases tumorigenicity in an aggressive murine renal carcinoma line, Renca. These cells do not express T beta R-II. Because the presence of T beta R-II in benign epithelial cells is ubiquitous, the ability to restore tumor suppressor activity in the Renca cell line with its introduction would elucidate the role of T beta R-II as a tumor suppressor gene. Methods. Renca cells were stably transfected with a retrovirus-mediated TPR-II expression vector. In vitro sensitivity to growth inhibitory effect of TGF-beta was assessed by the H-3-thymidine incorporation assay. For in vivo testing, xenograft tumors were produced by subcutaneous injection of tumor cells into immunodeficient nude mice. The tumorigenicity of these T beta R-II transfected cells was tested. Wild-type Renca cells and cells transfected with the control vector were also tested for comparison. Results. Expression of T beta R-II mRNA was evident in Renca cells after transfection with the T beta R-II construct. In vitro sensitivity to the growth inhibitory effect of TGF-beta was restored. This effect of TGF-beta was reversible with a neutralizing antibody specific for the extracellular domain of T beta R-II. Xenografts grown from T beta R-II transfected cells were significantly smaller, weighed less, and developed tumors later than those developed from wild-type Renca cells and those transfected with the control vector. Conclusions. We conclude that T beta R-II is a central mediator of tumorigenicity in Renca cells. As with other tumor suppressor genes, the loss of T beta R-II expression allows for the development of an aggressive phenotype. UROLOGY 54: 164-170, 1999. (C) 1999, Elsevier Science Inc. C1 Northwestern Univ, Sch Med, Dept Urol, Chicago, IL 60611 USA. Natl Canc Inst, Chemoprevent Lab, Bethesda, MD USA. RP Lee, C (reprint author), Northwestern Univ, Sch Med, Dept Urol, Tarry 11-715,303 E Chicago Ave, Chicago, IL 60611 USA. FU NCI NIH HHS [CA60553, CA69851] NR 21 TC 20 Z9 22 U1 0 U2 2 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 JUL PY 1999 VL 54 IS 1 BP 164 EP 170 DI 10.1016/S0090-4295(99)00093-X PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 213BA UT WOS:000081251100034 PM 10414746 ER PT J AU Ornstein, DK Andriole, GL AF Ornstein, DK Andriole, GL TI Testicular androgen ablation for prostate cancer - Reply SO UROLOGY LA English DT Letter C1 Natl Canc Inst, Urol Branch, Bethesda, MD 20814 USA. Washington Univ, Div Urol, St Louis, MO 63110 USA. RP Ornstein, DK (reprint author), Natl Canc Inst, Urol Branch, Bldg 10,Room 2B47, Bethesda, MD 20814 USA. NR 1 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 0090-4295 J9 UROLOGY JI UROLOGY PD JUL PY 1999 VL 54 IS 1 BP 194 EP 194 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 213BA UT WOS:000081251100042 ER PT J AU Shroyer, NF Lewis, RA Allikmets, R Singh, N Dean, M Leppert, M Lupski, JR AF Shroyer, NF Lewis, RA Allikmets, R Singh, N Dean, M Leppert, M Lupski, JR TI The rod photoreceptor ATP-binding cassette transporter gene, ABCR, and retinal disease: from monogenic to multifactorial SO VISION RESEARCH LA English DT Article DE ABCR gene; ATP-binding; age-related macular degeneration; pedigree ID AGE-RELATED MACULOPATHY; RECESSIVE STARGARDT DISEASE; GROWTH-FACTOR RECEPTOR-2; CYSTIC-FIBROSIS GENE; PERIPHERIN-RDS GENE; MACULAR DEGENERATION; RETINITIS-PIGMENTOSA; FUNDUS-FLAVIMACULATUS; CROUZON-SYNDROME; RIM PROTEIN AB The ABCR gene encodes a rod photoreceptor specific ATP-binding cassette transporter. Mutations in ABCR are associated with at least four inherited retinal dystrophies: Stargardt disease, Fundus Flavimaculatus, cone-rod dystrophy, and retinitis pigmentosa. A statistically significant increase in heterozygous ABCR alterations has been identified in patients with age-related macular degeneration (AMD). A pedigree is described which manifests both Stargardt disease and AMD in which an ABCR mutation cosegregates with both disease phenotypes. These data from this case report support the hypothesis that ABCR is a dominant susceptibility locus for AMD. Recent work regarding ABCR is reviewed and a model is presented in which decreased ABCR function correlates with severity of retinal disease. (C) 1999 Published by Elsevier Science Ltd. All rights reserved. C1 Baylor Coll Med, Cell & Mol Biol Program, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Baylor Coll Med, Dept Ophthalmol, Houston, TX 77030 USA. Texas Childrens Hosp, Houston, TX 77030 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21072 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Genom Divers, Frederick, MD 21072 USA. Univ Utah, Eccles Inst Human Genet, Dept Human Genet, Salt Lake City, UT 84112 USA. RP Lupski, JR (reprint author), Baylor Coll Med, Cell & Mol Biol Program, Houston, TX 77030 USA. RI Dean, Michael/G-8172-2012; OI Dean, Michael/0000-0003-2234-0631; Shroyer, Noah/0000-0002-5934-2852 NR 52 TC 85 Z9 86 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD JUL PY 1999 VL 39 IS 15 BP 2537 EP 2544 DI 10.1016/S0042-6989(99)00037-1 PG 8 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 192XN UT WOS:000080105200010 PM 10396622 ER PT J AU Marshall, NL Robeson, WW Keefe, N AF Marshall, NL Robeson, WW Keefe, N TI Gender equity in early childhood education SO YOUNG CHILDREN LA English DT Article ID PRESCHOOL-CHILDREN; FREE-PLAY; BEHAVIOR; SOCIALIZATION; GIRLS; TOYS C1 Wellesley Coll, Ctr Res Women, NICHD, Wellesley, MA 02181 USA. RP Marshall, NL (reprint author), Wellesley Coll, Ctr Res Women, NICHD, Wellesley, MA 02181 USA. RI Marshall, Nancy/C-3428-2012; OI Marshall, Nancy L/0000-0002-4799-2030 NR 56 TC 1 Z9 1 U1 2 U2 4 PU NATL ASSOC EDUC YOUNG CHILDREN PI WASHINGTON PA 1509 16TH ST., N.W., WASHINGTON, DC 20036-1426 USA SN 0044-0728 J9 YOUNG CHILDREN JI Young Child. PD JUL PY 1999 VL 54 IS 4 BP 9 EP 13 PG 5 WC Education & Educational Research SC Education & Educational Research GA 213BW UT WOS:000081253000004 ER PT J AU Roth, GS Ingram, DK Lane, MA AF Roth, GS Ingram, DK Lane, MA TI "Anti-aging" effects of dietary caloric restriction in primates SO ZEITSCHRIFT FUR GERONTOLOGIE UND GERIATRIE LA English DT Meeting Abstract C1 NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PLATZ DER DEUTSCHEN EINHEIT 25, D-64293 DARMSTADT, GERMANY SN 0044-281X J9 Z GERONTOL GERIATR JI Z. Gerontol. Geriatr. PD JUL PY 1999 VL 32 IS 2 SU 2 MA 50 BP 14 EP 14 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 217JC UT WOS:000081495400050 ER PT J AU Brant, LJ AF Brant, LJ TI Longitudinal methodology for characterizing preclinical disease SO ZEITSCHRIFT FUR GERONTOLOGIE UND GERIATRIE LA English DT Meeting Abstract C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PLATZ DER DEUTSCHEN EINHEIT 25, D-64293 DARMSTADT, GERMANY SN 0044-281X J9 Z GERONTOL GERIATR JI Z. Gerontol. Geriatr. PD JUL PY 1999 VL 32 IS 2 SU 2 MA 72 BP 20 EP 20 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 217JC UT WOS:000081495400072 ER PT J AU Rantanen, T AF Rantanen, T TI Strength and walking: Cross-sectional and longitudinal perspectives to disability. SO ZEITSCHRIFT FUR GERONTOLOGIE UND GERIATRIE LA English DT Meeting Abstract C1 Univ Jyvaskyla, Dept Hlth Sci, SF-40351 Jyvaskyla, Finland. NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PLATZ DER DEUTSCHEN EINHEIT 25, D-64293 DARMSTADT, GERMANY SN 0044-281X J9 Z GERONTOL GERIATR JI Z. Gerontol. Geriatr. PD JUL PY 1999 VL 32 IS 2 SU 2 MA 247 BP 65 EP 65 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 217JC UT WOS:000081495400244 ER PT J AU Schengrund, CL Kovac, P AF Schengrund, CL Kovac, P TI UDP-6-deoxy-6-fluoro-alpha-D-galactose binds to two different galactosyltransferases, but neither can effectively catalyze transfer of the modified galactose to the appropriate acceptor SO CARBOHYDRATE RESEARCH LA English DT Article DE methyl 6-deoxy-6-fluoro-alpha-D-galactopyranoside; 6-deoxy-6-fluoro-D-galactose; 1,2,3,4-tetra-O-acetyl-6-deoxy-6-fluoro-beta-D-galactopyranose; UDP-6-deoxy-6-fluoro-D-galactose; galactosyltransferase ID D-GALACTOPYRANOSIDE; DERIVATIVES AB The effect of substitution of the HO-6 of D-galactose with fluorine on the ability of alpha-(1 --> 3)-galactosyltransferase (EC 2.4.1.151) and beta-(1 --> 4)-galactosyltransferase (EC 2.4.1.22) to catalyze its transfer from UDP to an appropriate acceptor was determined. HPLC analyses indicated that each transferase properly catalyzed formation of the expected product [beta-D-Gal-(1 --> 4)-D-GlcNAc for the beta-(1 --> 4)-galactosyltransferase and alpha-D-Gal-(1 --> 3)-beta-D-Gal-(1 --> 4)-D-GlcNAc for the alpha-(1 --> 3)-D-galactosyltransferase] when UDP-alpha-D-Gal was the substrate. When UDP-6-deoxy-6-fluoro-alpha-D-galactose (6) was used in conjunction with each transferase, no product indicative of transfer of 6-deoxy-6-fluoro-D-galactose to its respective acceptor sugar was identified. 6-Deoxy-6-fluoro-D-galactose (3) was obtained by hydrolysis of methyl 6-deoxy-6-fluoro-alpha-D-galactopyranoside, synthesized by the selective fluorination of methyl alpha-D-galactopyranoside with diethylaminosulfur trifluoride (DAST), with aqueous trifluoroacetic acid. Acetylation of 3 gave crystalline 1,2,3,4-tetra-O-acetyl-6-deoxy-6-fluoro-beta-D-galactopyranose, which was converted to the corresponding 1-alpha-phosphate and used for the synthesis of 6. (C) 1999 Published by Elsevier Science Ltd. All rights reserved. C1 Penn State Univ, Coll Med, Dept Biochem & Mol Biol, Hershey, PA 17033 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Schengrund, CL (reprint author), Penn State Univ, Coll Med, Dept Biochem & Mol Biol, Hershey, PA 17033 USA. FU NINDS NIH HHS [NS35653] NR 13 TC 14 Z9 14 U1 2 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD JUN 30 PY 1999 VL 319 IS 1-4 BP 24 EP 28 DI 10.1016/S0008-6215(99)00104-4 PG 5 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 238JB UT WOS:000082706200003 PM 10520253 ER PT J AU Rhee, SG AF Rhee, SG TI Redox signaling: hydrogen peroxide as intracellular messenger SO EXPERIMENTAL AND MOLECULAR MEDICINE LA English DT Review DE redox; hydrogen peroxide; ROS; signaling ID THIOL-SPECIFIC ANTIOXIDANT; NF-KAPPA-B; EPIDERMAL GROWTH-FACTOR; NECROSIS-FACTOR-ALPHA; SMOOTH-MUSCLE CELLS; PROTEIN-KINASE-C; TYROSINE PHOSPHORYLATION; TRANSFORMING GROWTH-FACTOR-BETA-1; MAMMALIAN PEROXIREDOXIN; THIOREDOXIN PEROXIDASE AB Although superoxide anions (O-2(.-)) and H2O2 are generally considered to be toxic by-products of respiration, recent evidence suggests that the production of these reactive oxygen species (ROS) might be an integral component of membrane receptor signaling. In mammalian cells, a variety of extracellular. stimuli have recently been shown to induce a transient increase in the intracellular concentration of ROS, and specific inhibition of the ROS generation resulted in a complete blockage of stimulant-dependent signaling. In the next few years, therefore, a flurry of research activity is expected in relation to the elucidation of ROS production in response to receptor stimulation, identification of ROS target molecules, and investigation of ROS elimination. The goal of this report is to review our current knowledge of ROS-regulated signal transduction and propose future directions. C1 NHLBI, Lab Cell Singalling, NIH, Bethesda, MD 20892 USA. EM sgrhee@nih.gov NR 60 TC 414 Z9 434 U1 2 U2 28 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1226-3613 EI 2092-6413 J9 EXP MOL MED JI Exp. Mol. Med. PD JUN 30 PY 1999 VL 31 IS 2 BP 53 EP 59 PG 7 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 213WT UT WOS:000081296800001 PM 10410302 ER PT J AU Ford, PW Gustafson, KR McKee, TC Shigematsu, N Maurizi, LK Pannell, LK Williams, DE de Silva, ED Lassota, P Allen, TM Van Soest, R Andersen, RJ Boyd, MR AF Ford, PW Gustafson, KR McKee, TC Shigematsu, N Maurizi, LK Pannell, LK Williams, DE de Silva, ED Lassota, P Allen, TM Van Soest, R Andersen, RJ Boyd, MR TI Papuamides A-D, HIV-inhibitory and cytotoxic depsipeptides from the sponges Theonella mirabilis and Theonella swinhoei collected in Papua New Guinea SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ANTIFUNGAL CYCLIC-PEPTIDES; POTENT THROMBIN INHIBITORS; SERINE-PROTEASE INHIBITORS; MARINE NATURAL-PRODUCTS; ENANTIOMERICALLY PURE; CALLIPELTA SP; CYCLOTHEONAMIDES; GLYCOPEPTIDE; MOZAMBIQUE; ACIDS AB The novel cyclic depsipeptides papuamides A (1), B (2), C (3), and D (4) have been isolated from Papua New Guinea collections of the sponges Theonella mirabilis and Theonella swinhoei. Their structures were determined by a combination of spectroscopic analysis and chemical degradation and derivatization studies. In addition to glycine, alanine, and threonine, these peptides contain a number of unusual amino acids including 3,4-dimethylglutamine, beta-methoxytyrosine, 3-methoxyalanine, and 2,3-diaminobutanoic acid or 2-amino-2-butenoic acid residues. Papuamides A-D (1-4) are also the first marine-derived peptides reported to contain 3-hydroxyleucine and homoproline residues. These peptides also contain a previously undescribed 2,3-dihydroxy-2,6,8-trimethyldeca-(4Z,6E)-dienoic acid moiety N-linked to a terminal glycine residue. Papuamides A (1) and B (2) inhibited the infection of human T-lymphoblastoid cells by HIV-1(RF) in vitro with an EC50 of approximately 4 ng/mL. Compound 1 was also cytotoxic against a panel of human cancer cell lines with a mean IC50 of 75 ng/mL. C1 Univ British Columbia, Dept Chem, Vancouver, BC V6T 1Z1, Canada. Univ British Columbia, Dept Earth & Ocean Sci, Vancouver, BC V6T 1Z1, Canada. NCI, Frederick Canc Res & Dev Ctr, Lab Drug Discovery Res & Dev, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Boyd, MR (reprint author), Univ British Columbia, Dept Chem, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada. RI Shigematsu, Naoyuki/B-9374-2014; OI de Silva, E. Dilip/0000-0001-8822-7186 NR 32 TC 155 Z9 162 U1 3 U2 20 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 JUN 30 PY 1999 VL 121 IS 25 BP 5899 EP 5909 DI 10.1021/ja990582o PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA 212KX UT WOS:000081216800007 ER PT J AU Gunawardana, G Chatterjee, D George, KM Brennan, P Whittern, D Small, PLC AF Gunawardana, G Chatterjee, D George, KM Brennan, P Whittern, D Small, PLC TI Characterization of novel macrolide toxins, mycolactones A and B, from a human pathogen, Mycobacterium ulcerans SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article C1 NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Abbott Labs, Div Pharmaceut Prod, Abbott Pk, IL 60046 USA. Colorado State Univ, Dept Microbiol, Ft Collins, CO 80523 USA. RP Small, PLC (reprint author), NIAID, Rocky Mt Labs, NIH, S 4th St, Hamilton, MT 59840 USA. NR 8 TC 50 Z9 50 U1 0 U2 5 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 JUN 30 PY 1999 VL 121 IS 25 BP 6092 EP 6093 DI 10.1021/ja990017l PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 212KX UT WOS:000081216800039 ER PT J AU Glaab, WE Tindall, KR Skopek, TR AF Glaab, WE Tindall, KR Skopek, TR TI Specificity of mutations induced by methyl methanesulfonate in mismatch repair-deficient human cancer cell lines SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE mismatch repair; HPRT; methyl methanesulfonate; mutational specificity ID TRANSCRIPTION-COUPLED REPAIR; DNA-DAMAGE TOLERANCE; MAMMALIAN-CELLS; MUTS-ALPHA; MUTATOR PHENOTYPES; EXCISION-REPAIR; TUMOR-CELLS; HPRT LOCUS; GENE; HETERODIMER AB Recently, we showed that the cytotoxic and mutagenic response in human cells to the model S(N)2 alkylating agent methyl methanesulfonate (MMS) can be modulated by the mismatch repair (MMR) pathway. That is, human cancer cell lines defective in MMR are more resistant to the cytotoxic effects of MMS exposure and suffer more induced mutations at the HPRT locus than MMR-proficient cell lines. Since MMS produces little O-6-methylguanine (O-6-meG), the observed hypermutability and resistance to cytotoxicity in MMR-defective cells likely results from lesions other than O-6-meG. MMS produces a high yield of N7-methylguanine (N7-meG) and N3-methyladenine (N3-meA), which can lead to the formation of promutagenic abasic sites, and these lesions may be responsible for the observed cytotoxic and/or mutagenic effects of MMS. To further investigate the mechanism of MMS mutagenesis, two MMR-defective human cancer cell lines were treated with MMS and the frequency and the types of mutations produced at the HPRT locus were determined. MMS treatment (1.5 mM) produced a 1.6- and a 2.2-fold increase in mutations above spontaneous levels in HCT116 and DLD-1 cell lines, respectively. An average 3.7-fold increase in transversion mutations was observed, which accounted for greater than one-third of all induced mutations in both cell lines. In contrast, an average 1.6-fold increase was seen among transition mutations (the class expected from O-alkylation products). Since transversion mutations are not produced by O-6-meG, these findings suggest that abasic sites may be the lesion responsible for a large proportion of MMS mutagenicity in MMR-defective cells. Furthermore, these data suggest the MMS-induced damage, either abasic site-inducing base alterations (i.e., N7-meG and N3-meA) or the resulting abasic sites themselves, may be substrates for recognition and/or repair by MMR proteins. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Merck Res Labs, Dept Genet & Cellular Toxicol, W Point, PA 19486 USA. NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. RP Glaab, WE (reprint author), Merck Res Labs, Dept Genet & Cellular Toxicol, WP45-320, W Point, PA 19486 USA. NR 55 TC 34 Z9 34 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUN 30 PY 1999 VL 427 IS 2 BP 67 EP 78 DI 10.1016/S0027-5107(99)00091-3 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 214KQ UT WOS:000081327500001 PM 10393261 ER PT J AU Campeau, L Hunninghake, DB Knatterud, GL White, CW Domanski, M Forman, SA Forrester, JS Geller, NL Gobel, FL Herd, JA Hoogwerf, BJ Rosenberg, Y AF Campeau, L Hunninghake, DB Knatterud, GL White, CW Domanski, M Forman, SA Forrester, JS Geller, NL Gobel, FL Herd, JA Hoogwerf, BJ Rosenberg, Y CA Post CABG Trial Investigators TI Aggressive cholesterol lowering delays saphenous vein graft atherosclerosis in women, the elderly, and patients with associated risk factors - NHLBI post coronary artery bypass graft clinical trial SO CIRCULATION LA English DT Article DE bypass; grafting; atherosclerosis; risk factors ID SCANDINAVIAN SIMVASTATIN SURVIVAL; HEART-DISEASE; MYOCARDIAL-INFARCTION; MEN; REGRESSION; THERAPY; HYPERCHOLESTEROLEMIA; PROGRESSION; PRAVASTATIN; EVENTS AB Background-The NHLBI Post Coronary Artery Bypass Graft trial (Post CABG) showed that aggressive compared with moderate lowering of low-density lipoprotein-cholesterol (LDL-C) decreased obstructive changes in saphenous vein grafts (SVGs) by 31%.(1) Using lovastatin and cholestyramine when necessary, the annually determined mean LDL-C level ranged from 93 to 97 mg/dL in aggressively treated patients and from 132 to 136 mg/dL in the others (P<0.001). Methods and Results-The present study evaluated the treatment effect in subgroups defined by age, gender, and selected coronary heart disease (CHD) risk factors, ie, smoking, hypertension, diabetes mellitus, high-density lipoprotein cholesterol (HDL-C) <35 mg/dL, and triglyceride serum levels greater than or equal to 200 mg/dL at baseline. As evidenced by similar odds ratio estimates of progression (lumen diameter decrease greater than or equal to 0.6 mm) and lack of interactions with treatment, a similar beneficial effect of aggressive lowering was observed in elderly and young patients, in women and men, in patients with and without smoking, hypertension, or diabetes mellitus, and those with and without borderline high-risk triglyceride serum levels. The change in minimum lumen diameter was in the same direction for all subgroup categories, without significant interactions with treatment. Conclusions-Aggressive LDL-C lowering delays progression of atherosclerosis in SVGs irrespective of gender, age, and certain risk factors for CHD. C1 Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. Univ Montreal, Montreal, PQ, Canada. Maryland Med Res Inst, Post CABG Coordinating Ctr, Baltimore, MD 21210 USA. NHLBI, Bethesda, MD 20892 USA. Univ Minnesota, Minneapolis, MN USA. Minneapolis Heart Inst Fdn, Minneapolis, MN USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Baylor Coll Med, Houston, TX 77030 USA. RP Campeau, L (reprint author), Maryland Med Res Inst, Post CABG Coordinating Ctr, 600 Wyndhurst Ave, Baltimore, MD 21210 USA. FU NHLBI NIH HHS [N01-HC-75072, N01-HC-75073, N01-HC-75071] NR 29 TC 64 Z9 65 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 29 PY 1999 VL 99 IS 25 BP 3241 EP 3247 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 210DJ UT WOS:000081089600010 PM 10385497 ER PT J AU Stambaugh, K Elliott, GT Jacobson, KA Liang, BT AF Stambaugh, K Elliott, GT Jacobson, KA Liang, BT TI Additive effects of late preconditioning produced by monophosphoryl lipid A and the early preconditioning mediated by adenosine receptors and K-ATP channel SO CIRCULATION LA English DT Article DE myocardium; receptors; hypoxia; ions ID ISCHEMIA-REPERFUSION INJURY; MYOCARDIAL-INFARCTION; CARDIAC MYOCYTES; NITRIC-OXIDE; A MLA; DOGS; PROTECTION; RABBITS; PROTEIN; STRESS AB Background-The cardioprotective effect of preconditioning can be exerted within 1 to 2 hours after initial ischemia, termed classical or early preconditioning, or can reappear 24 hours later as second window or late preconditioning. The objective of this study was to study the interaction between late and early preconditioning and to determine the potential underlying mechanism. Methods and Results-Adenosine receptor agonists and a K-ATP channel opener were used to achieve early preconditioning, and Monophosphoryl lipid A (MLA) was used to induce late preconditioning. Cultured chick ventricular myocytes were used as a myocyte model of simulated ischemia and precondition in. Prior treatment of the myocyte with MLA caused a dose-dependent decrease in the ischemia-induced myocyte injury 24 hours later, consistent with a late preconditioning effect. L-NMMA, glibenclamide, or 5-hydroxydecanoic acid administered during the ischemia blocked the MLA effect. Twenty four hours after MLA treatment, a 5-minute exposure to ischemia, adenosine, adenosine A(1) agonist CCPA, or A(3) agonist resulted in less myocyte injury during the subsequent prolonged ischemia, as compared with cells pretreated with the vehicle and subsequently exposed to the same early preconditioning stimuli. In addition to its ability to enhance the early preconditioning, effect by A(1) and A(3) agonists, MLA pretreatment also increased the phorbol ester- and pinacidil-mediated early preconditioning effect. Conclusions- This study defined a novel interaction in which the cardioprotective effect of early preconditioning is additive to that of late preconditioning and raised the possibility that both agents can be used as combined therapy in the treatment of ischemic heart disease. C1 Univ Penn, Med Ctr, Dept Med, Div Cardiovasc, Philadelphia, PA 19104 USA. RIBI ImmunoChem Res Inc, Hamilton, MT USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD USA. RP Liang, BT (reprint author), Univ Penn, Med Ctr, Dept Med, Div Cardiovasc, 504 Johnson Pavil,3610 Hamilton Walk, Philadelphia, PA 19104 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NHLBI NIH HHS [R01-HL48225] NR 28 TC 14 Z9 21 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 JUN 29 PY 1999 VL 99 IS 25 BP 3300 EP 3307 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 210DJ UT WOS:000081089600019 PM 10385506 ER PT J AU Reddy, PH Charles, V Williams, M Miller, G Whetsell, WO Tagle, DA AF Reddy, PH Charles, V Williams, M Miller, G Whetsell, WO Tagle, DA TI Transgenic mice expressing mutated full-length HD cDNA: a paradigm for locomotor changes and selective neuronal loss in Huntington's disease SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES LA English DT Article DE Huntington's disease; polyglutamine expansions; trinucleotide repeat disorder; neurodegeneration; inclusion bodies; apoptosis ID DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY; INTRANUCLEAR INCLUSIONS; 3-NITROPROPIONIC ACID; CAG REPEATS; QUINOLINIC ACID; NEUROLOGICAL PHENOTYPE; WIDESPREAD EXPRESSION; TRINUCLEOTIDE REPEAT; EMBRYONIC LETHALITY; GENE HOMOLOG AB Huntington's disease (HD) is a progressive neurodegenerative disorder characterized clinically by motor and psychiatric disturbances and pathologically by neuronal loss and gliosis (reactive astrocytosis) particularly in the striatum and cerebral cortex. We have recently created HD full-length cDNA transgenic mouse models that may serve as a paradigm for HD. A more detailed characterization of these models is presented here. The transgene encoding nor mal huntingtin consists of 9417 bp of the huntingtin coding sequences including 16 tandem CAGs coding for polyglutamines as part of exon 1. The transgene is driven by a heterologous cytomegalovirus promoter. Five independent transgenic mouse lines were obtained using this construct. An additional six transgenic lines were obtained using full-length HD constructs that have been modified to include either 48 or 89 CAG repeat expansions. Southern blot and densitometric analyses indicated unique integration sites for the transgene in each of the lines with a copy number ranging from two to 22 copies. Widespread expression of the transgene in brain, heart, spleen, kidney, lung, liver and gonads from each line was determined by Western blot analyses. In the brain, transgene expression was found in cerebral cortex, striatum, hippocampus and cerebellum. Expression of the transgene was as much as five times the endogenous mouse huntingtin level. Phenotypically, only mice expressing 48 or 89 CAG repeats manifested progressive behavioural and motor dysfunction. Early behavioural abnormalities were characterized by trunk curling and clasping of both fore- and hindlimbs when the animals were suspended by their tails. Subsequently, these mice exhibited hyperkinetic movements, including heightened exploratory activities, unidirectional rotational behaviour, backflipping and excessive grooming that lasted for several weeks. Eventually, the animals progressed to a hypokinetic phase consisting of slowed movements and lack of response to sensory stimuli. Urine retention or incontinence was also a prominent feature of the hypokinetic phase. At the end stage of the disease process, HD48(B,D) and HD89(A-C) mice became akinetic just prior to death. Neuropathological examination of mice at various stages indicated that it was only during the hypokinetic phase and thereafter when selective neuronal loss was most apparent. Regions of neurodegeneration and loss included the striatum, cerebral cortex, thalamus and hippocampus. TUNEL staining indicated an apoptotic mode of cell death in these brain regions. Comparative neuronal counts after Nissl staining showed as much as 20% loss of small and medium neurons in the striatum in mice at the hypokinetic and akinetic stages. Reactive astrocytosis accompanied the areas of neurodegeneration and loss. Polyglutamine aggregates in the form of neuronal intranuclear inclusions and diffuse nuclear and perinuclear aggregations were found in a small percentage of neurons, including those in brain regions that are typically spared in HD. This observation suggests that polyglutamine aggregates may not be sufficient to cause neuronal loss in HD. In both behavioural and neuropathological analyses, wild-type and transgenic animals with 16 CAG repeats were indistinguishable from each other and do not exhibit the changes observed for mice carrying the 48 and 89 CAG repeat mutations. Thus, animals expressing the CAG repeat expansions appear to represent clinically analogous models for HD pathogenesis, and may also provide insights into the underlying pathophysiological mechanisms of other triplet repeat disorders. C1 Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. NIH, Off Res Serv, Vet Resources Program, Bethesda, MD 20892 USA. Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA. RP Tagle, DA (reprint author), Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bldg 49,Room 3A26,49 Convent Dr MSC 4442, Bethesda, MD 20892 USA. FU NINDS NIH HHS [NS-28236] NR 55 TC 51 Z9 52 U1 1 U2 2 PU ROYAL SOC LONDON PI LONDON PA 6 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T ROY SOC B JI Philos. Trans. R. Soc. Lond. Ser. B-Biol. Sci. PD JUN 29 PY 1999 VL 354 IS 1386 BP 1035 EP 1045 DI 10.1098/rstb.1999.0456 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 218UM UT WOS:000081570600011 PM 10434303 ER PT J AU Fischbeck, KH Lieberman, A Bailey, CK Abel, A Merry, DE AF Fischbeck, KH Lieberman, A Bailey, CK Abel, A Merry, DE TI Androgen receptor mutation in Kennedy's disease SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES LA English DT Article DE polyglutamine disease; motor neuron disease; androgen receptor ID BULBAR MUSCULAR-ATROPHY; NEURONAL INTRANUCLEAR INCLUSIONS; EXPANDED POLYGLUTAMINE PROTEIN; TRINUCLEOTIDE REPEAT; TRANSGENIC MICE; NUCLEAR INCLUSIONS; CAG REPEAT; GENE; AGGREGATION; STABILITY AB Kennedy's disease is an X-linked form of motor neuron disease caused by an expanded polyglutamine repeat in the androgen receptor. While the expansion mutation causes some loss of transcriptional activity by the androgen receptor, the predominant effect of expansion is probably a toxic gain of function, similar to the mechanism of other polyglutamine expansion diseases. Features of the neurodegenerative phenotype of Kennedy's disease have now been reproduced in transgenic animals and neuronal cell culture. Nuclear inclusions of mutant androgen receptor protein are found in these model systems and in autopsy samples from patients with Kennedy's disease. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. RP Fischbeck, KH (reprint author), NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. FU NINDS NIH HHS [NS32214] NR 26 TC 26 Z9 28 U1 0 U2 1 PU ROYAL SOC LONDON PI LONDON PA 6 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T ROY SOC B JI Philos. Trans. R. Soc. Lond. Ser. B-Biol. Sci. PD JUN 29 PY 1999 VL 354 IS 1386 BP 1075 EP 1078 DI 10.1098/rstb.1999.0461 PG 4 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 218UM UT WOS:000081570600016 PM 10434308 ER PT J AU Psaty, BM Furberg, CD Kuller, LH Bild, DE Rautaharju, PM Polak, JF Bovill, E Gottdiener, JS AF Psaty, BM Furberg, CD Kuller, LH Bild, DE Rautaharju, PM Polak, JF Bovill, E Gottdiener, JS TI Traditional risk factors and subclinical disease measures as predictors of first myocardial infarction in older adults - The cardiovascular health study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID CORONARY HEART-DISEASE; LEFT-VENTRICULAR MASS; FACTOR INTERVENTION TRIAL; SERUM-CHOLESTEROL LEVELS; BLOOD-PRESSURE; SYSTOLIC HYPERTENSION; MORTALITY RISK; MEN; WOMEN; STROKE AB Background: Risk factors for myocardial infarction (MI) have not been well characterized in older adults, and in estimating risk, we sought to assess the individual and joint contributions made by both traditional risk factors and measures of subclinical disease. Methods: In the Cardiovascular Health Study, we recruited 5888 adults aged 65 years and older from 4 US centers. At baseline in 1989-1990, participants underwent an extensive examination that included traditional risk factors such as blood pressure and fasting glucose level and measures of subclinical disease as assessed by electrocardiography, carotid ultrasonography, echocardiography, pulmonary function, and ankle-arm index. Participants were followed up with semiannual contacts, and all cardiovascular events were classified by the Morbidity and Mortality Committee. The main analytic technique was the Cox proportional hazards model. Results: At baseline, 1967 men and 2979 women had no history of an MI. After follow-up for an average of 4.8 years, there were 302 coronary events, which included 263 patients with MI and 39 with definite fatal coronary disease. The incidence was higher in men (20.7 per 1000 person-years) than women (7.9 per 1000 person-years). In all subjects, the incidence was strongly associated with age, increasing from 7.8 per 1000 person-years in subjects aged 65 to 69 years to 25.6 per 1000 person-years in subjects aged 85 years and older. Glucose level and systolic blood pressure were associated with the incidence of MI, but smoking and lipid measures were not. After adjustment for age and sex, the significant subclinical disease predictors of MI were borderline or abnormal ejection fraction by echocardiography, high levels of intimal-medial thickness of the internal carotid artery, and a low ankle-arm index. Forced vital capacity and electrocardiographic left ventricular mass did not enter the stepwise model. Excluding subjects with clinical cardiovascular diseases such as prior angina or congestive heart failure at baseline had little effect on these results. Risk factors were generally similar in men and women. Conclusions: After follow-up of 4.8 years, systolic blood pressure, fasting glucose level, and selected subclinical disease measures were important predictors of the incidence of MI in older adults. Uncontrolled high blood pressure may explain about one quarter of the coronary events in this population. C1 Cardiovasc Hlth Study, Coordinating Ctr, Seattle, WA 98101 USA. Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27103 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. Univ Vermont, Dept Pathol, Colchester, Essex, England. Georgetown Univ, Med Ctr, Div Cardiol, Washington, DC 20007 USA. RP Psaty, BM (reprint author), Cardiovasc Hlth Study, Coordinating Ctr, Suite 2105,1501 4th Ave, Seattle, WA 98101 USA. FU NHLBI NIH HHS [N01-HC-85081, N01-HC-85079, N01-HC-85080] NR 56 TC 106 Z9 107 U1 0 U2 1 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 JUN 28 PY 1999 VL 159 IS 12 BP 1339 EP 1347 DI 10.1001/archinte.159.12.1339 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 209QC UT WOS:000081058600008 PM 10386510 ER PT J AU Duncan, T Swint, C Smith, SB Wiggert, BN AF Duncan, T Swint, C Smith, SB Wiggert, BN TI Levels of retinoic acid and retinaldehyde dehydrogenase expression in eyes of the Mitf(vit) mouse model of retinal degeneration SO MOLECULAR VISION LA English DT Article ID VITILIGO MUTANT MICE; DEVELOPMENT IN-VIVO; TRANSCRIPTION FACTOR; MICROPHTHALMIA GENE; MELANOCYTE DEVELOPMENT; ZIPPER TRANSCRIPTION; 13-CIS-RETINOIC ACID; PIGMENT EPITHELIUM; BINDING PROTEIN; NEURAL RETINA AB PURPOSE: Several reports have characterized the retinal degeneration observed in the Mitf(vit) mutant mouse. Despite these reports, the factor(s) that may cause or modulate the degeneration still are not well defined; however, it is known that the photoreceptors of Mitf(vit) mice die through an apoptotic mechanism. We reported previously that retinoid metabolism in the RPE of Mitf(vit) mice is perturbed. Retinoids regulate genes via the RAR and RXR nuclear receptor pathway that are involved in numerous cellular responses including apoptosis. It is possible that retinoic acid (RA) modulates the retinal degeneration observed in the Mitf(vit) mice. The purpose of this study was to evaluate the levels of RA in whole eyes, as well as its distribution between neural retina and RPE, of the Mitf(vit) mutant mouse model. An additional purpose was to examine the expression of the RA generating enzyme, retinaldehyde dehydrogenase (AHD2), in the eyes of mutant and control mice. METHODS: The distribution of AHD2 in eyes of pre- and postnatal Mitf(vit) and C57BL/6 wild-type mice was determined immunohistochemically. Quantitative and qualitative analyses of RA were performed using reversed-phase high performance liquid chromatography (HPLC). RESULTS: The distribution of AHD2 in ocular tissues was similar between pre- and postnatal Mitf(vit) and C57BL/6 control mice. At postnatal week 10, however, a marked increase in AHD2 immunoreactivity was noted in the central dorsal neural retina of Mitf(vit) mice. No differences in the level of total RA in whole eyes were noted between Mitf(vit) and control mice at early postnatal ages. By 10 weeks of age there was a significant elevation of RA that was localized to the neural retina. CONCLUSIONS: In this study, we show a high level of AHD2 and RA in the neural retina of Mitf(vit) mice relative to control mice. It is possible that this elevation of RAs contributes to the retinal degeneration observed in Mitf(vit) mice either by inducing apoptosis or by enhancing the effect of some other factor(s) involved in the apoptotic pathway. C1 NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Med Coll Georgia, Dept Cellular Biol & Anat, Augusta, GA 30912 USA. Med Coll Georgia, Dept Ophthalmol, Augusta, GA 30912 USA. RP Wiggert, BN (reprint author), NEI, Retinal Cell & Mol Biol Lab, NIH, 6 Ctr Dr MSC 2740,Bldg 6,Room 338, Bethesda, MD 20892 USA. NR 58 TC 0 Z9 0 U1 0 U2 0 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUN 28 PY 1999 VL 5 IS 9 BP U1 EP U10 PG 10 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 240JW UT WOS:000082823700001 ER PT J AU Falloon, J AF Falloon, J TI Time to genotype for selection of antiretroviral regimens in previously treated patients? SO LANCET LA English DT Editorial Material ID RESISTANCE C1 NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. RP Falloon, J (reprint author), NIAID, Immunoregulat Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 6 TC 6 Z9 6 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 JUN 26 PY 1999 VL 353 IS 9171 BP 2173 EP 2174 DI 10.1016/S0140-6736(99)00128-2 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 210EC UT WOS:000081091300003 PM 10392975 ER PT J AU Fetsch, PA Powers, CN Zakowski, MF Abati, A AF Fetsch, PA Powers, CN Zakowski, MF Abati, A TI Anti-alpha-inhibin - Marker of choice for the consistent distinction between adrenocortical carcinoma and renal cell carcinoma in fine-needle aspiration SO CANCER CYTOPATHOLOGY LA English DT Article DE alpha-inhibin; immunocytochemistry; adrenocortical carcinoma; renal cell carcinoma; fine-needle aspiration ID MONOCLONAL-ANTIBODY; OVARIAN NEOPLASMS; TUMORS; EXPRESSION; ACTIVIN AB BACKGROUND, Anti-alpha-inhibin, an antibody directed against a peptide hormone, has been shown to be a useful diagnostic aid in surgical pathology material for the identification of sex cord-stromal neoplasms and recently has been described in adrenocortical carcinoma (ACC). The diagnosis of ACC versus renal cell carcinoma (RCC) may be difficult morphologically, particularly in fine-needle aspiration (FNA) material. To date, the immunohistochemical distinction of ACC from RCC is based on a panel of antibodies that include vimentin, cytokeratins, and epithelial membrane antigen. However, the reliability of this panel is weakened by inconsistent staining patterns. METHODS. Archival formalin fixed, paraffin embedded cell block sections from 45 FNAs of known primary and metastatic ACC and RCC as well as benign adrenocortical nodules were stained with anti-alpha-inhibin using an avidin-biotin procedure. All samples were microwave pretreated and a biotin block was performed to reduce the background stain due to the high endogenous biotin often present in these types of samples. RESULTS. All cases of ACC (n = 7; 100%) and benign adrenocortical cells (n = 15; 100%) were immunoreactive with the alpha-inhibin antibody, showing a diffuse cytoplasmic and granular staining pattern. The staining intensity and number of immunoreactive cells varied within each sample, with the cases of ACC having the greatest proportion of immunoreactive cells and the strongest intensity. None of the cases of RCC (n = 23; 0%) were immunoreactive with anti-alpha-inhibin, CONCLUSIONS. The morphologic distinction of ACC versus RCC in FNA material from renal, adrenal, and metastatic neoplasms is not always feasible based on cytology alone. However, due to the advent of the alpha-inhibin antibody, the reliable distinction of these entities now may be possible. The intense and specific immunostaining pattern for cells of adrenal origin, even in paucicellular samples, suggests potential for the widespread clinical utility of this marker by cytopathologists. (C) 1999 American Cancer Society. C1 NCI, Pathol Lab, Cytopathol Sect, NIH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Med Coll Virginia, Cytopathol Sect, Richmond, VA 23298 USA. Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. RP Abati, A (reprint author), NCI, Pathol Lab, Cytopathol Sect, NIH, Bldg 10,Room 2A19,10 Ctr Dr MSC 1500, Bethesda, MD 20892 USA. NR 24 TC 38 Z9 38 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 JUN 25 PY 1999 VL 87 IS 3 BP 168 EP 172 DI 10.1002/(SICI)1097-0142(19990625)87:3<168::AID-CNCR11>3.0.CO;2-V PG 5 WC Oncology; Pathology SC Oncology; Pathology GA 207NH UT WOS:000080942600011 PM 10385449 ER PT J AU Hamiche, A Sandaltzopoulos, R Gdula, DA Wu, C AF Hamiche, A Sandaltzopoulos, R Gdula, DA Wu, C TI ATP-dependent histone octamer sliding mediated by the chromatin remodeling complex NURF SO CELL LA English DT Article ID NUCLEOSOME CORE PARTICLE; YEAST SWI/SNF COMPLEX; IN-VITRO; TRANSCRIPTIONAL ACTIVATION; MULTISUBUNIT COMPLEX; GENE-PRODUCTS; DNA; BINDING; ISWI; MOBILITY AB Drosophila NURF is an ATP-dependent chromatin remodeling complex that contains ISWI, a member of the SW12/SNF2 family of ATPases. We demonstrate that NURF catalyzes the bidirectional redistribution of mononucleosomes reconstituted on hsp70 promoter DNA. In the presence of NURF, nucleosomes adopt one predominant position from an ensemble of possible locations within minutes. Movements occur in cis, with no transfer to competing DNA. Migrating intermediates trapped by fro III digestion reveal progressive nucleosome motion in increments of several base pairs. All four core histones are retained quantitatively during this process, indicating that the general integrity of the histone octamer is maintained. We suggest that NURF remodels nucleosomes by transiently decreasing the activation energy for short-range sliding of the histone octamer. C1 NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wu, C (reprint author), NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NR 75 TC 246 Z9 249 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JUN 25 PY 1999 VL 97 IS 7 BP 833 EP 842 DI 10.1016/S0092-8674(00)80796-5 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 211LP UT WOS:000081162800005 PM 10399912 ER PT J AU Murphy, E Cross, H Steenbergen, C AF Murphy, E Cross, H Steenbergen, C TI Sodium regulation during ischemia versus reperfusion and its role in injury SO CIRCULATION RESEARCH LA English DT Editorial Material ID NA+-H+ EXCHANGE; RAT HEARTS; CALCIUM; MYOCARDIUM; MECHANISM; RECOVERY; OVERLOAD; PH C1 Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27706 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Murphy, E (reprint author), 111 Alexander Dr,Room E216,Mail Drop D2-03,Box 12, Res Triangle Pk, NC 27707 USA. FU NHLBI NIH HHS [R01 HL039752] NR 15 TC 75 Z9 76 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUN 25 PY 1999 VL 84 IS 12 BP 1469 EP 1470 PG 2 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 211DU UT WOS:000081145300014 PM 10381900 ER PT J AU Finkel, T AF Finkel, T TI Thinking globally, acting locally - The promise of cardiovascular gene therapy SO CIRCULATION RESEARCH LA English DT Editorial Material ID NITRIC-OXIDE SYNTHASE; BLOOD-COAGULATION; EXPRESSION; INHIBITOR; INJECTION; ARTERIES; DELIVERY C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10,Room 7B15,10 Ctr Dr,MSC 1650, Bethesda, MD 20892 USA. NR 17 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUN 25 PY 1999 VL 84 IS 12 BP 1471 EP 1472 PG 2 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 211DU UT WOS:000081145300015 PM 10381901 ER PT J AU Hernandez-Sanchez, C Ito, Y Ferrer, J Reitman, M LeRoith, D AF Hernandez-Sanchez, C Ito, Y Ferrer, J Reitman, M LeRoith, D TI Characterization of the mouse sulfonylurea receptor 1 promoter and its regulation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RNA POLYMERASE-II; SENSITIVE K+ CHANNELS; PERSISTENT HYPERINSULINEMIC HYPOGLYCEMIA; PANCREATIC BETA-CELLS; INSULIN-SECRETION; GENE-EXPRESSION; GLUCOCORTICOID RECEPTOR; ATP; TRANSCRIPTION; KIR6.2 AB The ATP-sensitive potassium channels (K-ATP(+) channels) are heteromultimeric structures formed by a member of the sulfonylurea receptor (SUR) family and a member of the inwardly rectifying potassium channel family (Kir6.x), The K+,, channels play an essential role in nutrient-induced insulin secretion from the pancreatic beta-cell, We have cloned and characterized the promoter region of the mouse SUR1 gene, and have shown that it lacks CAAT and TATA boxes or an initiator element. Studies of transcription initiation in several tissues showed that there is a common SUR1 promoter in brain, heart, and pancreas and in the pancreatic beta-cell line, PTC3, The SUR1 gene uses multiple transcription start sites with the major site located 54 base pairs 5'-upstream of the translation initiation site. Transient transfection experiments in pancreatic p-cell lines showed that the proximal promoter fragment -84/+54 is sufficient for significant transcriptional activity. The proximal promoter region contains multiple SP1-binding sites, and cotransfection experiments of the SUR1 promoter-luciferase vector with SP1 expression Vector in Drosophila SL2 cells demonstrated a stimulatory effect of SP1 on SUR1 transcriptional activity. The mobility shift assays confirmed the interaction of the SP1 transcription factor with the proximal promoter region of the SUR1 gene. Together, these results indicate that SP1 may mediate transcription initiation of the SUR1 gene. In addition, we have described the coordinate regulation of the gene expression of both K-ATP(+),, channel subunits by glucocorticoids. SUR1 and Kir6,2 mRNA levels are down-regulated by similar to 40-50% in response to glucocorticoid treatment. Interestingly, the extent of the inhibitory effect as well as the kinetics and sensitivity are very similar for both mRNAs, Studies of mRNA turnover demonstrate that glucocorticoids most likely decrease the transcriptional activity of both SUR1 and Kir6,2 genes since glucocorticoids failed to affect the stability of each mRNA, Likewise, the reduction in mRNA levels was correlated with a decrease in SUR1 and Kir6,2 protein levels. C1 NIDDK, Sect Mol & Cellular Physiol, Diabet Branch, NIH, Bethesda, MD 20892 USA. Hosp Clin Barcelona, Dept Endocrinol, E-08036 Barcelona, Spain. RP Hernandez-Sanchez, C (reprint author), NIDDK, Sect Mol & Cellular Physiol, Diabet Branch, NIH, Rm 8D12,Bldg 10,10 Ctr Dr,MSC 1758, Bethesda, MD 20892 USA. RI Reitman, Marc/B-4448-2013; Hernandez Sanchez, Catalina/N-1737-2014; Ferrer, Jorge/A-3176-2012 OI Reitman, Marc/0000-0002-0426-9475; Hernandez Sanchez, Catalina/0000-0002-0846-5019; NR 38 TC 31 Z9 31 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 25 PY 1999 VL 274 IS 26 BP 18261 EP 18270 DI 10.1074/jbc.274.26.18261 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 209PJ UT WOS:000081056700020 PM 10373428 ER PT J AU Kelly, JD Inga, A Chen, FX Dande, P Shah, D Monti, P Aprile, A Burns, PA Scott, G Abbondandolo, A Gold, B Fronza, G AF Kelly, JD Inga, A Chen, FX Dande, P Shah, D Monti, P Aprile, A Burns, PA Scott, G Abbondandolo, A Gold, B Fronza, G TI Relationship between DNA methylation and mutational patterns induced by a sequence selective minor groove methylating agent SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ESCHERICHIA-COLI; POLYMERASE-BETA; NUCLEOTIDE INCORPORATION; FUNCTIONAL ASSAY; CELL-LINES; IN-VITRO; GLYCOSYLASE; MUTAGENESIS; ALKYLATION; DEFICIENT AB Me-lex, a methyl sulfonate ester appended to a neutral N-methylpyrrolecarboxamide-based dipeptide, was synthesized to preferentially generate N-3-methyladenine (3-MeA) adducts which are expected to be cytotoxic rather than mutagenic DNA lesions. In the present study, the sequence specificity for DNA alkylation by Me-lex was determined in the p53 cDNA through the conversion of the adducted sites into single strand breaks and sequencing gel analysis. In order to establish the mutagenic and lethal properties of Me-lex lesions, a yeast expression vector harboring the human wild-type p53 cDNA was treated in vitro with Me-lex, and transfected into a yeast strain containing the ADE2 gene regulated by a p53-responsive promoter. The results showed that: 1) more than 99% of the lesions induced by Me-lex are 3-MeA; 2) the co-addition of distamycin quantitatively inhibited methylation at all minor groove sites; 3) Me-lex selectively methylated A's that are in, or immediately adjacent to, the lex equilibrium binding sites; 4) all but 6 of the 33 independent mutations were base pair substitutions, the majority of which (17/33; 52%) were AT-targeted; 5) AT --> TA transversions were the predominant mutations observed (13/33; 39%); 6) 13 out of 38 (39%) independent mutations involved a single lex-binding site encompassing positions A(600-602), and 9 occurred at position 602 which is a real Me-lex mutation hotspot (n = 9, p < 10(-6), Poisson's normal distribution). A hypothetical model for the interpretation of mutational events at this site is proposed. The present work is the first report on mutational properties of Me-lex. Our results suggest that 3-MeA is not only a cytotoxic but also a premutagenic lesion which exerts this unexpected property in a strict sequence-dependent manner. C1 Univ Nebraska, Med Ctr, Eppley Inst Res Canc, Omaha, NE 69198 USA. Univ Nebraska, Med Ctr, Dept Pharmaceut Sci, Omaha, NE 69198 USA. Natl Canc Inst, IST, Mutagenesis Lab, I-16132 Genoa, Italy. Univ Leeds, Sch Med, Leeds LS2 9JT, W Yorkshire, England. Univ Genoa, Dept Oncol Biol & Genet, I-16132 Genoa, Italy. RP Gold, B (reprint author), Univ Nebraska, Med Ctr, Eppley Inst Res Canc, Omaha, NE 69198 USA. FU NCI NIH HHS [CA36727] NR 35 TC 36 Z9 37 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 25 PY 1999 VL 274 IS 26 BP 18327 EP 18334 DI 10.1074/jbc.274.26.18327 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 209PJ UT WOS:000081056700028 PM 10373436 ER PT J AU Brosh, RM Orren, DK Nehlin, JO Ravn, PH Kenny, MK Machwe, A Bohr, VA AF Brosh, RM Orren, DK Nehlin, JO Ravn, PH Kenny, MK Machwe, A Bohr, VA TI Functional and physical interaction between WRN helicase and human replication protein A SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-BINDING-PROTEIN; WERNER-SYNDROME PROTEIN; NUCLEOTIDE EXCISION-REPAIR; SYNDROME GENE-PRODUCT; ESCHERICHIA-COLI; SACCHAROMYCES-CEREVISIAE; SYNDROME CELLS; BLOOMS-SYNDROME; CALF THYMUS; EXONUCLEASE AB The human premature aging disorder Werner syndrome (WS) is associated with a large number of symptoms displayed in normal aging. The WRN gene product, a DNA helicase, has been previously shown to unwind short DNA duplexes (less than or equal to 53 base pairs) in a reaction stimulated by single-stranded DNA-binding proteins. We have studied the helicase activity of purified WRN protein on a variety of DNA duplex substrates to characterize the unwinding properties of the enzyme in greater detail. WRN helicase can catalyze unwinding of long duplex DNA substrates up to 849 base pairs in a reaction dependent on human replication protein A (hRPA). Escherichia coli SSB and bacteriophage T4 gene 32 protein (gp32) completely failed to stimulate WRN helicase to unwind long DNA duplexes indicating a specific functional interaction between WRN and hRPA. So far, there have been no reports of any physical interactions between WRN helicase and other proteins. In support of the functional interaction, we demonstrate a direct interaction between WRN and hRPA by coimmunoprecipitation of purified proteins. The physical and functional interaction between WRN and hRPA suggests that the two proteins may function together in vivo in a pathway of DNA metabolism such as replication, recombination, or repair. C1 NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. Aarhus Univ, DK-8000 Aarhus C, Denmark. Montefiore Med Ctr, Albert Einstein Canc Ctr, Bronx, NY 10467 USA. RP Brosh, RM (reprint author), NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. NR 53 TC 219 Z9 221 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 25 PY 1999 VL 274 IS 26 BP 18341 EP 18350 DI 10.1074/jbc.274.26.18341 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 209PJ UT WOS:000081056700030 PM 10373438 ER PT J AU Meacci, E Vasta, V Moorman, JP Bobak, DA Bruni, P Moss, J Vaughan, M AF Meacci, E Vasta, V Moorman, JP Bobak, DA Bruni, P Moss, J Vaughan, M TI Effect of Rho and ADP-ribosylation factor GTPases on phospholipase D activity in intact human adenocarcinoma A549 cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; GTP-BINDING PROTEIN; DIFFICILE TOXIN-B; BREFELDIN-A; GUANINE-NUCLEOTIDE; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; DEPENDENT ACTIVATION; SELECTIVE-INHIBITION; HUMAN NEUTROPHILS; GOLGI-APPARATUS AB Phospholipase D (PLD) has been implicated as a crucial signaling enzyme in secretory pathways. Two 20-kDa guanine nucleotide-binding proteins, Rho and ADP-ribosylation factor (ARF), are involved in the regulation of secretion and can activate PLD in vitro. We investigated in intact (human adenocarcinoma A549 cells) the role of RhoA and ARF in activation of PLD by phorbol 12-myristate 13-acetate, bradykinin, and/or sphingosine 1-phosphate, To express recombinant Clostridium botulinum C3 exoenzyme (using double subgenomic recombinant Sindbis virus C3), an ADP-ribosyltransferase that inactivates Rho, or dominant-negative Rho containing asparagine at position 19 (using double subgenomic recombinant Sindbis virus Rho19N), cells were infected with Sindbis virus, a novel vector that allows rapid, high level expression of heterologous proteins. Expression of C3 toxin or Rho19N increased basal and decreased phorbol 12-myristate 13-acetate-stimulated PLD activity. Bradykinin or sphingosine 1-phosphate increased PLD activity with additive effects that were abolished in cells expressing C3 exoenzyme or Rho19N, In cells expressing C3, modification of Rho appeared to be incomplete, suggesting the existence of pools that differed in their accessibility to the enzyme. Similar results were obtained with cells scrape-loaded in the presence of C3; however, results with virus infection were more reproducible. To assess the role of ARF, cells were incubated with brefeldin A (BFA), a fungal metabolite that disrupts Golgi structure and inhibits enzymes that catalyze ARF activation by accelerating guanine nucleotide exchange. BFA disrupted Golgi structure, but did not affect basal or agonist-stimulated PLD activity, i.e. it did not alter a rate limiting step in PLD activation, It also had no effect on Rho-stimulated PLD activity, indicating that RhoA action did not involve a BFA-sensitive pathway, A novel PLD activation mechanism, not sensitive to BFA and involving RhoA, was identified in human airway epithelial cells by use of a viral infection technique that preserves cell responsiveness. C1 NHLBI, Pulmonary Crit Care Med Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. Univ Florence, Dipartimento Sci Biochim, I-50134 Florence, Italy. Univ Virginia, Sch Med, Dept Med, Charlottesville, VA 22908 USA. RP Moss, J (reprint author), NHLBI, Pulmonary Crit Care Med Branch, Natl Inst Hlth, Rm 5N-307,Bldg 10,10 Ctr Dr,MSC 1434, Bethesda, MD 20892 USA. RI Bruni, Paola/A-1151-2008; OI Bruni, Paola/0000-0002-1151-3413 FU NIGMS NIH HHS [R01 GM 54572] NR 50 TC 54 Z9 54 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 25 PY 1999 VL 274 IS 26 BP 18605 EP 18612 DI 10.1074/jbc.274.26.18605 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 209PJ UT WOS:000081056700063 PM 10373471 ER PT J AU Enkemann, SA Pavur, KS Ryazanov, AG Berger, SL AF Enkemann, SA Pavur, KS Ryazanov, AG Berger, SL TI Does prothymosin alpha affect the phosphorylation of elongation factor 2? SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FACTOR-II; HL-60 CELLS; HISTONE H1; IN-VITRO; C-MYC; GENE; EXPRESSION; PROTEIN; PROLIFERATION; THYMOSIN-ALPHA-1 AB Prothymosin alpha is a small, acidic, essential nuclear protein that plays a poorly defined role in the proliferation and survival of mammalian cells. Recently, Vega et al. proposed that exogenous prothymosin alpha can specifically increase the phosphorylation of eukaryotic elongation factor 2 (eEF-2) in extracts of NIH3T3 cells (Vega, F. V., Vidal, A., Hellman, U., Wernstedt, C., and Dominguez, F. (1998) J. Biol. Chem. 273, 10147-10152). Using similar lysates prepared by four methods (detergent lysis, Dounce homogenization, digitonin permeabilization, and sonication) and three preparations of prothymosin alpha, one of which was purified by gentle means (the native protein, and a histidine-tagged recombinant prothymosin alpha expressed either in bacteria or in COS cells), we failed to find a response. A reconstituted system composed of eEF-2, recombinant eEF-2 kinase, calmodulin, and calcium was also unaffected by prothymosin alpha. However, unlike our optimized buffer, Vega's system included a phosphatase inhibitor, 50 mM fluoride, which when evaluated in our laboratories severely reduced phosphorylation of all species. Under these conditions, any procedure that decreases the effective fluoride concentration will relieve the inhibition and appear to activate. Our data do not support a direct relationship between the function of prothymosin a and the phosphorylation of eEF-2. C1 NCI, Sect Genes & Genes Prod, Natl Inst Hlth, Bethesda, MD 20892 USA. Univ Med & Dent New Jersey, Dept Pharmacol, Robert Wood Johnson Med Sch, Piscataway, NJ 08854 USA. Univ Med & Dent New Jersey, Med & Canc Inst, Robert Wood Johnson Med Sch, Piscataway, NJ 08854 USA. RP NCI, Sect Genes & Genes Prod, Natl Inst Hlth, Bldg 37,Rm 5D-10,37 Convent Dr, Bethesda, MD 20892 USA. EM bergers@pop.nci.nih.gov NR 52 TC 8 Z9 8 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 JUN 25 PY 1999 VL 274 IS 26 BP 18644 EP 18650 DI 10.1074/jbc.274.26.18644 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 209PJ UT WOS:000081056700068 PM 10373476 ER PT J AU Zhou, X Park, SI Moustafa, ME Carlson, BA Crain, PF Diamond, AM Hatfield, DL Lee, BJ AF Zhou, X Park, SI Moustafa, ME Carlson, BA Crain, PF Diamond, AM Hatfield, DL Lee, BJ TI Selenium metabolism in Drosophila - Characterization of the selenocysteine tRNA population SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSFER-RNA POPULATION; TRANSFER RNASEC; MASS-SPECTROMETRY; MAMMALIAN-CELLS; GENE; UGA; CHROMOSOMES; ANTICODON; SYSTEM AB The selenocysteine (Sec) tRNA population in Drosophila melanogaster is aminoacylated with serine, forms selenocysteyl-tRNA, and decodes UGA. The K-m of Sec tRNA and serine tRNA for seryl-tRNA synthetase is 6.67 and 9.45 nM, respectively. Two major bands of Sec tRNA were resolved by gel electrophoresis, Both tRNAs were sequenced, and their primary structures were indistinguishable and colinear with that of the corresponding single copy gene. They are 90 nucleotides in length and contain three modified nucleosides, 5-methylcarboxymethyluridine, N-6-isopentenyladenosine, and pseudouridine, at positions 34, 37, and 55, respectively. Neither form contains 1-methyladenosine at position 58 or 5-methylcarboxymethyl-2'-O-methyluridine which are characteristically found in Sec tRNA of higher animals. We conclude that the primary structures of the two bands of Sec tRNA resolved by electrophoresis are indistinguishable by the techniques employed and that See tRNAs in Drosophila may exist in different conformational forms. The Sec tRNA gene maps to a single locus on chromosome 2 at position 47E or F, To our knowledge, Drosophila is the lowest eukaryote in which the Sec tRNA population has been characterized to date. C1 Seoul Natl Univ, Inst Mol Biol & Genet, Genet Mol Lab, Seoul 151742, South Korea. NCI, Sect Mol Biol Selenium, Lab Basic Res, NIH, Bethesda, MD 20892 USA. Univ Utah, Dept Med Chem, Salt Lake City, UT 84112 USA. Univ Illinois, Dept Human Nutr & Dietet, Chicago, IL 60612 USA. RP Lee, BJ (reprint author), Seoul Natl Univ, Inst Mol Biol & Genet, Med Genet Lab, Seoul 151742, South Korea. FU NCI NIH HHS [R01 CA81153]; NIGMS NIH HHS [R01 GM29812] NR 31 TC 9 Z9 9 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 25 PY 1999 VL 274 IS 26 BP 18729 EP 18734 DI 10.1074/jbc.274.26.18729 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 209PJ UT WOS:000081056700079 PM 10373487 ER EF