FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Park, KS Hoffmann, C Kim, HO Padgett, WL Daly, JW Brambilla, R Motta, C Abbracchio, MP Jacobson, KA AF Park, KS Hoffmann, C Kim, HO Padgett, WL Daly, JW Brambilla, R Motta, C Abbracchio, MP Jacobson, KA TI Activation and desensitization of rat A(3)-adenosine receptors by selective adenosine derivatives and xanthine-7-ribosides SO DRUG DEVELOPMENT RESEARCH LA English DT Article DE xanthines; adenosine derivatives; nucleosides; adenylyl cyclase; guanine nucleotides ID A(3) RECEPTOR; MOLECULAR-CLONING; PHOSPHOLIPASE-C; ANTAGONISTS; CELLS; EXPRESSION; AGONISTS; AFFINITY; BRAIN AB Xanthine and adenosine derivatives, known to bind to recombinant rat A(3) adenosine receptors stably expressed in Chinese hamster ovary cells, were characterized in a functional assay consisting of activation of A(3) receptor-stimulated binding of [S-35]GTP gamma S in rat RBL-2H3 cell membranes. 1,3-Dibutylxanthine-7-riboside-5'-N-methylcarboxamide (DBXRM, 7b), previously shown to inhibit adenylyl cyclase via rat A(3) receptors with full efficacy, appeared to be a partial agonist at the rat A(3) receptor of RBL-2H3 cells. Full agonists, such as Cl-IB-MECA or I-AB-MECA, were more potent and effective than the partial agonist DBXRM in causing desensitization of rat A(3) receptors, as indicated by loss of [S-35]GTP gamma S binding. At A(1) receptors, antagonism of agonist-elicited inhibition of rat adipocyte adenylyl cyclase was observed for several xanthine-7-riboside derivatives that had been shown to be full agonists at rat A(3) receptors. A new xanthine riboside (3'-deoxyDBXRM, 7c) was synthesized and found to be a partial agonist at rat A(3) receptors and an antagonist at rat A(1) receptors. Thus, it is possible for the same compound to stimulate one adenosine receptor subtype (A(3)) and block another subtype (A(1)) within the same species. Drug Dev. Res. 44:97-105, 1998. (C) 1998 Wiley-Liss, Inc.(dagger) C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Univ Milan, Sch Pharm, Inst Pharmacol Sci, Milan, Italy. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, NIH, Bldg 8A,Rm B1A-17, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009; Abbracchio, Maria Pia/B-9342-2014 OI Jacobson, Kenneth/0000-0001-8104-1493; Abbracchio, Maria Pia/0000-0002-7833-3388 FU Intramural NIH HHS [Z01 DK031117-20, Z99 DK999999] NR 33 TC 8 Z9 8 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 JUN-JUL PY 1998 VL 44 IS 2-3 BP 97 EP 105 DI 10.1002/(SICI)1098-2299(199806/07)44:2/3<97::AID-DDR7>3.0.CO;2-5 PG 9 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 123YM UT WOS:000076153300007 PM 23487508 ER PT J AU Lazarus, LH Bryant, SD Cooper, PS Guerrini, R Balboni, G Salvadori, S AF Lazarus, LH Bryant, SD Cooper, PS Guerrini, R Balboni, G Salvadori, S TI Design of delta-opioid peptide antagonists for emerging drug applications SO DRUG DISCOVERY TODAY LA English DT Review ID RECEPTOR ANTAGONIST; DELTORPHIN ANALOGS; CONFORMATIONAL-ANALYSIS; TETRAHYDROISOQUINOLINE-3-CARBOXYLIC ACID; STEREOCHEMICAL REQUIREMENTS; DIKETOPIPERAZINE FORMATION; ENKEPHALIN ANALOGS; BINDING-AFFINITY; AMINO-ACIDS; POTENT AB The need for delta-receptor-selective opioid antagonists has led to their development based on structure-activity relationships of delta- and mu-opioid agonists. The unusual amino acid 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), found in a series of H-Tyr-Tic-Phe-(Phe)-OH peptides, is an essential feature of derivatives discussed in this article. Elimination of Phe yields the H-Tyr-Tic-OH dipeptide antagonists, while substitution of Tyr by 2',6'-dimethyl-L-tyrosine (Dmt) gives H-Dmt-Tic-OH and numerous potent, high-affinity and ultraselective delta-opioid antagonists. This article reviews the emergence of derivatives based on the Tyr-Tic and Dmt-Tic pharmacophores as lead structures, and discusses potential clinical and therapeutic applications. C1 NIEHS, LCBRA, Res Triangle Pk, NC 27709 USA. Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. Univ Ferrara, Ctr Biotechnol, I-44100 Ferrara, Italy. RP Lazarus, LH (reprint author), NIEHS, LCBRA, POB 12233, Res Triangle Pk, NC 27709 USA. EM lazarus@niehs.nih.gov; sal@dns.unife.it OI Guerrini, Remo/0000-0002-7619-0918 NR 101 TC 39 Z9 41 U1 1 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD JUN PY 1998 VL 3 IS 6 BP 284 EP 294 DI 10.1016/S1359-6446(98)01187-8 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ZT769 UT WOS:000074123800009 ER PT J AU El-Masri, HA Portier, CJ AF El-Masri, HA Portier, CJ TI Physiologically based pharmacokinetics model of primidone and its metabolites phenobarbital and phenylethylmalonamide in humans, rats, and mice SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID BLOOD PARTITION-COEFFICIENTS; LIPID COMPOSITIONS; ORGANIC-CHEMICALS; TISSUE; ALGORITHM; MOUSE AB Physiologically based pharmacokinetic modeling of the parent chemical primidone and its two metabolites phenobarbital and phenylethylmalonamide (PEMA) was applied to investigate the differences of primidone metabolism among humans, rats, and mice. The model simulated previously published pharmacokinetic data of the parent chemical and its metabolites in plasma and brain tissues from separate studies of the three species. Metabolism of primidone and its metabolites varied widely among a sample of three human subjects from two separate studies, Estimated primidone metabolism, as expressed by the maximal velocity V-max, ranged from 0 to 0.24 mg . min(-1) . kg(-1) for the production of phenobarbital and from 0.003 to 0.02 mg . min(-1) . kg(-1) for the production of PEMA among three human subjects. Further model simulations indicated that rats were more efficient at producing and clearing phenobarbital and PEMA than mice. However, the overall metabolism profile of primidone and its metabolites in mice indicated that mice were at higher risk of toxicity owing to higher residence of phenobarbital in their tissues and owing to the carcinogenic potential of phenobarbital as illustrated in long-term bioassays, This result was in agreement with a recently finished National Toxicology Program (NTP) carcinogenicity study of primidone in rats and mice. C1 NIEHS, Lab Comp Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. RP El-Masri, HA (reprint author), NIEHS, Lab Comp Biol & Risk Anal, MD A3-06,POB 12233, Res Triangle Pk, NC 27709 USA. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 31 TC 27 Z9 28 U1 0 U2 6 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 JUN PY 1998 VL 26 IS 6 BP 585 EP 594 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ZU557 UT WOS:000074210000013 PM 9616196 ER PT J AU Chen, N Radko, SP Chrambach, A AF Chen, N Radko, SP Chrambach, A TI Separation and microgram-scale isolation of sea urchin egg granules by electrophoresis in polyvinylpyrrolidone solution, using horizontal gel electrophoresis apparatus with fluorescence detector SO ELECTROPHORESIS LA English DT Article DE polymer solution; subcellular particle; isolation; horizontal gel electrophoresis ID POLYMER-SOLUTIONS; CAPILLARY ELECTROPHORESIS; POLYACRYLAMIDE; MECHANISMS; PARTICLES; FRAGMENTS; PROTEINS; FUSION AB A homogenate of sea urchin (Lytechinus pictus) eggs rich in exocytotic membrane vesicles (granules) was subjected to analytical and preparative electrophoresis in the commercial automated horizontal gel electrophoresis apparatus (HPGE-1000, LabIntelligence, Belmont, CA) capable of intermittent scanning of the migration path, using buffered solutions of polyvinylpyrrolidone (PVP). The nonfluorescent granules were detected by "fluorescence reduction", i.e., a decrease of fluorescence intensity due to the absorbance and/or light scattering properties of the particle. Granules migrated at linear migration rates in buffers ranging from 0 to 2.5% PVP. Two bands were observed and optimally separated in 1.5% PVP solution. As shown by sodium dodecyl sulfate (SDS)-polypeptide patterns, the material recovered from the bands was qualitatively indistinguishable from the two major fractions A and C of granules previously separated by free-flow electrophoresis in the absence of polymer. Ferguson plot analysis failed to provide the sizes of the granules in view of the narrow PVP concentration range available for mobility measurement and the unavailability of chemically homogeneous size standards. 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, Bldg 10,Rm 9D50, Bethesda, MD 20892 USA. EM acc@cu.nih.gov NR 34 TC 4 Z9 4 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUN PY 1998 VL 19 IS 7 BP 1195 EP 1204 DI 10.1002/elps.1150190721 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA ZV360 UT WOS:000074296800020 PM 9662183 ER PT J AU Chestkov, V Baibakov, B Radko, SP Chrambach, A AF Chestkov, V Baibakov, B Radko, SP Chrambach, A TI Separation of viable from radiation-induced apoptotic lymphocytes by free-flow electrophoresis SO ELECTROPHORESIS LA English DT Article DE apoptotic lymphocytes; isolation; free-flow electrophoresis ID PROGRAMMED CELL-DEATH; SODIUM-CHLORIDE; T-CELLS; SUBPOPULATIONS AB A human lymphocyte population undergoing apoptosis in vitro due to gamma-irradiation was fractionated by free-flow electrophoresis in triethanolamine Na-acetate buffers, containing up to 50 mM NaCl, with pH 6.0, 7.2 and 8.5, made isotonic by addition of sucrose. As shown by a flow cytometric analysis of the eluate, the distribution of apoptotic lymphocytes is shifted to the range of higher electrophoretic mobilities relative to that of viable ones at pH 8.5, yielding cell fractions enriched in apoptotic cells by a factor of 3 to 5. The difference in rates of electrophoretic migration observed at a mildly alkaline pH but not at a neutral or mildly acidic one suggests that the surface of apoptotic lymphocytes is more acidic than that of viable ones. C1 NICHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. NIH, NASA, Ctr Tissue Culture, Bethesda, MD 20892 USA. RP Chrambach, A (reprint author), NICHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bldg 10,Rm 9D50, Bethesda, MD 20892 USA. NR 17 TC 2 Z9 3 U1 1 U2 3 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUN PY 1998 VL 19 IS 7 BP 1211 EP 1214 DI 10.1002/elps.1150190723 PG 4 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA ZV360 UT WOS:000074296800022 PM 9662185 ER PT J AU Chrambach, A Chen, N AF Chrambach, A Chen, N TI Preparative electrophoresis in "sieving media" of subcellular-sized particles SO ELECTROPHORESIS LA English DT Article; Proceedings Paper CT Meeting of the International-Council-of-Electrophoresis-Societies (ICES 97) CY MAR 23-27, 1997 CL SEATTLE, WASHINGTON SP Int Council Electrophoresis Societies DE preparative electrophoresis; polymer solutions; sieving ID CAPILLARY ELECTROPHORESIS; POLYMER-SOLUTIONS; SDS-PROTEIN; APPARATUS; SEPARATION; RECOVERY AB The commercial gel electrophoresis apparatus with intermittent scanning of the migration path and preparative capacity (HPGE-1000, LabIntelligence) is applicable to polymer solutions as well as gels. Unresolved rat liver microsomes can be isolated from 11-15% polyvinylpyrrolidone (PVP) solution by means of a syringe. The automated band isolation technique applied under resolving conditions in dilute polymer solutions allowed for the sequential isolation of three microsome components with 85, 76 and 75 % recovery, respectively, under strict control of the dimensions of the volumetric collection module of the HPGE-1000 apparatus. Separations of unlabeled microsomes and sea urchin egg components in dilute polymer solutions have been performed, using detection by "fluorescence reduction". The unlabeled major component of a sea urchin egg homogenate has been isolated from electrophoresis in 1.5% PVP (M-r = 10(6)) solution in 25-50% yield (0.24-4 mu g/8 lanes of the HPGE-1000 apparatus). However, since separations of both microsomes and sea urchin egg granules in dilute polymer solutions are restricted to a narrow range of polymer concentrations, their retardation coefficients, K-R,= d(log mobility)/d(polymer concentration), are not ascertained. 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, Bldg 10,Rm 9D50, Bethesda, MD 20892 USA. EM acc@cu.nih.gov NR 15 TC 4 Z9 4 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUN PY 1998 VL 19 IS 8-9 BP 1279 EP 1283 DI 10.1002/elps.1150190810 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA ZY715 UT WOS:000074652100009 PM 9694265 ER PT J AU Chrambach, A Radko, SP AF Chrambach, A Radko, SP TI Towards predicting mobility and resolution in polymeric media: Some first steps SO ELECTROPHORESIS LA English DT Article; Proceedings Paper CT Meeting of the International-Council-of-Electrophoresis-Societies (ICES 97) CY MAR 23-27, 1997 CL SEATTLE, WASHINGTON SP Int Council Electrophoresis Societies DE electrophoresis; polymer media; mobility; resolution ID CAPILLARY ELECTROPHORESIS; GEL-ELECTROPHORESIS; SCATTERING; SEPARATIONS; MECHANISMS; DISPERSION; PARTICLES; MODEL AB Particle size-dependent retardation ("molecular sieving") in electrophoresis can be achieved in polymer solutions or gels. In the semidilute concentration range of polymer solutions, mobility of "rigid, spherical" particles can be predicted from their size (in the size range less than 20 nm radius), the screening length specific for the particular polymer and a constant that can be experimentally determined for a polymer. That constant could be universal for all hydrophilic uncharged polymers. Band spreading in polymer solutions is constant over a range of particle sizes and polymer concentrations and increases beyond that range. Presumably the critical division between the two ranges occurs when the diameter of the particle exceeds the screening length of the polymer network. Resolution, defined as separation divided by the sum of bandwidths, can thus be predicted for a limited particle size and polymer concentration range. In gels, resolution can be estimated from the slopes and free mobility intercepts of the Ferguson plot. However, the previous computation of resolution needs to be revised in view of the fact that band spreading in gels proceeds in proportion to time, presumably through interaction with the polymer, and not as a function of the square root of time as would be the case if band spreading resulted from diffusion. 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, Bldg 10,Rm 9D50, Bethesda, MD 20892 USA. NR 24 TC 4 Z9 4 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUN PY 1998 VL 19 IS 8-9 BP 1284 EP 1287 DI 10.1002/elps.1150190811 PG 4 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA ZY715 UT WOS:000074652100010 PM 9694266 ER PT J AU Tajima, T Fujieda, K Mikami, A Igarashi, Y Nakae, J Cutler, GB AF Tajima, T Fujieda, K Mikami, A Igarashi, Y Nakae, J Cutler, GB TI Prenatal diagnosis of steroid 21-hydroxylase deficiency by the modified polymerase chain reaction to detect splice site mutation in the CYP21 gene SO ENDOCRINE JOURNAL LA English DT Article DE steroid 21-hydroxylase deficiency; prenatal diagnosis; polymerase-chain reaction; chorionic villus sampling ID CONGENITAL ADRENAL-HYPERPLASIA; POINT MUTATIONS AB A splicing junction mutation at nucleotide 656 (A-> G substitution, I2G) in the steroid 21-hydroxylase gene (CYP21) is the most frequently detected mutation in patients with the salt-wasting and simple-virilizing forms of steroid 21-hydroxylase deficiency (approximately 60%). In this disease, prenatal diagnosis and treatment to minimize the effects of excess androgen in affected females has been advocated. Therefore, to detect the I2G mutation rapidly, accurately, and without the use of radioisotope, we developed a modified polymerase chain reaction (PCR) with a mismatched 3' nucleotide primer to introduce a new restriction site upon PCR amplification of the mutant allele. This allowed the mutant allele to be identified readily by restriction enzyme digestion of the PCR product, and subsequently this PCR product was subjected to restriction enzyme digestion for diagnosis. Chorionic villus biopsy samples (CVS) were obtained at 10 to 11 weeks gestation from two females carrying fetuses at risk for steroid 21-hydroxylase deficiency. Prenatal diagnosis was successful in both cases. One affected female was treated with dexamethasone to term. In the other case, treatment was withdrawn at an early stage when testing revealed a normal fetus. The results demonstrate the rapid and accurate detection of the I2G mutation by this method, thereby indicating the feasibility of for prenatal diagnosis of the I2G mutation. C1 NICHHD, Sect Dev Endocrinol, Dev Endocrinol Branch, Bethesda, MD 20892 USA. Hokkaido Univ, Sch Med, Dept Pediat, Sapporo, Hokkaido 0608638, Japan. Sapporo City Inst Publ Hlth, Sapporo, Hokkaido 0608638, Japan. Igarashi Pediat Clin, Sendai, Miyagi 9813203, Japan. RP Tajima, T (reprint author), NICHHD, Sect Dev Endocrinol, Dev Endocrinol Branch, Bldg 10,Room 10N262, Bethesda, MD 20892 USA. RI Toshihiro, Tajima/A-5720-2012 NR 17 TC 6 Z9 7 U1 0 U2 0 PU JAPAN ENDOCRINE SOCIETY PI TOKYO PA C/O DEPT VETERINARY PHYSIOL, VET MED SCI, UNIV TOKYO, 1-1-1 YAYOI, BUNKYO-KU, TOKYO, 113, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD JUN PY 1998 VL 45 IS 3 BP 291 EP 295 DI 10.1507/endocrj.45.291 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZZ156 UT WOS:000074701300002 PM 9790262 ER PT J AU Fueshko, SM Key, S Wray, S AF Fueshko, SM Key, S Wray, S TI Luteinizing hormone releasing hormone (LHRH) neurons maintained in nasal explants decrease LHRH messenger ribonucleic acid levels after activation of GABA(A) receptors SO ENDOCRINOLOGY LA English DT Article ID GAMMA-AMINOBUTYRIC-ACID; ANTERIOR HYPOTHALAMIC AREA; SLEEP-INDUCING PEPTIDE; IN-SITU HYBRIDIZATION; MEDIAL PREOPTIC AREA; GENE-EXPRESSION; INDUCED DEPOLARIZATION; OLFACTORY PLACODE; MALE-RAT; OVARIECTOMIZED RATS AB Inhibition of the LHRH system appears to play an important role in preventing precocious activation of the hypothalamic-pituitary-gonadal axis. Evidence points to gamma-aminobutyric acid (GABA) as the major negative regulator of postnatal LHRH neuronal activity. Changes in LHRH messenger RNA (mRNA) levels after alterations of GABAergic activity have been reported in vivo. However, the extent to which GABA acts directly on LHRH neurons to effect LHRH mRNA levels has been difficult to ascertain. The present work, evaluates the effect of GABAergic activity, via GABA(A) receptors, on LHRH neuropeptide gene expression in LHRH neurons maintained in olfactory explants generated from E11.5 mouse embryos. These explants maintain large numbers of primary LHRH neurons that migrate from bilateral olfactory pits in a directed manner. Using in situ hybridization histochemistry and single cell analysis, we report dramatic alterations in LHRH mRNA levels. Inhibition of spontaneous synaptic activity by GABA(A) antagonists, bicuculline (10(-5) M) or picrotoxin (10(-4) M), or of electrical activity by tetrodotoxin (TTX, 10(-6) M) significantly increased LHRH mRNA levels. In contrast, LHRH mRNA levels decreased in explants cultured with the GABA(A) receptor agonist, muscimol (10(-4) M), or KCl (50 mM). The observed responses suggest that LHRH neurons possess functional pathways linking GABA(A) receptors to repression of neuropeptide gene expression and indicate that gene expression in embryonic LHRH neurons, outside the CNS, is highly responsive to alterations in neuronal activity. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Wray, S (reprint author), NINDS, Neurochem Lab, NIH, Bldg 36,Rm 4D-12, Bethesda, MD 20892 USA. EM swray@codon.nih.gov OI wray, susan/0000-0001-7670-3915 NR 51 TC 27 Z9 27 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 JUN PY 1998 VL 139 IS 6 BP 2734 EP 2740 DI 10.1210/en.139.6.2734 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZP744 UT WOS:000073784100011 PM 9607779 ER PT J AU Mancilla, EE De Luca, F Uyeda, JA Czerwiec, FS Baron, J AF Mancilla, EE De Luca, F Uyeda, JA Czerwiec, FS Baron, J TI Effects of fibroblast growth factor-2 on longitudinal bone growth SO ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 79th Annual Meeting of the Endocrine-Society CY JUN 10-14, 1997 CL MINNEAPOLIS, MN SP Endocrine Soc ID RABBIT COSTAL CHONDROCYTES; FACTOR RECEPTOR-3; PROTEOGLYCAN SYNTHESIS; TRANSMEMBRANE DOMAIN; PLATE CHONDROCYTES; MOUSE; ACHONDROPLASIA; STIMULATION; DIFFERENTIATION; ORGANOGENESIS AB In vivo, fibroblast growth factor-2 (FGF-2) inhibits longitudinal bone growth. Similarly, activating FGF receptor 3 mutations impair growth in achondroplasia and thanatophoric dysplasia. To investigate the underlying mechanisms, we chose a fetal rat metatarsal organ culture system that would maintain growth plate histological architecture. Addition of FGF-2 to the serum-free medium inhibited longitudinal growth. We next assessed each major component of longitudinal growth: proliferation, cellular hypertrophy, and cartilage matrix synthesis. Surprisingly, FGF-2 stimulated proliferation, as assessed by [H-3]thymidine incorporation. However, autoradiographic studies demonstrated that this increased proliferation occurred only in the perichondrium, whereas decreased labeling was seen in the proliferative and epiphyseal chondrocytes. FGF-2 also caused a marked decrease in the number of hypertrophic chondrocytes. To assess cartilage matrix synthesis, we measured (SO4)-S-35, incorporation into newly synthesized glycosaminoglycans. Low concentrations (10 ng/ml) of FGF-S stimulated cartilage matrix production, but high concentrations (1000 ng/ml) inhibited matrix production. We conclude that FGF-2 inhibits longitudinal bane growth by three mechanisms: decreased growth plate chondrocyte proliferation, decreased cellular hypertrophy, and, at high concentrations, decreased cartilage matrix production These effects may explain the impaired growth seen in patients with achondroplasia and related skeletal dysplasias. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Baron, J (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC 1862, Bethesda, MD 20892 USA. EM Jeffrey_Baron@nih.gov NR 23 TC 58 Z9 63 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 JUN PY 1998 VL 139 IS 6 BP 2900 EP 2904 DI 10.1210/en.139.6.2900 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZP744 UT WOS:000073784100032 PM 9607800 ER PT J AU Suzuki, K Kobayashi, Y Katoh, R Kohn, LD Kawaoi, A AF Suzuki, K Kobayashi, Y Katoh, R Kohn, LD Kawaoi, A TI Identification of thyroid transcription factor-1 in C cells and parathyroid cells SO ENDOCRINOLOGY LA English DT Article ID THYROTROPIN RECEPTOR GENE; ENHANCER-BINDING PROTEIN; THYROGLOBULIN PROMOTER; EXPRESSION; CALCIUM; LUNG; MECHANISMS; PITUITARY; CULTURE; GROWTH AB We have identified thyroid transcription factor-1 (TTF-1) mRNA in parafollicular C cells of the adult rat thyroid and in parathyroid cells; in each case the signal is stronger than in the thyrocytes themselves. We additionally identify TTF-1 RNA in other adult rat tissues not previously recognized to contain TTF-1 in developmental or knockout studies: basal layer cells of flattened squamous epithelium in skin and esophagus, three layers of the retina, i.e. pigmented epithelium, inner granular layer, and ganglion cell layer, and three areas of the brain, i.e. anterior pituitary, cerebellum, and hippocampus. Based on the array of cells that are shown to contain TTF-1 in this report, we speculate that TTF-1 may have a role in the regulation of genes important in calcium homeostasis in the intact organism as well as different tissues. C1 Yamanashi Med Univ, Dept Pathol, Yamanashi 40938, Japan. NIDDKD, Cell Regulat Sect, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Suzuki, K (reprint author), Yamanashi Med Univ, Dept Pathol, Yamanashi 40938, Japan. NR 23 TC 50 Z9 50 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 JUN PY 1998 VL 139 IS 6 BP 3014 EP 3017 DI 10.1210/en.139.6.3014 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZP744 UT WOS:000073784100045 PM 9607813 ER PT J AU Fitzgerald, EF Schell, LM Marshall, EG Carpenter, DO Suk, WA Zejda, JE AF Fitzgerald, EF Schell, LM Marshall, EG Carpenter, DO Suk, WA Zejda, JE TI Environmental pollution and child health in Central and Eastern Europe SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material DE air pollution; Central Europe; child health; Eastern Europe; environmental pollution; heavy metals ID AIR-POLLUTION; LEAD-EXPOSURE AB For the last 50 years, the economic and industrial development of the nations of Central and Eastern Europe has been achieved at the cost of environmental degradation. The health risks posed by this pollution to children and the steps necessary to ameliorate such risks are only beginning to be investigated. At a recent conference in Poland, sponsored in part by the National Institute of Environmental Health Sciences, participants from II countries in the region, together with scientists from Western Europe and the United States, met to share information regarding pediatric environmental health in Central and Eastern Europe, to consider methodologic issues in the design and conduct of such studies, and to discuss preventive strategies. This report summarizes the deliberations, outlines problem areas such as heavy metals and air pollution, delineates research and training needs to help Central and Eastern Europeans deal more effectively with such problems, and recommends specific future actions and collaborative efforts. C1 SUNY Albany, Sch Publ Hlth, Albany, NY 12203 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Inst Occupat Med & Environm Hlth, Sosnowiec, Poland. RP Fitzgerald, EF (reprint author), SUNY Albany, Sch Publ Hlth, 2 Univ Pl,Room 130, Albany, NY 12203 USA. RI Fitzgerald, Edward/F-4087-2010 FU NIEHS NIH HHS [3P43ES0491306S1] NR 40 TC 11 Z9 11 U1 8 U2 12 PU US DEPT HEALTH HUMAN SERVICES PUBLIC HEALTH SERVICE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SERVICES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 1998 VL 106 IS 6 BP 307 EP 311 DI 10.1289/ehp.98106307 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 110KV UT WOS:000075380600015 PM 9618345 ER PT J AU Landrigan, PJ Carlson, JE Bearer, CF Cranmer, JS Bullard, RD Etzel, RA Groopman, J McLachlan, JA Perera, FP Reigart, JR Robison, L Schell, L Suk, WA AF Landrigan, PJ Carlson, JE Bearer, CF Cranmer, JS Bullard, RD Etzel, RA Groopman, J McLachlan, JA Perera, FP Reigart, JR Robison, L Schell, L Suk, WA TI Children's health and the environment: A new agenda for prevention research SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article; Proceedings Paper CT 1st National Research Conference on Childrens Environmental Health - Research, Practice, Prevention, and Policy CY FEB 21-23, 1997 CL WASHINGTON, D.C. SP Childrens Environm Hlth Network, US Natl Canc Inst, Div Canc Epidemiol & Genet, Med Univ S Carolina, Environm Hazards Assessment Program, California Dept Hlth Serv, Environm Hlth Investigat Branch, US Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Public Hlth Inst, US Agcy Toxic Subst & DIs Registry, US EPA, US NICHHD, US Natl Inst Environm Hlth Sci DE environmental health; pediatrics; environmental toxicology; health policy ID INFANT-DEATH-SYNDROME; PUBLIC-HEALTH; POLYCHLORINATED-BIPHENYLS; CHILDHOOD CANCERS; UNITED-STATES; LEAD-EXPOSURE; SMOKING; EPIDEMIOLOGY; DISEASE; TRENDS AB Patterns of illness in American children have changed dramatically in this century. The ancient infectious diseases have largely been controlled. The major diseases confronting children now are chronic and disabling conditions termed the "new pediatric morbidity" - asthma mortality has doubled; leukemia and brain cancer have increased in incidence; neurodevelopmental dysfunction is widespread; hypospadias incidence has doubled. Chemical toxicants in the environment as well as poverty, racism, and inequitable access to medical care are factors known and suspected to contribute to causation of these pediatric diseases. Children are at risk of exposure to over 15,000 high-production-volume synthetic chemicals, nearly all of them developed in the past 50 years. These chemicals are used widely in consumer products and are dispersed in the environment. More than half are untested for toxicity. Children appear uniquely vulnerable to chemical toxicants because of their disproportionately heavy exposures and their inherent biological susceptibility. To prevent disease of environmental origin in America's children, the Children's Environmental Health Network (CEHN) calls for a comprehensive, national, child-centered agenda. This agenda must recognize children's vulnerabilities to environmental toxicants. It must encompass a) a new prevention-oriented research focus, b) a new child-centered paradigm for health risk assessment and policy formulation; and c) a campaign to educate the public, health professionals, and policy makers that environmental disease is caused by preventable exposures and is therefore avoidable. To anchor the agenda, CEHN calls for longterm, stable investment and for creation of a national network of pediatric environmental health research and prevention centers. C1 CUNY Mt Sinai Sch Med, Dept Community Med, New York, NY 10029 USA. Childrens Environm Hlth Network, Emeryville, CA USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Arkansas, Sch Med, Little Rock, AR 72204 USA. Clark Univ, Atlanta, GA USA. Ctr Dis Control & Prevent, Atlanta, GA USA. Johns Hopkins Sch Hyg & Publ Hlth, Baltimore, MD USA. Tulane Univ, Sch Med, New Orleans, LA 70112 USA. Columbia Univ, Sch Publ Hlth, New York, NY USA. Med Univ S Carolina, Charleston, SC 29425 USA. Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. SUNY Albany, Albany, NY 12222 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Landrigan, PJ (reprint author), CUNY Mt Sinai Sch Med, Dept Community Med, 1 Gustave L Levy Pl,Box 1057, New York, NY 10029 USA. EM plandrigan@smtplink.mssm.edu NR 60 TC 77 Z9 78 U1 1 U2 12 PU US DEPT HEALTH HUMAN SERVICES PUBLIC HEALTH SERVICE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SERVICES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 1998 VL 106 SU 3 BP 787 EP 794 DI 10.2307/3434190 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 110WJ UT WOS:000075404300002 PM 9646038 ER PT J AU Suk, WA Collman, GW AF Suk, WA Collman, GW TI Genes and the environment: Their impact on children's health SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article; Proceedings Paper CT 1st National Research Conference on Childrens Environmental Health - Research, Practice, Prevention, and Policy CY FEB 21-23, 1997 CL WASHINGTON, D.C. SP Childrens Environm Hlth Network, US Natl Canc Inst, Div Canc Epidemiol & Genet, Med Univ S Carolina, Environm Hazards Assessment Program, California Dept Hlth Serv, Environm Hlth Investigat Branch, US Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Public Hlth Inst, US Agcy Toxic Subst & DIs Registry, US EPA, US NICHHD, US Natl Inst Environm Hlth Sci DE children; genetic; exposure; environment; susceptibility; genes; vulnerability; developmental; risk ID AMINOLEVULINIC-ACID DEHYDRATASE; LEAD WORKERS; BLOOD LEAD; POLYMORPHISM; POLLUTION; CHILDHOOD; ISOZYMES; TOXICITY; EXPOSURE; HUMANS AB Because the human population is biologically diverse and genetically heterogeneous, it is not surprising that differences in susceptibility to disease among individuals with or without exposure to environmental agents exist. Individuals van! greatly in their susceptibility to disease. This is true of adults and children. The etiologies of many diseases of childhood are due to a combination of factors, including genetic susceptibility and environmental exposures during vulnerable periods of development. Genes regulate cellular growth and development, DNA replication and repair, the metabolism of endogenous agents in the body, and the metabolism and excretion of exogenous agents that the body comes in contact with in the environment. This regulation varies over the life span, contributing to the cellular consequences of the environmental exposures. This paper summarizes the contributions of generics in understanding the etiology of environmentally induced diseases in children. The use of biomarkers of genetic susceptibility in the study of these diseases will be discussed. Future research needs for expanding our knowledge of the interactions between genetic and environmental components of childhood diseases will be presented. C1 NIEHS, Div Extramural Res & Training, Off Program Dev, Res Triangle Pk, NC 27709 USA. NIEHS, Div Extramural Res & Training, Chem Exposures & Mol Biol Branch, Res Triangle Pk, NC 27709 USA. RP Suk, WA (reprint author), NIEHS, Div Extramural Res & Training, Off Program Dev, MD EC-27,POB 12233, Res Triangle Pk, NC 27709 USA. NR 20 TC 19 Z9 19 U1 1 U2 3 PU US DEPT HEALTH HUMAN SERVICES PUBLIC HEALTH SERVICE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SERVICES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 1998 VL 106 SU 3 BP 817 EP 820 DI 10.2307/3434195 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 110WJ UT WOS:000075404300007 PM 9646043 ER PT J AU Whyatt, RM Santella, RM Jedrychowski, W Garte, SJ Bell, DA Ottman, R Gladek-Yarborough, A Cosma, G Young, TL Cooper, TB Randall, MC Manchester, DK Perera, FP AF Whyatt, RM Santella, RM Jedrychowski, W Garte, SJ Bell, DA Ottman, R Gladek-Yarborough, A Cosma, G Young, TL Cooper, TB Randall, MC Manchester, DK Perera, FP TI Relationship between ambient air pollution and DNA damage in Polish mothers and newborns SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article; Proceedings Paper CT 1st National Research Conference on Childrens Environmental Health - Research, Practice, Prevention, and Policy CY FEB 21-23, 1997 CL WASHINGTON, D.C. SP Childrens Environm Hlth Network, US Natl Canc Inst, Div Canc Epidemiol & Genet, Med Univ S Carolina, Environm Hazards Assessment Program, California Dept Hlth Serv, Environm Hlth Investigat Branch, US Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Public Hlth Inst, US Agcy Toxic Subst & DIs Registry, US EPA, US NICHHD, US Natl Inst Environm Hlth Sci DE PAH-DNA adducts; air pollution; cigarette smoking; CYP1A1 MSPl RFLP; GSTM1; newborns; Poland ID ENVIRONMENTAL TOBACCO-SMOKE; TRANSFERASE CLASS-MU; HUMAN CANCER RISK; LUNG-CANCER; AROMATIC HYDROCARBON; HUMAN-PLACENTA; ADDUCT LEVELS; CYTOCHROME-P450IA1 GENE; MATERNAL SMOKING; PASSIVE SMOKING AB Industrialized regions in Poland are characterized by high ambient pollution, including polycyclic aromatic hydrocarbons (PAHs) from coal burning for industry and home healing. In experimental bioassays, certain PAHs are transplacental carcinogens and developmental toxicants. Biologic markers can facilitate evaluation of effects of environmental PAHs on the developing infant. We measured the amount of PAHs bound to DNA (PAH-DNA adducts) in maternal and umbilical white blood cells. The cohort consisted of 70 mothers and newborns from Krakow, Poland, an industrialized city with elevated air pollution. Modulation of adduct levels by genotypes previously linked to risk of lung cancer, specifically glutathione S-transferase M1 (GSTM1) and cytochrome P4501A1 (CYP1A1) Mspi restriction fragment length polymorphism (RFLP), was also investigated. There was a dose-related increase in maternal and newborn adduct levels with ambient pollution at the women's place of residence among subjects who were not employed away from home (p less than or equal to 0.05). Maternal smoking (active and passive) significantly increased maternal (p less than or equal to 0.01) but not newborn adduct levels. Neither CYP1A1 Mspl nor GSTM1 polymorphisms was associated with maternal adducts. However, adducts were significantly higher in newborns heterozygous or homozygous for the CYP1A1 Mspl RFLP compared to newborns without the RFLP (p = 0.04). Results indicate that PAM-induced DNA damage in mothers and newborns is increased by ambient air pollution. In the fetus, this damage appears to be enhanced by the CYP1A1 Mspl polymorphism. C1 Columbia Univ, Sch Publ Hlth, Div Environm Hlth Sci, New York, NY 10032 USA. Jagiellonian Univ, Coll Med, Krakow, Poland. NYU Med Ctr, New York, NY 10016 USA. NIEHS, Res Triangle Pk, NC 27709 USA. New York State Psychiat Inst, New York, NY 10032 USA. Colorado State Univ, Ft Collins, CO 80523 USA. Univ Colorado, Denver, CO 80202 USA. RP Perera, FP (reprint author), Columbia Univ, Sch Publ Hlth, Div Environm Hlth Sci, 60 Haven Ave,B-1, New York, NY 10032 USA. EM fpp1@columbia.edu RI Ottman, Ruth/O-2371-2013; OI Garte, Seymour/0000-0003-3284-5975 FU NCI NIH HHS [R01CA-35809, R01CA-39174]; NIEHS NIH HHS [P01-ESO5294] NR 71 TC 79 Z9 81 U1 0 U2 2 PU US DEPT HEALTH HUMAN SERVICES PUBLIC HEALTH SERVICE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SERVICES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 1998 VL 106 SU 3 BP 821 EP 826 DI 10.2307/3434196 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 110WJ UT WOS:000075404300008 PM 9646044 ER PT J AU Zahm, SH Ward, MH AF Zahm, SH Ward, MH TI Pesticides and childhood cancer SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article; Proceedings Paper CT US EPA Conference on Preventable Causes of Cancer in Children CY SEP 15-16, 1997 CL ARLINGTON, VIRGINIA SP US EPA DE children; cancer; pesticides; insecticides; herbicides; leukemia; brain tumors; neuroblastoma; Wilms' tumor sarcoma; lymphoma; colorectum; testes ID MALIGNANT BRAIN-TUMORS; NON-HODGKINS-LYMPHOMA; SOUTH-WALES CHILDREN; RISK-FACTORS; PARENTAL OCCUPATION; WILMS-TUMOR; 2,4-DICHLOROPHENOXYACETIC ACID; ENVIRONMENTAL-FACTORS; COLORECTAL-CARCINOMA; PATERNAL OCCUPATION AB Children are exposed to potentially carcinogenic pesticides from use in homes, schools, other buildings, lawns and gardens, through food and contaminated drinking water, from agricultural application drift, overspray, or off-gassing, and from carry-home exposures of parents occupationally exposed to pesticides. Parental exposure during the child's gestation or even preconception may also be important. Malignancies linked to pesticides in case reports or case-control studies include leukemia, neuroblastoma, Wilms' tumor, soft-tissue sarcoma, Ewing's sarcoma, non-Hodgkin's lymphoma, and cancers of the brain, colorectum, and testes. Although these studies have been limited by nonspecific pesticide exposure information, small numbers of exposed subjects, and the potential for case-response bias, it is noteworthy that many of the reported increased risks are of greater magnitude than those observed in studies of pesticide-exposed adults, suggesting that children may be particularly sensitive to the carcinogenic effects of pesticides. Future research should include improved exposure assessment, evaluation of risk by age at exposure, and investigation of possible genetic-environment interactions. There is potential to prevent at least some childhood cancer by reducing or eliminating pesticide exposure. C1 NCI, Div Canc Etiol, Occupat Epidemiol Branch, Bethesda, MD 20892 USA. RP Zahm, SH (reprint author), NCI, Div Canc Etiol, Occupat Epidemiol Branch, 6130 Execut Blvd,Room 418, Bethesda, MD 20892 USA. EM zahms@epndce.nci.nih.gov RI Zahm, Shelia/B-5025-2015 NR 112 TC 196 Z9 209 U1 3 U2 22 PU US DEPT HEALTH HUMAN SERVICES PUBLIC HEALTH SERVICE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SERVICES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 1998 VL 106 SU 3 BP 893 EP 908 DI 10.2307/3434207 PG 16 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 110WJ UT WOS:000075404300019 PM 9646054 ER PT J AU Colt, JS Blair, A AF Colt, JS Blair, A TI Parental occupational exposures and risk of childhood cancer SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article; Proceedings Paper CT US EPA Conference on Preventable Causes of Cancer in Children CY SEP 15-16, 1997 CL ARLINGTON, VIRGINIA SP US EPA DE children; cancer; occupation; occupational exposure; leukemia; lymphoma; brain tumor; neuroblastoma; Wilms tumor ID NERVOUS-SYSTEM TUMORS; NON-HODGKINS-LYMPHOMA; PATERNAL OCCUPATION; BRAIN-TUMORS; WILMS TUMOR; INTRACRANIAL NEOPLASMS; RADIATION EXPOSURE; IONIZING-RADIATION; OXFORD SURVEY; WEST CUMBRIA AB Occupational exposures of parents might be related to cancer in their offspring. Forty-eight published studies on this topic have reported relative risks for over 1000 specific occupation/cancer combinations. Virtually ail of the studies employed the case-control design. Occupations and exposures of fathers were investigated much more frequently than those of the mother. Information about parental occupations was derived through interviews or from birth certificates and other administrative records. Specific exposures were typically estimated by industrial hygienists or were self-reported. The studies have several limitations related to the quality of the exposure assessment, small numbers of exposed cases, multiple comparisons, and possible bias toward the reporting of positive results. Despite these limitations, they provide evidence that certain parental exposures may be harmful to children and deserve further study. The strongest evidence is for childhood leukemia and paternal exposure to solvents, paints, and employment in motor vehicle-related occupations; and childhood nervous system cancers and paternal exposure to paints. To more clearly evaluate the importance of these and other exposures in future investigations, we need improvements in four areas: a) more careful attention must be paid to maternal exposures; b) studies should employ more sophisticated exposure assessment techniques; c) careful attention must be paid to the postulated mechanism, timing, and route of exposure; and d) if postnatal exposures are evaluated, studies should provide evidence that the exposure is actually transferred from the workplace to the child's environment. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Colt, JS (reprint author), NCI, Div Canc Epidemiol & Genet, 6130 Execut Blvd,Room 418, Bethesda, MD 20892 USA. EM coltj@epndce.nci.nih.gov NR 61 TC 77 Z9 83 U1 2 U2 4 PU US DEPT HEALTH HUMAN SERVICES PUBLIC HEALTH SERVICE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SERVICES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 1998 VL 106 SU 3 BP 909 EP 925 DI 10.2307/3434208 PG 17 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 110WJ UT WOS:000075404300020 PM 9646055 ER PT J AU Yurdaydin, C Swain, MG Mininberg, ED Vergalla, J Kleiner, D Paul, SM Jones, EA AF Yurdaydin, C Swain, MG Mininberg, ED Vergalla, J Kleiner, D Paul, SM Jones, EA TI Effect of inhibition of ornithine decarboxylase activity in a model of acute hepatocellular necrosis SO EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY LA English DT Article DE hepatic encephalopathy; thioacetamide; polyamines; ornithine ID ACUTE LIVER-FAILURE; HEPATIC-ENCEPHALOPATHY; RAT-LIVER; ALPHA-DIFLUOROMETHYLORNITHINE; POLYAMINE METABOLISM; ALCOHOLIC HEPATITIS; NITRIC-OXIDE; REGENERATION; AMINOTRANSFERASE; PUTRESCINE AB Objective The effect of blockade of the enzyme ornithine decarboxylase by difluoromethylornithine (DFMO) on hepatocellular necrosis and survival in rats treated with thioacetamide (TAA) was investigated. Design In one experiment, the effect of DFMO on survival of rats with TAA-induced acute hepatocellular necrosis was determined. In another experiment, blood and liver specimens were obtained from DFMO or saline-treated rats 24 h after the administration of TAA for determinations of serum alanine aminotransferase (ALT) and liver content of polyamines and microsomal cytochrome P-450 and for assessment of hepatic histology, Methods Liver polyamines were determined by reversed-phase HPLC and microsomal cytochrome P-450 content by dithionite-difference spectroscopy of CO-treated homogenates, The severity of hepatocellular necrosis was scored blindly. Results TAA-treated rats that received DFMO survived longer than saline-treated controls (P < 0.01). Serum ALT and liver putrescine concentrations were lower and the histological severity of acute hepatocellular necrosis was less in DFMO-treated rats with TAA-induced hepatocellular necrosis than in saline-treated controls (P < 0.05, P < 0.01 and P < 0.05, respectively). Total cytochrome P-450 levels were similar in DFMO and saline-treated rats with TAA-induced hepatocellular necrosis. Conclusions DFMO increases survival in TAA-induced fulminant hepatic failure by decreasing the severity of acute hepatocellular necrosis. The beneficial effects of DFMO do not appear to be mediated by its effects on polyamine metabolism, but may be attributable to an effect of DFMO on thioacetamide metabolism or on an alternative pathway of ornithine metabolism, Eur J Gastroenterol Hepatol 10:503-507 (C) 1998 Lippincott-Raven Publishers. C1 NIDDK, Liver Dis Sect, Bethesda, MD USA. RP Yurdaydin, C (reprint author), Ankara Univ, Sch Med, Cebeci Tip Fak, Dept Gastroenterol, TR-06100 Ankara, Turkey. EM yurdaydi@dialp.ankara.edu.tr OI Kleiner, David/0000-0003-3442-4453 NR 36 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0954-691X J9 EUR J GASTROEN HEPAT JI Eur. J. Gastroenterol. Hepatol. PD JUN PY 1998 VL 10 IS 6 BP 503 EP 507 DI 10.1097/00042737-199806000-00012 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA ZX147 UT WOS:000074484100012 PM 9855067 ER PT J AU Oswald, IP Caspar, P Wynn, TA Scharton-Kersten, T Williams, ME Hieny, S Sher, A James, SL AF Oswald, IP Caspar, P Wynn, TA Scharton-Kersten, T Williams, ME Hieny, S Sher, A James, SL TI Failure of P strain mice to respond to vaccination against schistosomiasis correlates with impaired production of IL-12 and up-regulation of Th2 cytokines that inhibit macrophage activation SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE monocyte/macrophage; schistosome; vaccination; cytokine; IL-12 ID NON-LIVING VACCINE; GROWTH-FACTOR-BETA; PROTECTIVE IMMUNITY; INTERFERON-GAMMA; ATTENUATED CERCARIAE; MONOCLONAL-ANTIBODY; INDUCED RESISTANCE; NITRIC-OXIDE; MANSONI; CELLS AB In contrast to most inbred strains, P mice fail to develop significant resistance to Schistosoma mansoni infection as a result of vaccination with either radiation-attenuated cercariae or schistosome antigens plus Bacillus Calmette Guerin, and this failure correlates with defects in macrophage larvicidal activity. Supernatant fluids from antigen-treated in vitro cultures of splenocytes from vaccinated P mice demonstrate less macrophage stimulatory activity than do supernatants from cells of vaccine-responsive strains such as C57BL/6. This is not due either to diminished production of the macrophage-activating cytokine IFN-gamma by P mice, or to a lesser responsiveness of macrophages from P mice to activation by IFN gamma. Rather, P splenocytes produce two-to threefold higher amounts of IL-4 and IL-10, cytokines which down-regulate the cytotoxic potential of IFN gamma-treated macrophages. Thus, the macrophage-activating potential of cytokine preparations from vaccinated P mice can be completely recovered by in vitro treatment with antibodies to IL-4 or IL-10. Moreover, lower levels of IL-12, a cytokine involved in promoting development of Th1 responses, are produced by splenocytes from P mice as compared to C57BL/6 counterparts. These studies indicate that a genetic predisposition toward an impaired production of IL-12 and an increased production of down-regulatory Th2 cytokines correlate with low response to vaccination against S. mansoni. C1 INRA, Lab Pharmacol Toxicol, F-31931 Toulouse 9, France. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Oswald, IP (reprint author), INRA, Lab Pharmacol Toxicol, 180 Chemin Tournefeuille,BP3, F-31931 Toulouse 9, France. EM ioswald@toulouse.inra.fr RI Wynn, Thomas/C-2797-2011; OSWALD, Isabelle/A-8497-2013; OI OSWALD, Isabelle/0000-0001-9918-277X NR 37 TC 9 Z9 13 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUN PY 1998 VL 28 IS 6 BP 1762 EP 1772 DI 10.1002/(SICI)1521-4141(199806)28:06<1762::AID-IMMU1762>3.0.CO;2-J PG 11 WC Immunology SC Immunology GA ZV003 UT WOS:000074258400004 PM 9645357 ER PT J AU Mackall, CL Punt, JA Morgan, P Farr, AG Gress, RE AF Mackall, CL Punt, JA Morgan, P Farr, AG Gress, RE TI Thymic function in young/old chimeras: substantial thymic T cell regenerative capacity despite irreversible age-associated thymic involution SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE thymus; aging; immune reconstitution ID BONE-MARROW TRANSPLANTATION; MONOCLONAL-ANTIBODIES; LYMPHOCYTES-T; INTENSIVE CHEMOTHERAPY; EPITHELIAL-CELLS; MICE; RECEPTOR; ANTIGEN; EXPRESSION; MOUSE AB Age-associated thymic involution results in a diminished capacity to regenerate T cell populations, although the magnitude of this effect is unknown. In this report, thymic function was studied in aged vs. young adult mice after lethal irradiation and administration of T cell-depleted bane marrow (BM) from young mice. Abnormalities observed in aged thymi (reduced thymocyte numbers, histologic abnormalities) were not reversed by administration of young BM via bone marrow transplantation (BMT), but agend thymi displayed a normal thymocyte subset distribution and appropriately deleted Mts-reactive T cells after BMT. Aged BMT recipients regenerated significantly reduced numbers of splenic T cells compared to young recipients and showed increased peripheral expansion of thymic emigrants since a higher proportion of BM-derived T cells expressed a memory phenotype in aged vs. young BMT recipients. Because peripheral expansion of thymic emigrants could substantially increase the number of thymic progeny present in the spleen, we sought to measure thymic T cell regenerative capacity after BMT in a setting devoid of peripheral expansion. To do this, TCR-transgenic (Tg(+))T cell-depleted BM was administered to aged and young recipients lacking antigen specific for the Tg(+) TCR. Aged recipients regenerated approximately 50 % of the TCR Tg(+) cells regenerated in young BMT recipients, providing evidence that even very aged thymi retain the capacity to regenerate significant numbers of mature T cell progeny. Therefore, thymic function is reduced with aged but it is not lost, suggesting.that therapeutic approaches to enhance thymic function may be successful even in very aged hosts. C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98195 USA. RP Mackall, CL (reprint author), Bldg 10,Rm 13N240,10 Ctr Dr MSC 1928, Bethesda, MD 20892 USA. NR 37 TC 107 Z9 109 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUN PY 1998 VL 28 IS 6 BP 1886 EP 1893 DI 10.1002/(SICI)1521-4141(199806)28:06<1886::AID-IMMU1886>3.0.CO;2-M PG 8 WC Immunology SC Immunology GA ZV003 UT WOS:000074258400017 PM 9645370 ER PT J AU Okabe, S Vicario-Abejon, C Segal, M McKay, RDG AF Okabe, S Vicario-Abejon, C Segal, M McKay, RDG TI Survival and synaptogenesis of hippocampal neurons without NMDA receptor function in culture SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE cell culture; dendritic spine; hippocampus; knockout mice; synapse formation ID CORTICAL CELL-CULTURE; GLUTAMATE NEUROTOXICITY; PATTERN-FORMATION; RAT; BRAIN; CORTEX; ROLES; BDNF; MICE AB Physiological and morphological properties of cultured hippocampal neurons were measured to investigate whether NMDA receptors play a role in survival and differentiation. Neurons dissociated from mouse embryos with different NMDAR1 genotypes were grown in culture. Electrophysiological analysis verified the absence of NMDA receptor-mediated currents in neurons taken from homozygous mutant (NR1 -/-) embryos. The number of surviving hippocampal neurons was 2.5-fold higher in cultures from the NR1 -/- embryos compared with wild type (NR1 +/+) and heterozygous (NR1 +/-) controls. Despite the lack of NMDA receptor function, NR1 -/- neurons formed synapsin I-positive presynaptic boutons associated with MAP2ab-positive dendrites in culture. Confocal microscopic analysis of Dil labelled neurons confirmed the presence of dendritic spines on NR1 -/- neurons with 80% of the density found in NR1 +/+ neurons. These results suggest that the NMDA receptor has little effect on general features of neuronal differentiation. In contrast, there is clear effect on neuronal survival. This finding establishes neuron number in standard culture conditions as a measure of NMDA receptor activity. C1 NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. RP Okabe, S (reprint author), Natl Inst Biosci & Human Technol, Mol Neurobiol Lab, 1-1 Higashi, Tsukuba, Ibaraki 305, Japan. RI Vicario-Abejon, Carlos/G-2814-2016 NR 28 TC 27 Z9 28 U1 0 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 JUN PY 1998 VL 10 IS 6 BP 2192 EP 2198 DI 10.1046/j.1460-9568.1998.00233.x PG 7 WC Neurosciences SC Neurosciences & Neurology GA ZR740 UT WOS:000074009000026 PM 9753105 ER PT J AU Spence, SE Keller, JR Ruscetti, FW McCauslin, CS Gooya, JM Funakoshi, S Longo, DL Murphy, WJ AF Spence, SE Keller, JR Ruscetti, FW McCauslin, CS Gooya, JM Funakoshi, S Longo, DL Murphy, WJ TI Engraftment of ex vivo expanded and cycling human cord blood hematopoietic progenitor cells in SCID mice SO EXPERIMENTAL HEMATOLOGY LA English DT Article DE xenograft; hematopoiesis; severe combined immune deficiency; gene therapy; in vivo ID SEVERE COMBINED IMMUNODEFICIENCY; IMMUNE-DEFICIENT MICE; STEM-CELLS; BONE-MARROW; GENE TRANSDUCTION; PRECURSOR CELLS; GROWTH-FACTORS; MURINE MARROW; HU MOUSE; DIFFERENTIATION AB The ability of human hematopoietic cells to engraft SCID mice provides a useful model in which to study the efficiency of retroviral gene transfer and expression in primitive stem cells. In this regard, it is necessary to determine whether SCID mice can be engrafted by cycling human hematopoietic progenitor cells. Human cord blood cells from 12 different donors were cultured in vitro for 6 days with interleukin-3 and stem cell factor. Phenotypic analysis indicated that hematopoietic cells were induced to cycle and the number of progenitors was expanded, thus making them targets for retroviral gene transfer. The cells were then transferred to SCID mice. Human hematopoietic progenitor cell engraftment was assessed up to 7 weeks later by growth of human progenitor cells in soft agar. After in vitro culture under conditions used for retroviral gene transfer, human cord blood hematopoietic cells engrafted the bone marrow and spleen of SCID mice. Interestingly, cultured cord blood cells engrafted after intraperitoneal but not after intravenous injection. Furthermore, engraftment of cord blood cells was observed in mice receiving no irradiation before transfer of the human cells, suggesting that competition for space in the marrow is not a limiting factor when these cells have been cultured. Administration of human cytokines after transfer of human cord blood cells to SCID mice was also not required for engraftment. Thus, engraftment of SCID mice with human hematopoietic cells cultured under conditions suitable for gene transfer may provide an in vivo assay for gene transfer to early human hematopoietic progenitor cells. 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, Lab Leukocyte Biol, Frederick, MD 21702 USA. NIA, NIH, Baltimore, MD 21224 USA. RP Spence, SE (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Bldg 567,POB B, Frederick, MD 21702 USA. NR 36 TC 13 Z9 13 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 1998 VL 26 IS 6 BP 507 EP 514 PG 8 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA ZQ411 UT WOS:000073858500008 PM 9620284 ER PT J AU Borlongan, CV Saporta, S Sanberg, PR AF Borlongan, CV Saporta, S Sanberg, PR TI Intrastriatal transplantation of rat adrenal chromaffin cells seeded on microcarrier beads promote long-term functional recovery in hemiparkinsonian rats SO EXPERIMENTAL NEUROLOGY LA English DT Article DE adrenal chromaffin cells; microcarrier beads; Parkinson's disease; neural transplantation; 6-hydroxydopamine; asymmetrical motor behaviors ID IN-VITRO CHARACTERIZATION; PARKINSONS-DISEASE; GROWTH-FACTOR; MEDULLA GRAFTS; TYROSINE-HYDROXYLASE; GENE-EXPRESSION; BRAIN INJURY; ASTROCYTES; SURVIVAL; MICROGLIA AB Possible biologic treatments for Parkinson's disease, a disorder caused by the deterioration of dopaminergic neurons bridging the nigrostriatal system, have recently focused on fetal cell transplantation. Because of ethical and tissue availability issues concerning fetal cell transplantation, alternative cell sources are being developed. The adrenal medulla has been used as a cell transplant source because of the capacity of the cells to provide catecholamines and to transform into a neuronal phenotype. However, adrenal tissue transplants have shown limited success, primarily because of their lack of long-term viability. Recently, seeding adrenal chromaffin cells on microcarrier beads has been shown to enhance the cell viability following neural transplantation. In the present study, we further investigated whether transplantation of rat adrenal chromaffin cells seeded on microcarrier beads into the striatum of 6-hydroxydopamine-induced hemimpar-kinsonian rats would result in a sustained functional recovery. Behavioral tests using the apomorphine-induced rotational and elevated body swing tests up to 12 months posttransplantation revealed a significant behavioral recovery in animals that received adrenal chromaffin cells seeded on microcarrier beads compared to animals that received adrenal chromaffin cells alone, medium alone, or beads alone. Histological examination of tissue at 14 months posttransplantation revealed evidence of tyrosine hydroxylase-positive cells and an on-going glial response in animals transplanted with adrenal chromaffin cells seeded on microcarrier beads, in contrast to absence of such immunoreactive responses in the other groups. These findings support a facilitator role for microcarrier beads in transplantation of adrenal chromaffin cells or other cells that are easily rejected by the CNS. (C) 1998 Academic Press. C1 Univ S Florida, Coll Med, Dept Surg, Div Neurol Surg, Tampa, FL 33612 USA. Univ S Florida, Coll Med, Dept Neurol, Div Neurol Surg, Tampa, FL 33612 USA. Univ S Florida, Coll Med, Dept Psychiat, Div Neurol Surg, Tampa, FL 33612 USA. Univ S Florida, Coll Med, Dept Pharmacol, Div Neurol Surg, Tampa, FL 33612 USA. Univ S Florida, Coll Med, Dept Anat, Div Neurol Surg, Tampa, FL 33612 USA. RP Borlongan, CV (reprint author), NIDA, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Borlongan, Cesar/0000-0002-2966-9782 NR 45 TC 30 Z9 30 U1 1 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 1998 VL 151 IS 2 BP 203 EP 214 DI 10.1006/exnr.1998.6790 PG 12 WC Neurosciences SC Neurosciences & Neurology GA ZV800 UT WOS:000074342500004 PM 9628755 ER PT J AU Ellis, SL Shakarian, AM Dwyer, DM AF Ellis, SL Shakarian, AM Dwyer, DM TI Leishmania: Amastigotes synthesize conserved secretory acid phosphatases during human infection SO EXPERIMENTAL PARASITOLOGY LA English DT Article DE Leishmania; amastigotes; secretory acid phosphatase; protozoan pathogen; leishmaniasis ID VISCERAL LEISHMANIASIS; DONOVANI PROMASTIGOTES; MONOCLONAL-ANTIBODIES; MACROPHAGES INVITRO; LIPOPHOSPHOGLYCAN; SURFACE; IDENTIFICATION; MULTIPLICATION; RESPONSES; PROTEINS AB Leishmania donovani is the major causative agent of Old World human visceral leishmaniasis (VL). In vitro, both promastigotes and axenic amastigotes of L. donovani constitutively secrete soluble acid phosphatases (SAcPs), which contain conserved antigenic epitopes. These SAcPs are the most abundant and best characterized secretory proteins of this parasite. The aim of this study was to determine whether this enzyme was produced by intracellular amastigotes during the course of human infection. To that end, sera from acutely infected leishmaniasis patients were tested for anti-SAcP antibodies using L. donovani promastigote culture supernatants. Our results showed that VL patient sera from different endemic foci immunoprecipitated parasite SAcP enzyme activity. Further, these VL patient sera recognized the 110- and 130-kDa SAcPs in both Western blots and radioimmunoprecipitation assays. Results of tunicamycin experiments demonstrated that VL patient anti-SAcP antibodies were directed against the polypeptide backbone of the parasite SAcPs. In addition, both radiolabeled L. donovani SAcPs and native enzyme activities were immunoprecipitated by sera from patients with various forms of cutaneous leishmaniasis. Together these studies demonstrate that Leishmania amastigotes produce SAcPs during the course of human infections. C1 NIAID, Div Intramural Res, Parasit Dis Lab, Cell Biol Sect,NIH, Bethesda, MD 20892 USA. RP Dwyer, DM (reprint author), NIAID, Div Intramural Res, Parasit Dis Lab, Cell Biol Sect,NIH, 9000 Rockville Pike,Bldg 4,Room 126, Bethesda, MD 20892 USA. NR 31 TC 21 Z9 21 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4894 J9 EXP PARASITOL JI Exp. Parasitol. PD JUN PY 1998 VL 89 IS 2 BP 161 EP 168 DI 10.1006/expr.1998.4298 PG 8 WC Parasitology SC Parasitology GA ZT861 UT WOS:000074135600003 PM 9635439 ER PT J AU Ribeiro, JMC Mather, TN AF Ribeiro, JMC Mather, TN TI Ixodes scapularis: Salivary kininase activity is a metallo dipeptidyl carboxypeptidase SO EXPERIMENTAL PARASITOLOGY LA English DT Article DE tick saliva; bradykinin; kininase; angiotensin-converting enzyme ID ANGIOTENSIN-CONVERTING ENZYME; BOOPHILUS-MICROPLUS; SCHISTOSOMA-MANSONI; CONCEALED ANTIGEN; MUSCA-DOMESTICA; TICKS; PURIFICATION; PHARMACOLOGY; COMPLEMENT; BRADYKININ AB Saliva and salivary gland homogenates of Ixodes scapularis contain a dipeptidyl carboxypeptidase activity that accounts for the previously described salivary kininase activity of this tick. Reversed phase HPLC and laser desorption mass spectrography of the reaction product!; identified bradykinin fragment 1-7 and 1-5 as being produced subsequent to incubation of purified salivary kininase with bradykinin. The activity was inhibited by captopril and EDTA and was activated by cobalt and manganese, a behavior similar to that displayed by angiotensin-converting enzymes of vertebrate and invertebrate origins. (C) 1998 Academic Press. C1 NIAID, Parasit Dis Lab, Sect Med Entomol, NIH, Bethesda, MD 20892 USA. Univ Rhode Isl, Ctr Vector Borne Dis Res, Kingston, RI 02881 USA. RP Ribeiro, JMC (reprint author), NIAID, Parasit Dis Lab, Sect Med Entomol, NIH, 9000 Rockville Pike,Bldg 4,Room 126, Bethesda, MD 20892 USA. OI Ribeiro, Jose/0000-0002-9107-0818 FU NIAID NIH HHS [AI 37230] NR 31 TC 61 Z9 61 U1 1 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4894 J9 EXP PARASITOL JI Exp. Parasitol. PD JUN PY 1998 VL 89 IS 2 BP 213 EP 221 DI 10.1006/expr.1998.4296 PG 9 WC Parasitology SC Parasitology GA ZT861 UT WOS:000074135600009 PM 9635445 ER PT J AU Su, XZ Carucci, DJ Wellems, TE AF Su, XZ Carucci, DJ Wellems, TE TI Plasmodium falciparum: Parasite typing by using a multicopy microsatellite marker, PfRRM SO EXPERIMENTAL PARASITOLOGY LA English DT Article DE Malaria; genetic diversity; simple sequence length polymorphisms; interspersed repetitive elements; genetic fingerprinting ID DNA C1 NIAID, LPD, NIH, Bethesda, MD 20892 USA. USN, Med Res Inst, Rockville, MD 20852 USA. RP Su, XZ (reprint author), NIAID, LPD, NIH, Bldg 4,Room 126, Bethesda, MD 20892 USA. EM xsu@helix.nih.gov OI Su, Xinzhuan/0000-0003-3246-3248 NR 14 TC 38 Z9 39 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4894 J9 EXP PARASITOL JI Exp. Parasitol. PD JUN PY 1998 VL 89 IS 2 BP 262 EP 265 DI 10.1006/expr.1998.4299 PG 4 WC Parasitology SC Parasitology GA ZT861 UT WOS:000074135600015 PM 9635451 ER PT J AU Connor, HD Thurman, RG Chen, G Poyer, JL Janzen, EG Mason, RP AF Connor, HD Thurman, RG Chen, G Poyer, JL Janzen, EG Mason, RP TI Clarification of the relationship between free radical spin trapping and carbon tetrachloride metabolism in microsomal systems SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE free radical; spin-trapping; carbon tetrachloride; trichloromethyl radical; electron spin resonance; glutathione; rat liver microsomes ID RAT-LIVER; INVIVO; ADDUCT; BROMOTRICHLOROMETHANE; HEPATOCYTES; ACTIVATION; PRODUCTS; INVITRO; CCL4 AB It has been proposed that the C-phenyl-N-tert-butylnitrone/trichloromethyl radical adduct (PBN/(CCl3)-C-.) is metabolized to either the C-phenyl-N-tert-butylnitrone/carbon dioxide anion radical adduct (PBN/(CO2-)-C-.) or the glutathione (GSH) and CCl4-dependent PBN radical adduct (PBN/[GSH-(CCl3)-C-.]). Inclusion of PBN/(CCl3)-C-. in microsomal incubations containing GSH, nicotinamide adenine dinucleotide phosphate (NADPH), or GSH plus NADPH produced no electron spin resonance (ESR) spectral data indicative of the formation of either the PBN/[GSH-(CCl3)-C-.] or PBN/(CO2-)-C-. radical adducts. Microsomes alone or with GSH had no effect on the PBN/(CCl3)-C-. radical adduct. Addition of NADPH to a microsomal system containing PBN/(CCl3)-C-. presumably reduced the radical adduct to its ESR-silent hydroxylamine because no ESR signal was observed. The Folch extract of this system produced an ESR spectrum that was a composite of two radicals, one of which had hyperfine coupling constants identical to those of PBN/(CCl3)-C-.. We conclude that PBN/(CCl3)-C-. is not metabolized into either PBN/[GSH-(CCl3)-C-.] or PBN/(CO2-)-C-. in microsomal systems. (C) 1998 Elsevier Science Inc. C1 Kentucky Wesleyan Coll, Owensboro, KY 42301 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Pharmacol, Chapel Hill, NC USA. Univ Guelph, Ontario Vet Coll, Dept Clin Studies, Guelph, ON N1G 2W1, Canada. Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. RP Mason, RP (reprint author), NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 18 TC 5 Z9 5 U1 0 U2 1 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 JUN PY 1998 VL 24 IS 9 BP 1364 EP 1368 DI 10.1016/S0891-5849(97)00460-7 PG 5 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA ZT981 UT WOS:000074148900002 PM 9641253 ER PT J AU Schoenfeld, P Cook, D Hamilton, F Laine, L Morgan, D Peterson, W AF Schoenfeld, P Cook, D Hamilton, F Laine, L Morgan, D Peterson, W CA Evidence Based Gastroenterology Steering Grp TI An evidence-based approach to gastroenterology therapy SO GASTROENTEROLOGY LA English DT Article ID BLEEDING ESOPHAGEAL-VARICES; ENDOSCOPIC LIGATION; SCLEROTHERAPY; OCTREOTIDE; TRIALS; BIAS C1 NIDDK, Digest Dis Program, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. Natl Naval Med Ctr, Div Gastroenterol, Bethesda, MD USA. McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. McMaster Univ, Med Ctr, Div Gastroenterol, Hamilton, ON, Canada. Univ So Calif, Med Ctr, Div Gastrointestinal & Liver Dis, Los Angeles, CA USA. Univ Texas, Sch Med, Dallas, TX 75230 USA. Dallas Vet Affairs Med Ctr, Med Serv, Dallas, TX USA. RP Hamilton, F (reprint author), NIDDK, Digest Dis Program, Div Digest Dis & Nutr, NIH, Natcher Bldg,Room 6An-12B, Bethesda, MD 20892 USA. NR 21 TC 40 Z9 40 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 1998 VL 114 IS 6 BP 1318 EP 1325 DI 10.1016/S0016-5085(98)70439-1 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA ZQ211 UT WOS:000073833900027 PM 9609770 ER PT J AU Riccioni, T Cirielli, C Wang, X Passaniti, A Capogrossi, MC AF Riccioni, T Cirielli, C Wang, X Passaniti, A Capogrossi, MC TI Adenovirus-mediated wild-type p53 overexpression inhibits endothelial cell differentiation in vitro and angiogenesis in vivo SO GENE THERAPY LA English DT Article DE gene therapy; adenovirus; angiogenesis; p53; endothelium ID IN-VIVO; GENE-TRANSFER; LUNG-CANCER; GROWTH-FACTOR; RECOMBINANT ADENOVIRUS; EXPRESSION VECTOR; TUMOR-CELLS; APOPTOSIS; INTEGRIN; THERAPY AB Gene therapy with the tumor suppressor gene p53 induces cancer cell apoptosis in vitro and in vivo and inhibits tumor growth in nude mice. We hypothesized that in addition to cancer cell apoptosis, a replication-deficient adenovirus vector which carries the cDNA for human wild-type p53 (AdCMV.p53) may also modulate endothelial cell function and inhibit angiogenesis. Human umbilical vein endothelial cells (HUVEC) were infected at different multiplicities of infection (MOI) with either AdCMV.p53, the control vector null or were not infected. Western blot analysis showed p53 overexpression up to 7 days after infection with AdCMV.p53. HUVEC proliferation was either not affected (20 and 50 MOI) or inhibited to comparable levels (100 MOI; P<0.05) in AdCMV.p53- and AdCMV.null-infected versus uninfected cells. HUVEC different into capillary-like structures on reconstituted basement membrane proteins (Matrigel) was assessed 48 h after infection (100 MOI).After 18 h on Matrigel the capillary-like network formed by AdCMV.p53-infected HUVEC was less extensive th-an that formed by both AdCMV.null-infected and uninfected control cells (P<0.05 versus either control). in contrast, conditioned medium from AdCMV.p53-infected HUVEC did not modulate endothelial cell differentiation on Matrigel. The effect of AdCMV.p53 on angiogenesis in vivo was assessed by injecting this vector subcutaneously in mice; 3 days later Matrigel containing basic fibroblast growth factor (bFGF) was injected at the same site. Ir? other experiments AdCMV.p53 was injected simultaneously with an Ad vector coding for vascular endothelial growth factor (AdCMV.VEGF(165)) into the rat perirenal fat tissue. AdCMV.p53 significantly inhibited neovascularization induced by bFGF within the Matrigel plugs (P<0.05) or by AdCMV.VEGF(165) in the fat tissue (P <0.05). Thus, the anti-angiogenic effect of Ad-mediated wild-type p53 overexpression may contribute to the ability of this viral vector to inhibit tumor growth. C1 IRCCS, Lab Patol Vasc, Ist Dermatopat Immacolata, I-00167 Rome, Italy. NIA, Gene Therapy Unit, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. NIA, Biol Chem Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Capogrossi, MC (reprint author), IRCCS, Lab Patol Vasc, Ist Dermatopat Immacolata, Via Monti Creta 104, I-00167 Rome, Italy. NR 41 TC 44 Z9 46 U1 2 U2 4 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD JUN PY 1998 VL 5 IS 6 BP 747 EP 754 DI 10.1038/sj.gt.3300681 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA ZU961 UT WOS:000074253900004 PM 9747454 ER PT J AU Krajcikova, D Hartley, RW Sevcik, J AF Krajcikova, D Hartley, RW Sevcik, J TI Ribonuclease inhibitor from Streptomyces aureofaciens SO GENERAL PHYSIOLOGY AND BIOPHYSICS LA English DT Article DE RNase inhibitor; Streptomyces aureofaciens ID RESOLUTION; COMPLEX; SA C1 Slovak Acad Sci, Inst Mol Biol, Bratislava 84251, Slovakia. NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Krajcikova, D (reprint author), Slovak Acad Sci, Inst Mol Biol, Dubravska Cesta 21, Bratislava 84251, Slovakia. OI Krajcikova, Daniela/0000-0002-4024-2384 NR 11 TC 0 Z9 0 U1 0 U2 0 PU GENERAL PHYSIOL AND BIOPHYSICS PI BRATISLAVA PA INST OF MOLEC PHYSIOL GENETICS SLOVAK ACAD OF SCI VLARSKA 5, 83334 BRATISLAVA, SLOVAKIA SN 0231-5882 J9 GEN PHYSIOL BIOPHYS JI Gen. Physiol. Biophys. PD JUN PY 1998 VL 17 SU 1 BP 14 EP 16 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Physiology SC Biochemistry & Molecular Biology; Biophysics; Physiology GA 107RR UT WOS:000075223500006 PM 9789744 ER PT J AU de Caestecker, MP Parks, WT Frank, CJ Castagnino, P Bottaro, DP Roberts, AB Lechleider, RJ AF de Caestecker, MP Parks, WT Frank, CJ Castagnino, P Bottaro, DP Roberts, AB Lechleider, RJ TI Smad2 transduces common signals from receptor serine-threonine and tyrosine kinases SO GENES & DEVELOPMENT LA English DT Article DE SMAD; TGF-beta; signal transduction; protein phosphorylation; HGF; receptor kinases ID GROWTH-FACTOR-BETA; PLASMINOGEN-ACTIVATOR INHIBITOR; EPITHELIAL-CELLS; PROTEINS; PATHWAYS; TYPE-1; BMP-2 AB SMAD proteins mediate signals from receptor serine-threonine kinases (RSKs) of the TGP-beta superfamily. We demonstrate here that HGF and EGF, which signal through RTKs, can also mediate SMAD-dependent reporter gene activation and induce rapid phosphorylation of endogenous SMAD proteins by kinase(s) downstream of MEK1. HGF induces phosphorylation and nuclear translocation of epitope-tagged Smad2 and a mutation that blocks TGF-beta signaling also blocks HGF signal transduction. Smad2 may thus act as a common positive effector of TGE-beta- and HGF-induced signals and serve to modulate cross talk between RTK and RSK signaling pathways. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. RP Lechleider, RJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RI Bottaro, Donald/F-8550-2010; Tang, Amy/L-3226-2016 OI Bottaro, Donald/0000-0002-5057-5334; Tang, Amy/0000-0002-5772-2878 NR 38 TC 229 Z9 233 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUN 1 PY 1998 VL 12 IS 11 BP 1587 EP 1592 DI 10.1101/gad.12.11.1587 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA ZT982 UT WOS:000074149000003 PM 9620846 ER PT J AU Blanco, JCG Minucci, S Lu, JM Yang, XJ Walker, KK Chen, HW Evans, RM Nakatani, Y Ozato, K AF Blanco, JCG Minucci, S Lu, JM Yang, XJ Walker, KK Chen, HW Evans, RM Nakatani, Y Ozato, K TI The histone acetylase PCAF is a nuclear receptor coactivator SO GENES & DEVELOPMENT LA English DT Article DE histone acetylation; PCAF; RXR; RAR; steroid receptors; retinoids ID RETINOID-X RECEPTOR; TATA-BINDING PROTEIN; TRANSCRIPTIONAL ACTIVATION; HORMONE RECEPTORS; ACID RECEPTORS; DEPENDENT TRANSCRIPTION; GLUCOCORTICOID RECEPTOR; RESPONSE PATHWAYS; CONSERVED REGION; CO-REPRESSOR AB Whereas the histone acetylase PCAF has been suggested to be part of a coactivator complex mediating transcriptional activation by the nuclear hormone receptors, the physical and functional interactions between nuclear receptors and PCAF have remained unclear. Our efforts to clarify these relationships have revealed two novel properties of nuclear receptors. First, we demonstrate that the RXR/RAR heterodimer directly recruits PCAF from mammalian cell extracts in a ligand-dependent manner and that increased expression of PCAF leads to enhanced retinoid-responsive transcription. Second, we demonstrate that, in vitro, PCAF directly associates with the DNA-binding domain of nuclear receptors, independently of p300/CBP binding, therefore defining a novel cofactor interaction surface. furthermore, our results show that dissociation of corepressors enables ligand-dependent PCAF binding to the receptors. This observation illuminates how a ligand-dependent receptor function can be propagated to regions outside the ligand-binding domain itself. On the basis of these observations, we suggest that PCAF may play a more central role in nuclear receptor function than previously anticipated. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Salk Inst Biol Studies, La Jolla, CA 92037 USA. Howard Hughes Med Inst, La Jolla, CA 92037 USA. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RI Minucci, Saverio/J-9669-2012 NR 60 TC 318 Z9 321 U1 2 U2 9 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUN 1 PY 1998 VL 12 IS 11 BP 1638 EP 1651 DI 10.1101/gad.12.11.1638 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA ZT982 UT WOS:000074149000008 PM 9620851 ER PT J AU Pruitt, KD AF Pruitt, KD TI WebWise: Guide to the University of Washington genome center Web site SO GENOME RESEARCH LA English DT Article C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Pruitt, KD (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1054-9803 J9 GENOME RES JI Genome Res. PD JUN PY 1998 VL 8 IS 6 BP 572 EP 575 PG 4 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA ZX333 UT WOS:000074505000003 PM 9647632 ER PT J AU Deming, MS Dyer, KD Bankier, AT Piper, MB Dear, PH Rosenberg, HF AF Deming, MS Dyer, KD Bankier, AT Piper, MB Dear, PH Rosenberg, HF TI Ribonuclease k6: Chromosomal mapping and divergent rates of evolution within the RNase A gene superfamily SO GENOME RESEARCH LA English DT Article ID EOSINOPHIL-DERIVED NEUROTOXIN; PROTEIN-CODING GENES; MOLECULAR EVOLUTION; CATIONIC PROTEIN; ACID COMPOSITION; SEQUENCE; SUBSTITUTION; NUCLEOTIDE; FAMILY; LOCALIZATION AB We have localized the gene encoding human RNase k6 to within similar to 120 kb on the long (q) arm of chromosome 14 by HAPPY mapping. With this information, the relative positions of the six human RNase A ribonucleases that have been mapped to this locus can be inferred. To further our understanding of the individual lineages comprising the RNase A superfamily, we have isolated and characterized 10 novel genes orthologous to that encoding human RNase k6 from Great Ape, Old World, and New World monkey genomes. Each gene encodes a complete ORF with no less than 86% amino acid sequence identity to human RNase k6 with the eight cysteines and catalytic histidines (H-15 and H-123) and lysine (K-38) typically observed among members of the RNase A superfamily. interesting trends include an unusually low number of synonymous substituions (K-s) observed among the New World monkey RNase k6 genes. When considering nonsilent mutations, RNase k6 is a relatively stable lineage, With a nonsynonymous substitution rate of 0.40 x 10(-9) nonsynonymous substitutions/nonsynonymons site/year (ns/ns/yr). These results stand in contrast to those determined for the primate orthologs of the two closely related ribonucleases, the eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP), which have incorporated nonsilent mutations at very rapid rates (1.9 x 10(-9) and 2.0 x 10(-9) ns/ns/yr, respectively). The uneventful trends observed for RNase k6 serve to spotlight the unique nature of EDN and ECP and the unusual evolutionary constraints to which these two ribonuclease genes must be responding. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. MRC, Mol Biol Lab, Prot & Nucleic Acid Chem Div, Cambridge CB2 2QH, England. RP Rosenberg, HF (reprint author), NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. EM hr2k@nih.gov RI Dear, Paul/A-1162-2012 NR 39 TC 10 Z9 20 U1 1 U2 2 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1054-9803 J9 GENOME RES JI Genome Res. PD JUN PY 1998 VL 8 IS 6 BP 599 EP 607 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA ZX333 UT WOS:000074505000006 PM 9647635 ER PT J AU Kouprina, N Kawamoto, K Barrett, JC Larionov, V Koi, M AF Kouprina, N Kawamoto, K Barrett, JC Larionov, V Koi, M TI Rescue of targeted regions of mammalian chromosomes by in vivo recombination in yeast SO GENOME RESEARCH LA English DT Article ID TRANSFORMATION-ASSOCIATED RECOMBINATION; ESCHERICHIA-COLI; HUMAN DNA; SACCHAROMYCES-CEREVISIAE; ARTIFICIAL CHROMOSOMES; PLASMID RESCUE; CLONING; FRAGMENTS; VECTORS; CELLS AB In contrast to other animal cell lines, the chicken pre-B cell lymphoma line, DT40, exhibits a high level of homologous recombination, which can be exploited to generate site-specific alterations in defined target genes or regions. In addition, the ability to generate human/chicken monochromosomal hybrids in the DT40 cell line opens a way for specific targeting of human genes. Here we describe a new strategy for direct isolation of a human chromosomal region that is based on targeting of the chromosome with a vector containing a yeast selectable marker, centromere, and an ARS element. This procedure allows rescue of the targeted region by transfection of total genomic DNA into yeast spheroplasts. Selection For the yeast marker results in isolation of chromosome sequences in the form of large circular yeast artificial chromosomes (YACs) up to 170 kb in size containing the targeted region. These YACs are generated by homologous recombination in yeast between common repeated sequences in the targeted chromosomal fragment. Alternatively, the targeted region can be rescued as a linear YACs when a YAC fragmentation vector is included in the yeast transformation mixture. Because the entire isolation procedure of the chromosomal region, once a target insertion is obtained, can be accomplished in similar to 1 week, the new method greatly expands the utility of the homologous recombination-proficient DT40 chicken cell system. C1 NIEHS, Gene Mapping & Cloning Grp, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, Aging & Canc Sect, Res Triangle Pk, NC 27709 USA. RP Koi, M (reprint author), NIEHS, Gene Mapping & Cloning Grp, POB 12233, Res Triangle Pk, NC 27709 USA. EM larionov@niehs.nih.gov; koi@niehs.nih.gov RI Koi, Minoru/C-3489-2012 NR 27 TC 4 Z9 4 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1054-9803 J9 GENOME RES JI Genome Res. PD JUN PY 1998 VL 8 IS 6 BP 666 EP 672 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA ZX333 UT WOS:000074505000011 PM 9647640 ER PT J AU Lavedan, C Grabczyk, E Usdin, K Nussbaum, RL AF Lavedan, C Grabczyk, E Usdin, K Nussbaum, RL TI Long uninterrupted CGG repeats within the first exon of the human FMR1 gene are not intrinsically unstable in transgenic mice SO GENOMICS LA English DT Article ID FRAGILE-X-SYNDROME; HUMAN-DISEASE GENES; TRINUCLEOTIDE REPEAT; FOUNDER CHROMOSOMES; DNA; EXPANSION; INSTABILITY; METHYLATION; SITE; STABILITY AB Despite the increasing number of disorders known to result from trinucleotide repeat amplification, the molecular mechanism underlying these dynamic mutations is still unknown. In an attempt to create a mouse model for the CGG repeat instability seen in Fragile X syndrome, we constructed transgenes corresponding to FMR1 premutation alleles. While in humans these alleles would expand to full mutation with almost 100% certainty upon maternal transmission, they remain stable in our transgenic mice. Therefore, the presence of a large number of uninterrupted CGGs is not sufficient to cause instability in mice, even in the context of flanking human FMR1 sequences. (C) 1998 Academic Press. C1 NIDDKD, Lab Genet Dis Res, Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Bayview Med Ctr, Baltimore, MD 21224 USA. RP Nussbaum, RL (reprint author), NIDDKD, Lab Genet Dis Res, Natl Human Genome Res Inst, NIH, Bldg 49,Room 4A72,49 Convent Dr,MSC 4470, Bethesda, MD 20892 USA. EM rlnuss@nhgri.nih.gov NR 62 TC 40 Z9 40 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD JUN 1 PY 1998 VL 50 IS 2 BP 229 EP 240 DI 10.1006/geno.1998.5299 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA ZW041 UT WOS:000074367700011 PM 9653650 ER PT J AU Jain, PK Lalwani, AK Li, XC Singleton, TL Smith, TN Chen, A Deshmukh, D Verma, IC Smith, RJH Wilcox, ER AF Jain, PK Lalwani, AK Li, XC Singleton, TL Smith, TN Chen, A Deshmukh, D Verma, IC Smith, RJH Wilcox, ER TI A gene for recessive nonsyndromic sensorineural deafness (DFNB18) maps to the chromosomal region 11p14-p15.1 containing the Usher syndrome type 1C gene SO GENOMICS LA English DT Article ID LINKAGE AB Autosomal recessive nonsyndromic sensorineural deafness segregating in a large consanguineous Indian family was mapped to chromosome 11p14-p15.1 defining a new locus, DFNB18. A maximum lad scope of 4.4 at Theta = 0 was obtained for the polymorphic microsatellite marker D11S1888. Haplotype analysis localizes this gene between markers D11S1307 and D11S2368, which is approximately 1.6 cM and encompasses the region of Usher syndrome type 1C (USHP1C). We postulate that DFNB18 and USH1C are allelic variants of the same gene. (C) 1998 Academic Press. C1 NIDODS, Mol Genet Lab, NIH, Rockville, MD 20850 USA. Univ Calif San Francisco, Sch Med, Dept Otolaryngol Head & Neck Surg, Div Otol Neurotol & Skullbase Surg, San Francisco, CA 94143 USA. Univ Iowa, Dept Otolaryngol Head & Neck Surg, Mol Otolaryngol Res Labs, Iowa City, IA 52242 USA. Deshmukh Nursing Home, Ichalkaranji 416115, Maharashtra, India. All India Inst Med Sci, New Delhi 110029, India. RP Wilcox, ER (reprint author), NIDODS, Mol Genet Lab, NIH, 5 Res Court, Rockville, MD 20850 USA. FU NIDCD NIH HHS [1R01 DC02842, Z01 DC00026]; NIOSH CDC HHS [OH-93-N-016] NR 15 TC 34 Z9 34 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD JUN 1 PY 1998 VL 50 IS 2 BP 290 EP 292 DI 10.1006/geno.1998.5320 PG 3 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA ZW041 UT WOS:000074367700019 PM 9653658 ER PT J AU Ferrucci, L Guralnik, JM Cecchi, F Marchionni, N Salani, B Kasper, J Celli, R Giardini, S Heikkinen, E Jylha, M Baroni, A AF Ferrucci, L Guralnik, JM Cecchi, F Marchionni, N Salani, B Kasper, J Celli, R Giardini, S Heikkinen, E Jylha, M Baroni, A TI Constant hierarchic patterns of physical functioning across seven populations in five countries SO GERONTOLOGIST LA English DT Article DE disability; disablement process; aging ID LOWER-EXTREMITY FUNCTION; OLDER ADULTS; DISABILITY; HEALTH; PERFORMANCE; ELDERS; IADL; ADL AB This research was aimed at identifying critical steps in the decline in physical function that often parallels aging Six basic and nine instrumental activities of daily living (ADEs) were classified into four domains of disability characterized by specific underlying physical impairment. The hierarchical order of this classification was verified in two random samples representative of the older home-dwelling population. The concordance level of disability and results of performance-based measures of physical function were also tested. Finally, the cross-cultural reliability of the model was verified in seven population-based samples of older persons living in five European countries, In older persons the disabling process follows a general pattern of progression based on a typical sequence of impairments. C1 Osped I Faticini, Dept Geriatr, Ist Nazl Ricovero & Cura Anziani, Natl Res Inst, Florence, Italy. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Univ Florence, Inst Gerontol, Florence, Italy. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Hlth Policy & Planning, Baltimore, MD 21205 USA. Univ Jyvaskyla, Dept Hlth Sci, Jyvaskyla, Finland. Univ Jyvaskyla, Finnish Ctr Interdisciplinary Gerontol, Jyvaskyla, Finland. Univ Tampere, Sch Publ Hlth, FIN-33101 Tampere, Finland. RP Ferrucci, L (reprint author), INRCA, Geriatr Dept I Fraticini, Via Massoni 21, I-50139 Florence, Italy. NR 40 TC 44 Z9 45 U1 1 U2 2 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD JUN PY 1998 VL 38 IS 3 BP 286 EP 294 PG 9 WC Gerontology SC Geriatrics & Gerontology GA ZU200 UT WOS:000074172300002 PM 9640848 ER PT J AU Burvin, R LeRoith, D Harel, H Zloczower, M Marbach, M Karnieli, E AF Burvin, R LeRoith, D Harel, H Zloczower, M Marbach, M Karnieli, E TI The effect of acute insulin-like growth factor-II administration on glucose metabolism in the rat SO GROWTH HORMONE & IGF RESEARCH LA English DT Article DE insulin-like growth factor II; in vivo insulin action; glucose uptake; animal; hepatic glucose production ID MANNOSE 6-PHOSPHATE RECEPTOR; HUMAN FAT-CELLS; IGF-II; BINDING-PROTEINS; HEALTHY-ADULTS; HYPOGLYCEMIA; EXPRESSION; RESISTANCE; TRANSPORT; MUSCLE AB The in vivo effects of the insulin-like growth factor-II (IGF-II) on glucose metabolism is not yet well defined. To assess the acute effect of IGF-II administration on whole body glucose utilization and hepatic glucose production, we used the well-established euglycemic clamp technique and compared the effects in awake cannulated rats with those of insulin. Each animal underwent several 90-min euglycemic studies, alternating between IGF-II and insulin. Following IGF-II infusion, tissue glucose uptake was increased to 9.8+/-0.6 mg/kg/min (mean+/-SEM), which represented only 14% of the effect of insulin, despite the molar plasma concentration ratio of insulin: IGF-2 being 1.460. IGF-II and insulin infusion reduced hepatic glucose output by 49 and 75%, respectively. Thus, IGF-II, administered acutely, affects glucose homeostasis in a manner very similar to insulin, probably via the insulin receptors, although with significantly lower potency. (C) 1998 Churchill Livingstone. C1 Rambam Med Ctr, Inst Endocrinol Diabet & Metab, IL-31096 Haifa, Israel. Technion Israel Inst Technol, Bruce Rappaport Fac Med, IL-31096 Haifa, Israel. Beilinson Med Ctr, Dept Plast Surg, Petach Tikva, Israel. NIDDK, Diabet Branch, NIH, Bethesda, MD USA. Soroka Med Ctr, Endocrine Lab, Beer Sheva, Israel. RP Karnieli, E (reprint author), Rambam Med Ctr, Inst Endocrinol Diabet & Metab, POB 9002, IL-31096 Haifa, Israel. NR 29 TC 4 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 1096-6374 J9 GROWTH HORM IGF RES JI Growth Horm. IGF Res. PD JUN PY 1998 VL 8 IS 3 BP 205 EP 210 DI 10.1016/S1096-6374(98)80112-3 PG 6 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 131MF UT WOS:000076579300004 PM 10984308 ER PT J AU Baumann, P Romero, R Wilson, T AF Baumann, P Romero, R Wilson, T TI The role of gravidine, a phospholipase A(2) inhibitor, in parturition SO GYNAKOLOGISCH-GEBURTSHILFLICHE RUNDSCHAU LA German DT Article DE phospholipase A(2) inhibitor; gravidine; labor; parturition; amniotic fluid ID AMNIOTIC-FLUID; SECRETORY COMPONENT; ENDOGENOUS INHIBITOR; MICROBIAL INVASION; SPONTANEOUS LABOR; TERM; IGA; PURIFICATION; INFECTION; PRETERM AB Objective: What is the significance of gravidine, a phospholipase A(2) inhibitor, in parturition? Methods: Gravidine concentrations were measured in amniotic fluid obtained by transabdominal amniocentesis from women in labor at term and not in labor using a sensitive and specific ELISA. Results: (1) Amniotic fluid gravidine concentrations were lower in the presence than in the absence of labor. (2) Gravidine concentrations in the amniotic fluid of the forebag were higher than in the amniotic fluid of the upper compartment. (3) There was a positive correlation between gestational age and amniotic fluid gravidine concentrations. (4) No such correlation could be demonstrated between cervical dilation and amniotic fluid gravidine concentrations. Conclusion: These results suggest that gravidine may play a permissive role in the interplay with prostanoids in the mechanism of parturition. C1 Univ Lubeck, Klin Frauenheilkunde & Geburtshilfe Med, D-23538 Lubeck, Germany. Wayne State Univ, Perinatol Branch, NICHHD, Detroit, MI USA. Univ Dundee, Dept Obstet & Gynaecol, Dundee DD1 4HN, Scotland. RP Baumann, P (reprint author), Univ Lubeck, Klin Frauenheilkunde & Geburtshilfe Med, Ratzeburger Allee 160, D-23538 Lubeck, Germany. NR 23 TC 2 Z9 2 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1018-8843 J9 GYNAKOL GEBURT RUNDS JI Gynakol. Geburtshilfliche Rundsch. PD JUN PY 1998 VL 38 IS 1 BP 16 EP 20 DI 10.1159/000022221 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA ZU900 UT WOS:000074247600004 PM 9658711 ER PT J AU Zelmanowicz, A Hildesheim, A Sherman, ME Sturgeon, SR Kurman, RJ Barrett, RJ Berman, ML Mortel, R Twiggs, LB Wilbanks, GD Brinton, LA AF Zelmanowicz, A Hildesheim, A Sherman, ME Sturgeon, SR Kurman, RJ Barrett, RJ Berman, ML Mortel, R Twiggs, LB Wilbanks, GD Brinton, LA TI Evidence for a common etiology for endometrial carcinomas and malignant mixed mullerian tumors SO GYNECOLOGIC ONCOLOGY LA English DT Article ID FEMALE GENITAL-TRACT; MESODERMAL TUMORS; HISTOLOGIC TYPES; RISK-FACTORS; HUMAN UTERUS; CANCER; CARCINOSARCOMA; SARCOMAS; DIFFERENTIATION; EPIDEMIOLOGY AB Objective. To elucidate factors linked to the development of malignant mixed mullerian tumors (MMMT) and determine whether the risk factor profile for these tumors corresponds with that for the more common endometrial carcinomas. Methods. A multicenter case-control study of 424 women diagnosed with endometrial carcinoma, 29 women diagnosed with MMMT, and 320 community controls was conducted. Review of pathological reports and slides was performed to classify cases by histological type. All participants were asked to respond to a questionnaire which ascertained information on exposure to factors postulated to be linked to the development of uterine tumors. Results. Women with endometrial carcinomas and MMMTs were similar with respect to age and educational attainment. Women diagnosed with MMMTs were more likely than those diagnosed with carcinomas to be of African-American descent (28% vs 4%; P = 0.001). Weight, exogenous estrogen use, and nulliparity were related to risk of both tumor types. Marked obesity was associated with a 4.8-fold (95% CI = 3.0,7.6) increase in risk of carcinoma and a 3.2-fold (95% CI = 1.1,9.1) increase in risk of MMMT development. Use of exogenous estrogens increased the odds of developing carcinomas by 2-fold (95% CI = 1.3,3.2) and that of developing MMMTs by 1.8-fold (95% CI = 0.57,5.5). Nulliparity was associated with a 2.9-foId (95% CI = 1.9,4.8) increase in risk of carcinomas and a 1.7-fold (95% CI = 0.53,5.6) increase in risk of MMMTs, Oral contraceptive use protected against the development of both carcinomas (OR = 0.39; 95% CI = 0.26,0.58) and MMMTs (OR = 0.76; 95% CI = 0.25,2.3). Current smokers were at a reduced risk of developing endometrial carcinomas (OR = 0.34; 95% CI = 0.21,0.55) and MMMTs (OR = 0.57; 95% CI = 0.15,2.3), while former smokers were at an increased risk of MMMT (OR = 2.7; 95% CI = 1.1,6.8) but not carcinoma development (OR = 0.81; 95% CI = 0.56,1.2). Conclusion. Results from this study suggest that MMMTs and carcinomas have a similar risk factor profile. This observation is compatible with the hypothesis that the pathogenesis of these two histological types of uterine tumors is similar. (C) 1998 Academic Press. C1 NCI, Div Canc Epidemiol & Genet, Environm Epidemiol Branch, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Univ Calif Irvine, Dept Obstet & Gynecol, Irvine, CA 92717 USA. Penn State Univ, Milton S Hershey Med Ctr, Dept Obstet & Gynecol, Hershey, PA 17033 USA. Univ Minnesota, Hlth Sci Ctr, Dept Obstet & Gynecol, Minneapolis, MN 55455 USA. Rush Med Ctr, Dept Obstet & Gynecol, Chicago, IL USA. RP Hildesheim, A (reprint author), NCI, Div Canc Epidemiol & Genet, Environm Epidemiol Branch, 6130 Execut Blvd,EPN Room 443, Bethesda, MD 20892 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 30 TC 84 Z9 86 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUN PY 1998 VL 69 IS 3 BP 253 EP 257 DI 10.1006/gyno.1998.4941 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA ZV193 UT WOS:000074279700014 PM 9648597 ER PT J AU Gittelsohn, J Evans, M Helitzer, D Anliker, J Story, M Metcalfe, L Davis, S Cloud, PI AF Gittelsohn, J Evans, M Helitzer, D Anliker, J Story, M Metcalfe, L Davis, S Cloud, PI TI Formative research in a school-based obesity prevention program for Native American school children (Pathways) SO HEALTH EDUCATION RESEARCH LA English DT Article ID BODY-MASS INDEX; BLOOD-PRESSURE; HEART-DISEASE; CHILDHOOD; INDIANS; AGE AB This paper describes how formative research was developed and implemented to produce obesity prevention interventions among school children in six different Native American nations that are part of the Pathways study, The formative assessment work presented here was unique in several ways: (1) it represents the first time formative research methods have been applied across multiple Native American tribes; (2) it is holistic, including data collection from parents, children, teachers, administrators and community leaders; and (3) it was developed by a multi-disciplinary group, including substantial input from Native American collaborators. The paper describes the process of developing the different units of the protocol, how data collection was implemented and how analyses were structured around the identification of risk behaviors. An emphasis is placed on describing which units of the formative assessment protocol were most effective and which were less effective. C1 Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Int Hlth, Ctr Human Nutr, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Int Hlth, Div Human Nutr, Baltimore, MD 21205 USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Univ New Mexico, Sch Med, Dept Family & Community Med, Albuquerque, NM 87131 USA. Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. Univ Minnesota, Div Epidemiol Publ Hlth Nutr, Minneapolis, MN 55454 USA. Univ Arizona, Coll Med, Dept Physiol, Tucson, AZ 85721 USA. Univ New Mexico, Ctr Hlth Sci, Ctr Hlth Promot Nat Amer Communities, Albuquerque, NM 87131 USA. Youth & Family Serv Ctr Based Head Start, Rapid City, SD 57709 USA. RP Gittelsohn, J (reprint author), Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Int Hlth, Ctr Human Nutr, Baltimore, MD 21205 USA. FU NHLBI NIH HHS [U01 HL050905, U01 HL050867, U01 HL050869, U01 HL050885, U01 HL050907] NR 37 TC 44 Z9 44 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1153 J9 HEALTH EDUC RES JI Health Educ. Res. PD JUN PY 1998 VL 13 IS 2 BP 251 EP 265 DI 10.1093/her/13.2.251 PG 15 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA ZU194 UT WOS:000074171700010 PM 10181023 ER PT J AU Ory, MG Cooper, J Siu, AL AF Ory, MG Cooper, J Siu, AL TI Toward the development of a research agenda on organizational issues in the delivery of healthcare to older Americans SO HEALTH SERVICES RESEARCH LA English DT Editorial Material C1 NIA, Bethesda, MD 20892 USA. Mt Sinai Med Ctr, New York, NY 10029 USA. RP Ory, MG (reprint author), NIA, Bethesda, MD 20892 USA. NR 6 TC 3 Z9 3 U1 0 U2 0 PU HEALTH ADMINISTRATION PRESS PI MELROSE PARK PA C/O FOUNDATION AMER COLL HEALTHCARE EXECUTIVES 1951 CORNELL AVE, MELROSE PARK, IL 60160 USA SN 0017-9124 J9 HEALTH SERV RES JI Health Serv. Res. PD JUN PY 1998 VL 33 IS 2 BP 287 EP 297 PN 2 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA ZQ456 UT WOS:000073863900001 ER PT J AU Mandishona, E MacPhail, AP Gordeuk, VR Kedda, MA Paterson, AC Rouault, TA Kew, MC AF Mandishona, E MacPhail, AP Gordeuk, VR Kedda, MA Paterson, AC Rouault, TA Kew, MC TI Dietary iron overload as a risk factor for hepatocellular carcinoma in Black Africans SO HEPATOLOGY LA English DT Article ID HEMOCHROMATOSIS; LIVER; DNA; HEREDITARY; AFLATOXIN; MUTATION; GENE AB Although the iron-loading disease, hereditary hemochromatosis, has a strong causal association with hepatocellular carcinoma (HCC), the carcinogenic potential of dietary iron overload in Black Africans is not known. We investigated this potential by evaluating iron status, alcohol consumption, markers for hepatitis B (HBV) and C virus (HCV) infections, and exposure to dietary aflatoxin B-1 in 24 rural patients with this tumor, 48 race-, sex-, and age-matched hospital-based controls, and 75 related or unrelated close family members of the cancer patients. Iron overload was defined as a raised serum ferritin concentration in combination with a transferrin saturation greater than or equal to 60%, and was confirmed histologically when possible. Among 24 patients and 48 hospital controls, the risk of developing HCC in the iron-loaded subjects was 10.6 (95% confidence limits of 1.5 and 76.8) relative to individuals with normal iron status, after adjusting for alcohol consumption, chronic HBV and HBC infections, and exposure to aflatoxin B-1, The risk of HCC in subjects with HBV infection was 33.2 (7.2, 153.4) (odds ratio [95% confidence limits]), HCV infection 6.4 (0.3, 133.5), and alcohol consumption 2.0 (0.5, 8.2), Aflatoxin B-1 exposure did not appear to increase the risk of HCC. The population attributable risk of iron overload in the development of HCC was estimated to be 29%, Among 20 cancer patients and 75 family members, the risk of developing HCC with iron overload was 4.1 (0.5, 32.2), We conclude that dietary iron overload may contribute to the development of HCC in Black Africans. C1 Univ Witwatersrand, Sch Med, Dept Med, ZA-2193 Johannesburg, South Africa. George Washington Univ Ctr, Dept Med, Washington, DC USA. NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. RP Kew, MC (reprint author), Univ Witwatersrand, Sch Med, Dept Med, 7 York Rd, ZA-2193 Johannesburg, South Africa. FU NICHD NIH HHS [I-HD-3-3I96] NR 34 TC 88 Z9 89 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 JUN PY 1998 VL 27 IS 6 BP 1563 EP 1566 DI 10.1002/hep.510270614 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA ZQ460 UT WOS:000073864300014 PM 9620327 ER PT J AU Smedile, A Casey, JL Cote, PJ Durazzo, M Lavezzo, B Purcell, RH Rizzetto, M Gerin, JL AF Smedile, A Casey, JL Cote, PJ Durazzo, M Lavezzo, B Purcell, RH Rizzetto, M Gerin, JL TI Hepatitis D viremia following orthotopic liver transplantation involves a typical HDV virion with a hepatitis B surface antigen envelope SO HEPATOLOGY LA English DT Article ID DELTA-VIRUS; CHIMPANZEES; ANTIBODIES; NEUTRALIZATION; INFECTION; DISEASE; AGENT AB Patients receiving orthotopic liver transplantation (OLT) because of type D hepatitis frequently exhibit what appears to be an autonomous, or "isolated," hepatitis D virus (HDV) infection following the transplantation, with no evidence of hepatitis B virus (HBV) in the graft or in the serum. These observations have led to the hypothesis that HBV might not always be required for HDV infection, or that HDV could exist as a latent infection until rescued by HBV. Alternatively, an apparently autonomous HDV infection could be explained by coinfection of a small number of hepatocytes ,vith both viruses following transplantation, with a very low level of HBV expression that supports low-level HDV propagation. Our results are consistent with the latter hypothesis. Sensitive polymerase chain reaction (PCR)-based analysis of HBV and HDV viremia in transplantation patients with HDV infection previously characterized as isolated showed that HDV viremia was not independent of HBV viremia. Additional analyses, including PCR amplification, buoyant density analysis in a CsCl gradient, and immunoprecipitation with monoclonal hepatitis B surface antigen antibodies (anti-HBs), indicated that the posttransplant HDV particle is typical: it contains full-length HDV RNA and an envelope of hepatitis B surface antigen (HBsAg) and is not different from that found during the acute and chronic stages of HDV superinfection or coinfection, Moreover, an experimental test of the first hypothesis in chimpanzees did not support the idea that HDV can persist for several weeks as an isolated, latent infection that can be rescued subsequently by HBV. The data indicate, therefore, that latent HDV infection is not a factor in OLT recipients. We conclude that the HDV virion in the posttransplantation setting is typical, and that HDV viremia following OLT requires the helper function of HBV infection. C1 Georgetown Univ, Med Ctr, Div Mol Virol & Immunol, Rockville, MD 20852 USA. Osped Molinette, Div Gastroenterol, Torino, Italy. NIH, Infect Dis Lab, Bethesda, MD 20892 USA. RP Casey, JL (reprint author), Georgetown Univ, Med Ctr, Div Mol Virol & Immunol, 5640 Fishers Lane, Rockville, MD 20852 USA. FU NIAID NIH HHS [N01-AI-45179] NR 29 TC 37 Z9 38 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 JUN PY 1998 VL 27 IS 6 BP 1723 EP 1729 DI 10.1002/hep.510270636 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA ZQ460 UT WOS:000073864300036 PM 9620349 ER PT J AU Bornstein, SR Vaudry, H AF Bornstein, SR Vaudry, H TI Paracrine and neuroendocrine regulation of the adrenal gland - Basic and clinical aspects SO HORMONE AND METABOLIC RESEARCH LA English DT Editorial Material ID CHROMAFFIN CELLS; CORTEX; STIMULATION C1 NICHD, NIH, Bethesda, MD 20892 USA. Univ Rouen, European Inst Peptide Res IFRMP 23, Lab Cellular & Mol Neuroendocrinol, CNRS,UA,INSERM,U413, Mt St Aignan, France. RP Bornstein, SR (reprint author), NICHD, NIH, Bldg 10,10 N 242, Bethesda, MD 20892 USA. NR 42 TC 27 Z9 28 U1 0 U2 1 PU GEORG THIEME VERLAG PI STUTTGART PA P O BOX 30 11 20, D-70451 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD JUN-JUL PY 1998 VL 30 IS 6-7 BP 292 EP 296 DI 10.1055/s-2007-978887 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZX760 UT WOS:000074552400002 PM 9694552 ER PT J AU Marx, C Ehrhart-Bornstein, M Scherbaum, WA Bornstein, SR AF Marx, C Ehrhart-Bornstein, M Scherbaum, WA Bornstein, SR TI Regulation of adrenocortical function by cytokines - Relevance for immune-endocrine interaction SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE adrenal; HPA-axis; cytokines; immune; endocrine; interaction ID TRANSFORMING GROWTH-FACTOR; TUMOR-NECROSIS-FACTOR; RAT ADRENAL-GLAND; CELL DIFFERENTIATED FUNCTIONS; ACTH-INDUCED STEROIDOGENESIS; MESSENGER-RIBONUCLEIC-ACID; FACTOR-BETA; CORTICOSTERONE SECRETION; CORTISOL PRODUCTION; STEROID-PRODUCTION AB The importance of the hypothalamic-pituitary-adrenal-axis (HPA) for the regulation of immunological functions has been greatly appreciated in the past (1-3). Activation of the HPA axis due to a given stimulus leads to a stress response which modulates the immune response. The interactions between the immune system and HPA-axis may be characterized by a circuit which includes I) activation of the HPA-axis and initiation of the stress response which, in term, has immune-modulating properties; II) a feedback mechanism derived from the immune system which regulates the HPA-axis. Current concepts on these regulatory circuits mainly favor the action of cytokines as mediators of the immune-endocrine regulation circuits which have been shown to interfere with the endocrine system on all levels of the HPA-axis. Over the past few years, it has become evident that the adrenal gland, itself, as the main effector organ of the HPA-axis, is a major site for both synthesis and action of numerous cytokines. This review summarizes current knowledge on production, action, as well as functional implications of cytokine action within the adrenal gland during development, health and disease. C1 Univ Leipzig, Dept Internal Med 3, D-04103 Leipzig, Germany. Univ Dusseldorf, Diabet Forschungsinst, D-4000 Dusseldorf, Germany. NICHHD, NIH, Ctr Clin, Bethesda, MD USA. RP Marx, C (reprint author), Univ Leipzig, Dept Internal Med 3, Philipp Rosenthal Str 27, D-04103 Leipzig, Germany. EM med92dqi@studserv.uni-leipzig.de NR 64 TC 53 Z9 53 U1 0 U2 2 PU GEORG THIEME VERLAG PI STUTTGART PA P O BOX 30 11 20, D-70451 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD JUN-JUL PY 1998 VL 30 IS 6-7 BP 416 EP 420 DI 10.1055/s-2007-978907 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZX760 UT WOS:000074552400022 PM 9694572 ER PT J AU Ehrhart-Bornstein, M Hilbers, U AF Ehrhart-Bornstein, M Hilbers, U TI Neuroendocrine properties of adrenocortical cells SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE adrenal cortex; adrenal carcinoma; NCI-H295; neuroendocrine differentiation; neuronal cell adhesion molecule (NCAM); synaptophysin ID LEYDIG-CELLS; ADHESION MOLECULES; TUMORS; PHEOCHROMOCYTOMA; DIFFERENTIATION; ADRENOMEDULLIN; EXPRESSION; PEPTIDE; TISSUE; NCAM AB Recent data suggest that adrenocortical cells under pathological as well as under physiological conditions show neuroendocrine properties. Within the normal adrenal, this neuroendocrine differentiation seems to be restricted to cells of the zona glomerulosa and might be important for an autocrine regulation of adrenocortical function. In addition, such neuroendocrine differentiation is a common phenomenon in adrenocortical carcinomas and is therefore of clinical importance. In our studies, the expression of neuronal cell adhesion molecule (NCAM) could be shown in the zona glomerulosa of the normal human adrenal and in the human adrenocortical cell line NCI-H295 that also produces synaptophysin, a synaptic vesicle associated protein. In this chapter, data on neuroendocrine characteristics of adrenocortical cells are summarized and discussed. C1 NICHD, NIH, Bethesda, MD 20892 USA. Univ Leipzig, Dept Internal Med 3, Leipzig, Germany. RP Ehrhart-Bornstein, M (reprint author), NICHD, NIH, Bldg 10,Room 10 N262, Bethesda, MD 20892 USA. NR 26 TC 21 Z9 23 U1 0 U2 2 PU GEORG THIEME VERLAG PI STUTTGART PA P O BOX 30 11 20, D-70451 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD JUN-JUL PY 1998 VL 30 IS 6-7 BP 436 EP 439 DI 10.1055/s-2007-978911 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZX760 UT WOS:000074552400026 PM 9694576 ER PT J AU Stratakis, CA Kirschner, LS AF Stratakis, CA Kirschner, LS TI Clinical and genetic analysis of primary bilateral adrenal diseases (micro-and macronodular disease) leading to Cushing syndrome SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE primary pigmented adrenocortical disease (PPNAD); massive macronodular adrenocortical disease (MMAD); Carney complex; MEN 1; tumors; genetics ID GASTRIC-INHIBITORY POLYPEPTIDE; ENDOCRINE NEOPLASIA TYPE-1; PSAMMOMATOUS MELANOTIC SCHWANNOMA; ADRENOCORTICAL NODULAR DYSPLASIA; INCLUDING CARDIAC MYXOMA; CARNEY COMPLEX; SPOTTY PIGMENTATION; STEROIDOGENIC ENZYMES; ACTIVATING MUTATIONS; SPECIAL ASSOCIATIONS AB Primary bilateral adrenocortical diseases are rare entities that have recently been appreciated as potential causes of Cushing syndrome. They include (i) primary pigmented adrenocortical disease (PPNAD), also known as "micronodular adrenal disease", which is a genetic disorder that is often associated with Carney complex, and (ii) massive macronodular adrenocortical disease (MMAD), a rare disorder of unknown etiology that affects older adults. Carney complex is a multiple endocrine neoplasia (MEN) syndrome that affects not only the adrenal cortex, but also the pituitary, thyroid, and gonads. It is associated with pigmentation abnormalities as well as myxomas and other mesenchymal and neural crest neoplasms. The inheritance of the complex is autosomal dominant, and genetic mapping has shown that at least two loci are involved in its pathogenesis. MMAD appears to be an isolated finding in most cases, and a genetic defect has not yet been defined. Ectopic expression of hormone receptors has been implicated in several cases of MMAD, but an underlying deficit has not been detected. Bilateral adrenocortical hyperplasia has also been described in McCune-Albright syndrome and MEN type-1, but this finding is not always associated with hypercortisolism. The genetic defects for these diseases are known, but their role in adrenal cortex pathophysiology has not been fully elucidated. Identification of the molecular defects responsible for bilateral adrenocortical disorders is expected to shed light on many aspects of early adrenal gland differentiation and tumorigenesis. C1 NICHHD, Unit Genet & Endocrinol, SPE,DEB, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHHD, Unit Genet & Endocrinol, SPE,DEB, NIH, Bldg 10,Room 10 N262, Bethesda, MD 20892 USA. NR 83 TC 86 Z9 96 U1 0 U2 2 PU GEORG THIEME VERLAG PI STUTTGART PA P O BOX 30 11 20, D-70451 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD JUN-JUL PY 1998 VL 30 IS 6-7 BP 456 EP 463 DI 10.1055/s-2007-978914 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZX760 UT WOS:000074552400029 PM 9694579 ER PT J AU Quezado, MM Middleton, LP Bryant, B Lane, K Weiss, SW Merino, MJ AF Quezado, MM Middleton, LP Bryant, B Lane, K Weiss, SW Merino, MJ TI Allelic loss on chromosome 22Q in epithelioid sarcomas SO HUMAN PATHOLOGY LA English DT Article DE epithelioid sarcoma; NF2; PCR; loss of heterozygosity ID NF2 GENE; NEUROFIBROMATOSIS TYPE-2; TUMOR-SUPPRESSOR; MUTATIONS; DIFFERENTIATION; TRANSLOCATION; ANGIOSARCOMA; GRANULOMA; DIAGNOSIS; CANCER AB Epithelioid sarcomas are soft tissue tumors with an indolent, but potentially aggressive, clinical behavior. Distinction from other benign and malignant entities may be a diagnostic dilemma. In this study, we evaluate the presence of loss of heterozygosity (LOH) of chromosome 22q in tumor DNA from 13 epithelioid sarcomas, four epitheliold angiosarcomas, and two epithelioid hemangioendotheliomas, and investigate its possible role in diagnosis. LOH was detected in 6 of 10 (60%) of the informative epithelioid sarcomas. No allele loss was detected in the informative vascular tumors, three angiosarcomas, and two hemangioendotheliomas. Chromosome 22q carries the locus of a tumor suppressor gene, the neurofibromatosis 2 (NF2) gene, which has been shown to be lost or mutated in some NF2-related tumors, sporadic meningiomas, and vestibular schwannomas, as well as a few other tumors. Our data suggest that a region of chromosome 22q may be the locus of a tumor suppressor gene involved in the tumorigenesis of these neoplasms. Genetic alterations of yet unknown tumor suppressor genes in this region, or even the NF2 tumor suppressor gene, may play a role in epithelioid sarcomas tumorigenesis. The fact that LOH was only detected in epithelioid sarcomas and not in the vascular tumors studied suggests a possible role for this marker in diagnosis. HUM PATHOL 29:604-608. This is a US government work. There are no restrictions on its use. C1 NCI, Surg Pathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. Univ Michigan Hosp, Dept Pathol, Ann Arbor, MI 48109 USA. RP Merino, MJ (reprint author), NCI, Surg Pathol Sect, Pathol Lab, NIH, Bldg 10,Room 2N212,10 Ctr Dr, Bethesda, MD 20892 USA. NR 37 TC 19 Z9 20 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD JUN PY 1998 VL 29 IS 6 BP 604 EP 608 DI 10.1016/S0046-8177(98)80010-5 PG 5 WC Pathology SC Pathology GA ZT258 UT WOS:000074066600010 PM 9635681 ER PT J AU Middleton, LP Duray, PH Merino, MJ AF Middleton, LP Duray, PH Merino, MJ TI The histological spectrum of hemangiopericytoma: Application of immunohistochemical analysis including proliferative markers to facilitate diagnosis and predict prognosis SO HUMAN PATHOLOGY LA English DT Article DE hemangiopericytoma; immunohistochemistry; prognosis ID SOFT-TISSUE; MONOCLONAL-ANTIBODY; GLOMUS TUMORS; DIFFERENTIATION; EXPRESSION; ANTIGEN AB Hemangiopericytoma (HPC) is an uncommon vascular neoplasm thought to be derived from pericytes. Prediction of patient outcome is difficult based what is currently known about these tumors and histological parameters alone. We compiled 27 cases of HPC and evaluated the spectrum of histological features to investigate whether there was any correlation between histology, immunostaining, prognostic markers, and patient outcome. The following parameters were evaluated: vasculature, histological pattern (solid, myxoid, trabecular, alveolar), degree of cellular pleomorphism, necrosis, mitoses, and giant cell content. Immunohistochemistry was performed to determine the reactivity for CD 31, CD34, vimentin, actin, cytokeratin, S100, actin, and SMA Proliferative rate was analyzed using antibodies to PCNA and MIB1. Patient's age ranged from 8 months to 75 years (mean, 35; median, 31). Twenty of 27 cases were located in the extremities. The tumors were grossly described as lobulated and well circumscribed (n = 12) and nonencapsulated (n = 15). By histology, the characteristic ramifying or staghorn vasculature pattern was seen in all cases. A solid histological pattern was mixed with an alveolar pattern in three cases, trabecular pattern in six cases, and myxoid pattern in two cases. Tumor cells were uniform, polygonal to spindle-shaped, often with vesicular nuclei. Tumor giant cells were present in 9 of 27 cases; necrosis, in 11 of 27. Mitoses ranged from 0 to 14 per 10 high-power fields (HPF). Cellular pleomorphism was 1+ in nine cases, 2+ in 12 cases, and 3+ in six cases. Immunohistochemistry showed reactivity for CD34 and vimentin in all cases. Actin was focally positive in one case, and SUA. was focally positive in another. CD 31, cytokeratin, and S100 were uniformly nonreactive. Proliferative index measured by PCNA and MIBI ranged between less than 1% and 40% of tumor cells. Follow-up was available in 22 cases and ranged from 1 year to 15 years. Seven patients had metastases, and two recurred locally. Thirteen patients had no evidence of disease at last checkup. Parameters associated with recurrences or metastases include a trabecular pattern, the presence of necrosis, mitoses, vascular invasion, and cellular pleomorphism. Features associated with an aggressive biological behavior can be identified histologically. There was some, but not total, correlation between proliferative markers and tumor aggressiveness. HUM PATHOL 29:636-640. Copyright (C) 1998 by W.B. Saunders Company. C1 NCI, Dept Surg Pathol, Pathol Lab, Bethesda, MD 20892 USA. RP Merino, MJ (reprint author), NCI, Dept Surg Pathol, Pathol Lab, Bldg 10 Room 2n212,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 23 TC 46 Z9 55 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 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD JUN PY 1998 VL 29 IS 6 BP 636 EP 640 DI 10.1016/S0046-8177(98)80015-4 PG 5 WC Pathology SC Pathology GA ZT258 UT WOS:000074066600015 PM 9635686 ER PT J AU George, MS Speer, AM Molloy, M Nahas, Z Teneback, CC Risch, SC Arana, GW Ballenger, JC Post, RM AF George, MS Speer, AM Molloy, M Nahas, Z Teneback, CC Risch, SC Arana, GW Ballenger, JC Post, RM TI Low frequency daily left prefrontal rTMS improves mood in bipolar depression: A placebo-controlled case report SO HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL LA English DT Article DE depression; bipolar affective disorder; SPECT; imaging; transcranial magnetic stimulation ID TRANSCRANIAL MAGNETIC STIMULATION; LONG-TERM POTENTIATION; CORTEX AB Preliminary studies in unipolar depression indicate that daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) reduces symptoms of depression. rTMS treatment of depression occurring in the setting of bipolar disorder has been less well studied. To assess the efficacy and toxicity of rTMS in the depressed phase of bipolar disorder, we treated a man with bipolar disorder who was known to develop hypomania and mania with conventional antidepressants. A 47 year old man with Bipolar Disorder type I, depressed phase, was entered into a double-blind parallel treatment trial of left prefrontal rTMS. He was randomized to receive left prefrontal rTMS at low frequency (5 Hz) for 2 weeks, which was then followed by an open phase. The patient's Hamilton Depression scores decreased 44 per cent across the first 2 weeks. In an open extension, his mood further improved over another 2 weeks and he was gradually tapered from rTMS treatments. He had no side effects. Importantly, he did not develop mania, as had occurred with all prior antidepressant trials. After several months he experienced a recurrence of depressive symptoms, was retreated, and re-responded. Further studies are warranted to investigate the optimum dose, duration, location and frequency of rTMS treatments for the depressed phase of bipolar disorder. (C) 1998 John Wiley & Sons, Ltd. C1 Med Univ S Carolina, Dept Radiol, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Neurol, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Psychiat, Charleston, SC 29425 USA. Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. NIMH, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP George, MS (reprint author), Med Univ S Carolina, Dept Radiol, 171 Ashley Ave, Charleston, SC 29425 USA. NR 22 TC 21 Z9 21 U1 1 U2 2 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0885-6222 J9 HUM PSYCHOPHARM CLIN JI Hum. Psychopharmacol.-Clin. Exp. PD JUN PY 1998 VL 13 IS 4 BP 271 EP 275 PG 5 WC Clinical Neurology; Pharmacology & Pharmacy; Psychiatry; Psychology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry; Psychology GA ZV774 UT WOS:000074339800009 ER PT J AU Lujan, HD Conrad, JT Clark, CG Touz, MC Delbac, F Vivares, CP Nash, TE AF Lujan, HD Conrad, JT Clark, CG Touz, MC Delbac, F Vivares, CP Nash, TE TI Detection of microsporidia spore-specific antigens by monoclonal antibodies SO HYBRIDOMA LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CYST WALL PROTEIN; AIDS PATIENT; ENCEPHALITOZOON-CUNICULI; ENTEROCYTOZOON-BIENEUSI; FINE-STRUCTURE; IDENTIFICATION; ULTRASTRUCTURE; CULTURE; HELLEM AB Microsporidia (phylum Microspora) are unicellular parasites commonly found in invertebrates, fish, and laboratory animals; however, microsporidiosis is an emerging problem in patients with the acquired immunodeficiency syndrome (AIDS), The infective stage of these parasites is the spore, which possesses a rigid cell wall that protects the parasite outside its host, Little is known about their antigenic composition, Sensitive, reliable, and easily performed methods for identification and speciation are generally not available, Here, we report the production of 21 MAbs specific to spore antigens of several species of Microsporidia, MAbs were generated to purified spores of Encephalitozoon intestinalis and Encephalitozoon heliem, and their reactivities were tested against spores and intracellular developing forms of E., intestinalis, E, hellem, Encephalitozoon cuniculi, and Vittaforma corneae, Both species-specific and broad-reactivity MAbs were produced. Five MAbs reacted against the spores of all four species tested: 7 with 3 species, 6 with 2 species, 1 with E. intestinalis, and 4 with the polar tube of all species. Immunoelectron microscopy confirmed the reactivity of specific MAbs to the spore wall or the polar tube. These MAbs reacted to a few antigens as determined by Western blot, and none of the epitopes were periodate-sensitive. These MAbs may be useful in the diagnosis and speciation of Microsporidia as well in the purification, cloning, and detection of these antigens. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Natl Univ Cordoba, Dept Biol Chem, Sch Med, Cordoba, Argentina. Univ Blaise Pascal, UPESA CNRS 6023, LBCP, F-63177 Aubiere, France. RP Nash, TE (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 4,Room 126,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Clark, C Graham/0000-0002-0521-0977 NR 37 TC 32 Z9 33 U1 0 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0272-457X J9 HYBRIDOMA JI Hybridoma PD JUN PY 1998 VL 17 IS 3 BP 237 EP 243 DI 10.1089/hyb.1998.17.237 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Immunology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Immunology GA 104JA UT WOS:000075009900002 PM 9708825 ER PT J AU Cardillo, C Kilcoyne, CM Cannon, RO Panza, JA AF Cardillo, C Kilcoyne, CM Cannon, RO Panza, JA TI Racial differences in nitric oxide-mediated vasodilator response to mental stress in the forearm circulation SO HYPERTENSION LA English DT Article DE race; nitric oxide; stress; vasodilation ID DEPENDENT VASCULAR RELAXATION; ESSENTIAL-HYPERTENSION; L-ARGININE; REACTIVE HYPEREMIA; RESISTANCE VESSELS; BLOOD-PRESSURE; SMOOTH-MUSCLE; CAPACITY; BLACKS; PATHOPHYSIOLOGY AB An abnormal hemodynamic response to stressful stimuli has been proposed as a mechanism involved in the higher prevalence of hypertension in blacks. Given the important role of nitric oxide (NO) in the regulation of cardiovascular homeostasis, we investigated the possibility of racial differences in vascular NO activity during mental stress. To test this hypothesis, we compared the forearm blood flow (FBF) response to mental stress in 14 white and 12 black healthy subjects during intra-arterial infusion of either saline or NO synthesis inhibitor N-G-monomethyl-L-arginine (L-NMMA; 4 mu mol/min). We also examined vascular responses of the two groups to intra-arterial infusion of sodium nitroprusside (0.8 to 3.2 mu g/min), an exogenous NO donor. During saline infusion, the increase in FBF from baseline induced by mental stress was significantly higher in whites than in blacks (109+/-20% versus 58+/-8%; P=0.03). L-NMMA significantly reduced stress-induced increase in FBF in whites (from 109+/-20% to 54+/-11%; P=0.004) but not in blacks (from 58+/-8% to 42+/-10%; P=0.24); thus, the vasodilator effect of stress testing during L-NMMA was similar in whites and blacks (54+/-11% versus 42+/-10%; P=0.44). The vasodilator response to sodium nitroprusside was also lower in blacks than in whites (maximum flow, 6.9+/-2 versus 11.6+/-3.5 mL.min(-)1.dL(-1); P=0.001) and was not significantly modified by L-NMMA in either group. Our findings indicate that blacks have a reduced NO-dependent vasodilator activity during mental stress. This difference seems related to reduced sensitivity of smooth muscle to the vasodilator effect of NO and may play some role in the increased prevalence of hypertension and its complications in blacks. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Panza, JA (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10,Room 7B-15,10 Ctr Dr, Bethesda, MD 20892 USA. NR 37 TC 74 Z9 77 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD JUN PY 1998 VL 31 IS 6 BP 1235 EP 1239 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA ZR761 UT WOS:000074011100005 PM 9622135 ER PT J AU Stone, CD Smith, MF Greer, KL Jaszczak, RJ AF Stone, CD Smith, MF Greer, KL Jaszczak, RJ TI A combined half-cone beam and parallel hole collimation system for SPECT brain imaging SO IEEE TRANSACTIONS ON NUCLEAR SCIENCE LA English DT Article; Proceedings Paper CT 1997 Medical Imaging Conference CY NOV 13-15, 1997 CL ALBUQUERQUE, NEW MEXICO ID MAXIMUM-LIKELIHOOD RECONSTRUCTION; EMISSION-COMPUTED-TOMOGRAPHY; FILTERED BACKPROJECTION; ORDERED SUBSETS; ALGORITHM; PROJECTIONS; CT AB Our research group has recently examined new types of collimator designs with the goal of improving sensitivity and lesion detection for head imaging. One of these collimator designs is a half-cone beam collimator. However, the sensitivity is reduced as objects are removed from the focal line and it does not satisfy Tuy's sufficiency condition. Parallel hole collimation does not have this problem with axial blurring, however, values for sensitivity are not as large as for half-cone collimators. A potential configuration is to use one parallel hole collimator in conjunction with two half-cone beam collimators on a triple camera single photon emission computed tomography (SPECT) system. This might produce results that represent the best of both collimation systems. We acquired projection data with a Defrise disk phantom filled with Tc-99m. A half-cone beam collimator with a focal length of 50 cm was placed on one head of a triple camera SPECT system. A low energy super high resolution (LESR) parallel hole collimator was placed on a second head. Different projection data sets were combined to model acquisition in the three headed gamma camera with three half-cone beam collimators, two half-cone beam and one parallel beam collimators, one half-cone beam and two parallel beam collimators and three parallel beam collimators. Image reconstruction used a modified maximum likelihood maximization-expectation (ML-EM) algorithm. For the reconstruction with three half-cone beam collimators, we observe axial blurring. This is largely reduced with two half-cone beam and one parallel beam collimators. Graphs of the image profiles demonstrate that the blurring along the axial direction is decreased with the addition of parallel hole collimators. C1 Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. RP Stone, CD (reprint author), NIH, Dept Nucl Med, Bldg 10,Room 1C401,10 Ctr Dr, Bethesda, MD 20892 USA. NR 30 TC 9 Z9 9 U1 0 U2 0 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 0018-9499 J9 IEEE T NUCL SCI JI IEEE Trans. Nucl. Sci. PD JUN PY 1998 VL 45 IS 3 BP 1219 EP 1224 DI 10.1109/23.682006 PN 2 PG 6 WC Engineering, Electrical & Electronic; Nuclear Science & Technology SC Engineering; Nuclear Science & Technology GA ZU375 UT WOS:000074190800028 ER PT J AU Stevenson, B Bono, JL Schwan, TG Rosa, P AF Stevenson, B Bono, JL Schwan, TG Rosa, P TI Borrelia burgdorferi Erp proteins are immunogenic in mammals infected by tick bite, and their synthesis is inducible in cultured bacteria SO INFECTION AND IMMUNITY LA English DT Article ID LYME-DISEASE SPIROCHETE; OUTER-SURFACE-PROTEIN; IXODES-DAMMINI; CIRCULAR PLASMIDS; GENE FAMILY; IN-VIVO; EXPRESSION; TRANSMISSION; OSPF; B31 AB Borrelia burgdorferi, the causative agent of Lyme disease, can contain multiple genes encoding different members of the Erp lipoprotein family. Some arthropod-borne bacteria increase the synthesis of proteins required for transmission or mammalian infection when cultures are shifted from cool, ambient air temperature to a warmer, blood temperature. We found that all of the erp genes known to be encoded by infectious isolate B31 were differentially expressed in culture after a change in temperature, with greater amounts of message being produced by bacteria shifted fi om 23 to 35 degrees C than in those maintained at 23 degrees C. Mice infected with B31 by tick bite produced antibodies that recognized each of the Erp proteins within 4 weeks of infection, suggesting that the Erp proteins are produced by the bacteria during the early stages of mammalian infection and may play roles in transmission from ticks to mammals. Several of the B31 Erp proteins were also recognized by antibodies from patients with Lyme disease and may prove to be useful antigens for diagnostic testing or as components of a protective vaccine. C1 NIAID, Rocky Mt Labs, Microbial Struct & Funct Lab, NIH, Hamilton, MT 59840 USA. RP Stevenson, B (reprint author), Univ Kentucky, Coll Med, Dept Microbiol & Immunol, MS 415 UKMC, Lexington, KY 40536 USA. EM lkspic00@pop.uky.edu NR 50 TC 129 Z9 130 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD JUN PY 1998 VL 66 IS 6 BP 2648 EP 2654 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA ZP714 UT WOS:000073781100035 PM 9596729 ER PT J AU Feng, SL Hodzic, E Stevenson, B Barthold, SW AF Feng, SL Hodzic, E Stevenson, B Barthold, SW TI Humoral immunity to Borrelia burgdorferi N40 decorin binding proteins during infection of laboratory mice SO INFECTION AND IMMUNITY LA English DT Article ID OUTER-SURFACE-PROTEIN; LYME-DISEASE AGENT; IMMUNOLOGICAL CHARACTERIZATION; IN-VIVO; GENE; PLASMID; ANTIGEN; OSPA; EXPRESSION; INOCULATION AB A Borrelia burgdorferi N40 genomic expression library was screened with serum from actively infected mice to identify gene products that elicit protective immunity. A clone that contained a putative bicistronic operon containing two genes that encoded 20- and 22-kDa lipoproteins was identified and sequenced. These genes showed homology with the genes encoding decorin binding proteins DbpB and DbpA, respectively, of B. burgdorferi 297 and B31. N40-dbpA DNA hybridized with B. burgdorferi N40 DNA on a single 48-kb linear plasmid. Homologous genes could be amplified under various degrees of stringency by PCR or hybridized by Southern blotting from B. burgdorferi sensu stricto N40 and B31, and from B. burgdorferi sensu late PBI and 25015, but not PKo. Recombinant N40-DbpB and N40-DbpA were reactive with antibody in serum from infected mice, and serum was more reactive against N40-DbpA than against B. burgdorferi N40 recombinant P39, OspC, or OspA. Sera from mice infected with B. burgdorferi sensu late strains PKo and PBi were weakly reactive against N40-DbpB and N40-DbpA, and sera from mice infected with 25015 were moderately reactive, compared to sera from mice infected with B. burgdorferi N40. Hyperimmunization of mice with N40-DbpA, but not N40-DbpB, induced protective immunity against Syringe challenge with cultured B. burgdorferi N40. DbpA may therefore be one of the antigens responsible for eliciting protective antibody known to exist in serum from infected mice. DNA amplification and serology suggest that DbpB and DbpA are likely to have homologs throughout the B. burgdorferi sensu late family, but they are likely to be heterogeneous. C1 Univ Calif Davis, Sch Med, Ctr Comparat Med, Davis, CA 95616 USA. Univ Calif Davis, Sch Vet Med, Ctr Comparat Med, Davis, CA 95616 USA. NIAID, Rocky Mt Labs, Microbial Struct & Funct Lab, Hamilton, MT 59840 USA. RP Barthold, SW (reprint author), Univ Calif Davis, Sch Med, Ctr Comparat Med, 1 Shields Ave, Davis, CA 95616 USA. FU NIAID NIH HHS [AI-26815, R01 AI026815, AI-45253] NR 49 TC 68 Z9 70 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD JUN PY 1998 VL 66 IS 6 BP 2827 EP 2835 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA ZP714 UT WOS:000073781100062 PM 9596756 ER PT J AU Vidarsson, G Sigurdardottir, ST Gudnason, T Kjartansson, S Kristinsson, KG Ingolfsdottir, G Jonsson, S Valdimarsson, H Schiffman, G Schneerson, R Jonsdottir I AF Vidarsson, G Sigurdardottir, ST Gudnason, T Kjartansson, S Kristinsson, KG Ingolfsdottir, G Jonsson, S Valdimarsson, H Schiffman, G Schneerson, R Jonsdottir, I TI Isotypes and opsonophagocytosis of pneumococcus type 6B antibodies elicited in infants and adults by an experimental pneumococcus type 6B-tetanus toxoid vaccine SO INFECTION AND IMMUNITY LA English DT Article ID INFLUENZAE TYPE-B; STREPTOCOCCUS-PNEUMONIAE; CONJUGATE VACCINE; POLYSACCHARIDE VACCINE; HEALTHY-ADULTS; CHILDREN; DISEASE; RESPONSES; IGG2; PHAGOCYTOSIS AB Streptococcus pneumoniae is a major respiratory pathogen of infants, children, and the elderly. Polysaccharide vaccines have been useful in adult populations but do not elicit protective immunity in infants and young children. To enhance their immunogenicity, vaccines of pneumococcal polysaccharides conjugated to proteins are being developed. In this study antibody levels and opsonic activities were compared in sera of infants and adults injected with pneumococcal polysaccharide type 6B (Pn6B) conjugated to tetanus toroid (TT) (Pn6B-TT). Healthy infants were injected with Pn6B-TT; group A was injected at 3, 4, and 6 months of age, and group B was injected at 7 and 9 months of age. A booster injection was given at 18 months. Adults were injected once. Antibodies were measured by enzyme-linked immunosorbent assay and radioimmunoassay, and their functional activities were measured by opsonophagocytosis of radiolabelled pneumococci. In adults, increases in immunoglobulin M (IgM), IgG, IgA, IgG1, and IgG2 to Pn6B were observed. Infants reached adult levels of IgG1 anti-Pn6B after the primary injections. After the booster injection the infant groups had total IgG- and IgM-Pn6B antibody levels similar to those of adults. After the booster injection, IgG1 was the dominant infant anti-Pn6B isotype and at a level higher than in vaccinated adults, but IgA and IgG2 antibodies remained at very low levels. Opsonic activity increased significantly after Pn6B-TT injections; the highest infant sera showed opsonic activity comparable to that of vaccinated adults. Overall, opsonic activity correlated best with total and IgG anti-Pn6B antibodies (r = 0.741, r = 0.653, respectively; n = 35) and was highest in sera with high levels of all Pn6B antibody isotypes. The results indicate the protective potential of a pneumococcal 6B polysaccharide protein conjugate vaccine for young infants. C1 Natl Univ Hosp Reykjavik, Dept Immunol, Reykjavik Community Hlth Ctr, IS-101 Reykjavik, Iceland. Natl Univ Hosp Reykjavik, Dept Pediat, Reykjavik Community Hlth Ctr, IS-101 Reykjavik, Iceland. Natl Univ Hosp Reykjavik, Dept Microbiol, Reykjavik Community Hlth Ctr, IS-101 Reykjavik, Iceland. Reykjavik Hosp, Dept Med, Reykjavik, Iceland. SUNY, New York, NY USA. NICHD, Bethesda, MD USA. RP Jonsdottir I (reprint author), Natl Univ Hosp Reykjavik, Dept Immunol, Reykjavik Community Hlth Ctr, IS-101 Reykjavik, Iceland. EM ingileif@rsp.is RI Vidarsson, Gestur/A-9909-2009 OI Vidarsson, Gestur/0000-0001-5621-003X NR 39 TC 51 Z9 54 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD JUN PY 1998 VL 66 IS 6 BP 2866 EP 2870 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA ZP714 UT WOS:000073781100067 PM 9596761 ER PT J AU Huang, XZ Tall, B Schwan, WR Kopecko, DJ AF Huang, XZ Tall, B Schwan, WR Kopecko, DJ TI Physical limitations on Salmonella typhi entry into cultured human intestinal epithelial cells SO INFECTION AND IMMUNITY LA English DT Article ID TYPHIMURIUM INVASION; ESCHERICHIA-COLI; MAMMALIAN-CELLS; IPA PROTEINS; GROWTH-PHASE; HELA-CELLS; GIFU 10007; BACTERIA; PENETRATION; MACROPINOCYTOSIS AB Kinetic studies of Salmonella typhi invasion of LNT407 cells at different multiplicities of infection (MOIs) have revealed a strict physical limitation on S. typhi entry at MOIs of greater than or equal to 40. Staining of infected monolayers to distinguish intracellular from extracellular bacteria revealed that all monolayer cells are susceptible to infection and that internalized bacteria are typically contained in one to three separate clusters per cell during the first 60 min. Scanning and transmission electron microscopic analyses of time course-infected monolayers showed that at early times postinfection, bacteria bind to shortened, coalesced microvilli in one to three focal aggregate structures per host cell surface. As reported previously for S. typhimurium, focal aggregates progress to conical membrane ruffles that appear to engulf one or a few centrally contained S. typhi cells by a macro-pinocytic process, which enhanced the entry of simultaneously added Escherichia coli HB101 about 30-fold. Additionally, kinetic studies showed that at an MOI of similar or equal to 400, maximal S. typhi entry is virtually completed within 30 to 35 min. Monolayers pretreated with S. typhi for 30 min to saturate the entry process were severely reduced in the ability to internalize subsequently added kanamycin-resistant strains of S. typhi or S. typhimurium, but E. coli HB101(pRI203) expressing the cloned Yersinia inv gene was not reduced in entry. In invasion inhibition assays, anti-beta 1 integrin antibodies markedly reduced E. coli HB101(pRI203) invasion efficiency but did not reduce S. typhi entry. Collectively, these data provide direct physical and visual evidence which indicates that S. typhi organisms are internalized at a limited number (i.e., two to four) of sites on host cells. S. typhi and S. typhimurium likely share INT407 cell entry receptors which do not appear to be members of the beta 1 integrin superfamily. C1 US FDA, Ctr Biol Evaluat & Res, Lab Enter & STDs, HFM 440, Bethesda, MD 20892 USA. US FDA, Ctr Food Safety & Appl Nutr, Div Microbiol Studies, Washington, DC 20204 USA. RP Kopecko, DJ (reprint author), US FDA, Ctr Biol Evaluat & Res, Lab Enter & STDs, HFM 440, Bldg 29,NIH Campus, Bethesda, MD 20892 USA. OI Tall, Ben/0000-0003-0399-3629 NR 46 TC 24 Z9 24 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 JUN PY 1998 VL 66 IS 6 BP 2928 EP 2937 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA ZP714 UT WOS:000073781100075 PM 9596769 ER PT J AU Qoronfleh, MW Bortner, CA Schwartzberg, P Wilkinson, BJ AF Qoronfleh, MW Bortner, CA Schwartzberg, P Wilkinson, BJ TI Enhanced levels of Staphylococcus aureus stress protein GroEL and DnaK homologs early in infection of human epithelial cells SO INFECTION AND IMMUNITY LA English DT Article ID HEAT-SHOCK PROTEIN; CHLAMYDIA-TRACHOMATIS; BORRELIA-BURGDORFERI; SALMONELLA-TYPHIMURIUM; 60-KILODALTON ANTIGEN; BACTERIAL ADHERENCE; ESCHERICHIA-COLI; HELA-CELLS; EXPRESSION; INVASION AB Antibodies to Staphylococcus aureus heat shock proteins (Hsps) are present in the sera of patients with S. aureus endocarditis (M. W. Qoronfleh, W. Weraarchakul, and B. J. Wilkinson, Infect. Immun. 61:1567-1570, 1993). Although these proteins are immunogenic, their role in infection has not been established. We developed a cell culture system as a model to examine the potential involvement of staphylococcal Hsps in the initial events of infection. This study supports a model in which a clinical endocarditis isolate responds to host cell signals by selectively regulating the synthesis of numerous proteins, including the stress proteins Hsp60 (GroEL homolog) and Hsp70 (DnaK homolog) and a unique 58-kDa protein. C1 NCI, SAIC Frederick, Frederick Canc Res & Dev Ctr, Struct Biochem Program SBP, Frederick, MD 21702 USA. York Hosp, Dept Res, York, PA 17405 USA. Philadelphia Coll Osteopath Med, Dept Microbiol, Philadelphia, PA 19131 USA. Illinois State Univ, Dept Sci Biol, Microbiol Grp, Normal, IL 61790 USA. RP Qoronfleh, MW (reprint author), NCI, SAIC Frederick, Frederick Canc Res & Dev Ctr, Struct Biochem Program SBP, Bldg 320,POB B, Frederick, MD 21702 USA. NR 39 TC 20 Z9 20 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 JUN PY 1998 VL 66 IS 6 BP 3024 EP 3027 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA ZP714 UT WOS:000073781100092 PM 9596786 ER PT J AU Moore, TA Nutman, TB AF Moore, TA Nutman, TB TI Eosinophilia in the returning traveler SO INFECTIOUS DISEASE CLINICS OF NORTH AMERICA LA English DT Article ID NECATOR-AMERICANUS; STRONGYLOIDES-STERCORALIS; MAZZOTTI REACTION; HUMAN VOLUNTEERS; ENDEMIC REGIONS; EX-PRISONERS; INFECTION; SCHISTOSOMIASIS; FILARIASIS; TROPICS AB Eosinophilia is one of the most common laboratory abnormalities seen in the returning traveler. Although elevations in peripheral eosinophil levels can occur in a wide variety of disease processes, worldwide, helminth parasites are the major group of infectious agents responsible for eosinophilia. While often directed at helminth infections in their early stages of clinical evolution, the approach to the evaluation of the returning traveler with eosinophilia must consider the many causes of eosinophilia including those not casually related to travel. This article reviews the major parasitic causes of eosinophilia and provides a systematic approach to the evaluation of eosinophilia following travel. C1 NIAID, Parasit Dis Lab, NIH, Helminth Immunol Sect, Bethesda, MD 20892 USA. RP Nutman, TB (reprint author), NIAID, Parasit Dis Lab, NIH, Helminth Immunol Sect, 9000 Rockville Pike,Bldg 4,Room 126, Bethesda, MD 20892 USA. NR 81 TC 25 Z9 27 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 0891-5520 J9 INFECT DIS CLIN N AM JI Infect. Dis. Clin. North Am. PD JUN PY 1998 VL 12 IS 2 BP 503 EP + DI 10.1016/S0891-5520(05)70016-7 PG 21 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA ZZ605 UT WOS:000074746900015 PM 9658256 ER PT J AU Yi, ES Salgado, M Williams, S Kim, SJ Masliah, E Yin, SM Ulich, TR AF Yi, ES Salgado, M Williams, S Kim, SJ Masliah, E Yin, SM Ulich, TR TI Keratinocyte growth factor decreases pulmonary edema, transforming growth factor-beta and platelet-derived growth factor-BB expression, and alveolar type II cell loss in bleomycin-induced lung injury SO INFLAMMATION LA English DT Article ID KDA PROTEIN CC10; IN-VIVO; MESSENGER-RNA; RATS; FIBROSIS; PROLIFERATION; INSTILLATION; PNEUMOCYTES; MORTALITY; ENDOTOXIN AB Keratinocyte growth factor (KGF), a potent growth factor for type II pneumocytes and Clara cells, has been shown to prevent the end-stage pulmonary fibrosis and mortality in a rat model of bleomycin-induced lung injury. In this study, protective effects of KGF were explored during the earlier course of bleomycin-induced lung injury by studying protein exudation in alveolar edema fluids, pulmonary expression of transforming growth factor-beta (TGF beta) and platelet-derived growth factor-BE (PDGF-BB), and changes in type II pneumocytes and Clara cells after i.t. (intratracheal) bleomycin injection following KGF- or saline-pretreatment in rats. Total protein in bronchoalveolar lavage (BAL) fluids after bleomycin injury from KGF-pretreated rats was significantly lower than the levels in saline-pretreated rats. TGF beta protein in BAL fluids which peaked at day 3 after i.t. bleomycin in saline-pretreated lungs was not significantly increased at any time points in KGF-pretreated rats. PDGF-BB protein in whole lung tissues of KGF-pretreated rats also remained near normal throughout the course after i.t. bleomycin, in contrast to the significant increase in saline-pretreated rats. Numbers of type II, pneumocytes and Clara cells in KGF-pretreated lungs after a high dose of bleomycin were close to the normal in intact lungs. At the same dose of bleomycin injury, type II pneumocytes in saline-pretreated lungs were markedly decreased, while the number of Clara cells in these rats was relatively preserved as the pre-injury level. In conclusion, KGF prevents bleomycin-induced end-stage pulmonary injury and mortality probably at least partly by decreasing protein-rich pulmonary edema, protein expression of fibrogenic cytokines TGF beta and PDGF-BB, and type II cell loss during the course of lung injury. C1 Univ Calif San Diego, Sch Med, Dept Pathol, San Diego, CA 92103 USA. NCI, Chemoprevent Lab, Bethesda, MD 20892 USA. Amgen Inc, Thousand Oaks, CA 91320 USA. RP Yi, ES (reprint author), Univ Calif San Diego, Sch Med, Dept Pathol, San Diego, CA 92103 USA. NR 37 TC 52 Z9 56 U1 0 U2 3 PU PLENUM PUBL CORP PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0360-3997 J9 INFLAMMATION JI Inflammation PD JUN PY 1998 VL 22 IS 3 BP 315 EP 325 DI 10.1023/A:1022304317111 PG 11 WC Cell Biology; Immunology SC Cell Biology; Immunology GA ZM617 UT WOS:000073558100007 PM 9604718 ER PT J AU Yu, X Abe, R Hodes, RJ AF Yu, X Abe, R Hodes, RJ TI The role of B7-CD28 co-stimulation in tumor rejection SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE B7-1; B7-2; CD80; CD86; EL4 ID B7-2 COSTIMULATORY MOLECULES; T-CELLS; ANTITUMOR IMMUNITY; INDUCTION; EXPRESSION; CTLA-4; CD80; CD28; ACTIVATION; RESPONSES AB The role of B7 co-stimulatory signaling in in vivo tumor rejection remains incompletely characterized. In particular, the relative competence of B7-1 (CD80) and B7-2 (CD86) to provide effective co-stimulus is not well defined, and the identification of the T cell co-stimulatory receptor that mediates B7 co-stimulation in tumor rejection has not been addressed. These issues were studied by assessing rejection of B7-negative or B7-transfected tumor cells in CD28-expressing or CD28-deficient hosts. B7-negative EL4 tumor cells grew progressively in normal syngeneic C57BL/6 (B6) mice. In contrast EL4 cells transfected with either full length B7-1 or full length B7-2 were rejected, indicating that both B7-1 and B7-2 are competent to mediate rejection of EL4 tumor cells. Expression of truncated B7-1 or B7-2 products, with complete deletion of cytoplasmic domains, was as effective as expression of full length B7-1 or B7-2 in mediating rejection. In contrast to the rejection of B7-transfected EL4 cells observed in CD28-expressing syngeneic hosts, B7-1- and B7-2-positive EL4 cells as well as control EL4 cells grew progressively in CDP8-deficient mice, demonstrating the requirement for host expression of CD28 in B7-mediated tumor rejection. These results indicate that interaction of host CD28 with co-stimulatory extracellular B7-1 or B7-2 ligands expressed on tumor cells can play a necessary role in mediating tumor rejection. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NIA, NIH, Bethesda, MD 20892 USA. USN, Med Res Inst, Immune Cell Biol Program, Bethesda, MD 20889 USA. RP Yu, X (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B10, Bethesda, MD 20892 USA. NR 32 TC 25 Z9 28 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD JUN PY 1998 VL 10 IS 6 BP 791 EP 797 DI 10.1093/intimm/10.6.791 PG 7 WC Immunology SC Immunology GA ZW523 UT WOS:000074419500010 PM 9678760 ER PT J AU Rizzo, LV Xu, H Chan, CC Wiggert, B Caspi, RR AF Rizzo, LV Xu, H Chan, CC Wiggert, B Caspi, RR TI IL-10 has a protective role in experimental autoimmune uveoretinitis SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE experimental autoimmune uveoretinitis; IL-10 ID NONOBESE DIABETIC MICE; RETINOID-BINDING PROTEIN; MESSENGER-RNA EXPRESSION; CYTOKINE PRODUCTION; INTERLEUKIN-10; ENCEPHALOMYELITIS; RATS; INDUCTION; ARTHRITIS; PREVENTS AB The role of IL-10 in the regulation of ocular autoimmune disease was studied in experimental autoimmune uveoretinitis (EAU) elicited in mice by immunization with the retinal antigen interphotoreceptor retinoid binding protein. IL-10-deficient mice were susceptible to EAU, indicating that pathogenesis can occur without presence of IL-10, Treatment of normal mice with IL-10 for 5 days after uveitogenic immunization ameliorated subsequent EAU scores, and downregulated antigen-specific production of tumor necrosis factor-alpha and IFN-gamma. A concomitant treatment with IL-4 further reduced disease, and resulted in emergence of antigen-specific IL-4 and IL-10 production, as well as in enhancement of the IgG1 antibody isotype, IL-4 by itself was not protective. Only IL-10, but not IL-4, was able to inhibit the function of differentiated uveitogenic T cells in culture. Expression of mRNA for T(h)1 and T(h)2 cytokines in the eye during the course of EAU showed that while a T(h)1 pattern predominated early, IL-10 mRNA expression coincided with down-regulation of the T(h)1 response and resolution of EAU, Systemic neutralization of IL-10 during the expression phase of EAU resulted in elevated disease scores. Our results suggest that endogenous IL-10 limits expression of EAU and may play a role in the natural resolution of disease. The data further suggest that exogenous IL-10 may be useful in therapeutic control of autoimmune uveitis, While IL-10 by itself is sufficient to suppress T(h)1 effector development and function, a concomitant administration of IL-4 is required to shift the autoimmune response towards a non-pathogenic T(h)2 pathway. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr MSC 1857, Bethesda, MD 20892 USA. RI Rizzo, Luiz Vicente/B-4458-2009 NR 32 TC 89 Z9 94 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD JUN PY 1998 VL 10 IS 6 BP 807 EP 814 DI 10.1093/intimm/10.6.807 PG 8 WC Immunology SC Immunology GA ZW523 UT WOS:000074419500012 PM 9678762 ER PT J AU Wang, JM Su, S Gong, W Oppenheim, JJ AF Wang, JM Su, S Gong, W Oppenheim, JJ TI Chemokines, receptors, and their role in cardiovascular pathology SO INTERNATIONAL JOURNAL OF CLINICAL & LABORATORY RESEARCH LA English DT Review DE chemokines; receptors; atherosclerosis; reperfusion ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; SMOOTH-MUSCLE CELLS; NEUTROPHIL CHEMOTACTIC FACTOR; LOW-DENSITY-LIPOPROTEIN; ENDOTHELIAL-CELLS; INFLAMMATORY RESPONSE; HIV-1 INFECTION; GENE-EXPRESSION; INTERLEUKIN-8; IL-1 AB A superfamily of leukocyte chemotactic proteins, known as chemokines, has been identified during the past decade. Chemokines selectively attract and activate different leukocyte subpopulations and are key mediators of a variety of patho-physiological states, including hematopoiesis, inflammation, infection, allergy, atheroslerosis, reperfusion injury, as well as malignant tumors. Chemokines bind and activate a number of specific or promiscuous, G-protein-coupled seven-transmembrane receptors. Some of these receptors are utilized by human immunodeficiency virus type 1 as essential fusion co-factors. Further understanding of the role of chemokines and their receptors in host defense will help develop means by which the beneficial versus detrimental effects of these molecules can be balanced. C1 NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Div Basic Sci, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. RP Wang, JM (reprint author), NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Div Basic Sci, Bldg 560,Room 31-19, Frederick, MD 21702 USA. NR 60 TC 38 Z9 39 U1 0 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0940-5437 J9 INT J CLIN LAB RES JI Int. J. Clin. Lab. Res. PD JUN PY 1998 VL 28 IS 2 BP 83 EP 90 DI 10.1007/s005990050024 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA ZX645 UT WOS:000074539300002 PM 9689548 ER PT J AU Weed, DL McKeown, RE AF Weed, DL McKeown, RE TI Epidemiology and virtue ethics SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article ID SCIENTIFIC MISCONDUCT; DISEASE PREVENTION; CAUSAL INFERENCE; PUBLIC-HEALTH; SCIENCE; DEFINITION; INTEGRITY; PRUDENCE; FUTURE C1 NCI, Prevent Oncol Branch, Bethesda, MD 20892 USA. Univ S Carolina, Sch Publ Hlth, Ctr Bioeth, Columbia, SC 29208 USA. RP Weed, DL (reprint author), NCI, Prevent Oncol Branch, EPS T-41,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 61 TC 26 Z9 26 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 1998 VL 27 IS 3 BP 343 EP 348 DI 10.1093/ije/27.3.343 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 100CD UT WOS:000074795600001 PM 9698118 ER PT J AU Godwin, DA Player, MR Sowell, JW Michniak, BB AF Godwin, DA Player, MR Sowell, JW Michniak, BB TI Synthesis and investigation of urea compounds as transdermal penetration enhancers SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE transdermal drug delivery; ureas; hairless mouse; percutaneous penetration; hydrocortisone; skin retention ID IN-VITRO EVALUATION; AZONE ANALOGS; PERCUTANEOUS PENETRATION; PYRROLIDONE DERIVATIVES; HUMAN-SKIN; SERIES; HYDROCORTISONE; INDOMETHACIN; PERMEATION; DELIVERY AB Twelve urea and thiourea compounds were examined for their transdermal penetration enhancing properties in vitro using hairless mouse skin and hydrocortisone as a model drug. Skins were pretreated for 1 h with the enhancer in propylene glycol before application of the drug also in propylene glycol. Enhancement ratios (ER) were calculated for permeability coefficient (P), 24 h receptor concentration (Q(24)), and skin content of drug (SC) and compared to control values (no enhancer present). Control values for permeability coefficients were 0.71 +/- 0.27 cm h(-1), 24 h receptor concentration: 11.9 +/- 3.4 mu M, and skin content of drug 44.6 +/- 18.5 mu g g(-1). The most effective enhancer of the series was 1-dodecyl-3-methylthiourea. This enhancer produced the highest values for all three penetration parameters with a permeability coefficient 4.7 +/- 1.8 x 10(-4) cm h(-1) (ERp 6.6), a 24 h receptor concentration of 62.7 +/- 16.3 mu M (ERQ(024) 5.3), and a skin content of 90.1 +/- 17.7 mu g g(-1) (ERSC 2.0). A structure-activity relationship was observed in that the thio-substituted analogs were more effective enhancers than the; oxygen-containing compounds. Although these compounds show promise as penetration enhancers, further study is needed to determine their effectiveness with other drugs and their irritation potential. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Univ New Mexico, Coll Pharm, Hlth Sci Ctr, Dept Basic Pharmaceut Sci, Albuquerque, NM 87131 USA. NIDDKD, Med Chem Lab, Sect Biomed Chem, NIH, Bethesda, MD 20892 USA. Univ S Carolina, Coll Pharm, Dept Basic Pharmaceut Sci, Columbia, SC 29208 USA. RP Godwin, DA (reprint author), Univ New Mexico, Coll Pharm, Hlth Sci Ctr, Dept Basic Pharmaceut Sci, Albuquerque, NM 87131 USA. EM dgodwin@unm.edu NR 34 TC 20 Z9 22 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 J9 INT J PHARM JI Int. J. Pharm. PD JUN 1 PY 1998 VL 167 IS 1-2 BP 165 EP 175 DI 10.1016/S0378-5173(98)00060-X PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 104YB UT WOS:000075043400017 ER PT J AU Organisciak, DT Darrow, RM Barsalou, L Darrow, RA Krishnan, RK Kutty, G Wiggert, B AF Organisciak, DT Darrow, RM Barsalou, L Darrow, RA Krishnan, RK Kutty, G Wiggert, B TI Light history and age-related changes in retinal light damage SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article; Proceedings Paper CT 67th Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 21-26, 1996 CL FT LAUDERDALE, FLORIDA SP Assoc Res Vis & Ophthalmol ID RAT RETINA; PHOTORECEPTOR DEGENERATION; PHOTIC INJURY; VISIBLE-LIGHT; LIQUID-CHROMATOGRAPHY; MACULAR DEGENERATION; ASCORBIC-ACID; ALBINO-RATS; AMELIORATION; ANTIOXIDANTS AB PURPOSE. To determine the effects of age and long-term light-or dark-rearing environments on acute, intense-light-mediated retinal degeneration. METHODS. Male albino rats were maintained in a dim cyclic light environment or in darkness for as long as 1 year. When aged 2, 4, 8, and 12 months, some rats were given the synthetic antioxidant dimethylthiourea (DMTU) by intraperitoneal injection and were exposed to intense visible light for as long as 24 hours. Uninjected control rats were exposed to light at the same time. Other rats were treated with light Of lower intensity for various periods. Two weeks after intense-light treatment, photoreceptor cell degeneration was estimated by determining the level of rhodopsin and by measuring the content of photoreceptor cell DNA. Light-induced changes in retinal DNA were analyzed immediately after exposure by neutral gel electrophoresis and by 8-hydroxy-deoxyguanosine measurements. Expression of the antioxidative stress protein heme oxygenase-1 (HO-1) was determined by not-them blot analysis of mRNA in retinal extracts. RESULTS. At all ages, rats reared in cyclic dim-light conditions had lower rhodopsin levels than did rats reared in darkness; photoreceptor cell DNA levels were unaffected by the rearing environment. Senescent losses in rhodopsin and retinal DNA were significant after rats were 12 months old. Dim-light-reared rats exhibited an age-related increase in retinal light damage susceptibility, whereas dark-reared rats were equally susceptible to damage at all ages. In both types of rats, the mechanism of light-induced cell death involved an apoptotic process, visualized by the pattern of DNA fragments on electrophoretic gels. The process also induced the expression of HO-1 mRNA. Photoreceptor cell loss determined by biochemical measurement, DNA fragmentation, and HO-1 induction were dramatically reduced by the administration of DMTU. CONCLUSIONS. The age-related increase in susceptibility to retinal light damage in rats is influenced by their long-term daily light history. Decreasing retinal irradiance by dark-rearing eliminates the age-related increase in light damage, suggesting a correlation between light environment and retinal gene expression associated with damage. In all rats, retinal light damage resulted in a pattern of DNA. fragmentation consistent with apoptotic cell death and in an increased expression of HO-1 mRNA. Antioxidant treatment greatly reduced apoptosis and HO-1 expression. This indicates that light damage involves an oxidative process that may also trigger apoptosis in the retina. The sat aging model may provide useful insights into the role of light environment associated with retinal degeneration in an aging human population. C1 Wright State Univ, Dept Biochem & Mol Biol, Sch Med, Dayton, OH 45435 USA. Wright State Univ, Dept Ophthalmol, Sch Med, Dayton, OH 45435 USA. NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Wright State Univ, Petticrew Res Lab, Sch Med, Dayton, OH 45435 USA. RP Organisciak, DT (reprint author), Wright State Univ, Dept Biochem & Mol Biol, Sch Med, 3640 Colonel Glenn Highway, Dayton, OH 45435 USA. FU NEI NIH HHS [EY1959] NR 47 TC 95 Z9 110 U1 1 U2 7 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUN PY 1998 VL 39 IS 7 BP 1107 EP 1116 PG 10 WC Ophthalmology SC Ophthalmology GA ZQ631 UT WOS:000073887400005 PM 9620069 ER PT J AU Contopoulos-Ioannidis, DG Ioannidis, JPA AF Contopoulos-Ioannidis, DG Ioannidis, JPA TI Maternal cell-free viremia in the natural history of perinatal HIV-1 transmission - A meta-analysis SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY LA English DT Article DE perinatal transmission; HIV-1; viral load; meta-analysis; ROC curves; SROC curves ID IMMUNODEFICIENCY-VIRUS TYPE-1; TO-CHILD TRANSMISSION; VIRAL LOAD; ZIDOVUDINE TREATMENT; INFANT TRANSMISSION; DIAGNOSTIC-TEST; INFECTION; RISK; ACCURACY AB We performed a meta-analysis of the predictive value of maternal cell-free viral load in vertical HIV-1 transmission, including 9 cohorts with 1115 mother-infant pairs (696 untreated and 419 treated women). The pooled rate of transmission in untreated women was 21.3% (95% confidence interval [CI], 18.3%-24.5%). The rates of transmission for untreated women in the <1000 copies/ml, 1000 to 9999 copies/ml, and greater than or equal to 10,000 copies/ml categories were 5% (95% CI, 2%-11%), 15% (95% CI, 11%-20%) and 37% (95% CI, 29%-46% by random effects), respectively. The area under the receiver operating characteristic (ROC) curve in individual studies ranged from 0.67 to 1.00. The predictive performance of RNA differed between cohorts in which different percentages of transmitters had RNA values >10,000 copies/ml. When 95% of transmitters have RNA values >1000 copies/ml, 77% of nontransmitters would also have values above this cutoff Transmission rates for treated women in the 1000 to 9999 copies/ml category (7%; 95% CI, 4%-11%,) and greater than or equal to 10,000 copies/ml category (18%; 95% CI, 12%-27%) were probably lower than those for untreated women, whereas the transmission rate for treated women with <1000 copies/ml was 5% (95% CI, 2%-11%). Thus, the risk gradient between RNA categories seems attenuated in treated women. Several aspects of the design, analysis, and reporting of research in this area may be improved in the future with attention to selection and observer biases, multivariate adjustment, and technical consistency. Maternal HIV-1 RNA is a modest predictor of transmission for individual mothers, but a strong predictor of the average risk in groups of untreated mothers. Its discriminatory power is better in untreated than in treated populations and is better in cohorts with a high prevalence of elevated viral load values than in cohorts with generally low levels of viremia. C1 NIAID, HIV Res Branch, Div Aids, NIH, Bethesda, MD 20892 USA. George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Pediat Infect Dis, Washington, DC USA. RP Ioannidis, JPA (reprint author), NIAID, HIV Res Branch, Div Aids, NIH, Solar Bldg,Room 2C31,6003 Execut Blvd, Bethesda, MD 20892 USA. EM ji24m@nih.gov RI Ioannidis, John/G-9836-2011 NR 39 TC 40 Z9 40 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 1077-9450 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. PD JUN 1 PY 1998 VL 18 IS 2 BP 126 EP 135 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA ZU166 UT WOS:000074168900004 PM 9637577 ER PT J AU O'Brien, TR Rosenberg, PS Yellin, F Goedert, JJ AF O'Brien, TR Rosenberg, PS Yellin, F Goedert, JJ TI Longitudinal HIV-1 RNA levels in a cohort of homosexual men SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY LA English DT Article DE longitudinal HIV-1; RNA levels; homosexual men; AIDS; epidemiology ID HUMAN-IMMUNODEFICIENCY-VIRUS; INFECTION; PLASMA; QUANTITATION; VIREMIA; CELLS; TIME; AIDS; PCR AB HIV-1 RNA levels measured during early chronic infection strongly prediet subsequent clinical events. In the short term, HIV-I is in a steady stale, but the stability of viral levels over time is incompletely understood. We used reverse transcriptase polymerase chain reaction (RT-PCR) to examine changes in serum HIV-I RNA levels in 111 HIV-l-infected homosexual men during the period from 1982 to 1992 and their relation to clinical outcomes. HIV-I RNA levels increased by a median of 0.08 log(10) copieslmliyear (p = .0001). HIV-1 RNA levels rose either gradually or abruptly for the majority of subjects; 41% had no increase. Among subjects surviving at least 8 years, HIV-1 RNA was stable during the first 4 years after seroconversion (median, 0.00 log(10) copies/ml/year), but rose in years five through eight (median, 0.06 log(10) copies/ml/year; p = .04). The annual HIV-1 RNA level was more predictive of AIDS (relative hazard [RH], 1.75 per 0.5 log difference; 95% confidence interval [CI], 1.38-2.21; likelihood ratio [LR], 26.2) than the initial level alone (RH, 1.39; 95% CI, 1.10-1.76; LR, 8.5). We conclude that most HIV-1-infected persons lack a long-term viral setpoint and that failure to account for evolution of the viral level can lead to underestimation of the risk of progression. C1 NCI, Viral Epidemiol Branch, Publ Hlth Serv, US Dept Hlth & Human Serv, Rockville, MD 20852 USA. NCI, Biostat Branch, Rockville, MD 20852 USA. Comp Sci Corp, Cincinnati, OH 45202 USA. RP O'Brien, TR (reprint author), NCI, Viral Epidemiol Branch, Publ Hlth Serv, US Dept Hlth & Human Serv, EPN 434,6130 Execut Blvd, Rockville, MD 20852 USA. NR 22 TC 54 Z9 54 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 1077-9450 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. PD JUN 1 PY 1998 VL 18 IS 2 BP 155 EP 161 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA ZU166 UT WOS:000074168900007 PM 9637580 ER PT J AU Halbur, PG Rothschild, MF Thacker, BJ Meng, XJ Paul, PS Bruna, JD AF Halbur, PG Rothschild, MF Thacker, BJ Meng, XJ Paul, PS Bruna, JD TI Differences in susceptibility of Duroc, Hampshire, and Meishan pigs to infection with a high virulence strain (VR2385) of porcine reproductive and respiratory syndrome virus (PRRSV) SO JOURNAL OF ANIMAL BREEDING AND GENETICS-ZEITSCHRIFT FUR TIERZUCHTUNG UND ZUCHTUNGSBIOLOGIE LA English DT Article ID ISOLATE ATCC VR-2332; LELYSTAD-VIRUS; SWINE INFERTILITY; DISEASE; PATHOGENICITY; PATHOGENESIS; FETUSES; ANTIGEN; SOWS AB The objective of this research was to determine if there is genetic influence on the resistance or susceptibility to PRRSV-induced disease and lesions. Pigs of three breeds from two or three litters per ere randomly assigned to treatment or control groups. Treatment consisted of inoculation with a well characterized, high virulence strain (VR2385) of PRRSV. Duroc, Hampshire, and Meishan pigs were weaned at 9-10 days of age and inoculated with PRRSV at 22-38 days of age. Animals were housed and cared for according to approved animal use and care standards. Pigs were inoculated intranasally with 5 ml of cell culture media containing 10(5.8) S TCID50 of PRRSV VR2385. Controls were mock-infected. Clinical disease scores and rectal temperatures were recorded daily. Macroscopic lesion scores were estimated at necropsy at 10 days post inoculation. All organ systems were examined microscopically in a blinded fashion. Serum antibody response was measured by an indirect immunofluorescence assay. Hampshire pigs had significantly more severe macroscopic lung lesion scores (43.0 +/- 3.7) than Duroc (29.43 +/- 3.3) or Meishan (25.0 +/- 3.5) plgs. Meishan pigs had significantly less PRRSV antigen detected in the lungs. Significantly more Meishan plgs had myocarditis and encephalitis. Duroc plgs had significantly lower normalized serum antibody titres to PRRSV. Differences in severity and distribution of PRRSV-induced lesions, and in normalized serum antibody response to PRRSV may be in part influenced by pig genetic factors. The ability to select animals which are less susceptible to the devastating consequences of PRRSV infection would be of tremendous value to the swine industry. C1 Iowa State Univ, Coll Vet Med, Vet Diagnost Lab, Ames, IA 50011 USA. Iowa State Univ, Dept Anim Sci, Ames, IA 50011 USA. NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Halbur, PG (reprint author), Iowa State Univ, Coll Vet Med, Vet Diagnost Lab, Ames, IA 50011 USA. RI Meng, X.J./B-8769-2009 OI Meng, X.J./0000-0002-2739-1334 NR 29 TC 58 Z9 61 U1 0 U2 3 PU BLACKWELL WISSENSCHAFTS-VERLAG GMBH PI BERLIN PA KURFURSTENDAMM 57, D-10707 BERLIN, GERMANY SN 0931-2668 J9 J ANIM BREED GENET JI J. Anim. Breed. Genet.-Z. Tierz. Zungt. Biol. PD JUN PY 1998 VL 115 IS 3 BP 181 EP 189 PG 9 WC Agriculture, Dairy & Animal Science SC Agriculture GA ZU731 UT WOS:000074228800002 ER PT J AU Rosen, MJ Sorkin, JD Goldberg, AP Hagberg, JM Katzel, LI AF Rosen, MJ Sorkin, JD Goldberg, AP Hagberg, JM Katzel, LI TI Predictors of age-associated decline in maximal aerobic capacity: A comparison of four statistical models SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE exercise; heteroscedasticity; weighted least squares; loglinear model; ratio ID BODY-SIZE; EXERCISE; MEN; VO2MAX; RATIOS; WOMEN AB Studies assessing changes in maximal aerobic capacity (V(over dot)O-2max) associated with aging have traditionally employed the ratio of V(over dot)O-2max to body weight. Log-linear, ordinary least-squares, and weighted least-squares models may avoid some of the inherent weaknesses associated with the use of ratios. In this study we used four different methods to examine the age-associated decline in V(over dot)O-2max in a cross-sectional sample of 276 healthy men, aged 45-80 yr. Sixty-one of the men were aerobically trained athletes, and the remainder were sedentary. The model that accounted for the largest proportion of variance was a weighted least-squares model that included age, fat-free mass, and an indicator variable denoting exercise training status. The model accounted for 66% of the variance in V(over dot)O-2max and satisfied all the important general linear model assumptions. The other approaches failed to satisfy one or more of these assumptions. The results indicated that V(over dot)O-2max declines at the same rate in athletic and sedentary men (0.24 l/min or 9%/decade) and that 35% of this decline (0.08 l.min(-1).decade(-1)) is due to the age-associated loss of fat-free mass. C1 Univ Maryland, Dept Med, Div Gerontol, College Pk, MD 20742 USA. Baltimore Vet Affairs Med Ctr, Geriatr Serv, Ctr Geriatr Res Educ & Clin, Baltimore, MD 21201 USA. NIA, Clin Invest Lab, Metab Sect, Baltimore, MD 21224 USA. Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. RP Rosen, MJ (reprint author), 42 Haymkt Ln, Bryn Mawr, PA 19010 USA. FU NIA NIH HHS [R01-AG-07660, K07-AG-00608, P01-AG-04402] NR 35 TC 39 Z9 40 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD JUN PY 1998 VL 84 IS 6 BP 2163 EP 2170 PG 8 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA ZR297 UT WOS:000073960000042 PM 9609813 ER PT J AU Tsai, HF Chang, YC Washburn, RG Wheeler, MH Kwon-Chung, KJ AF Tsai, HF Chang, YC Washburn, RG Wheeler, MH Kwon-Chung, KJ TI The developmentally regulated alb1 gene of Aspergillus fumigatus: Its role in modulation of conidial morphology and virulence SO JOURNAL OF BACTERIOLOGY LA English DT Article ID INVASIVE PULMONARY ASPERGILLOSIS; ACID SYNTHASE GENE; NIDULANS WA-GENE; CRYPTOCOCCUS-NEOFORMANS; POLYKETIDE SYNTHASE; MELANIN BIOSYNTHESIS; COLLETOTRICHUM-LAGENARIUM; ALKALINE PROTEASE; MOLECULAR CHARACTERIZATION; WANGIELLA-DERMATITIDIS AB Aspergillus fumigatus, an important opportunistic pathogen which commonly affects neutropenic patients, produces conidia with a bluish-green color. We identified a gene, alb1, which is required for conidial pigmentation. The alb1 gene encodes a putative polyketide synthase, and disruption of alb1 resulted in an albino conidial phenotype. Expression of alb1 is developmentally regulated, and the 7-kb transcript is detected only during the conidiation stage. The alb1 mutation was found to block 1,3,6,8-tetrahydroxynaphthalene production, indicating that alb1 is involved in dihydroxynaphthalene-melanin biosynthesis. Scanning electron microscopy studies showed that the alb1 disruptant exhibited a smooth conidial surface, whereas complementation of the alb1 deletion restored the echinulate wild-type surface. Disruption of alb1 resulted in a significant increase in C3 binding on conidial surfaces, and the conidia of the alb1 disruptant were ingested by human neutrophils at a higher rate than were those of the wild type. The alb1-complemented strain producing bluish-green conidia exhibited inefficient C3 binding and neutrophil-mediated phagocytosis quantitatively similar to those of the wild type. Importantly, the alb1 disruptant had a statistically significant loss of virulence compared to the wild-type and alb1-complemented strains in a murine model. These results suggest that disruption of alb1 causes pleiotropic effects on conidial morphology and fungal virulence. C1 NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Sch Med, Dept Internal Med, Infect Dis Sect, Winston Salem, NC 27006 USA. USDA ARS, Cotton Pathol Res Unit, So Crops Res Lab, College Stn, TX 77845 USA. RP Kwon-Chung, KJ (reprint author), NIAID, Clin Invest Lab, NIH, Bldg 10,Room 11C304,10 Ctr Dr,MSC 1882, Bethesda, MD 20892 USA. EM June_Kwon-Chung@NIH.GOV FU NIAID NIH HHS [AI-01036] NR 69 TC 210 Z9 229 U1 2 U2 9 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 JUN PY 1998 VL 180 IS 12 BP 3031 EP 3038 PG 8 WC Microbiology SC Microbiology GA ZT524 UT WOS:000074096500003 PM 9620950 ER PT J AU Lam, K Rao, VSR Qasba, PK AF Lam, K Rao, VSR Qasba, PK TI Molecular modeling studies on binding of bFGF to heparin and its receptor FGFR1 SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Article ID FIBROBLAST GROWTH-FACTOR; AFFINITY RECEPTORS; ENDOTHELIAL-CELLS; SULFATE; DIMERIZATION; MITOGENESIS; ACTIVATION; IDENTIFICATION; PROTEOGLYCANS; DOMAINS AB Sugar induced protein-protein interactions play an important role in several biological processes. The carbohydrate moieties of proteoglycans, the glycosaminoglycans, bind to growth factors with a high degree of specificity and induce interactions with growth factor receptors, thereby regulate the growth factor activity. We have used molecular modeling method to study the modes of binding of heparin or heparan sulfate proteoglycans (HSPGs) to bFGF that leads to the dimerization of FGF receptor 1 (FGFR1) and activation of receptor tyrosine kinase. Homology model of FGFR1 Ig D(II) D(III) domains was built to investigate the interactions between heparin, bFGF and FGFR1. The structural requirements to bridge the two monomeric bFGF molecules by heparin or HSPGs and to simulate the dimerization and activation of FGFR1 have been examined. A structural model of the biologically functional dimeric bFGF-heparin complex is proposed based on: (a) the stability of dimeric complex, (b) the favorable binding energies between heparin and 6FGF molecules, and (c) its accessibility to FGFR1. The modeled complex between heparin, bFGF and FGFR1 has a stoichiometry of 1 heparin: 2 bFGF: 2 FGFR1.The structural properties of the proposed model of bFGF/heparin/FGFR1 complex are consistent with the binding mechanism of FGF to its receptor, the receptor dimerization, and the reported site-specific mutagenesis and biochemical cross-linking data. In the proposed model heparin bridges the two bFGF monomers in a specific orientation and the resulting complex induces FGF receptor dimerization, suggesting that in the oligosaccharide induced recognition process sugars orient the molecules in a way that brings about specific protein-protein or protein-carbohydrate interactions. C1 NCI, Frederick Canc Res & Dev Ctr, Struct Glycobiol Sect, Lab Expt & Computat Biol, Frederick, MD 21702 USA. RP Qasba, PK (reprint author), NCI, Frederick Canc Res & Dev Ctr, Struct Glycobiol Sect, Lab Expt & Computat Biol, Frederick, MD 21702 USA. EM qasba@helix.nih.gov NR 37 TC 19 Z9 19 U1 0 U2 1 PU ADENINE PRESS INC PI GUILDERLAND PA PO BOX 355/340, GUILDERLAND, NY 12084 USA SN 0739-1102 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD JUN PY 1998 VL 15 IS 6 BP 1009 EP 1027 PG 19 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZV426 UT WOS:000074303400001 PM 9669548 ER PT J AU Mussolino, ME Looker, AC Madans, JH Langlois, JA Orwoll, ES AF Mussolino, ME Looker, AC Madans, JH Langlois, JA Orwoll, ES TI Risk factors for hip fracture in white men: The NHANES I Epidemiologic Follow-up Study SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article ID BONE-MINERAL DENSITY; RADIOGRAPHIC ABSORPTIOMETRY; DIETARY CALCIUM; SECULAR TRENDS; ELDERLY MEN; BLACK-WOMEN; WEIGHT; MASS; AGE; PREDICTION AB This prospective population-based study assessed predictors of hip fracture risk in white men, Participants were members of the Epidemiologic Follow-up Study cohort of the First National Health and Nutrition Examination Survey, a nationally representative sample of noninstitutionalized civilians who were followed for a maximum of 22 years, A cohort of 2879 white men (2249 in the nutrition and weight-loss subsample, 1437 in the bone density subsample) aged 45-74 years at baseline (1971-1975) were observed through 1992, Ninety-four percent of the original cohort were successfully traced. Hospital records and death certificates were used to identify a total of 71 hip fracture cases (61 in the nutrition and weight-loss subsample, 26 in the bone-density subsample), Among the factors evaluated were age at baseline, previous fractures other than hip, body mass index, smoking status, alcohol consumption, nonrecreational physical activity, weight loss from maximum, calcium intake, number of calories, protein consumption, chronic disease prevalence, and phalangeal bone density, The risk adjusted relative risk (RR) of hip fracture was significantly associated with presence of one or more chronic conditions (RR = 1.91, 95% confidence interval ICI] = 1.19-3.06), weight loss from maximum greater than or equal to 10% (RR = 2.27, 95% CI 1.13-4.59), and 1 SD change in phalangeal bone density (RR = 1.73, 95% CI 1.11-2.68), No other variables were significantly related to hip fracture risk Although based on a small number of cases, this is one of the first prospective studies to relate weight loss and bone density to hip fracture risk in men. C1 Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Epidemiol, Hyattsville, MD 20782 USA. NIA, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Portland VA Med Ctr, Portland, OR 97201 USA. RP Mussolino, ME (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Epidemiol, 6525 Belcrest Rd,Room 730, Hyattsville, MD 20782 USA. OI Orwoll, Eric/0000-0002-8520-7355 NR 56 TC 123 Z9 124 U1 0 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUN PY 1998 VL 13 IS 6 BP 918 EP 924 DI 10.1359/jbmr.1998.13.6.918 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZR283 UT WOS:000073958600002 PM 9626622 ER PT J AU Siegel, RM Martin, DA Zheng, LX Ng, SY Bertin, J Cohen, J Lenardo, MJ AF Siegel, RM Martin, DA Zheng, LX Ng, SY Bertin, J Cohen, J Lenardo, MJ TI Death-effector filaments: Novel cytoplasmic structures that recruit caspases and trigger apoptosis SO JOURNAL OF CELL BIOLOGY LA English DT Article ID SIGNALING COMPLEX; FAS; PROTEASE; CYTOTOXICITY; AUTOIMMUNITY; RECEPTOR; PATHWAYS; PROTEINS; MODEL AB The death-effector domain (DED) is a critical protein interaction domain that recruits caspases into complexes with members of the TNF-receptor superfamily. Apoptosis can also be induced by expressing certain DED-containing proteins without surface receptor cross-linking. Using Green Fluorescent Protein to examine DED-containing proteins in living cells, we show that these proteins cause apoptosis by forming novel cytoplasmic filaments that recruit and activate pro-caspase zymogens. Formation of these filaments, which we term death-effector filaments, was blocked by coexpression of viral antiapoptotic DED-containing proteins, but not by bcl-2 family proteins. Thus, formation of death-effector filaments allows a regulated intracellular assembly of apoptosis-signaling complexes that can initiate or amplify apoptotic stimuli independently of receptors at the plasma membrane. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Lenardo, MJ (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N311, Bethesda, MD 20892 USA. EM mlenardo@atlas.niaid.nih.gov RI Siegel, Richard/C-7592-2009 OI Siegel, Richard/0000-0001-5953-9893 NR 42 TC 179 Z9 181 U1 0 U2 1 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 JUN 1 PY 1998 VL 141 IS 5 BP 1243 EP 1253 DI 10.1083/jcb.141.5.1243 PG 11 WC Cell Biology SC Cell Biology GA ZT864 UT WOS:000074135900013 PM 9606215 ER PT J AU Buto, S Tagliabue, E Ardini, E Magnifico, A Ghirelli, C van den Brule, F Castronovo, V Colnaghi, MI Sobel, ME Menard, S AF Buto, S Tagliabue, E Ardini, E Magnifico, A Ghirelli, C van den Brule, F Castronovo, V Colnaghi, MI Sobel, ME Menard, S TI Formation of the 67-kDa laminin receptor by acylation of the precursor SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE monomeric laminin receptor; receptor maturation; acylation ID CELL-SURFACE RECEPTOR; FATTY-ACID SYNTHESIS; BINDING PROTEIN; TUMOR INVASION; MESSENGER-RNA; METASTASIS; CARCINOMA; PROGRESSION; EXPRESSION; CANCER AB Even though the involvement of the 67-kDa laminin receptor (67LR) in tumor invasiveness has been clearly demonstrated, its molecular structure remains an open problem, since only a full-length gene encoding a 37-kDa precursor protein (37LRP) has been isolated so far. A pool of recently obtained monoclonal antibodies directed against the recombinant 37LRP molecule was used to investigate the processing that leads to the formation of the 67-kDa molecule. In soluble extracts of A431. human carcinoma cells, these reagents recognize the precursor molecule as well as the mature 67LR and a 120-kDa molecule. The recovery of these proteins was found to be strikingly dependent upon the cell solubilization conditions: the 67LR is soluble in NP-40-lysis buffer whereas the 37LRP is NP-40-insoluble. Inhibition of 67LR formation by cerulenin indicates that acylation is involved in the processing of the receptor. It is likely a palmitoylation process, as indicated by sensitivity of NP-40-soluble extracts to hydroxylamine treatment. Immunoblotting assays performed with a polyclonal serum directed against galectin3 showed that both the 67- and the 120-kDa proteins carry gatectin3 epitopes whereas the 37LRP does not. These data suggest that the 67LR is a heterodimer stabilized by strong intramolecular hydrophobic interactions, carried by fatty acids bound to the 37LRP and to a galectin3 cross-reacting molecule. (C) 1998 Wiley-Liss, Inc. C1 Ist Nazl Tumori, Div Expt Oncol E, I-20133 Milan, Italy. Univ Liege 1, Metastasis Res Lab, Liege, Belgium. NCI, Mol Pathol Sect, Bethesda, MD 20892 USA. RP Colnaghi, MI (reprint author), Ist Nazl Studio & Cura Tumori, Via G Venezian 1, I-20133 Milan, Italy. EM colnaghi@istitutotumori.mi.it RI Tagliabue, Elda/B-9377-2017 OI Tagliabue, Elda/0000-0001-9877-2903 NR 26 TC 93 Z9 99 U1 1 U2 9 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD JUN 1 PY 1998 VL 69 IS 3 BP 244 EP 251 DI 10.1002/(SICI)1097-4644(19980601)69:3<244::AID-JCB2>3.0.CO;2-R PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZJ526 UT WOS:000073225500002 PM 9581863 ER PT J AU Sinz, EH Kochanek, PM Heyes, MP Wisniewski, SR Bell, MJ Clark, RSB DeKosky, ST Blight, AR Marion, DW AF Sinz, EH Kochanek, PM Heyes, MP Wisniewski, SR Bell, MJ Clark, RSB DeKosky, ST Blight, AR Marion, DW TI Quinolinic acid is increased in CSF and associated with mortality after traumatic brain injury in humans SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM 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 DE head injury; macrophage; hypothermia; inflammation; tryptophan; kynurenine ID CONVERT L-TRYPTOPHAN; INTRAVENTRICULAR INFUSION; MONONUCLEAR PHAGOCYTES; NEURONAL SURVIVAL; ATTENUATION; METABOLISM; MECHANISM; ISCHEMIA; DISEASE; MK-801 AB We tested the hypothesis that quinolinic acid, a tryptophan-derived N-methyl-D-aspartate agonist produced by macrophages and microglia, would be increased in CSF after severe traumatic brain injury (TBI) in humans, and that this increase would be associated with outcome. We also sought to determine whether therapeutic hypothermia reduced CSF quinolinic acid after injury. Samples of CSF (n = 230) were collected from ventricular catheters in 39 patients (16 to 73 years Old) during the first week after TBI, (Glasgow Coma Scale [GCS] < 8). As part of an ongoing study, patients were randomized within 6 hours after injury to either hypothermia (32 degrees C) or normothermia (37 degrees C) treatments for 24 hours. Otherwise, patients received standard neurointensive care. Quinolinic acid was measured by mass spectrometry. Univariate and multivariate analyses were used to compare CSF quinolinic acid concentrations with age, gender, GCS, time after injury, mortality, and treatment (hypothermia versus normothermia). Quinolinic acid concentration in CSF increased maximally to 463 +/- 128 nmol/L (mean +/- SEM) at 72 to 83 hours after TBI. Normal values for quinolinic acid concentration in CSF are less than 50 nmol/L. Quinolinic acid concentration was increased 5- to 50-fold in many patients. There was a powerful association between time after TBI and increased quinolinic acid (P < 0.00001), and quinolinic acid was higher in patients who died than in survivors (P = 0.003), Age, gender, GCS, and treatment (32 degrees C versus 37 degrees C) did not correlate with CSF quinolinic acid. These data reveal a large increase in quinolinic acid concentration in CSF after TBI in humans and raise the possibility that this macrophage-derived excitotoxin may contribute to secondary damage. C1 Univ Pittsburgh, Med Ctr, Safar Ctr Resuscitat Res, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Med Ctr, Brain Trauma Res Ctr, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Anesthesiol & Crit Care Med, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Pediat, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Neurol Surg, Pittsburgh, PA 15260 USA. NIMH, Bethesda, MD 20892 USA. Univ N Carolina, Chapel Hill, NC USA. RP Kochanek, PM (reprint author), Univ Pittsburgh, Med Ctr, Safar Ctr Resuscitat Res, 434 5th Ave,Suite 201, Pittsburgh, PA 15260 USA. RI Kochanek, Patrick/D-2371-2015; OI Kochanek, Patrick/0000-0002-2627-913X; Wisniewski, Stephen/0000-0002-3877-9860 FU NINDS NIH HHS [NS30318] NR 34 TC 42 Z9 44 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 1998 VL 18 IS 6 BP 610 EP 615 PG 6 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA ZT870 UT WOS:000074136600002 PM 9626184 ER PT J AU Mohanakumar, KP Hanbauer, I Chiueh, CC AF Mohanakumar, KP Hanbauer, I Chiueh, CC TI Neuroprotection by nitric oxide against hydroxyl radical-induced nigral neurotoxicity SO JOURNAL OF CHEMICAL NEUROANATOMY LA English DT Article; Proceedings Paper CT 3rd International Neuroscience Conference of the Society-of-Neuroscientists-of-Africa / 2nd Regional Congress of the International-Brain-Research-Organisation CY APR 20-27, 1997 CL CAPE TOWN, SOUTH AFRICA SP Soc Neuroscientists Africa, Int Brain Res Org DE ferrous citrate; Parkinson's disease; dopamine; lipid peroxidation; free radical; striatum; substantia nigra ID PARKINSONIAN SUBSTANTIA-NIGRA; INDUCED LIPID-PEROXIDATION; CENTRAL-NERVOUS-SYSTEM; DOPAMINERGIC-NEURONS; HYDROGEN-PEROXIDE; IN-VIVO; SUPEROXIDE-DISMUTASE; SELECTIVE INCREASE; CITRATE COMPLEX; BASAL GANGLIA AB We investigated the effects of nitric oxide on an in vitro and in vivo generation of hydroxyl radicals, and in vivo neurotoxicity caused by intranigral infusion of ferrous citrate in rats. The formation of hydroxyl radicals in vitro, without exogenous hydrogen peroxide, was dose-dependent. Some nitric oxide donors (e.g. sodium nitroprusside) stimulated, while others (nitroglycerin, diethylamine/nitric oxide, nitric oxide in Ringer's solution) suppressed hydroxyl radical generation in vitro. A significant increase in extra-cellular hydroxyl radicals was detected in a brain microdialysis study. Intranigral infusion of ferrous citrate caused long-lasting lipid peroxidation and dopamine depletion in the ipsilateral nigral region and striatum, respectively. Sub-acute dopamine depletion in the striatum was positively correlated with acute lipid peroxidation in substantia nigra. Intranigral administration of nitric oxide did not affect striatal dopamine. Interestingly, nitric oxide in Ringer's protected nigral neurones against the oxidative injury. The results demonstrate that a regional increase in the levels of iron can result in hydroxyl radical generation and lipid peroxidation leading to neurotoxicity. It also demonstrates that exogenous nitric oxide can act as hydroxyl radical scavenger and protect neurones from oxidative injury. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIMH, Unit Neurotox & Neuroprotect, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Biochem Pharmacol Lab, NIH, Bethesda, MD 20892 USA. Indian Inst Chem Biol, Neurochem Lab, Div Pharmacol & Expt Therapeut, Calcutta 700032, W Bengal, India. RP Mohanakumar, KP (reprint author), NIMH, Unit Neurotox & Neuroprotect, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. EM iichbio@giasc101.vsnl.net.in NR 77 TC 55 Z9 56 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0891-0618 J9 J CHEM NEUROANAT JI J. Chem. Neuroanat. PD JUN PY 1998 VL 14 IS 3-4 BP 195 EP 205 DI 10.1016/S0891-0618(98)00032-5 PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 111CD UT WOS:000075419000010 PM 9704898 ER PT J AU Bornstein, MH Haynes, MO Painter, KM AF Bornstein, MH Haynes, MO Painter, KM TI Sources of child vocabulary competence: a multivariate model SO JOURNAL OF CHILD LANGUAGE LA English DT Article ID MATERNAL SPEECH; YOUNG-CHILDREN; UNITED-STATES; 2 SUBGROUPS; LANGUAGE; INFANT; GENDER; DETERMINANTS; SETTINGS; MOTHERS AB This study examines sources of individual variation in child vocabulary competence in the context of a multivariate developmental ecological model. Maternal sociodemographic characteristics, personological characteristics, and vocabulary, as well as child gender, social competence, and vocabulary competence were evaluated simultaneously in 126 children aged I;8 and their mothers. Measures of child vocabulary competence included two measures each of spontaneous speech, experimenter assessments, and maternal reports. Maternal measures, from proximal to distal, included vocabulary, verbal intelligence, personality, attitudes toward parenting, knowledge of parenting, and SES. Structural equation modelling supported several direct unique predictive relations: child gender (girls higher) and social competence as well as maternal attitudes toward parenting predicted child vocabulary competence, and mothers' vocabulary predicted child vocabulary comprehension and two measures of mother-reported child Vocabulary expression. In addition, children's vocabulary competence was influenced indirectly by mothers' vocabulary, social personality, and knowledge of child development. Maternal vocabulary itself was positively influenced by SES, maternal verbal intelligence, and mothers' knowledge about parenting. Individual variation in child vocabulary competence might best be understood as arising within a nexus of contextual factors both proximal and distal to the child. C1 NICHHD, Comparat Ethol Lab, NIH, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), NICHHD, Comparat Ethol Lab, NIH, Bldg 31 Room B2B15,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov NR 55 TC 111 Z9 111 U1 1 U2 13 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0305-0009 J9 J CHILD LANG JI J. Child Lang. PD JUN PY 1998 VL 25 IS 2 BP 367 EP 393 DI 10.1017/S0305000998003456 PG 27 WC Psychology, Developmental; Linguistics; Psychology, Experimental SC Psychology; Linguistics GA 124DE UT WOS:000076165400006 PM 9770912 ER PT J AU Martin, A AF Martin, A TI Knowing and remembering: Here's to you, Lou Costa SO JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY LA English DT Biographical-Item C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Martin, A (reprint author), NIMH, Lab Brain & Cognit, Bldg 10,Room 4C-104,10 Ctr Dr,MSC 1366, Bethesda, MD 20892 USA. RI martin, alex/B-6176-2009 NR 2 TC 0 Z9 0 U1 0 U2 0 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 1380-3395 J9 J CLIN EXP NEUROPSYC JI J. Clin. Exp. Neuropsychol. PD JUN PY 1998 VL 20 IS 3 BP 299 EP 301 DI 10.1076/jcen.20.3.299.818 PG 3 WC Psychology, Clinical; Clinical Neurology; Psychology SC Psychology; Neurosciences & Neurology GA 142MM UT WOS:000077204300001 PM 9845157 ER PT J AU Randolph, C Tierney, MC Mohr, E Chase, TN AF Randolph, C Tierney, MC Mohr, E Chase, TN TI The repeatable battery for the assessment of neuropsychological status (RBANS): Preliminary clinical validity SO JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY LA English DT Article ID MINI-MENTAL STATE; ALZHEIMERS-DISEASE; HUNTINGTONS-DISEASE; COGNITIVE IMPAIRMENT; SEMANTIC MEMORY; RATING-SCALE; DEMENTIA; EXPLICIT AB Neuropsychological assessment of older individuals with dementing illnesses has suffered from a lack of appropriately designed test instruments. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was developed for the dual purposes of identifying and characterizing abnormal cognitive decline in the older adult and as a neuropsychological screening battery for younger patients. The entire battery takes less than 30 minutes to administer, and yields scaled scores for five cognitive domains. The current study reports preliminary clinical validity results with the RBANS, comparing very mildly demented patients with a diagnosis of probable Alzheimer's disease (n = 20) to patients with Huntington's disease (rt = 20) and normal controls (n = 40). Although the patient groups had essentially identical total scores on the RBANS, they exhibited opposite profiles, differing significantly on four of the five subsections. The AD patients performed most poorly on Language, and Delayed Memory subsections, while the HD patients obtained their lowest scaled scores on the Attention and the Visuospatial/Constructional subsections. These results are consistent with the neuropsychological profiles of these dementing disorders derived from lengthier standardized tests and experimental investigations. In addition, even those patients who performed above the suggested cut-off points on the MMSE and the Dementia Rating Scale scored significantly below their controls on the RBANS. These data suggest that the RBANS is effective at both detecting and characterizing dementia of different etiologies. C1 Loyola Univ, Med Ctr, Dept Neurol, Maywood, IL 60153 USA. NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. Univ Ottawa, Royal Ottawa Hosp, Ottawa, ON, Canada. RP Randolph, C (reprint author), 111 Noah Wabash,Suite 1021, Chicago, IL 60602 USA. NR 32 TC 512 Z9 531 U1 5 U2 35 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 1380-3395 J9 J CLIN EXP NEUROPSYC JI J. Clin. Exp. Neuropsychol. PD JUN PY 1998 VL 20 IS 3 BP 310 EP 319 DI 10.1076/jcen.20.3.310.823 PG 10 WC Psychology, Clinical; Clinical Neurology; Psychology SC Psychology; Neurosciences & Neurology GA 142MM UT WOS:000077204300005 PM 9845158 ER PT J AU Jurado, MA Junque, C Vendrell, P Treserras, P Grafman, J AF Jurado, MA Junque, C Vendrell, P Treserras, P Grafman, J TI Overestimation and unreliability in "feeling-of-doing" judgments about temporal ordering performance: Impaired self-awareness following frontal lobe damage SO JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY LA English DT Article ID PASSIVE-AVOIDANCE; AMNESIC PATIENTS; KNOWING PHENOMENON; MEMORY FUNCTIONS; METAMEMORY; KNOWLEDGE; LESIONS; RECALL; PSYCHOPATHY; BEHAVIOR AB "Feeling-of-doing" accuracy in a temporal ordering task in 33 patients with frontal lobe lesions and a matched control group was investigated. The temporal ordering task used word lists that had high, medium, or no semantic interrelatedness. Patients with frontal lobe lesions showed an impairment in temporal ordering across all three word lists. Both groups performed better on the lists with higher semantic interrelatedness. Patients with frontal lobe lesions overestimated their ability to order words accurately. On the less semantically interrelated lists, metamemory judgment in patients with frontal lesions did not correlate with their performance. These results indicate that both temporal order judgment and metacognitive decisions about temporal order judgment are subserved by the prefrontal cortex and further clarifies the role of the frontal lobes in behavioral monitoring. C1 Univ Barcelona, Dept Psiquiat & Psicobiol, Barcelona 08035, Spain. Sta Creu & St Pau Hosp, Barcelona, Spain. NIH, Bethesda, MD 20892 USA. RP Jurado, MA (reprint author), Univ Barcelona, Dept Psiquiat & Psicobiol, Passeig Vall Hebron 171, Barcelona 08035, Spain. RI Vendrell, Pere/B-4392-2011; Junque, Carme/B-4400-2011; JURADO, MARIA ANGELES/E-1745-2011; OI Vendrell, Pere/0000-0001-8918-5440; Junque, Carme/0000-0002-6381-3063; JURADO, MARIA ANGELES/0000-0002-9403-1670; Grafman, Jordan H./0000-0001-8645-4457 NR 50 TC 16 Z9 19 U1 1 U2 6 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 1380-3395 J9 J CLIN EXP NEUROPSYC JI J. Clin. Exp. Neuropsychol. PD JUN PY 1998 VL 20 IS 3 BP 353 EP 364 DI 10.1076/jcen.20.3.353.816 PG 12 WC Psychology, Clinical; Clinical Neurology; Psychology SC Psychology; Neurosciences & Neurology GA 142MM UT WOS:000077204300009 PM 9845162 ER PT J AU Chrousos, GP Gold, PW AF Chrousos, GP Gold, PW TI A healthy body in a healthy mind - and vice versa - The damaging power of "uncontrollable" stress SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material ID GLUCOCORTICOID-RECEPTOR GENE; BIOCHEMICAL MANIFESTATIONS; CORTISOL SECRETION; DEPRESSION; DISEASE; POLYMORPHISM; ABNORMALITIES; NEUROBIOLOGY; METABOLISM; RESISTANCE C1 NIH, Bethesda, MD 20892 USA. RP Chrousos, GP (reprint author), NIH, Bldg 10,Room 10N262,10 Ctr Dr MSC 1862, Bethesda, MD 20892 USA. EM George_Chrousos@NIH.Gov NR 24 TC 187 Z9 193 U1 1 U2 15 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 1998 VL 83 IS 6 BP 1842 EP 1845 DI 10.1210/jc.83.6.1842 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZT221 UT WOS:000074062200003 PM 9626106 ER PT J AU Anderson, T Bardin, CW Barrett-Conner, E Black, C Borwhat, M Burger, H Clarkson, T Cobleigh, M Cosman, F Hayes, H Douglas, MS Dunaif, A Ford, J Ganz, P Gleason, S Goodwin, P Goss, P Green, B Gretz, E Harvey, J Hazzard, W Helzlsouer, K Jordan, VC Josse, R Keleghan, J Kleerekoper, M Lewis, J Llewellyn-Thomas, H Loprinzi, C Mark, M Martin, A Martin, H Miesfeldt, S Moore, M Nachtigall, L New, M O'Connor, A Olsen, M Parker, B Parnes, H Perlman, J Pinkerton, J Powles, T Prior, J Pritchard, K Ragaz, J Railey, E Komen, SG Rumen, N Ropka, M Ross, RK Santen, R Sawka, C Sellin, R Slingluff, C Swain, S Tysenhouse, P Watts, N Whamond, E Wills, M AF Anderson, T Bardin, CW Barrett-Conner, E Black, C Borwhat, M Burger, H Clarkson, T Cobleigh, M Cosman, F Hayes, H Douglas, MS Dunaif, A Ford, J Ganz, P Gleason, S Goodwin, P Goss, P Green, B Gretz, E Harvey, J Hazzard, W Helzlsouer, K Jordan, VC Josse, R Keleghan, J Kleerekoper, M Lewis, J Llewellyn-Thomas, H Loprinzi, C Mark, M Martin, A Martin, H Miesfeldt, S Moore, M Nachtigall, L New, M O'Connor, A Olsen, M Parker, B Parnes, H Perlman, J Pinkerton, J Powles, T Prior, J Pritchard, K Ragaz, J Railey, E Komen, SG Rumen, N Ropka, M Ross, RK Santen, R Sawka, C Sellin, R Slingluff, C Swain, S Tysenhouse, P Watts, N Whamond, E Wills, M CA Hormone Fdn Susan G Komen Breast Canc Fdn Canadian Breast Canc Res Initiative Natl Canc Inst Canada Endocrine Soc Univ Virginia Canc Ctr Woman's Place TI Treatment of estrogen deficiency symptoms in women surviving breast cancer SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID HORMONE-REPLACEMENT THERAPY; BONE-MINERAL DENSITY; HEALTHY POSTMENOPAUSAL WOMEN; HOT FLASHES; SERUM-CHOLESTEROL; HEART-DISEASE; RISK-FACTORS; DOUBLE-BLIND; TAMOXIFEN; PREVENTION C1 Univ Virginia, Hlth Sci Ctr, Div Endocrinol, Charlottesville, VA 22908 USA. Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland. Univ Calif San Diego, La Jolla, CA 92093 USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC 27109 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL USA. Columbia Univ, Coll Phys, Helen Hayes Hosp, New York, NY 10027 USA. Harvard Univ, Brigham & Womens Hosp, Cambridge, MA 02138 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. Mt Sinai Hosp, Toronto, ON, Canada. Toronto Hosp, Toronto, ON M5T 2S8, Canada. Cornell Univ, Sch Med, Ithaca, NY 14853 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. Northwestern Univ, Sch Med, Evanston, IL 60208 USA. Univ Toronto, Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. NCI, Bethesda, MD 20892 USA. Wayne State Univ, Detroit, MI 48202 USA. Mayo Clin, Rochester, MN USA. New York Sch Med, New York, NY USA. St Elizabeth Hosp, Washington, DC 20032 USA. Loeb Res Ottawa Civ Hosp, Ottawa, ON, Canada. Univ Wisconsin, Madison, WI 53706 USA. Royal Marsden Hosp, London, England. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. Univ Texas, MD Anderson Cancer Ctr, Austin, TX USA. Emory Univ, Sch Med, Atlanta, GA 30322 USA. RP Santen, R (reprint author), Univ Virginia, Hlth Sci Ctr, Div Endocrinol, POB 334,Room 4023, Charlottesville, VA 22908 USA. RI Jordan, V. Craig/H-4491-2011; OI Burger, Henry/0000-0002-5333-6144 NR 44 TC 30 Z9 31 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 1998 VL 83 IS 6 BP 1993 EP 2000 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZT221 UT WOS:000074062200027 ER PT J AU Schmidt, HHJ Stuhrmann, M Shamburek, R Schewe, CK Ebhardt, M Zech, LA Buttner, C Wendt, M Beisiegel, U Brewer, HB Manns, MP AF Schmidt, HHJ Stuhrmann, M Shamburek, R Schewe, CK Ebhardt, M Zech, LA Buttner, C Wendt, M Beisiegel, U Brewer, HB Manns, MP TI Delayed low density lipoprotein (LDL) catabolism despite a functional intact LDL-apolipoprotein B particle and LDL-receptor in a subject with clinical homozygous familial hypercholesterolemia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID DEFECTIVE APOLIPOPROTEIN-B-100; II HYPERLIPOPROTEINEMIA; PROLIFERATION ASSAY; IN-VITRO; BINDING; PROTEIN; MUTATION; CHOLESTEROL; IDENTIFICATION; GENE AB We identified a 38-yr-old male patient with the clinical expression of homozygous familial hypercholesterolemia presenting as severe coronary artery disease, tendon and skin xanthomas, arcus lipoides, and joint pain. The genetic trait seems to be autosomal recessive. Interestingly, serum concentrations of cholesterol responded well to diet and statins. We had no evidence of an abnormal low density Lipoprotein (LDL)-apolipoprotein B (apoB) particle, which was isolated from the patient using the U937 proliferation assay as a functional test of the LDL-binding capacity. The apoB 3500 and apoB 3531 defects were ruled out by PCR. In addition, we found no evidence for a defect within the LDL-receptor by skin fibroblast analysis, linkage analysis, single-strand conformational polymorphism and Southern blot screening across the entire LDL-receptor gene. The in vivo kinetics of radioiodinated LDL-apoB were evaluated in the proband and three normal controls, subsequently. The LDL-apoB isolated from the patient showed a normal catabolism, confirming an intact LDL particle. In contrast the fractional catabolic rate (d(-1)) of autologous LDL in the subject and the normal controls revealed a remarkable delayed catabolism of the patient's LDL (0.15 us. 0.33-0.43 d(-1)). In addition, the elevation of LDL-cholesterol in the patient resulted from an increased production rate with 22.8 mg/kg per day us. 12.7-15.7 mg/kg per day. These data indicate that there is another catabolic defect beyond the apoB and LDL-receptor gene causing familial hypercholesterolemia. C1 Hannover Med Sch, Gastroenterol & Hepatol Abt, D-30623 Hannover, Germany. Hannover Med Sch, Abt Humangenet, D-30623 Hannover, Germany. Univ Munich, Med Klin 1, Munich, Germany. Univ Hamburg, Klin Eppendorf, Hamburg, Germany. NHLBI, NIH, Mol Dis Branch, Bethesda, MD 20892 USA. RP Schmidt, HHJ (reprint author), Hannover Med Sch, Gastroenterol & Hepatol Abt, D-30623 Hannover, Germany. NR 43 TC 23 Z9 23 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 1998 VL 83 IS 6 BP 2167 EP 2174 DI 10.1210/jc.83.6.2167 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZT221 UT WOS:000074062200055 PM 9626156 ER PT J AU Eisenhofer, G Keiser, H Friberg, P Mezey, E Huynh, TT Hiremagalur, B Ellingson, T Duddempudi, S Eijsbouts, A Lenders, JWM AF Eisenhofer, G Keiser, H Friberg, P Mezey, E Huynh, TT Hiremagalur, B Ellingson, T Duddempudi, S Eijsbouts, A Lenders, JWM TI Plasma metanephrines are markers of pheochromocytoma produced by catechol-O-methyltransferase within tumors SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID VESICULAR MONOAMINE TRANSPORTER; EXTRANEURONAL METABOLISM; DIAGNOSIS; LOCALIZATION; CELLS; 3,4-DIHYDROXYPHENYLGLYCOL; NOREPINEPHRINE; EXPRESSION; HUMANS; RATS AB This study examined whether the high sensitivity of plasma free metanephrines for diagnosis of pheochromocytoma may result from production of free metanephrines within tumors. Presence in pheochromocytomas of catechol-O-methyltransferase (COMT), the enzyme responsible for conversion of catecholamines to metanephrines, was confirmed by Western blot analysis, enzyme assay, and immunohistochemistry. Western blot analysis and enzyme assay indicated that membrane-bound and not soluble COMT was the predominant form of the enzyme in pheochromocytoma. Immunohistochemistry revealed colocalization of COMT in the same chromaffin cells where catecholamines are translocated into storage vesicles by the vesicular monoamine transporter. Levels of free metanephrines in pheochromocytoma over 10,000 times higher than plasma concentrations in the same patients before removal of tumors indicated production of metanephrines within tumors. Comparisons of the production of metanephrines in patients with pheochromocytoma with production from catecholamines released or infused into the circulation indicated that more than 93% of the consistently elevated levels of circulating free metanephrines in patients with pheochromocytoma are derived from metabolism before and not after release of catecholamines into the circulation. The data indicate that the elevated plasma levels of free metanephrines in patients with pheochromocytoma are derived from catecholamines produced and metabolized within tumors. Some tumors do not secrete catecholamines, but all appear to metabolize catecholamines to free metanephrines, thus explaining the better sensitivity of plasma free metanephrines over other tests for diagnosis of pheochromocytoma. C1 NINDS, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Hypertens Endocrine Branch, NIH, Bethesda, MD 20892 USA. Univ Gothenburg, Dept Clin Physiol, Gothenburg, Sweden. Univ Nijmegen St Radboud Hosp, Dept Rheumatol, NL-6500 HB Nijmegen, Netherlands. Univ Nijmegen St Radboud Hosp, Dept Internal Med, NL-6500 HB Nijmegen, Netherlands. RP Eisenhofer, G (reprint author), NINDS, Clin Neurosci Branch, NIH, Bldg 10,Room 4D20,10 Ctr Dr, Bethesda, MD 20892 USA. EM ge@box-g.nih.gov RI Lenders, J.W.M./L-4487-2015 NR 30 TC 142 Z9 150 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 JUN PY 1998 VL 83 IS 6 BP 2175 EP 2185 DI 10.1210/jc.83.6.2175 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZT221 UT WOS:000074062200056 PM 9626157 ER PT J AU Mitsiades, N Poulaki, V Kotoula, V Mastorakos, G Tseleni-Balafouta, S Koutras, DA Tsokos, M AF Mitsiades, N Poulaki, V Kotoula, V Mastorakos, G Tseleni-Balafouta, S Koutras, DA Tsokos, M TI Fas/Fas ligand up-regulation and BCL-2 down-regulation may be significant in the pathogenesis of Hashimoto's thyroiditis SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PROGRAMMED CELL-DEATH; FAS-LIGAND; MEDIATED APOPTOSIS; ANTIGEN-EXPRESSION; MOLECULAR-CLONING; IN-VITRO; ACTIVATION; SURVIVAL; DISEASE; PROTEIN AB Hashimoto's thyroiditis (HT) is an autoimmune disorder characterized by diffuse thyroid lymphocytic infiltration and follicle destruction. Cross-linking of the Fas receptor with its own ligand (FasL) triggers apoptosis in various systems, whereas the Bcl-2 protooncogene inhibits apoptotic cell death. The involvement of Fas, Fast, and Bcl-2 in the apoptotic process in HT was evaluated in 15 thyroid tissue samples from patients with HT stained for apoptosis and for Fas, Fast, and Bcl-2 protein expression. Eight samples from healthy thyroid tissue were used for comparison. Thyroid follicles in HT samples exhibited strong staining for Fas and Fast and a high percentage of apoptosis (30.3 +/- 14.5%, mean +/- SD), in contrast to normal control follicles that exhibited moderate Fas, minimal or no Fast, and hardly any apoptosis. Immunostaining for Bcl-2 was high in normal, and weak in involved, thyroid follicles. Infiltrating lymphocytes stained weakly for Fast and strongly for Bcl-2. We conclude that follicular cells in HT undergo apoptosis by concomitant up-regulation of Fast and Fas and down-regulation of Bcl-2 protein. The lymphocytes do not seem to be directly engaged in the process with their own Fast, but they may provide the appropriate cytokine milieu that, in turn, upregulates Fas and/or Fast leading to apoptosis. C1 NIH, Pathol Lab, Bethesda, MD 20892 USA. Evgenidion Hosp, Endocrine Unit, Athens, Greece. Univ Athens, Dept Pathol, Athens, Greece. RP Mitsiades, N (reprint author), NIH, Pathol Lab, Bldg 10,Room 2A-10,9000 Rockville Pike, Bethesda, MD 20892 USA. EM nmitsiad@box-n.nih.gov NR 29 TC 75 Z9 83 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 1998 VL 83 IS 6 BP 2199 EP 2203 DI 10.1210/jc.83.6.2199 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZT221 UT WOS:000074062200059 PM 9626160 ER PT J AU Hakim, AA Ross, GW Curb, JD Rodriguez, BL Burchfiel, CM Sharp, DS Yano, K Abbott, RD AF Hakim, AA Ross, GW Curb, JD Rodriguez, BL Burchfiel, CM Sharp, DS Yano, K Abbott, RD TI Coffee consumption in hypertensive men in older middle-age and the risk of stroke: The Honolulu heart program SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE coffee; hypertension; stroke; epidemiology; risk factor ID JAPANESE MEN; PHYSICAL-ACTIVITY; THROMBOEMBOLIC STROKE; SERUM-CHOLESTEROL; DISEASE; CAFFEINE; HAWAII; HOMOCYSTEINE; ASSOCIATION; INFARCTION AB Objective: To examine the association between coffee consumption and the development of stroke in men at high risk for cardiovascular disease. Methods: Coffee intake was observed from 1965 to 1968 in a cohort of men enrolled in the Honolulu Heart Program with follow-up for incident stroke over a 25-year period. Subjects were 499 hypertensive men (having systolic or diastolic blood pressures at or above 140 and 90 mm Hg, respectively) in older middle-age (55 to 68 years) when follow-up began. Past and current cigarette smokers were excluded from follow up. Results: In the course of follow-up, 76 men developed a stroke. After age-adjustment, risk of thromboembolic stroke increased significantly with increases in coffee consumption (P = 0.002). No relationships were observed with hemorrhagic stroke. When adjusted for other factors, the risk of thromboembolic stroke was more than doubled for men who consumed three cups of coffee per day as compared to nondrinkers of coffee (RR = 2.1; 95% CI = 1.2-3.7). Conclusions: Although in need of further confirmation, consumption of coffee appears to he positively associated with an increased risk of thromboembolic stroke in hypertensive men in older middle-age. Findings suggest that it may be prudent to advise older middle-aged men with hypertension who consume large amounts of coffee to consider reducing their coffee intake. Published 1998 Elsevier Science Inc. C1 Univ Virginia, Sch Med, Dept Hlth Evaluat Sci, Div Biostat & Epidemiol, Charlottesville, VA 22908 USA. Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. Dept Vet Affairs, Honolulu, HI USA. Univ Hawaii, John A Burns Sch Med, Dept Med, Honolulu, HI 96822 USA. Kuakini Med Ctr, Honolulu Heart Program, Honolulu, HI USA. National Heart Lung & Blood Institute, Epidemiol & Biometry Program, Honolulu Epidemiol Res Sect, Honolulu, HI USA. RP Abbott, RD (reprint author), Univ Virginia, Sch Med, Dept Hlth Evaluat Sci, Div Biostat & Epidemiol, Box 600, Charlottesville, VA 22908 USA. FU NCRR NIH HHS [P20 RR/AI 11091]; NHLBI NIH HHS [N01-HC-05102] NR 40 TC 34 Z9 36 U1 1 U2 2 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 JUN PY 1998 VL 51 IS 6 BP 487 EP 494 DI 10.1016/S0895-4356(98)00023-7 PG 8 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA ZU152 UT WOS:000074167500006 PM 9635997 ER PT J AU Dybul, M Kinter, A Ruiz, M Fauci, AS AF Dybul, M Kinter, A Ruiz, M Fauci, AS TI Promethean thymus? SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Dybul, M (reprint author), NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NR 11 TC 7 Z9 7 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN 1 PY 1998 VL 101 IS 11 BP 2299 EP 2300 DI 10.1172/JCI3929 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA ZU136 UT WOS:000074165900001 PM 9616200 ER PT J AU Dorman, SE Holland, SM AF Dorman, SE Holland, SM TI Mutation in the signal-transducing chain of the interferon-gamma receptor and susceptibility to mycobacterial infection SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE IFN type II; IFN receptors; atypical Mycobacterium infections; TNF-alpha; signal transduction ID HERPES-SIMPLEX VIRUS; IFN-GAMMA; LEISHMANIA-MAJOR; DEFICIENT MICE; GENE; TUBERCULOSIS; ACTIVATION; RESISTANCE; RESPONSES; IMMUNITY AB IFN-gamma is critical in the immune response to mycobacterial infections, and deficits in IFN-gamma production and response have been associated with disseminated nontuberculous mycobacterial infections. Mutations in the IFN-gamma receptor ligand-binding chain (IFN gamma R1) have been shown to confer susceptibility to severe infection with nontuberculous mycobacteria. However, mutations in the IFN-gamma receptor signal-transducing chain (IFN gamma R2) have not been described. We describe a child with disseminated Mycobacterium fortuitum and M. avium complex infections and absent IFN-gamma signaling due to a mutation in the extracellular domain of IFN gamma R2. In vitro cytokine production by patient PBMCs showed 75% less PHA-induced IFN-gamma production than in normal cells, while patient PHA-induced TNF-alpha production was normal. The normal augmentation of TNF-or production when IFN-gamma was added to endotoxin was absent from patient cells, Expression of IFN gamma R1 was normal, but there was no phosphorylation of Stat1 in response to IFN-gamma stimulation. DNA sequence analysis of the gene for IFN gamma R2 showed a homozygous dinucleotide deletion at nucleotides 278 and 279, resulting in a premature stop codon in the protein extracellular domain. This novel gene defect associated with disseminated nontuberculous mycobacterial infection emphasizes the critical role that IFN-gamma plays In host defense against mycobacteria. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Room 11N103,10 Ctr Dr,MSC 1886, Bethesda, MD 20892 USA. NR 28 TC 302 Z9 307 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN 1 PY 1998 VL 101 IS 11 BP 2364 EP 2369 DI 10.1172/JCI2901 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA ZU136 UT WOS:000074165900008 PM 9616207 ER PT J AU Lew, J Reichelderfer, P Fowler, M Bremer, J Carrol, R Cassol, S Chernoff, D Coombs, R Cronin, M Dickover, R Fiscus, S Herman, S Jackson, B Kornegay, J Kovacs, A McIntosh, K Meyer, W Michael, N Mofenson, L Moye, J Quinn, T Robb, M Vahey, M Weiser, B Yeghiazarian, T AF Lew, J Reichelderfer, P Fowler, M Bremer, J Carrol, R Cassol, S Chernoff, D Coombs, R Cronin, M Dickover, R Fiscus, S Herman, S Jackson, B Kornegay, J Kovacs, A McIntosh, K Meyer, W Michael, N Mofenson, L Moye, J Quinn, T Robb, M Vahey, M Weiser, B Yeghiazarian, T TI Determinations of levels of human immunodeficiency virus type 1 RNA in plasma: Reassessment of parameters affecting assay outcome SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article; Proceedings Paper CT Workshop on Technology Utilization for HIV-1 Blood Evaluation and Standardization in Pediatrics - a Special EMphasis on Plasma RNA Assays CY JUN 17-18, 1996 CL WASHINGTON, D.C. SP NIAID ID HIV-1 RNA; ZIDOVUDINE TREATMENT; VIRAL LOAD; QUANTIFICATION; QUANTITATION; AMPLIFICATION; TRANSMISSION; PROGRESSION; INFECTION; AIDS C1 NIAID, NIH, DAIDS, Bethesda, MD 20892 USA. NICHD, Bethesda, MD USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. Organon Teknika Corp, Durham, NC USA. Ottawa Gen Hosp, Res Inst, Ottawa, ON K1H 8L6, Canada. Chiron Diagnost, Emeryville, CA USA. Univ Washington, Seattle, WA 98195 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ So Calif, Los Angeles, CA USA. Univ N Carolina, Chapel Hill, NC USA. Roche Mol Syst, Branchburg, NJ USA. Johns Hopkins Univ, Baltimore, MD USA. Quest Diagnost, Baltimore, MD USA. Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. Childrens Hosp, Boston, MA 02115 USA. Walter Reed Army Inst Res, Rockville, MD USA. New York State Dept Hlth, Wadsworth Ctr Labs & Res, Albany, NY 12201 USA. RP Lew, J (reprint author), NIAID, NIH, DAIDS, 6003 Execut Blvd, Bethesda, MD 20892 USA. EM jl1w@nih.gov OI Mofenson, Lynne/0000-0002-2818-9808; moye, john/0000-0001-9976-8586 FU CIT NIH HHS [ACTG 96VC010]; NCRR NIH HHS [M01 RR000046]; NIAID NIH HHS [U01 AI025868, N0-AI-35172, U01 AI027535, U01 AI035004]; NICHD NIH HHS [N01-HD-3-3162, U01 HD032632] NR 38 TC 56 Z9 56 U1 0 U2 0 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 JUN PY 1998 VL 36 IS 6 BP 1471 EP 1479 PG 9 WC Microbiology SC Microbiology GA ZN392 UT WOS:000073641300001 PM 9620364 ER PT J AU Conville, PS Witebsky, FG AF Conville, PS Witebsky, FG TI Variables affecting results of sodium chloride tolerance test for identification of rapidly growing mycobacteria SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID CHELONAE; AMPLIFICATION; FEATURES; COMPLEX AB The sodium chloride tolerance test is often used in the identification of rapidly growing mycobacteria, particularly for distinguishing between Mycobacterium abscessus and Mycobacterium chelonae, This test, however, is frequently unreliable for the identification of some species. In this study we examined the following variables: medium manufacturer, inoculum concentration, and atmosphere and temperature of incubation. Results show that reliability is improved if the test and control slants are inoculated with an organism suspension spectrophotometrically equal to a 1 McFarland standard. Slants should be incubated at 35 degrees C in ambient air and checked weekly for ? weeks. Growth on control slants should be critically evaluated to determine the adequacy of the inoculum; colonies should number greater than 50., Salt-containing media should be examined carefully to detect pinpoint or tiny colonies, and colonies should number greater than 50 for a positive reaction. Concurrent use of a citrate slant may be helpful for distinguishing between M., abscessus and M., chelonae, Molecular methodologies are probably the most reliable means for the identification of rapidly growing mycobacteria and should be used, if possible, when unequivocal species identification is of particular importance. C1 NIH, Microbiol Serv, Dept Clin Pathol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Conville, PS (reprint author), NIH, Microbiol Serv, Dept Clin Pathol, Warren Grant Magnuson Clin Ctr, 10 Ctr Dr MSC 1508, Bethesda, MD 20892 USA. NR 15 TC 11 Z9 12 U1 0 U2 0 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 JUN PY 1998 VL 36 IS 6 BP 1555 EP 1559 PG 5 WC Microbiology SC Microbiology GA ZN392 UT WOS:000073641300013 PM 9620376 ER PT J AU Muller, FMC Werner, KE Kasai, M Francesconi, A Chanock, SJ Walsh, TJ AF Muller, FMC Werner, KE Kasai, M Francesconi, A Chanock, SJ Walsh, TJ TI Rapid extraction of genomic DNA from medically important yeasts and filamentous fungi by high-speed cell disruption SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID DEOXYRIBONUCLEIC-ACID; PCR; DIFFERENTIATION; AMPLIFICATION; SOIL; RNA AB Current methods of DNA extraction from different fungal pathogens are often time-consuming and require the use of toxic chemicals. DNA isolation from some fungal organisms is difficult due to cell walls or capsules that are not readily susceptible to lysis, We therefore investigated a new and rapid DNA isolation method using high-speed cell disruption (HSCD) incorporating chaotropic reagents and lysing matrices in comparison to standard phenol-chloroform (PC) extraction protocols for isolation of DNA from three medically important yeasts (Candida albicans, Cryptococcus neoformans, and Trichosporon beigelii) and two filamentous fungi (Aspergillus fumigatus and Fusarium solani), Additional extractions by HSCD were performed on Saccharomyces cerevisiae, Pseudallescheria boydii, and Rhizopus arrhizus., Two different inocula (10(8) and 10(7) CFU) were compared for optimization of obtained yields, The entire extraction procedure was performed on as many as 12 samples within 1 h compared to 6 h for PC extraction. In comparison to the PC procedure, HSCD DNA extraction demonstrated significantly greater yields for 10(8) CFU of C., albicans, T., beigelii, A. fumigatus, and F., solani (P less than or equal to 0.005), 10(7) CFU of C. neoformans (P less than or equal to 0.05), and 10(7) CFU of A. fumigatus (P less than or equal to 0.01), Yields were within the same range for 10(8) CFU of C., neoformans and 10(7) CFU of C., albicans for both HSCD extraction and PC extraction, For 10(7) CFU of T., beigelii, PC extraction resulted in a greater yield than did HSCD (P less than or equal to 0.05), Yields obtained from 10(8) and 10(7) CFU were significantly greater for filamentous fungi than for yeasts by the HSCD extraction procedure (P < 0.0001). By the PC extraction procedure, differences were not significant. For all eight organisms, the rapid extraction procedure resulted in good yield, integrity, and quality of DNA as demonstrated by restriction fragment length polymorphism, PCR, and random amplified polymorphic DNA, We conclude that mechanical disruption of fungal cells by HSCD is a safe, rapid, and efficient procedure for extracting genomic DNA from medically important yeasts and especially from filamentous fungi. C1 NCI, Pediat Oncol Branch, Immunocompromised Host Sect, NIH, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), NCI, Pediat Oncol Branch, Immunocompromised Host Sect, NIH, Bldg 10,Room 13N240, Bethesda, MD 20892 USA. EM frank.mueller@mail.uni-wuerzburg.de; walsht@pbmac.nci.nih.gov NR 29 TC 77 Z9 82 U1 2 U2 14 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 JUN PY 1998 VL 36 IS 6 BP 1625 EP 1629 PG 5 WC Microbiology SC Microbiology GA ZN392 UT WOS:000073641300027 PM 9620390 ER PT J AU Smith, RD Galla, JH Skahan, K Anderson, P Linnemann, CC Ault, GS Ryschkewitsch, CF Stoner, GL AF Smith, RD Galla, JH Skahan, K Anderson, P Linnemann, CC Ault, GS Ryschkewitsch, CF Stoner, GL TI Tubulointerstitial nephritis due to a mutant polyomavirus BK virus strain, BKV(Cin), causing end-stage renal disease SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; JC-VIRUS; PROMOTER ENHANCER; DNA-SEQUENCES; HUMAN BRAIN; T-ANTIGEN; INFECTION; IMMUNODEFICIENT; INDIVIDUALS; BINDING AB A renal biopsy from a 36-year-old man with AIDS showed a severe tubulointerstitial nephritis with intranuclear inclusions in epithelial cells. Electron microscopy revealed the characteristic findings of a polyomavirus (PyV) infection, and immunofluorescence indicated the presence of BK virus (BKV) antigen. Inoculation of rhesus monkey kidney cell cultures both with urine and with buffy coat blood cells resulted in a cytopathic response which was subsequently confirmed to be due to BKV. Further characterization of the viral the kidney by PCR amplification and Southern blot analysis with PyV and strain-specific primers and probes indicated that the virus was closely related to the BK(Dun) strain but different in its apparent sequence arrangement. Subsequent cycle sequencing showed a dinucleotide mutation of TG-->AA which substitutes hydrophilic Gin for hydrophobic Leu in a sequence homologous to an origin DNA-binding domain of simian virus 40 T antigen. It is suggested that the mutation and a coding region rearrangement of this strain of BKV designated BKV(Cin) has the potential to alter viral DNA replication and enhance pathogenicity. C1 Univ Cincinnati, Dept Pathol, Cincinnati, OH 45267 USA. Univ Cincinnati, Dept Internal Med, Cincinnati, OH 45267 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Smith, RD (reprint author), Univ Cincinnati, Dept Pathol, 231 Bethesda Ave,POB 670529, Cincinnati, OH 45267 USA. NR 31 TC 78 Z9 78 U1 0 U2 0 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 JUN PY 1998 VL 36 IS 6 BP 1660 EP 1665 PG 6 WC Microbiology SC Microbiology GA ZN392 UT WOS:000073641300033 PM 9620396 ER PT J AU Segal, BH Walsh, TJ Liu, JM Wilson, JD Kwon-Chung, KJ AF Segal, BH Walsh, TJ Liu, JM Wilson, JD Kwon-Chung, KJ TI Invasive infection with Fusarium chlamydosporum in a patient with aplastic anemia SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID ANTIFUNGAL SUSCEPTIBILITY; DIAGNOSIS; CANCER; FUNGI; HOST AB We report the first case of invasive disease caused by Fusarium chlamydosporum. The patient had aplastic anemia with prolonged neutropenia and was treated with immunosuppressive therapy. While she was receiving empirical amphotericin B, a dark crusted lesion developed on her nasal turbinate. Histologic analysis revealed invasive hyaline hyphae and some darkly pigmented structures that resembled conidia of dematiaceous molds. Only after the mold was grown in culture were characteristic colonial morphology, phialides, conidia, and chlamydospores evident, thus permitting the identification of F. chlamydosporum. This case illustrates the ever-increasing spectrum of pathogenic Fusarium spp. in immunocompromised patients and emphasizes the potential pitfalls in histologic diagnosis, which may have important treatment implications. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NIAID, Mol Biol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NCI, Immunocompromised Host Sect, Pediat Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Segal, BH (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Room 11N103, Bethesda, MD 20892 USA. NR 29 TC 28 Z9 30 U1 0 U2 0 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 JUN PY 1998 VL 36 IS 6 BP 1772 EP 1776 PG 5 WC Microbiology SC Microbiology GA ZN392 UT WOS:000073641300056 PM 9620419 ER PT J AU Rinder, H Janitschke, K Aspock, H Da Silva, AJ Deplazes, P Fedorko, DP Franzen, C Futh, U Hunger, F Lehmacher, A Meyer, CG Molina, JM Sandfort, J Weber, R Loscher, T AF Rinder, H Janitschke, K Aspock, H Da Silva, AJ Deplazes, P Fedorko, DP Franzen, C Futh, U Hunger, F Lehmacher, A Meyer, CG Molina, JM Sandfort, J Weber, R Loscher, T CA Diagnostic Multicenter Study Grp Microsporidia TI Blinded, externally controlled multicenter evaluation of light microscopy and PCR for detection of microsporidia in stool specimens SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID POLYMERASE CHAIN-REACTION; SUBUNIT RIBOSOMAL-RNA; VIRUS-INFECTED PATIENTS; ENTEROCYTOZOON-BIENEUSI; MYCOBACTERIUM-TUBERCULOSIS; ENCEPHALITOZOON HELLEM; SEPTATA-INTESTINALIS; IDENTIFICATION; DIAGNOSIS; AIDS AB The quality parameters for the detection of microsporidia in identical sets of 50 stool samples were determined for six laboratories where technicians used light microscopy and for six laboratories where technicians used PCR. The average overall sensitivities were 67% (89% for patient samples only) for the PCR laboratories and 54% (80% for patient samples only) for the light microscopy laboratories. Specificities were 98 and 95%, respectively. Differences in results were most apparent between the individual laboratories rather than between the two major methods used. C1 Univ Munich, Dept Trop Med & Infect Dis, D-80802 Munich, Germany. Robert Koch Inst, D-1000 Berlin, Germany. Auguste Viktoria Hosp, Berlin, Germany. Humboldt Univ, Inst Trop Med, Berlin, Germany. Med Policlin, Virchow Clin, Berlin, Germany. Univ Cologne, Clin Internal Med 1, Cologne, Germany. Bernhard Nocht Inst, Hamburg, Germany. Inst Hyg, Dept Bacteriol, Hamburg, Germany. Univ Vienna, Inst Hyg, Vienna, Austria. Ctr Dis Control & Prevent, Atlanta, GA 30341 USA. NIH, Bethesda, MD 20892 USA. Univ Zurich, Inst Parasitol, CH-8057 Zurich, Switzerland. Univ Zurich Hosp, Div Infect Dis & Hosp Epidemiol, CH-8091 Zurich, Switzerland. Univ Paris 07, Dept Infect Dis, Hosp St Louis, Paris, France. RP Rinder, H (reprint author), Univ Munich, Dept Trop Med & Infect Dis, Leopoldstr 5, D-80802 Munich, Germany. EM rinder@lrz.uni-muenchen.de RI Weber, Rainer/D-5175-2012; Infektiologie, USZ/A-6921-2011 NR 24 TC 31 Z9 34 U1 0 U2 0 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 JUN PY 1998 VL 36 IS 6 BP 1814 EP 1818 PG 5 WC Microbiology SC Microbiology GA ZN392 UT WOS:000073641300069 PM 9620432 ER PT J AU Haddy, TB Adde, MA McCalla, J Domanski, MJ Datiles, M Meehan, SC Pikus, A Shad, AT Valdez, I Vivino, LL Magrath, IT AF Haddy, TB Adde, MA McCalla, J Domanski, MJ Datiles, M Meehan, SC Pikus, A Shad, AT Valdez, I Vivino, LL Magrath, IT TI Late effects in long-term survivors of high-grade non-Hodgkin's lymphomas SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 38th Annual Meeting of the American-Society-of-Hematology CY DEC 06-10, 1996 CL ORLANDO, FLORIDA SP Amer Soc Hematol, US Dept Vet Affairs Merit Res Funds, NIH ID ACUTE LYMPHOBLASTIC-LEUKEMIA; 2ND MALIGNANT NEOPLASMS; COMBINED MODALITY TREATMENT; NONCLEAVED-CELL LYMPHOMA; ACUTE MYELOID-LEUKEMIA; RISK-FACTORS; COMBINATION CHEMOTHERAPY; DOXORUBICIN THERAPY; BURKITTS-LYMPHOMA; VIRAL-INFECTIONS AB Purpose: To evaluate long-term survivors of high-grade non-Hodgkin's lymphomas (NHLs) for late effects and to attempt to assess the relative contributions of the primary treatment modalities to these late effects. Patients and Methods: Of 103 young survivors followed vp for 1 to 20 years, 74 patients were interviewed and underwent various investigations, and an additional 12 patients were interviewed only, Of the 86 patients, 65 had previously suffered from small noncleaved-cell lymphoma, 16 from lymphoblastic lymphoma, and five from large-cell lymphoma. Results: Left ventricular dysfunction was identified in eight of 57(14.0%) patients who had received doxorubicin (DOX) in doses greater than 200 mg/m(2), of whom four were symptomatic and four were asymptomatic. A ninth patient required a pacemaker. Of the 86 patients, 23 (26.7%) reported pregnancies, 18 of whom had 30 children. Two of the 86 (2.3%) patients developed second cancers. Other major late effects included posttransfusion viral hepatitis, eight patients; CNS toxicity, two patients; endocrine impairment, 14 patients; vitamin B-12 deficiency, two patients; esophageal stricture, one patient; urinary tract problems, two patients; and musculoskeletal defects, three patients. Major late effects occurred in 11 of 21 (52.4%) patients who had received radiation as well as chemotherapy, eight of 22 (36.4%) patients who had surgical resections as well as chemotherapy, and 17 of 74 (23.0%) patients who had received chemotherapy alone. Conclusion: The predominant major late effects observed were late cardiac toxicity related to DOX therapy and hepatitis C virus infection that presumably resulted from blood product transfusions administered before the introduction of screening for the hepatitis C virus. Fertility was not greatly impaired, and second malignancies were uncommon. No patient had clinically significant impairment of growth. Radiation appeared to increase the likelihood of late effects. C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. NEI, Ophthalm Genet & Clin Serv Branch, NIH, Bethesda, MD 20892 USA. NIDR, Clin Invest Branch, NIH, Bethesda, MD 20892 USA. NIDOCD, Div Intramural Res, NIH, Bethesda, MD USA. RP Magrath, IT (reprint author), NCI, Pediat Oncol Branch, NIH, Bldg 10,Room 13N240, Bethesda, MD 20892 USA. EM magrathi@exchange.nih.gov OI Datiles, Manuel III B./0000-0003-4660-1664 NR 54 TC 45 Z9 45 U1 0 U2 5 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN PY 1998 VL 16 IS 6 BP 2070 EP 2079 PG 10 WC Oncology SC Oncology GA ZQ948 UT WOS:000073919200011 PM 9626206 ER PT J AU Biddle, AK DeVellis, RF Henderson, G Fasick, SB Danis, M AF Biddle, AK DeVellis, RF Henderson, G Fasick, SB Danis, M TI The health insurance puzzle: A new approach to assessing patient coverage preferences SO JOURNAL OF COMMUNITY HEALTH LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Health-Services-Research CY JUN 08-11, 1996 CL ATLANTA, GEORGIA SP Assoc Hlth Serv Res ID CARE AB Previous studies of preferences for health insurance benefits have required individuals to make a series of complex and repetitive decisions, and have assumed that ail insured benefits are desirable. This study reports the development and testing of a simple, innovative instrument to measure preferences for health insurance benefits. The newly developed instrument (Puzzle) is designed to allow subjects to select health benefits in a way that underscores the trade-offs dictated by budgets and costs. A "puzzle-like" frame representing budget constraints and "puzzle piece" benefit cards proportionately sized to represent the premium price of a single year's coverage comprise the instrument In a comparison procedure (Money Game), participants "purchase" individual benefits by exchanging "play" money for benefit tokens. The Puzzle's utility was assessed by examining the convergence of results from both instruments and the subject's ratings of and preference for the instruments. One hundred five elderly Medicare enrollees seen in the general Internal Medicine outpatient clinic of a major southeastern teaching hospital were interviewed. Subjects answered interviewer-administered questionnaires and completed both the Puzzle and the Money Game. Both McNemar's test and Kendall's tau-b indicated a high degree of concordance between benefit choices made using the two instruments. Descriptive statistics demonstrated that the Puzzle was clear, easy to use, understandable, and preferred to the Money Game. The results suggest that the Puzzle is a promising tool for assessing health insurance coverage preferences under circumstances of limited expenditures, which can be modified for use with various populations who face limited insurance benefits. C1 Univ N Carolina, Chapel Hill, NC 27599 USA. NIH, Dept Clin Bioeth, Bethesda, MD USA. RP Biddle, AK (reprint author), Univ N Carolina, CB 7400, Chapel Hill, NC 27599 USA. EM Andrea_Biddle@unc.edu OI Biddle, Andrea/0000-0003-0273-7439 NR 13 TC 5 Z9 5 U1 1 U2 2 PU HUMAN SCI PRESS INC PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0094-5145 J9 J COMMUN HEALTH JI J. Community Health PD JUN PY 1998 VL 23 IS 3 BP 181 EP 194 DI 10.1023/A:1018716414735 PG 14 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA ZP574 UT WOS:000073767100002 PM 9615294 ER PT J AU Bonner, FB AF Bonner, FB TI Cancer among black families: Diffusion as a strategy of prevention and intervention SO JOURNAL OF COMPARATIVE FAMILY STUDIES LA English DT Article AB Compared with Whites, African Americans experience nearly 50% greater mortality rates for cancer, heart disease and stroke, cirrhosis, diabetes, accidents and homicides, and infant mortality. This is despite recent unprecedented increases in knowledge and capacity to diagnose, treat and cure disease. To seek a better understanding of this situation, at least in one area(cancer), comprehensive information has been gathered by the Cancer Education Prevention and Research Office (CEPRO) at Howard University. The overriding goal of this project is to increase knowledge about and participation of African Americans in prevention and intervention behavior. Towards this end a quasi-experimental health intervention model is used to measure changes in a group of intervening variables (such as health promotion knowledge, awareness and behavior), which research indicates should influence the dependent variable of cancer incidence. Preliminary data has shown that African American women are more likely to seek information, actively participate in programs, and are generally the source of information for family members. The findings also indicate that younger, less well-educated segments of the African American population are less likely to participate in screening and early detection efforts. Thus, outreach strategies to strengthen prevention and intervention and to increase survivor rates of cancer in the African American community may rest with women. C1 Howard Univ, CEPRO, NBLIC, NCI, Washington, DC 20059 USA. RP Bonner, FB (reprint author), Howard Univ, CEPRO, NBLIC, NCI, Annex 11,Room 204,5th & W St NW, Washington, DC 20059 USA. NR 8 TC 1 Z9 1 U1 0 U2 1 PU J COMPARATIVE FAMILY STUDIES PI CALGARY PA UNIV CALGARY-DEPT SOCIOLOGY 2500 UNIVERSITY DRIVE NW, CALGARY, AB T2N 1N4, CANADA SN 0047-2328 J9 J COMP FAM STUD JI J. Comp. Fam. Stud. PD SUM PY 1998 VL 29 IS 2 BP 349 EP + PG 13 WC Family Studies SC Family Studies GA 144BY UT WOS:000077294900009 ER PT J AU Crits-Christoph, P Siqueland, L Chittams, J Barber, JP Beck, AT Frank, A Liese, B Luborsky, L Mark, D Mercer, D Onken, LS Najavits, LM Thase, ME Woody, G AF Crits-Christoph, P Siqueland, L Chittams, J Barber, JP Beck, AT Frank, A Liese, B Luborsky, L Mark, D Mercer, D Onken, LS Najavits, LM Thase, ME Woody, G TI Training in cognitive, supportive-expressive, and drug counseling therapies for cocaine dependence SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article ID COLLABORATIVE RESEARCH-PROGRAM; LIMITED DYNAMIC PSYCHOTHERAPY; INTERPERSONAL PSYCHOTHERAPY; DEPRESSION; OUTCOMES; SCALE AB This study assessed the effects of training on the performance of 65 therapists in delivering manual-guided therapies to 202 cocaine-dependent patients, Changes in ratings of therapists' adherence and competence was assessed in 3 treatment modalities: supportive-expressive dynamic therapy (SE), cognitive therapy (CT), and individual drug counseling. Effects of manual-guided training on the therapeutic alliance were also assessed. Training effects were examined through a hierarchical linear modeling approach that examined changes both within cases and across training cases. A large effect across cases was detected for training in CT. Supportive-expressive therapists and individual drug counselors demonstrated statistically significant learning trends over sessions but not over training cases. Training in SE and CT did not have a negative impact on the therapeutic alliance, although alliance scores for trainees in drug counseling initially decreased but then rebounded to initial levels. C1 Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. Brookside Hosp, Nashua, NH USA. Univ Kansas, Dept Family Med, Lawrence, KS 66045 USA. NIDA, Bethesda, MD USA. McLean Hosp, Dept Psychiat, Cambridge, MA USA. Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. Univ Pittsburgh, Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA 15213 USA. RP Crits-Christoph, P (reprint author), Room 700,3600 Market St, Philadelphia, PA 19104 USA. EM crits@landru.cpr.upenn.edu OI barber, jacques/0000-0002-8762-2595 FU NIDA NIH HHS [R01 DA012249, U18 DA007090, U18-DA07090, U18-DA07663, U18-DA07673] NR 34 TC 86 Z9 86 U1 6 U2 10 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD JUN PY 1998 VL 66 IS 3 BP 484 EP 492 DI 10.1037//0022-006X.66.3.484 PG 9 WC Psychology, Clinical SC Psychology GA ZU589 UT WOS:000074213200004 PM 9642886 ER PT J AU Post, RM AF Post, RM TI Anticonvulsant effects of ECT and rTMS: Implications for treatment of depresion. SO JOURNAL OF ECT LA English DT Meeting Abstract C1 NIMH, NIH, 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 1095-0680 J9 J ECT JI J. ECT PD JUN PY 1998 VL 14 IS 2 BP 134 EP 134 DI 10.1097/00124509-199806000-00022 PG 1 WC Behavioral Sciences; Psychiatry SC Behavioral Sciences; Psychiatry GA 268NM UT WOS:000084422500021 ER PT J AU Phung, QH Winter, DB Cranston, A Tarone, RE Bohr, VA Fishel, R Gearhart, PJ AF Phung, QH Winter, DB Cranston, A Tarone, RE Bohr, VA Fishel, R Gearhart, PJ TI Increased hypermutation at G and C nucleotides in immunoglobulin variable genes from mice deficient in the MSH2 mismatch repair protein SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE biological sciences; genetics; genes, immunoglobulin; mutation; DNA repair ID SOMATIC HYPERMUTATION; AFFINITY MATURATION; GERMINAL-CENTERS; IMMUNE-RESPONSE; HUMAN-CELLS; SEQUENCES; MUTATION; CANCER; DNA; DIVERSIFICATION AB Rearranged immunoglobulin variable genes are extensively mutated after stimulation of B lymphocytes by antigen. Mutations are likely generated by an error-prone DNA polymerase, and the mismatch repair pathway may process the mispairs. To examine the role of the MSH2 mismatch repair protein in hypermutation, Msh2(-/-) mice were immunized with oxazolone, and B cells were analyzed for mutation in their V(k)Oxl light chain genes. The frequency of mutation in the repair-deficient mice was similar to that in Msh2(+/+) mice, showing that MSH2-dependent mismatch repair does not cause hypermutation. However, there was a striking bias for mutations to occur at germline G and C nucleotides. The results suggest that the hypermutation pathway frequently mutates G C pairs, and a MSH2-dependent pathway preferentially corrects mismatches at G and C. C1 NIA, Mol Genet Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Grad Program Immunol, Baltimore, MD 21205 USA. Thomas Jefferson Univ, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA. NCI, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Gearhart, PJ (reprint author), NIA, Mol Genet Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NCI NIH HHS [R01 CA056542, CA-56542, CA-67007, R01 CA067007] NR 43 TC 146 Z9 146 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 1 PY 1998 VL 187 IS 11 BP 1745 EP 1751 DI 10.1084/jem.187.11.1745 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA ZT738 UT WOS:000074120200003 PM 9607916 ER PT J AU Davidson, WF Giese, T Fredrickson, TN AF Davidson, WF Giese, T Fredrickson, TN TI Spontaneous development of plasmacytoid tumors in mice with defective Fas-Fas ligand interactions SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE lpr; gld; Fas; Fas ligand; lymphoma ID MATURE T-CELLS; NECROSIS-FACTOR-ALPHA; LPR MICE; B-CELLS; LYMPHOPROLIFERATIVE SYNDROME; MONOCLONAL-ANTIBODY; AUTOIMMUNE SYNDROME; GASTRIC LYMPHOMA; GENE-MUTATIONS; DEFICIENT MICE AB B cell malignancies arise with increased frequency in aging individuals and in patients with genetic or acquired immunodeficiency (e.g., AIDS) or autoimmune diseases. The mechanisms of lymphomagenesis in these individuals are poorly understood. In this report we investigated the possibility that mutations at the Fas (lpr) and Fasl (gld) loci, which prevent Fas-mediated apoptosis and cause an early onset benign lymphoid hyperplasia and autoimmunity, also predispose mice to malignant lymphomas later in life. Up to 6 mo of age, hyperplasia in lpr and gld mice results from the predominant accumulation of polyclonal T cell subsets and smaller numbers of polyclonal B cells and plasma cells. Here, we examined C3H-lpr, C3H-gld, and BALB-gld mice 6-15 mo of age for the emergence of clonal T and B cell populations and found that a significant proportion of aging mice exclusively developed B cell malignancies with many of the hallmarks of immunodeficiency-associated B lymphomas. By 1 yr of age,similar to 60% of BALB-gld and 30% of C3H-gld mice had monoclonal B cell populations that grew and metastasized in scid recipients but in most cases were rejected by immunocompetent mice. The tumors developed in a milieu greatly enriched for plasma cells, CD23(-) B cells and immunodeficient memory T cells and variably depleted of B220(+) DN T cells. Growth factor-independent cell lines were established from five of the tumors. The majority of the tumors were CD23(-) and IgH isotype switched and a high proportion was CD5(+) and dull Mac-1(+). Considering their Ig secretion and morphology in vivo, most tumors were classified as malignant plasmacytoid lymphomas. The delayed development of the gld tumors indicated that genetic defects in addition to the Fas/Fasl mutations were necessary for malignant transformation. Interestingly, none of the tumors showed changes in the genomic organization of c-Myc but many had one of more somatically-acquired MuLV proviral integrations that were transmitted in scid passages and cell lines. Therefore, insertional mutagenesis may be a mechanism for transformation in gld B cells. Our panel of in vivo passaged and in vitro adapted gld lymphomas will be a valuable tool for the future identification of genetic abnormalities associated with B cell transformation in aging and autoimmune mice. C1 NCI, Genet Lab, NIH, Bethesda, MD 20892 USA. NCI, Registry Expt Canc, NIH, Bethesda, MD 20892 USA. RP Davidson, WF (reprint author), Amer Red Cross, Holland Lab, Dept Immunol, 15601 Crabbs Branch Way, Rockville, MD 20855 USA. EM davidson@hlsun.redcross.org NR 67 TC 125 Z9 126 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 1 PY 1998 VL 187 IS 11 BP 1825 EP 1838 DI 10.1084/jem.187.11.1825 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA ZT738 UT WOS:000074120200010 PM 9607923 ER PT J AU Matsuda, A Motoya, S Kimura, S McInnis, R Maizel, AL Takeda, A AF Matsuda, A Motoya, S Kimura, S McInnis, R Maizel, AL Takeda, A TI Disruption of lymphocyte function and signaling in CD45-associated protein-null mice SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE CD45-AP; CD45; Lck; gene targeting; signal transduction ID CD45 PHOSPHOTYROSINE PHOSPHATASE; TYROSINE-PHOSPHATASE; CYTOPLASMIC DOMAIN; CELL MATURATION; T-CELLS; ACTIVATION; KINASE; TRANSMEMBRANE; IDENTIFICATION; TRANSDUCTION AB CD45-AP specifically associates with CD45, a protein tyrosine phosphatase essential for lymphocyte differentiation and antigen receptor-mediated signal transduction. CD45 is thought to mediate antigen receptor signaling by dephosphorylating regulatory tyrosine residues on Src family protein tyrosine kinases such as Lck. However, the mechanism for regulating CD45 protein tyrosine phosphatase activity remains unclear. CD45-AP-null mice were created to examine the role of CD45-AP in CD45-mediated signal transduction. T and B lymphocytes showed reduced proliferation in response to antigen receptor stimulation. Both mixed leukocyte reaction and cytotoxic T lymphocyte functions of T cells were also markedly decreased in CD45-AP-null mice. Interestingly, the interaction between CD45 and Lck was significantly reduced in CD45-AP-null T cells, indicating that CD45-AP directly or indirectly mediates the interaction of CD45 with Lck. Our data indicate that CD45-AP is required for normal antigen receptor signaling and function in lymphocytes. C1 Roger Williams Hosp Brown Univ, Dept Pathol, Providence, RI 02908 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Takeda, A (reprint author), Roger Williams Hosp Brown Univ, Dept Pathol, 825 Chalkstone Ave, Providence, RI 02908 USA. FU NIGMS NIH HHS [GM-48188] NR 28 TC 25 Z9 27 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 JUN 1 PY 1998 VL 187 IS 11 BP 1863 EP 1870 DI 10.1084/jem.187.11.1863 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA ZT738 UT WOS:000074120200013 PM 9607926 ER PT J AU Shimizu, YK Igarashi, H Kiyohara, T Shapiro, M Wong, DC Purcell, RH Yoshikura, H AF Shimizu, YK Igarashi, H Kiyohara, T Shapiro, M Wong, DC Purcell, RH Yoshikura, H TI Infection of a chimpanzee with hepatitis C virus grown in cell culture SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID NON-B HEPATITIS; NON-A AB Culture supernatant harvested from Daudi cells, a lymphoplastoid cell line, after 58 days of infection with the H77 strain of hepatitis C virus (HCV), was inoculated into a chimpanzee. HCV RNA, as detected by RT-PCR, first appeared in the serum and liver 5 and 6 weeks, respectively, after inoculation. Peripheral blood mononuclear cells (PBMC) collected on week 7 were also positive for HCV RNA. The major sequences of hypervariable region 1 (HVR1) of the viral genome recovered from the inoculated chimpanzee were the ones which were the majority in the original H77 inoculum and not those which were in the majority in the culture supernatant, Only the sequence recovered from PBMC was the same as the major one found in the cell culture. C1 Univ Tokyo, Fac Med, Dept Hepatitis Virol, SKBB,Bunkyo Ku, Tokyo 1130033, Japan. Univ Tokyo, Fac Med, Dept Microbiol, Bunkyo Ku, Tokyo 1130033, Japan. Natl Inst Hlth, Dept Viral Dis & Vaccine Control, Tokyo 2080011, Japan. NIH, Infect Dis Lab, Bethesda, MD 20892 USA. RP Shimizu, YK (reprint author), Univ Tokyo, Fac Med, Dept Hepatitis Virol, SKBB,Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan. NR 14 TC 38 Z9 39 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 JUN PY 1998 VL 79 BP 1383 EP 1386 PN 6 PG 4 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA ZQ634 UT WOS:000073887700007 PM 9634078 ER PT J AU Robinet, E Certoux, JM Ferrand, C Maples, P Hardwick, A Cahn, JY Reynolds, CW Jacob, W Herve, P Tiberghien, P AF Robinet, E Certoux, JM Ferrand, C Maples, P Hardwick, A Cahn, JY Reynolds, CW Jacob, W Herve, P Tiberghien, P TI A closed culture system for the ex vivo transduction and expansion of human T lymphocytes SO JOURNAL OF HEMATOTHERAPY LA English DT Article ID BONE-MARROW TRANSPLANTATION; CELL DEPLETION; GENE AB A phase I clinical trial is currently being performed at our institution, with the aim of evaluating the feasibility and toxicity related to the administration of herpes simplex thymidine kinase gene-expressing human primary T lymphocytes following allogeneic hematopoietic stem cell transplantation. The need for safe and standardized preparation conditions for gene-modified cells is crucial. We describe the closed culture system used in the current trial for ex vivo retroviral-mediated gene transfer and transduced cell selection. Cell handling is performed in closed systems using a sterile connection device that avoids opening the culture system. Cell numbers during the production process increased from 93 +/- 16 on day 0 to 440 +/- 92 x 10(6) on day 12 (7.2 +/- 1.4-fold increase) (n = 11). Transduction efficiency before and after G418 resistance-based selection was 13.5 +/- 3.8% and 90.0 +/- 1.4%, respectively. Safety and efficacy testing included a search for replication-competent retrovirus, endotoxins, Mycoplasm, and bacterial contamination (n = 0/9), PCR-DNA, % CD3 + cells (91 +/- 2%), and viability after thawing (82 +/- 3%). Effective working time from day 0 to day 12 is similar to 20 h. The closed system we developed allows for safe and reproducible ex vivo preparation of gene-modified primary T lymphocytes for clinical use. C1 Estab Transfus Sanguine Franche Comte, Lab Therapeut Immunomol, F-25020 Besancon, France. Baxter Healthcare Corp, Round Lake, IL 60073 USA. CHU Minjoz, Besancon, France. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Genet Therapy Inc, Gaithersburg, MD 20878 USA. RP Robinet, E (reprint author), Estab Transfus Sanguine Franche Comte, Lab Therapeut Immunomol, 1 Bd Alexandre Fleming BP 1937, F-25020 Besancon, France. NR 11 TC 41 Z9 41 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1061-6128 J9 J HEMATOTHER JI J. Hematother. PD JUN PY 1998 VL 7 IS 3 BP 205 EP 215 DI 10.1089/scd.1.1998.7.205 PG 11 WC Hematology; Medicine, Research & Experimental; Transplantation SC Hematology; Research & Experimental Medicine; Transplantation GA ZR003 UT WOS:000073925400002 PM 9621254 ER PT J AU Bagrov, AY Fedorova, OV AF Bagrov, AY Fedorova, OV TI Effects of endogenous digitalis-like factors (EDLF) on Na/K pump (NKP) isoforms in human arteries SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract C1 NIA, NIH, Baltimore, MD 21224 USA. IM Sechenov Evolutionary Physiol & Biochem Inst, St Petersburg 194223, Russia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 1998 VL 16 SU 2 MA P1718 BP S134 EP S134 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 111MU UT WOS:000075442200702 ER PT J AU de Oliveira, AM Correa, FMA Saavedra, JM AF de Oliveira, AM Correa, FMA Saavedra, JM TI Functional cardiovascular correlates of an atypical angiotensin II receptor identified in the gerbil SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract C1 USP, Sch Pharm, Ribeirao Preto, SP, Brazil. USP, Sch Med Ribeirao Preto, Ribeirao Preto, SP, Brazil. NIMH, Bethesda, MD 20892 USA. RI maria, ana /G-8106-2014 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 1998 VL 16 SU 2 MA P810 BP S72 EP S72 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 111MU UT WOS:000075442200379 ER PT J AU Eisenhofer, G Rundqvist, B Friberg, P AF Eisenhofer, G Rundqvist, B Friberg, P TI Determinants of cardiac norepinephrine turnover and tyrosine hydroxylation during sympathetic activation SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Univ Gothenburg, Gothenburg, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 1998 VL 16 SU 2 MA P2343 BP S182 EP S182 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 111MU UT WOS:000075442200956 ER PT J AU Elisenhofer, G Keiser, HR Friberg, P Mezey, E Hiremagalur, B Lenders, JWM AF Elisenhofer, G Keiser, HR Friberg, P Mezey, E Hiremagalur, B Lenders, JWM TI Plasma metanephrines are markers of pheochromocytoma produced by catechol-O-methyltransferase within tumors SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Univ Nijmegen St Radboud Hosp, NL-6500 HB Nijmegen, Netherlands. Univ Gothenburg, Gothenburg, Sweden. RI Lenders, J.W.M./L-4487-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 1998 VL 16 SU 2 MA P27001 BP S195 EP S195 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 111MU UT WOS:000075442201028 ER PT J AU Goldstein, DS AF Goldstein, DS TI Non-invasive diagnosis of sympathetic neurocirculatory failure SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 1998 VL 16 SU 2 MA P2318 BP S177 EP S177 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 111MU UT WOS:000075442200931 ER PT J AU Goldstein, DS Katzper, M Kopin, IJ AF Goldstein, DS Katzper, M Kopin, IJ TI Kinetic model for the fate of the sympathoneural imaging agent 6-[F-18]-fluorodopamine in the human heart SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 1998 VL 16 SU 2 MA P2312 BP S176 EP S176 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 111MU UT WOS:000075442200925 ER PT J AU Goldstein, DS Golczynska, A Lenders, J Stuhlmuller, J Holmes, C Rea, RF Grossman, E AF Goldstein, DS Golczynska, A Lenders, J Stuhlmuller, J Holmes, C Rea, RF Grossman, E TI A test of the epinephrine hypothesis in humans SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 1998 VL 16 SU 2 MA 14W5 BP S33 EP S33 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 111MU UT WOS:000075442200166 ER PT J AU Lenders, JWM Keiser, HR Friberg, P Willemsen, JJ Eisenhofer, G AF Lenders, JWM Keiser, HR Friberg, P Willemsen, JJ Eisenhofer, G TI Plasma free metanephrines provide superior markers of pheochromocytoma than other neurochemical tests SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract C1 Univ Gothenburg, Gothenburg, Sweden. NIH, Bethesda, MD 20892 USA. Univ Nijmegen, St Radboud Hosp, Nijmegen, Netherlands. RI Lenders, J.W.M./L-4487-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 1998 VL 16 SU 2 MA P1819 BP S149 EP S149 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 111MU UT WOS:000075442200784 ER PT J AU Levy, D AF Levy, D TI The transition from hypertension to overt heart failure SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract C1 NHLBI, Framingham Heart Study, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 1998 VL 16 SU 2 MA 11W3 BP S26 EP S26 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 111MU UT WOS:000075442200125 ER PT J AU Nwachuku, CE Cutler, JA Payne, GH Proschan, MA Ford, CE Davis, BR Pressel, SL Hawkins, CM AF Nwachuku, CE Cutler, JA Payne, GH Proschan, MA Ford, CE Davis, BR Pressel, SL Hawkins, CM CA ALLHAT Res Grp TI Regional differences in attainment of goal blood pressure (BP) among treated hypertensive patients in the United States SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract C1 Univ Texas, Sch Publ Hlth, Houston, TX USA. NHLBI, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 1998 VL 16 SU 2 MA 9Z6 BP S22 EP S22 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 111MU UT WOS:000075442200106 ER PT J AU Torpy, DJ Gordon, RD Stowasser, M Huggard, PR Chroussos, GP Stratakis, CA AF Torpy, DJ Gordon, RD Stowasser, M Huggard, PR Chroussos, GP Stratakis, CA TI Linkage analysis for familial hyperaldosteronism type II: Exclusion of linkage to the aldosterone synthase and angiotensin II receptor genes SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract C1 NICHD, Dev Endocrinol Branch, NIH, Bethesda, MD USA. Greenslopes Hosp, Hypertens Unit, Brisbane, Qld, Australia. RI Stowasser, Michael/F-4121-2010 NR 5 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 1998 VL 16 SU 2 MA P1508 BP S112 EP S112 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 111MU UT WOS:000075442200586 ER PT J AU Huang, H Pannetier, C Hu-Li, J Paul, WE AF Huang, H Pannetier, C Hu-Li, J Paul, WE TI Transient transfection of primary T helper cells by particle-mediated gene transfer SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE transfection; IL-4; reporter gene; primary T cells ID INTERLEUKIN-4; PROMOTER; DELIVERY AB The study of the molecular basis of normal CD4 + T cell function, such as the control of commitment to the TH1 or TH2 phenotypes has been difficult due to the resistance of these cells to transfection by conventional methods. We used antibodies specific to T cell surface molecules to immobilize these cells and optimized conditions for transiently transfecting them by means of particle-mediated gene transfer. Using this technique, a construct encompassing - 577 to + 1 of the IL-4 promoter allowed transcription of a luciferase reporter gene in recently-differentiated TH2 cells stimulated by anti-CD3, consistent with regulation of endogenous IL-4 gene expression. (C) 1998 Published by Elsevier Science B.V. All rights reserved. C1 NIAID, Immunol Lab, Bethesda, MD 20892 USA. RP Paul, WE (reprint author), NIAID, NIH, Immunol Lab, Bldg 10,Room 11N311,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. NR 7 TC 9 Z9 9 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JUN 1 PY 1998 VL 215 IS 1-2 BP 173 EP 177 DI 10.1016/S0022-1759(98)00088-X PG 5 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 116HB UT WOS:000075717500018 PM 9744759 ER PT J AU Doherty, TM Sher, A AF Doherty, TM Sher, A TI IL-12 promotes drug-induced clearance of Mycobacterium avium infection in mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; STIMULATORY FACTOR INTERLEUKIN-12; INTERFERON-GAMMA PRODUCTION; IFN-GAMMA; COMPLEX INFECTION; IMMUNE-RESPONSES; FACTOR-ALPHA; RECOMBINANT INTERLEUKIN-12; IMMUNOREGULATORY FUNCTIONS; PROINFLAMMATORY CYTOKINE AB The intracellular pathogen Mycobacterium avium is a major cause of opportunistic infection in AIDS patients and is difficult to manage using conventional chemotherapeutic approaches. In the current study, we describe a strategy for the treatment of M., avium in T cell-deficient hosts based on the simultaneous administration of antibiotics and the immunomodulatory cytokine IL-12, In contrast to SCID mice, which were partially resistant, animals lacking a functional IL-12 p40 gene were found to be highly susceptible to M., avium infection, suggesting that the cytokine can control bacterial growth even in immunodeficient mice. Indeed, rIL-12 that was injected into infected SCID mice in high doses caused small but significant reductions in splenic pathogen loads. Moreover, a lower dose of IL-12, when combined with the antimycobacterial drags clarithromycin or rifabutin, induced a decrease in bacterial numbers that was significantly greater than that resulting from Me administration of the cytokine or drop alone. A similar synergistic effect of IL-12 and antibiotics was seen when immunocompetent mice were treated with the same regimen. The activity of IL-12 in these experiments was shown to be dependent upon the induction of endogenous IFN-gamma. Nevertheless, IFN-gamma itself, even when given at a higher dose than IL-12, failed to significantly enhance antibiotic clearance of bacteria, Together these findings suggest that IL-12 may be a particularly potent adjunct for chemotherapy of M., avium infection in immunocompromised individuals and may result in more effective control of the pathogen without the need for increased drug dosage. C1 NIAID, Parasit Dis Lab, NIH, Immunobiol Sect, Bethesda, MD 20892 USA. RP Doherty, TM (reprint author), NIAID, Parasit Dis Lab, NIH, Immunobiol Sect, Bldg 4,Room B1-06,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 59 TC 62 Z9 63 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 1998 VL 160 IS 11 BP 5428 EP 5435 PG 8 WC Immunology SC Immunology GA ZP269 UT WOS:000073735400031 PM 9605144 ER PT J AU Siders, WM Wright, PW Hixon, JA Alvord, WG Back, TC Wiltrout, RH Fenton, RG AF Siders, WM Wright, PW Hixon, JA Alvord, WG Back, TC Wiltrout, RH Fenton, RG TI T cell- and NK cell-independent inhibition of hepatic metastases by systemic administration of an IL-12-expressing recombinant adenovirus SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERFERON-INDUCIBLE PROTEIN-10; STIMULATORY FACTOR INTERLEUKIN-12; LYMPHOCYTE MATURATION FACTOR; MURINE RENAL-CARCINOMA; ANGIOGENESIS IN-VIVO; IFN-GAMMA PRODUCTION; CYTOTOXIC ACTIVITY; TUMOR-REGRESSION; GENE-THERAPY; IL-12 AB IL-12 is a potent immunoregulatory cytokine that has been shown to mediate tumor regression in a variety of tumor models. We describe the construction of AdCMV-IL-12, a recombinant adenovirus that encodes both subunits of IL-12 under transcriptional control of the CMV promoter. This recombinant virus efficiently infects a wide variety of cell types leading to the production of high levels of biologically active IL-12, Because the liver is a primary site of infection after i.v.-administered adenovirus, we tested the therapeutic efficacy of this virus in a murine hepatic metastasis tumor model, Systemic administration of AdCMV-IL-12 dramatically inhibited the formation of 3-day Renca hepatic metastases (mean of 16 metastases per liver) compared with the control virus AdCMV-beta gal (mean of 209) or vehicle alone (mean of 272), Histologic analysis indicated that metastatic growth inhibition was accompanied by a dramatic perivascular infiltrate consisting of T Cells, macrophages, and neutrophils, Therapeutic efficacy was not diminished in animals depleted of CD4(+) or CD8(+) T cells, or in SCID mice, even after NK cell ablation, In the latter case, a hepatic perivascular infiltrate composed of macrophages and neutrophils was observed after AdCMV-IL-12-treatment, while numerous activated Kupffer cells were noted in the hepatic parenchyma, Analysis of therapy-induced changes in hepatic gene expression demonstrated increased levels of IP-10 and Mig RNAs, but no increase in iNOS, Fas, or Fast RNA levels was observed. Our data suggest a model of metastatic growth inhibition mediated by nonlymphocyte effector cells including macrophages and neutrophils and that may involve anti-angiogenic chemokines. C1 NCI, Frederick Canc Res & Dev Ctr, Dept Expt Transplantat & Immunol, Div Clin Sci, Frederick, MD USA. Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD USA. NCI, Frederick Canc Res & Dev Ctr, Expt Immunol Lab, Div Basic Sci, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Data Management Serv, Frederick, MD 21702 USA. RP Fenton, RG (reprint author), Univ Maryland, Greenebaum Canc Ctr, 22 S Green St, Baltimore, MD 21201 USA. NR 56 TC 54 Z9 58 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 1998 VL 160 IS 11 BP 5465 EP 5474 PG 10 WC Immunology SC Immunology GA ZP269 UT WOS:000073735400036 PM 9605149 ER PT J AU Domachowske, JB Dyer, KD Bonville, CA Rosenberg, HF AF Domachowske, JB Dyer, KD Bonville, CA Rosenberg, HF TI Recombinant human eosinophil-derived neurotoxin/RNase 2 functions as an effective antiviral agent against respiratory syncytial virus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID RIBONUCLEASE GENE FAMILY; CATIONIC PROTEIN; SCHISTOSOMA-MANSONI; GRANULE PROTEINS; MOLECULAR-CLONING; CELL-LINE; INFECTION; BLOOD; INHIBITION; ANTIBODY AB A dose-dependent decrease in infectivity was observed on introduction of eosinophils into suspensions of respiratory syncytial virus group B (RSV-B). This antiviral effect was reversed by ribonuclease inhibitor, suggesting a role for the eosinophil secretory ribonucleases. Recombinant eosinophil-derived neurotoxin (rhEDN), the major eosinophil ribonuclease, promoted a dose-dependent decrease in RSV-B infectivity, with a 40-fold reduction observed in response to 50 nM rhEDN. Ribonucleolytically inactivated rhEDN (rhEDNdK(38)) had no antiviral activity. Semiquantitative reverse transcriptase-polymerase chain reaction demonstrated loss of viral genomic RNA in response to rhEDN, suggesting that this protein promotes the direct ribonucleolytic destruction of extracellular virions. Ribonuclease A had no antiviral activity even at similar to 1000-fold higher concentrations, suggesting that rhEDN has unique features other than ribonuclease activity that are crucial to its effectiveness. These results suggest that rhEDN may have potential as a therapeutic agent for prevention or treatment of disease caused by RSV. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. SUNY Hlth Sci Ctr, Dept Pediat, Syracuse, NY 13210 USA. RP Rosenberg, HF (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Room 11N104,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hr2k@nih.gov NR 69 TC 157 Z9 161 U1 2 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN PY 1998 VL 177 IS 6 BP 1458 EP 1464 DI 10.1086/515322 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA ZP618 UT WOS:000073771500003 PM 9607820 ER PT J AU Thomas, DL Villano, SA Riester, KA Hershow, R Mofenson, LM Landesman, SH Hollinger, FB Davenny, K Riley, L Diaz, C Tang, HB Quinn, TC AF Thomas, DL Villano, SA Riester, KA Hershow, R Mofenson, LM Landesman, SH Hollinger, FB Davenny, K Riley, L Diaz, C Tang, HB Quinn, TC CA Women Infants Transmission Study TI Perinatal transmission of hepatitis C virus from human immunodeficiency virus type 1-infected mothers SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 18th Joint US/Japan Hepatitis Panel Conference CY NOV, 1996 CL NAGASAKI, JAPAN ID TO-INFANT TRANSMISSION; NON-B-HEPATITIS; RECOMBINANT INTERFERON-ALFA; POLYMERASE CHAIN-REACTION; VERTICAL TRANSMISSION; RNA LEVELS; NON-A; CHILD TRANSMISSION; CONTROLLED TRIAL; INFECTION AB Antepartum plasma hepatitis C virus (HCV) RNA was quantified in 155 mothers coinfected with HCV and human immunodeficiency virus type 1 (HIV-1), and HCV RNA was serially assessed in their infants. Of 155 singleton infants born to HCV antibody-positive mothers, 13 (8.4%) were HCV infected. The risk of HCV infection was 3.2-fold greater in HIV-l-infected infants compared with HIV-1-uninfected infants (17.1% of 41 vs. 5.4% of 112, P = .04). The median concentration of plasma HCV RNA was higher among the 13 mothers with HCV-infected infants (2.0 x 10(6) copies/mL) than among the 142 mothers with HCV-negative infants (3.5 x 10(5) copies/mL; P < .001), and there were no instances of HCV transmission from 40 mothers with HCV RNA concentrations of <10(5) copies/mL. Women dually infected with HIV-I and HCV but with little or no detectable HCV RNA should be reassured that the risk of perinatal transmission of HCV is exceedingly low. C1 Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. NIDA, NIH, Rockville, MD USA. NICHD, Pediat Adolescent & Maternal AIDS Branch, NIH, Rockville, MD USA. NIAID, NIH, Bethesda, MD 20892 USA. New England Res Inst, Watertown, MA 02172 USA. Boston City Hosp, Dept Obstet & Gynecol, Boston, MA 02118 USA. Univ Illinois, Coll Med, Chicago, IL USA. Univ Illinois, Sch Publ Hlth, Chicago, IL USA. SUNY Hlth Sci Ctr, Div Infect Dis, Brooklyn, NY 11203 USA. Columbia Presbyterian Hosp, Dept Pediat, New York, NY USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Univ Puerto Rico, San Juan, PR 00936 USA. RP Thomas, DL (reprint author), Johns Hopkins Univ, Sch Med, Div Infect Dis, 1147E Ross Res Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. RI Quinn, Thomas/A-2494-2010; OI Mofenson, Lynne/0000-0002-2818-9808 FU NIAID NIH HHS [AI-34858, AI-40035]; NIDA NIH HHS [DA-00232] NR 55 TC 132 Z9 139 U1 0 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN PY 1998 VL 177 IS 6 BP 1480 EP 1488 DI 10.1086/515315 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA ZP618 UT WOS:000073771500006 PM 9607823 ER PT J AU Kavlick, MF Wyvill, K Yarchoan, R Mitsuya, H AF Kavlick, MF Wyvill, K Yarchoan, R Mitsuya, H TI Emergence of multi-dideoxynucleoside-resistant human immunodeficiency virus type 1 variants, viral sequence variation, and disease progression in patients receiving antiretroviral chemotherapy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HIGH-LEVEL RESISTANCE; POL GENE-MUTATIONS; REVERSE-TRANSCRIPTASE; COMBINATION THERAPY; DRUG-RESISTANCE; ZIDOVUDINE AZT; 2',3'-DIDEOXYCYTIDINE; SUSCEPTIBILITY; INHIBITORS; PASSAGE AB A set of five reverse transcriptase mutations, which include Q151M, is known to confer multidideoxynucleoside resistance (MDR) in human immunodeficiency virus type 1 (HIV-1). MDR mutations were found in 6 (17%) HIV-I isolates from 36 patients, most of whom were receiving long-term combination therapy. Q151M was among the first of the substitutions to appear. Additional substitutions were observed, although none were common among all 6 patients, Certain zidovudine-related mutations were not observed together with the MDR mutations, indicating possible enzymatic constraint. During chemotherapy, the HIV-1 RNA levels in the 6 patients initially decreased and then rose. Initially, CD4 cell counts also responded favorably but were near or below baseline beyond 40 months of therapy. Such loss of clinical benefits appeared to coincide with the appearance of the MDR mutations. A common background genotype was not observed among HIV-1 isolates with or without MDR. C1 NCI, Expt Retrovirol Sect, Med Branch, NIH, Bethesda, MD 20892 USA. NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Mitsuya, H (reprint author), NCI, Expt Retrovirol Sect, Med Branch, NIH, Bldg 10,Rm 5A11, Bethesda, MD 20892 USA. NR 31 TC 58 Z9 60 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN PY 1998 VL 177 IS 6 BP 1506 EP 1513 DI 10.1086/515324 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA ZP618 UT WOS:000073771500010 PM 9607827 ER PT J AU Ockenhouse, CF Sun, PF Lanar, DE Wellde, BT Hall, BT Kester, K Stoute, JA Magill, A Krzych, U Farley, L Wirtz, RA Sadoff, JC Kaslow, DC Kumar, S Church, LWP Crutcher, JM Wizel, B Hoffman, S Lalvani, A Hill, AVS Tine, JA Guito, KP de Taisne, C Anders, R Horii, T Paoletti, E Ballou, WR AF Ockenhouse, CF Sun, PF Lanar, DE Wellde, BT Hall, BT Kester, K Stoute, JA Magill, A Krzych, U Farley, L Wirtz, RA Sadoff, JC Kaslow, DC Kumar, S Church, LWP Crutcher, JM Wizel, B Hoffman, S Lalvani, A Hill, AVS Tine, JA Guito, KP de Taisne, C Anders, R Horii, T Paoletti, E Ballou, WR TI Phase I/IIa safety, immunogenicity, and efficacy trial of NYVAC-Pf7, a pox-vectored, multiantigen, multistage vaccine candidate for Plasmodium falciparum malaria SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID GENETICALLY ENGINEERED POXVIRUSES; GLYCOPROTEIN-D; BIOLOGICAL-ACTIVITY; ESCHERICHIA-COLI; ENVELOPE GENE; LIVE VACCINES; VIRUS; PROTECTION; PROTEIN; HERPES AB Candidate malaria vaccines have failed to elicit consistently protective immune responses against challenge with Plasmodium falciparum. NYVAC-Pf7, a highly attenuated vaccinia virus with 7 P. falciparum genes inserted into its genome, was tested in a phase I/IIa safety, immunogenicity, and efficacy vaccine trial in human volunteers. Malaria genes inserted into the NYVAC genome encoded proteins from all stages of the parasite's life cycle. Volunteers received three immunizations of two different dosages of NYVAC-Pf7. The vaccine was safe and well tolerated but variably immunogenic. While antibody responses were generally poor, cellular immune responses were detected in >90% of the volunteers. Of the 35 volunteers challenged with the bite of 5 P. falciparum-infected Anopheles mosquitoes, 1 was completely protected, and there was a significant delay in time to parasite patency in the groups of volunteers who received either the low or high dose of vaccine compared with control volunteers. C1 Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Dept Immunol, Washington, DC 20307 USA. USN, Med Res Inst, Malaria Program, Bethesda, MD USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Oxford, Inst Mol Med, Oxford, England. Virogenet Corp, Troy, NY USA. Connaught Labs Inc, Swiftwater, PA 18370 USA. Pasteur Merieux Connaught, Marcy Letoile, France. Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, Australia. Osaka Univ, Microbial Dis Res Inst, Osaka, Japan. RP Ockenhouse, CF (reprint author), Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Dept Immunol, Washington, DC 20307 USA. EM LTC_Chris_Ockenhouse@wrsmtp-ccmail.army.mil RI HILL, Adrian/C-1306-2008; Kester, Kent/A-2114-2011; Lanar, David/B-3560-2011 OI Kester, Kent/0000-0002-5056-0802; NR 27 TC 167 Z9 176 U1 0 U2 4 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN PY 1998 VL 177 IS 6 BP 1664 EP 1673 DI 10.1086/515331 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA ZP618 UT WOS:000073771500030 PM 9607847 ER PT J AU af Geijersstam, V Kibur, M Wang, ZH Koskela, P Pukkala, E Schiller, J Lehtinen, M Dillner, J AF af Geijersstam, V Kibur, M Wang, ZH Koskela, P Pukkala, E Schiller, J Lehtinen, M Dillner, J TI Stability over time of serum antibody levels to human papillomavirus type 16 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 15th International Papillomavirus Workshop CY DEC 01-09, 1996 CL BRISBANE, AUSTRALIA ID HPV DNA; NEOPLASIA; CAPSIDS; COHORT; WOMEN AB The stability over time of serum IgG antibody levels to human papillomavirus type 16 (HPV-16) was determined by comparing the HPV-16 capsid antibody levels in serial serum samples of an age-stratified random subsample of 1656 primiparous mothers resident in Helsinki who were followed until their second pregnancy, on average 29.5 months later. The correlation between the first and second pregnancy HPV-16 serum antibody levels of the same woman was high, even when >4 years had elapsed between pregnancies (r = .822). Between negativity, indeterminate results, or quartiles of positivity, the predictive values for being classified in the same category on both occasions ranged between 42% and 91%. Correlation coefficients, predictive values, and kappa coefficients between serial samples all were comparable with those of repeat analyses of the same sample, indicating that HPV capsid antibody levels are generally stable during several years of follow-up. C1 Karolinska Inst, Ctr Microbiol & Tumor Biol, S-17177 Stockholm, Sweden. Inst Clin & Expt Med, Dept Biostat & Epidemiol, Tallinn, Estonia. Univ Tampere, Sch Publ Hlth, Natl Publ Hlth Inst, Dept Infect Dis Epidemiol Helsinki & Oulu, FIN-33101 Tampere, Finland. Finnish Canc Registry, FIN-00170 Helsinki, Finland. NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Dillner, J (reprint author), Karolinska Inst, Ctr Microbiol & Tumor Biol, Box 280, S-17177 Stockholm, Sweden. EM Joakim.Dillner@mtc.ki.se NR 14 TC 74 Z9 75 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN PY 1998 VL 177 IS 6 BP 1710 EP 1714 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA ZP618 UT WOS:000073771500037 PM 9607854 ER PT J AU Mayers, D Bethel, J Wainberg, MA Weislow, O Schnittman, S AF Mayers, D Bethel, J Wainberg, MA Weislow, O Schnittman, S CA Div AIDS Treat Res Init 003 Study Gr TI Human immunodeficiency virus proviral DNA from peripheral blood and lymph nodes demonstrates concordant resistance mutations to zidovudine (codon 215) and didanosine (codon 74) SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID REVERSE-TRANSCRIPTASE; COMBINATION THERAPY; DRUG-RESISTANCE; DISEASE; STAGE AB Genotypes that confer drug resistance were evaluated in human immunodeficiency virus (HIV) proviral DNA obtained from peripheral blood mononuclear cells (PBMC) and lymphoid tissue at baseline and after 8 weeks of therapy with zidovudine alone or in combination with didanosine from 22 patients (8 zidovudine-naive and 14 zidovudine-experienced). There was evidence of zidovudine resistance at codon 215 in 27.3% (6/22) of patients. All 20 patients evaluable for codon 74 (site of didanosine resistance) had virus that remained wild type during the 8-week study period, When HIV proviral DNA from PBMC was compared, with that from lymphoid tissue, 94.7% (18/19) of evaluable samples were concordant at codon 215 at baseline, while 85.7% (12/14) were concordant at week 8, Resistance in PBMC (but not in lymphoid tissue) developed in 1 of 8 zidovudine-naive patients; an increased proportion of resistant strains in PBMC (but not in lymphoid tissue) was observed in 2 of 14 zidovudine-experienced patients. These results suggest high concordance for drug resistance mutations in HIV proviral DNA from blood and lymph node tissue. C1 USN, Med Res Inst, Bethesda, MD USA. NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. WESTAT Inc, Rockville, MD USA. SRA Technol, Rockville, MD USA. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Washington, DC 20307 USA. Sir Mortimer B Davis Jewish Hosp, Montreal, PQ H3T 1E2, Canada. RP Mayers, D (reprint author), 8901 Wisconsin Ave,POB 207, Bethesda, MD 20889 USA. FU NIAID NIH HHS [AI-15123] NR 15 TC 6 Z9 6 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN PY 1998 VL 177 IS 6 BP 1730 EP 1733 DI 10.1086/517433 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA ZP618 UT WOS:000073771500042 PM 9607859 ER PT J AU Dittmer, U Hunsmann, G AF Dittmer, U Hunsmann, G TI Antiviral CD4 cell response in simian immunodeficiency virus-infected macaques SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID APOPTOSIS C1 German Primate Ctr, Dept Virol & Immunol, Gottingen, Germany. RP Dittmer, U (reprint author), NIAID, NIH, Persistent Viral Dis Lab, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM udittmer@atlas.niaid.nih.gov NR 10 TC 2 Z9 2 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN PY 1998 VL 177 IS 6 BP 1771 EP 1771 DI 10.1086/517414 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA ZP618 UT WOS:000073771500053 PM 9607870 ER PT J AU Guru, SC Manickam, P Crabtree, JS Olufemi, SE Agarwal, SK Debelenko, LV Zhuang, Z Lubensky, IA Kester, MB Kim, YS Heppner, C Weisemann, JM Boguski, MS Wang, Y Roe, BA Burns, AL Liotta, LA Spiegel, AM Emmert-Buck, MR Marx, SJ Collins, FS Chandrasekharappa, SC AF Guru, SC Manickam, P Crabtree, JS Olufemi, SE Agarwal, SK Debelenko, LV Zhuang, Z Lubensky, IA Kester, MB Kim, YS Heppner, C Weisemann, JM Boguski, MS Wang, Y Roe, BA Burns, AL Liotta, LA Spiegel, AM Emmert-Buck, MR Marx, SJ Collins, FS Chandrasekharappa, SC TI Identification and characterization of the multiple endocrine neoplasia type 1 (MEN1) gene SO JOURNAL OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 6th International Workshop on Multiple Endocrine Neoplasia and von Hippel-Lindau Disease CY JUN 25-28, 1997 CL NOORDWIJKERHOUT, NETHERLANDS DE 11q13; contig; LOH; MEN-1; menin; mutations; transcripts ID HUMAN DNA; FRAGMENTS; CLONING; VECTOR AB For nearly a decade since the mapping of the multiple endocrine neoplasia type 1 (MEN1) locus to 11q13 and the suggestion that it is a tumour suppressor gene, efforts have been made to identify the gene responsible for this familial cancer syndrome, Recently, we have identified the MEN1 gene by the positional cloning approach. This effort involved construction of a 2.8-Mb physical map (D11S480-D11S913) based primarily on a bacterial clone contig, Using these resources, 20 new polymorphic markers were isolated which helped to reduce the interval for candidate genes by haplotype analysis in families and by loss of heterozygosity (LOH) studies in approximately 200 tumours, utilizing laser-assisted microdissection to obtain tumour cells with minimal or no admixture by normal cells. The interval was narrowed by LOH to only 300 kb, and nearly 20 new transcripts that map to this region of 11q13 were isolated and characterized. One of the transcripts was found. by dideoxyfingerprinting and cycle sequencing to harbour deleterious germline mutations in affected individuals from MEN-1 kindreds and therefore identified as the MEN1 gene, The type of germline mutations and the identification of mutations in sporadic tumours support the Knudson's two-hit model of tumorigenesis for MEN-1, Efforts are being made to identify the function of the MEN1 gene-encoded protein, menin, and to study its role in tumorigenesis. C1 Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Metab Dis Branch, Bethesda, MD USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. NIH, Natl Ctr Biotechnol Informat, NLM, Bethesda, MD 20892 USA. Univ Oklahoma, Dept Chem, Norman, OK 73019 USA. Univ Oklahoma, Dept Biochem, Norman, OK 73019 USA. RP Chandrasekharappa, SC (reprint author), Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bldg 49,Room 3E-13,49 Convent Dr,MSC 4442, Bethesda, MD 20892 USA. EM chandra@nhgri.nih.gov RI Agarwal, Sunita/D-1428-2016 OI Agarwal, Sunita/0000-0002-7557-3191 NR 23 TC 26 Z9 26 U1 1 U2 2 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 1998 VL 243 IS 6 BP 433 EP 439 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA ZZ238 UT WOS:000074709400005 PM 9681840 ER PT J AU Marx, SJ Agarwal, SK Kester, MB Heppner, C Kim, YS Emmert-Buck, MR Debelenko, LV Lubensky, IA Zhuang, Z Guru, SC Manickam, P Olufemi, SE Skarulis, MC Doppman, JL Alexander, RH Liotta, LA Collins, FS Chandrasekharappa, SC Spiegel, AM Burns, AL AF Marx, SJ Agarwal, SK Kester, MB Heppner, C Kim, YS Emmert-Buck, MR Debelenko, LV Lubensky, IA Zhuang, Z Guru, SC Manickam, P Olufemi, SE Skarulis, MC Doppman, JL Alexander, RH Liotta, LA Collins, FS Chandrasekharappa, SC Spiegel, AM Burns, AL TI Germline and somatic mutation of the gene for multiple endocrine neoplasia type 1 (MEN1) SO JOURNAL OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 6th International Workshop on Multiple Endocrine Neoplasia and von Hippel-Lindau Disease CY JUN 25-28, 1997 CL NOORDWIJKERHOUT, NETHERLANDS DE gastrinoma; oncogene; parathyroid adenoma; tumour suppressor ID PRIMARY PARATHYROID HYPERPLASIA; TUMOR-SUPPRESSOR GENE; PRIMARY HYPERPARATHYROIDISM; CHROMOSOME-11; METHYLATION; SCREEN; MAPS AB Dideoxyfingerprinting was used to screen for germline and somatic MEN1 mutations. This method, applied to a panel of germline DNA from 15 probands with multiple endocrine neoplasia type 1 (MEN-1), allowed confident discovery of the MEN1 gene, Germline MEN1 mutation has been found in 47 out of 50 probands with familial MEN-1, in 7 out of 8 cases with sporadic MEN-1, and in 1 out of 3 cases with atypical sporadic MEN-1. Germline MEN1 mutation was not found in any of five probands with familial hyperparathyroidism. Somatic MEN1 mutations were found in 7 out of 33 parathyroid tumours not associated with MEN-1. Allowing for repeating mutations, a total of 47 different germline or somatic MEN1 mutations have been identified. Most predict inactivation of the encoded 'menin' protein, supporting expectations that MEN1 is a tumour suppressor gene, The 16 observed missense mutations were distributed across the gene, suggesting that many domains are important to its as yet unknown functions. C1 NIDDK, Genet & Endocrinol Sect, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NHGRI, Lab Gene Transfer, NIH, Bethesda, MD USA. NIH, Dept Diagnost Radiol, CC, Bethesda, MD USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Marx, SJ (reprint author), NIDDK, Genet & Endocrinol Sect, Metab Dis Branch, NIH, Bldg 10,Room 9C-101, Bethesda, MD 20892 USA. EM StephenM@ambintra.niddk.nih.gov RI Agarwal, Sunita/D-1428-2016 OI Agarwal, Sunita/0000-0002-7557-3191 NR 41 TC 31 Z9 32 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 1998 VL 243 IS 6 BP 447 EP 453 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA ZZ238 UT WOS:000074709400007 PM 9681842 ER PT J AU Jensen, RT AF Jensen, RT TI Management of the Zollinger-Ellison syndrome in patients with multiple endocrine neoplasia type 1 SO JOURNAL OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 6th International Workshop on Multiple Endocrine Neoplasia and von Hippel-Lindau Disease CY JUN 25-28, 1997 CL NOORDWIJKERHOUT, NETHERLANDS DE gastric carcinoid tumour; gastrinoma; islet tumour; omeprazole ID SOMATOSTATIN-RECEPTOR SCINTIGRAPHY; GASTRIC HYPERSECRETORY STATES; LONG-TERM EFFICACY; DUODENAL GASTRINOMAS; AGGRESSIVE RESECTION; PANCREATIC TUMORS; GASTROENTEROPANCREATIC TUMORS; ENDOSCOPIC ULTRASONOGRAPHY; ACID HYPERSECRETION; SURGICAL-TREATMENT AB Zollinger-Ellison syndrome (ZES) is the most common symptomatic pancreatic endocrine tumour in patients with MEN-1. Besides the treatment of the usual endocrinopathies seen in patients with MEN-1, the treatment of the ZES requires attention be paid to controlling the gastric acid hypersecretion, to dealing with the gastrinomas per se which are malignant in 18-60% of cases, and to the diagnosis and treatment of gastric carcinoid tumours, that are increasingly seen in these patients. In this article the current management of each of the areas is reviewed and what is known or uncertain discussed, based on our studies at the NIH and data from others. Data from 231 patients including 45 with MEN-1 and 186 without MEN-1 is contrasted in this report. Gastric acid hypersecretion has been controlled in all patients medically with MEN-1 and ZES at the NIH for up to 22 years, The current drugs of choice are H+-K+ ATPase inhibitors and twice a day dosing is recommended, Periods of parenteral drug therapy (surgery, etc.) and pregnancy require important modifications. The appropriate surgical therapy of the gastrinoma is controversial. Eighty per cent of patients have a duodenal gastrinoma and 20-30% have a pancreatic tumour. Recent studies suggest gastrinoma enucleation combined with duodenotomy rarely results in cure. Aggressive surgery (Whipple resection) can result in cure of gastrinoma but effect on survival is unclear. There are important differences in gastrinoma location, extent, and percentage with aggressive disease in patients with or without MEN-1, which are discussed. Confusion has occurred because of lack of information on the natural history of the gastrinoma compared to the other pancreatic endocrine tumours that occur in MEN-1 and survival data from patients with and without MEN-1 is contrasted. The occurrence of gastric carcinoids in patients with and without MEN-1 with ZES is contrasted and the areas of certainty and disagreement reviewed. C1 NIDDK, NIH, DDB, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIDDK, NIH, DDB, Bldg 10,Room 9C103,10 Ctr Dr MSC 1804, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov NR 92 TC 108 Z9 111 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 1998 VL 243 IS 6 BP 477 EP 488 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA ZZ238 UT WOS:000074709400011 PM 9681846 ER PT J AU Chrousos, GP Stratakis, CA AF Chrousos, GP Stratakis, CA TI Carney complex and the familiar lentiginosis syndromes: link to inherited neoplasias and developmental disorders, and genetic loci SO JOURNAL OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 6th International Workshop on Multiple Endocrine Neoplasia and von Hippel-Lindau Disease CY JUN 25-28, 1997 CL NOORDWIJKERHOUT, NETHERLANDS DE Carney complex; familial cancer; lentiginosis ID ENDOCRINE OVERACTIVITY; SPOTTY PIGMENTATION; MYXOMAS; CANCER AB Lentigines, synonymous but not identical to freckles or ephelides, are common skin lesions. In a small number of patients, however, these lesions constitute part of genetic syndromes that are associated with inherited forms of neoplasias or other pathologic processes of the cardiovascular, endocrine, and gastrointestinal systems. The familial lentiginoses, as these syndromes are collectively known, include Carney complex, the LEOPARD and Peutz-Jeghers syndromes, and the newly described 'syndrome of arterial dissections with lentiginosis'; isolated, familial lentiginosis has also been described. In the majority of the reported kindreds with these syndromes, the lesions were inherited in an autosomal dominant manner. The specific genes that are responsible for these disorders have remained elusive, but the genetic loci of Carney complex and Peutz-Jeghers syndromes were recently identified on chromosomes 2p 16 and distal 19p, respectively, Cytogenetic:studies of tumours from patients with Carney complex suggest that the gene responsible for most patients with this syndrome may not have a tumour suppression function, We suggest that the genes responsible for the lentiginosis syndromes are important regulators of melanocyte function, they participate in the pleiotropy of human pigmentation, and are involved in the function, growth and proliferation of neural crest and mesenchymal cells. C1 NICHHD, Dev Endocrinol Branch, Sect Pediat Endocrinol, NIH, Bethesda, MD 20892 USA. RP Chrousos, GP (reprint author), NICHHD, Dev Endocrinol Branch, Sect Pediat Endocrinol, NIH, Bldg 10,Room 10N 262,9000 Rockville Pike, Bethesda, MD 20892 USA. EM George_Chrousos@nih.gov NR 26 TC 14 Z9 14 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 1998 VL 243 IS 6 BP 573 EP 579 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA ZZ238 UT WOS:000074709400026 PM 9681861 ER PT J AU Farber, JM AF Farber, JM TI Chemokines and lymphocytes: Novel receptors and HIV SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Article; Proceedings Paper CT Midwest AFMR Symposium CY SEP 26, 1997 CL CHICAGO, ILLINOIS ID INFECTION; TRANSMISSION; GENE; IDENTIFICATION; PATHOGENESIS; MIP-1-ALPHA; PROGRESSION; INDIVIDUALS; MIP-1-BETA; CORECEPTOR C1 NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Farber, JM (reprint author), NIAID, Clin Invest Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 32 TC 2 Z9 2 U1 0 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD JUN PY 1998 VL 46 IS 5 BP 197 EP 203 PG 7 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA ZZ442 UT WOS:000074729800002 PM 9676051 ER PT J AU Remaley, AT Farsi, BD Shirali, AC Hoeg, JM Brewer, HB AF Remaley, AT Farsi, BD Shirali, AC Hoeg, JM Brewer, HB TI Differential rate of cholesterol efflux from the apical and basolateral membranes of MDCK cells SO JOURNAL OF LIPID RESEARCH LA English DT Article DE cholesterol efflux; high density lipoprotein; cholesterol; atherosclerosis ID HIGH-DENSITY-LIPOPROTEIN; RED-BLOOD-CELLS; EPITHELIAL-CELLS; LIPID-COMPOSITION; EXCHANGE; POLARITY; KINETICS AB Epithelial cells contain two distinct membrane surfaces, the apical and basolateral plasma membranes, which have different lipid and protein compositions, In order to assess the effect of the compositional differences of the apical and basolateral membranes on their ability to undergo cholesterol efflux, MDCK cells were radiolabeled with [H-3]cholesterol and grown as a polarized monolayer on filter inserts, that separate the upper apical compartment from the lower basolateral compartment, The rate of cholesterol efflux from the basolateral membrane into media containing HDL in the basolateral compartment was 6.3%/h +/- 0.7, whereas HDL-mediated efflux from the apical membrane was approximately 3-fold slower (1.9%/h +/- 0.3). In contrast, Fu5AH cells, which do not form distinct polarized membrane domains, had a similar rate of HDL-mediated cholesterol efflux into the apical and basolateral compartments. Similar to HDL, other cholesterol accepters, namely LDL, bovine serum albumin, and a lipid emulsion, also showed a decreased rate of cholesterol efflux from the apical membrane surface versus the basolateral membrane, Compared to the basolateral membrane, the apical membrane was also found to be more resistant to cholesterol oxidase treatment, to bind less HDL, and to take up less cholesterol from the medium. In conclusion, cholesterol efflux occurred less readily from the apical membrane than from the basolateral membrane for all types of accepters tested. These results suggest that differences in the composition of the apical and basolateral membrane lead to a relative decrease in cholesterol desorption from the apical membrane and hence a reduced rate of cholesterol efflux. C1 NIH, Dept Clin Pathol, Ctr Clin, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Remaley, AT (reprint author), NIH, Dept Clin Pathol, Ctr Clin, Bldg 10-2C-431, Bethesda, MD 20892 USA. NR 21 TC 13 Z9 13 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 JUN PY 1998 VL 39 IS 6 BP 1231 EP 1238 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZT264 UT WOS:000074067200011 PM 9643354 ER PT J AU Rubinson, KA Cook, JA Mitchell, JB Murugesan, R Krishna, MC Subramanian, S AF Rubinson, KA Cook, JA Mitchell, JB Murugesan, R Krishna, MC Subramanian, S TI FT-EPR with a nonresonant probe: Use of a truncated coaxial line SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE nonresonant; coaxial FT-EPR probe; magnetic resonance probes ID RESONANCE AB A truncated transmission line probe (TLP) has been utilized to excite and detect time domain responses after pulsed excitation in electron paramagnetic resonance (EPR) spectroscopic experiments in the frequency range 200-400 MHz, The TLP device is a modified short-circuited coaxial line, which allows the irradiation of the sample by the traveling wave B-1 fields in the frequency range of kilohertz to 30 GHz. In EPR studies at 300 MHz carrier frequency, with 10 W incident power, a 45 degrees pulse is 45 ns in duration. This corresponds to a 0.9-G B-1 field, Using the TLP, time-domain responses from the solid N-methyl pyridinium tetracyanoquinodimethane (TCNQ) were collected at 200, 250, 300, and 350 MHz, with the range limited by the amplifiers. In addition two tubes containing TCNQ placed side-by-side vertically dong the axis of the probe were used to collect time domain responses in the presence of magnetic field gradients to test the feasibility of two-dimensional imaging using a TLP. The magnetic field gradient was steered in the xz plane and 36 projections were collected at 5 degrees intervals, Using filtered back-projection image reconstruction, the two-dimensional spatial image in the xz plane was obtained at good resolution. (C) 1998 Academic Press. C1 Five Oaks Res Inst, Cincinnati, OH 45238 USA. NCI, NIH, Radiat Biol Sect, Bethesda, MD 20892 USA. RP Rubinson, KA (reprint author), Five Oaks Res Inst, 354 Oakwood Pk Dr, Cincinnati, OH 45238 USA. NR 16 TC 7 Z9 7 U1 1 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD JUN PY 1998 VL 132 IS 2 BP 255 EP 259 DI 10.1006/jmre.1998.1409 PG 5 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA ZU605 UT WOS:000074214800008 ER PT J AU Ghabrah, TM Tsarev, S Yarbough, PO Emerson, SU Strickland, GT Purcell, RH AF Ghabrah, TM Tsarev, S Yarbough, PO Emerson, SU Strickland, GT Purcell, RH TI Comparison of tests for antibody to hepatitis E virus SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE hepatitis E; antibody; HEV genome ID LINKED-IMMUNOSORBENT-ASSAY; INSECT CELLS; ENZYME; IDENTIFICATION; DIAGNOSIS; PAKISTAN; PROTEIN; IGG AB The results of serologic tests for hepatitis E virus have varied widely from laboratory to laboratory, making interpretation of seroepidemiologic studies difficult. The present study com pares serologic results with different antigens and tests developed in two laboratories for their ability to diagnose hepatitis E and measure antibody prevalence in a high risk population in Saudi Arabia. The results confirm that tests based upon open reading frame (ORF) 3 of HEV are of limited value for seroepidemiologic studies, whereas ORF2-based antigens have broad utility and yield data that are reproducible in more than one laboratory. (C) 1998 Wiley-Liss, Inc. C1 NIAID, LID, Hepatitis Viruses Sect, NIH, Bethesda, MD 20892 USA. Genelabs Technol Inc, Redwood City, CA USA. King Abdulaziz Univ, Coll Med & Allied Sci, Dept Community Med & Primary Hlth Care, Jeddah 21413, Saudi Arabia. Univ Maryland, Dept Epidemiol & Prevent Med, Int Hlth Program, Baltimore, MD 21201 USA. RP Purcell, RH (reprint author), NIAID, LID, Hepatitis Viruses Sect, NIH, Bldg 7 Room 202,7 Ctr Dr,MSC 0740, Bethesda, MD 20892 USA. NR 17 TC 57 Z9 70 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 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD JUN PY 1998 VL 55 IS 2 BP 134 EP 137 DI 10.1002/(SICI)1096-9071(199806)55:2<134::AID-JMV9>3.0.CO;2-3 PG 4 WC Virology SC Virology GA ZL210 UT WOS:000073409800009 PM 9598934 ER PT J AU Couse, JF Korach, KS AF Couse, JF Korach, KS TI Exploring the role of sex steroids through studies of receptor deficient mice SO JOURNAL OF MOLECULAR MEDICINE-JMM LA English DT Review DE androgen receptor; estrogen receptor; gonads; infertility; mammary gland; progesterone receptor; sexual behavior ID MESSENGER-RIBONUCLEIC-ACID; EPIDERMAL GROWTH-FACTOR; OSTEOBLAST-LIKE CELLS; FEMINIZED TFM MOUSE; ESTROGEN-RECEPTOR; PROGESTERONE-RECEPTOR; ANDROGEN RECEPTOR; TESTICULAR FEMINIZATION; TARGETED DISRUPTION; LUTEINIZING-HORMONE AB Decades of study have described a number roles fulfilled by the steroid hormones and their respective receptors in sexual differentiation and development, reproductive function and behavior, and more recently in the function and maintenance of non-reproductive organ systems, such as skeletal muscle, bone and coronary tissues. The biologi cal effects of the steroid hormones are believed to be mediated in part by specific receptor proteins that demonstrated great specificity for their respective steroid ligands. Much of the experimental research of the functions of the sex steroid receptors has depended upon in vitro systems as well as in vivo methods that require surgical castration or the pharmacological administration of hormone antagonists. However, recently developed techniques that allow for manipulation of the mouse genome have been utilized to generate transgenic animals that lack functional estrogen or progesterone receptors. These transgenic animals, combined with the naturally existing Tfm mice which lack functional androgen receptor, now provide in vivo models for further study of the various actions of the sex steroids and their receptors. This review attempts to describe and compare the various phenotypes that result in each of these lines of mice, with emphasis on the development and function of the reproductive systems as well as reproductive behavior. C1 NIEHS, Receptor Biol Sect, Div Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), NIEHS, Receptor Biol Sect, Div Reprod & Dev Toxicol, NIH, MD B3-02,POB 12233, Res Triangle Pk, NC 27709 USA. OI Korach, Kenneth/0000-0002-7765-418X NR 111 TC 67 Z9 69 U1 2 U2 5 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0946-2716 J9 J MOL MED-JMM JI J. Mol. Med. PD JUN PY 1998 VL 76 IS 7 BP 497 EP 511 DI 10.1007/s001090050244 PG 15 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA ZR305 UT WOS:000073960800007 PM 9660168 ER PT J AU Boyer, PA Skolnick, P Fossom, LH AF Boyer, PA Skolnick, P Fossom, LH TI Chronic administration of imipramine and citalopram alters the expression of NMDA receptor subunit mRNAs in mouse brain - A quantitative in situ hybridization study SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE imipramine; citalopram; antidepressants; NMDA ID D-ASPARTATE RECEPTORS; MESSENGER-RNAS; 1-AMINOCYCLOPROPANECARBOXYLIC ACID; ANTIDEPRESSANT TREATMENTS; DISTINCT DISTRIBUTIONS; MOLECULAR DIVERSITY; RAT HIPPOCAMPUS; DEPRESSION; CHANNEL; ANTAGONISTS AB Chronic administration of antidepressants produces region-specific adaptive changes in the radioligand binding properties of N-methyl-D-aspartate (NMDA) receptors. We hypothesized that this effect of chronic antidepressant administration was owing to an alteration in NMDA receptor subunit composition. This hypothesis was examined using in situ hybridization with [S-35]-labeled riboprobes to quantify the impact of chronic (16 d) injection with either imipramine (15 mg/kg) or citalopram (20 mg/kg) on the levels of transcripts encoding NMDA receptor subunits in mouse brain. These antidepressants altered the levels of mRNA encoding the zeta-subunit in a parallel fashion, with both drugs either reducing transcript levels (e.g., in the cortex, cerebellum, thalamus, and striatum) or producing no substantial effects (e.g., hippocampus). In contrast, these antidepressants often produced distinct, region-specific effects on mRNA levels encoding the epsilon family of subunits. For example, citalopram treatment produced widespread reductions in epsilon 1-subunit mRNA levels (e.g., in frontal cortex, CA2 of hippocampus, and amygdala), whereas imipramine reduced levels of this transcript only in the amygdala. Conversely, imipramine treatment produced widespread reductions in epsilon 2-subunit mRNA levels (e.g., in cortex, CA1-4 of hippocampus, and amygdala), whereas the effects of citalopram on levels of this transcript were largely restricted to amygdala. These findings indicate that long-term antidepressant treatment produces region-specific changes in expression of transcripts for NMDA receptor subunits, presumably altering NMDA receptor composition. Because subunit composition determines the physiological and pharmacological properties of NMDA receptors, these changes may play a critical role in the therapeutic actions of structurally diverse antidepressants. C1 Lilly Corp Ctr, Neurosci Discovery, Indianapolis, IN 46225 USA. NIDDK, Neurosci Lab, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Anat & Cell Biol, Bethesda, MD 20814 USA. RP Skolnick, P (reprint author), Lilly Corp Ctr, Neurosci Discovery, Indianapolis, IN 46225 USA. NR 52 TC 111 Z9 115 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD JUN PY 1998 VL 10 IS 3 BP 219 EP 233 DI 10.1007/BF02761776 PG 15 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 118XF UT WOS:000075865700005 PM 9770644 ER PT J AU Li, SX Dumdei, EJ Blunt, JW Munro, MHG Robinson, WT Pannell, LK AF Li, SX Dumdei, EJ Blunt, JW Munro, MHG Robinson, WT Pannell, LK TI Theonellapeptolide IIIe, a new cyclic peptolide from the New Zealand deep water sponge, Lamellomorpha strongylata SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID OKINAWAN MARINE SPONGE; AMINO-ACIDS; CHROMATOGRAPHY; LACTONES; IE AB The structure, stereochemistry, and conformation of theonellapeptolide IIIe (1), a new 36-membered ring cyclic peptolide from the New Zealand deep-water sponge Lamellomorpha strongylata, is described. The sequence of the cytotoxic peptolide was determined through a combination of NMR and MS-MS techniques and confirmed by X-ray crystal structure analysis, which, with chiral HPLC, established the absolute stereochemistry. C1 Univ Canterbury, Dept Chem, Christchurch 1, New Zealand. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Blunt, JW (reprint author), Univ Canterbury, Dept Chem, Christchurch 1, New Zealand. OI Blunt, John/0000-0003-4053-4376 NR 15 TC 18 Z9 18 U1 1 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD JUN PY 1998 VL 61 IS 6 BP 724 EP 728 DI 10.1021/np970417r PG 5 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA ZX308 UT WOS:000074502400004 PM 9644054 ER PT J AU Eiden, LE AF Eiden, LE TI The cholinergic gene locus SO JOURNAL OF NEUROCHEMISTRY LA English DT Review DE choline acetyltransferase; acetylcholine; vesicular acetylcholine transporter; cholinergic gene ID VESICULAR ACETYLCHOLINE TRANSPORTER; ACETYLTRANSFERASE MESSENGER-RNA; SMALL SYNAPTIC VESICLES; NERVE GROWTH-FACTOR; ALZHEIMERS-DISEASE; CAENORHABDITIS-ELEGANS; RAT-BRAIN; VESAMICOL BINDING; SENILE DEMENTIA; NEUROTRANSMITTER TRANSPORTERS AB Messenger RNAs and the cognate gene(s) encoding choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT) have been cloned from mammals and several other animal classes in the last decade. These have provided molecular tools for investigating acetylcholine synthesis and packaging into synaptic vesicles, the genesis of cholinergic vesicles, and the development and senescence of the cholinergic nervous system. VAChT and ChAT have been found to share a common gene locus and regulatory elements for gene transcription. The cholinergic gene locus represents a previously undiscovered type of neuronal transcriptional unit controlling chemically coded neurotransmission. In vitro assays for the transport function of VAChT have shed light on the bioenergetics of amine accumulation in secretory vesicles. Manipulation of VAChT expression in vivo has demonstrated unequivocally the primacy of vesicular exocytosis as the mode of transmitting quanta of acetylcholine at the neuromuscular junction, as in vivo manipulation of acetylcholinesterase levels has demonstrated the importance of acetylcholine metabolism in the regulation of complex functions such as cognition. Light and electron microscopic visualization of VAChT, complementing previous ChAT immunohistochemistry, has improved understanding of the genesis and function of the cholinergic vesicle, neuron, and synapse. These advances should accelerate the development of "cholinergic" pharmacological and gene therapeutic approaches to treatment of human diseases that are associated with cholinergic surfeit and insufficiency. C1 NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, NIH, 36 Convent Dr,MSC 4090, Bethesda, MD 20892 USA. OI Eiden, Lee/0000-0001-7524-944X NR 139 TC 142 Z9 145 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 1998 VL 70 IS 6 BP 2227 EP 2240 PG 14 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA ZN457 UT WOS:000073647800001 PM 9603187 ER PT J AU Sterneck, E Johnson, PF AF Sterneck, E Johnson, PF TI CCAAT/enhancer binding protein beta is a neuronal transcriptional regulator activated by nerve growth factor receptor signaling SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE CCAAT enhancer binding protein beta; nerve growth factor; Trk tyrosine kinase receptor; mitogen-activated protein kinase site mutation; brain; PC12 cells ID C/EBP-BETA; NF-M; PHEOCHROMOCYTOMA CELLS; SYNAPTIC TRANSMISSION; CORTICAL ASTROCYTES; TARGETED DISRUPTION; NEUROTROPHIC FACTOR; MESSENGER-RNA; TRK RECEPTOR; GENE AB CCAAT/enhancer binding protein beta (C/EBP beta) is a transcriptional regulator of the basic leucine zipper family. By in situ hybridization analysis, we found that C/EBP beta is widely expressed in the CNS of adult mice, including cells of the hippocampus and dentate gyrus and cerebellar Purkinje and granule cells. Expression of C/EBP beta had also been reported in the PC12 cell line, which undergoes differentiation to neuron-like cells in response to nerve growth factor (NGF), We show that C/EBP beta mRNA expression increases while protein levels decrease during differentiation of PC12 cells. In transactivation assays, C/EBP beta activity was stimulated by NGF receptor signaling. Mutations of a phosphorylation site for mitogen-activated protein kinase in C/EBP beta affected its capacity to transactivate in a promoter-specific manner. Our data identify the C/EBP beta protein and gene as direct downstream targets of the NGF receptor and suggest a role for C/EBP beta in neurotrophin signaling in the brain. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Eukaryot Transcript Regulat Grp, Frederick, MD 21702 USA. RP Johnson, PF (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Eukaryot Transcript Regulat Grp, POB B, Frederick, MD 21702 USA. RI Johnson, Peter/A-1940-2012 OI Johnson, Peter/0000-0002-4145-4725 NR 46 TC 74 Z9 74 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 1998 VL 70 IS 6 BP 2424 EP 2433 PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA ZN457 UT WOS:000073647800021 PM 9603207 ER PT J AU Ginsberg, L Xuereb, JH Gershfeld, NL AF Ginsberg, L Xuereb, JH Gershfeld, NL TI Membrane instability, plasmalogen content, and Alzheimer's disease SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE membrane stability; plasmalogens; Alzheimer's disease; critical unilamellar state; bilayer; neurodegeneration ID PHOSPHOLIPID SURFACE BILAYERS; AIR-WATER-INTERFACE; APOLIPOPROTEIN-E; ANIMAL-CELLS; BRAIN; TEMPERATURE; GENE; SPECIFICITY; LIPIDS; STATE AB The normal stability of the cell membrane bilayer depends on its lipid composition being appropriate to the ambient (physiological) temperature, T(p). Membrane lipid composition may be altered by disease such that the bilayer is only stable at a new critical temperature, T*, which may differ from T(p), In Alzheimer's disease (AD) temporal cortex, a defect of lipid composition has previously been identified, namely, a decrease in the ratio of plasmalogen to nonplasmalogen ethanolamine glycerophospholipids. Furthermore, for AD temporal cortex neural membranes, T* much less than T(p), a finding confirmed in the pres ent study in a larger series than previously, using a new method for obtaining T*. This inequality between T* and T(p) has been proposed as a putative contributory pathogenetic mechanism leading to membrane destabilisation in AD brain. The plasmalogen deficiency could account for the change in T* in AD, as shown by experiments where T* was measured for artificial lipid mixtures simulating brain membranes with varying plasmalogen/nonplasmalogen ratios. The critical temperature was found to be very sensitive to small alterations in plasmalogen content. C1 Royal Free Hosp, Sch Med, Dept Clin Neurosci, London NW3 2PF, England. Univ London, Dept Clin Neurol, Inst Neurol, London WC1N 3BG, England. Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. NIAMSD, Phys Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ginsberg, L (reprint author), Royal Free Hosp, Sch Med, Dept Clin Neurosci, Rowland Hill St, London NW3 2PF, England. RI Ginsberg, Lionel/C-8704-2009 NR 35 TC 53 Z9 57 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 1998 VL 70 IS 6 BP 2533 EP 2538 PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA ZN457 UT WOS:000073647800033 PM 9603219 ER PT J AU Lu, ZM Winters, CA Ralston, E AF Lu, ZM Winters, CA Ralston, E TI Altered subcellular localization patterns of ferritin and beta-actin mRNAs in muscle cultures, resulting from incomplete penetration of digoxigenin-labelled riboprobes SO JOURNAL OF NEUROCYTOLOGY LA English DT Article ID INSITU HYBRIDIZATION; MESSENGER-RNA; ELECTRON-MICROSCOPY; SEQUENCES; FIXATION; PRESERVATION; LOCATION; PROTEINS; MYOTUBES; EMBRYOS AB Protocols for in situ hybridization (ISH) of cultured cells often include storage in alcohol at -20 degrees C between fixation of the cultures and the ISH procedure. In experiments aimed at localizing ferritin mRNA in C2 muscle cultures by ISH with digoxigenin-labelled riboprobes, we have noticed that omission of the ethanol storage dramatically changed the pattern of mRNA localization. In cultures stored in 50%, 70%, or 90% ethanol for at least 15 min, ferritin signal was stronger on myotubes than myoblasts bur. was uniformly distributed over both. In untreated cultures, the signal was patchy, concentrated on the extremities of the elongated myoblasts and very sparse in myotubes. Similar results were obtained with a probe to p-actin used as a control, except that signal was higher in myoblasts in all conditions. When the probes were reduced in size to similar to 100 bases from 561 for ferritin and 1150 for actin, the pattern became uniform, regardless of prehybridization treatment. The patchy pattern disappeared when cells were treated with RNase A following hybridization, suggesting that it is non-specific, despite its absence in cultures hybridized with a sense probe. We conclude that incomplete access of RNA probes can result not only in a reduced ISH signal but also in artefactual patterns of mRNA localization. C1 NIH, Natl Inst Neurol Disorders & Stroke, Neurobiol Lab, Bethesda, MD 20892 USA. RP Lu, ZM (reprint author), NIH, Natl Inst Neurol Disorders & Stroke, Neurobiol Lab, Bldg 10, Bethesda, MD 20892 USA. NR 26 TC 0 Z9 0 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0300-4864 J9 J NEUROCYTOL JI J. Neurocytol. PD JUN PY 1998 VL 27 IS 6 BP 411 EP 418 DI 10.1023/A:1006932426837 PG 8 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 173NE UT WOS:000078986000002 PM 10192522 ER PT J AU Pozzo-Miller, LD Moreira, JE Llinas, RR AF Pozzo-Miller, LD Moreira, JE Llinas, RR TI The first-order giant neurons of the giant fiber system in the squid: electrophysiological and ultrastructural observations SO JOURNAL OF NEUROCYTOLOGY LA English DT Article ID MEMBRANE STRUCTURE; SYNAPSE; GLUTAMATE; RELEASE; ESCAPE AB The giant fiber system controlling mantle contraction used for jet propulsion in squid consists of two sets of three giant neurons organized in tandem. The somata of the 1st- and 2nd-order giant cells are located in the brain, while the perikarya of the 3rd-order giant cells are encountered in the stellate ganglia of the mantle. The somata and dendrites of one fused pair of 1st-order giant cells are thought to receive synaptic input from the eye, statocyst, skin proprioceptors, and supraesophageal lobes. To define the cellular properties for integration of such an extensive synaptic load, especially given its diversity, intracellular recordings and electron microscopic observations were performed on 1st-order giant cells in an isolated head preparation. Spontaneous bursts of action potentials and spikes evoked by extracellular stimulation of the brachial lobe were sensitive to the Na+ channel blocker TTX. Action potentials were also abolished by recording with microelectrodes containing the membrane-impermeant, use-dependent Na+ channel blocker QX-314. The small action potential amplitude and the abundant synaptic input imply that the spike initiation zone is remotely located from the recording site. The high spontaneous activity in the isolated head preparation, as well as the presence of synaptic junctions resembling inhibitory synapses, suggest; that afferent synapses on 1st-order giant neurons might represent the inhibitory control of the giant fiber system. The characterization of the electroresponsive properties of the 1st-order giant neurons will provide a description of the single cell integrative properties that trigger the rapid jet propulsion necessary for escape behavior in squid. C1 Marine Biol Lab, Woods Hole, MA 02543 USA. NIH, NINDS, Neurobiol Lab, Bethesda, MD 20892 USA. NYU, Med Ctr, Dept Physiol & Neurosci, New York, NY 10016 USA. RP Univ Alabama Birmingham, Dept Neurobiol, C1RC 4291791 6th Ave S, Birmingham, AL 35294 USA. NR 44 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-4864 J9 J NEUROCYTOL JI J. Neurocytol. PD JUN PY 1998 VL 27 IS 6 BP 419 EP 429 DI 10.1023/A:1006984410908 PG 11 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 173NE UT WOS:000078986000003 PM 10192523 ER PT J AU Pare, M Guitton, D AF Pare, M Guitton, D TI Brain stem omnipause neurons and the control of combined eye-head gaze saccades in the alert cat SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID PONTINE RETICULAR-FORMATION; DIRECT INHIBITORY PROJECTION; MONKEY SUPERIOR COLLICULUS; BURSTER-DRIVING NEURONS; PAUSE NEURONS; TECTORETICULOSPINAL SYSTEM; VESTIBULOOCULAR REFLEX; ELECTRICAL-STIMULATION; OCULOMOTOR SYSTEM; ORIENTING EYE AB When the head is unrestrained, rapid displacements of the visual axis-gaze shifts (eye-re-space)-are made by coordinated movements of the eyes (eye-re-head) and head (head-re-space). To address the problem of the neural control of gaze shifts, we studied and contrasted the discharges of omnipause neurons (OPNs) during a variety of combined eye-head gaze shifts and head-fixed eye saccades executed by alert cats. OPNs discharged tonically during intersaccadic intervals and at a reduced level during slow perisaccadic gaze movements sometimes accompanying saccades. Their activity ceased for the duration of the saccadic gaze shifts the animal executed, either by head-fixed eye saccades alone or by combined eye-head movements. This was true for all types of gaze shifts studied: active movements to visual targets; passive movements induced by whole-body rotation or by head rotation about stationary body; and electrically evoked movements by stimulation of the caudal part of the superior colliculus (SC), a central structure for gaze control. For combined eye-head gaze shifts, the OPN pause was therefore not correlated to the eye-in-head trajectory. For instance, in active gaze movements, the end of the pause was better correlated with the gaze end than with either the eye saccade end or the time of eye counterrotation. The hypothesis that cat OPNs participate in controlling gaze shifts is supported by these results, and also by the observation that the movements of both the eyes and the head were transiently interrupted by stimulation of OPNs during gaze shifts. However, we found that the OPN pause could be dissociated from the gaze-motor-error signal producing the gaze shift. First, OPNs resumed discharging when perturbation of head motion briefly interrupted a gaze shift before its intended amplitude was attained. Second, stimulation of caudal SC sites in head-free cat elicited large head-free gaze shifts consistent with the creation of a large gaze-motor-error signal. However, stimulation of the same sites in head-fixed cat produced small "goal-directed" eye saccades, and OPNs paused only for the duration of the latter; neither a pause nor an eye movement occurred when the same stimulation was applied with the eyes at the goal location. We conclude that OPNs can be controlled by neither a simple eye control system nor an absolute gaze control system. Our data cannot be accounted for by existing models describing the control of combined eye-head gaze shifts and therefore put new constraints on future models, which will have to incorporate all the various signals that act synergistically to control gaze shifts. C1 McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada. McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada. RP Pare, M (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. FU NEI NIH HHS [EY-08216] NR 100 TC 53 Z9 53 U1 2 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUN PY 1998 VL 79 IS 6 BP 3060 EP 3076 PG 17 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA ZV958 UT WOS:000074359400020 PM 9636108 ER PT J AU Quaia, C Optican, LM AF Quaia, C Optican, LM TI Commutative saccadic generator is sufficient to control a 3-D ocular plant with pulleys SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID MONKEY SUPERIOR COLLICULUS; PURSUIT EYE-MOVEMENTS; PONTINE RETICULAR-FORMATION; TO-POSITION TRANSFORMATION; LISTINGS LAW; OCULOMOTOR CONTROL; VELOCITY; BEHAVIOR; NUCLEUS; ROTATIONS AB One-dimensional models of oculomotor control rely on the fact that, when rotations around only one axis are considered, angular velocity is the derivative of orientation. However, when rotations around arbitrary axes [3-dimensional (3-D) rotations] are considered, this property does not hold, because 3-D rotations are noncommutative. The noncommutativity of rotations has prompted a long debate over whether or not the oculomotor system has to account for this property of rotations by employing noncommutative operators. Recently, Raphan presented a model of the ocular plant that incorporates the orbital pulleys discovered, and qualitatively modeled, by Miller and colleagues. Using one simulation, Raphan showed that the pulley model could produce realistic saccades even when the neural controller is commutative. However, no proof was offered that the good behavior of the Raphan-Miller pulley model holds for saccades different from those simulated. We demonstrate mathematically that the Raphan-Miller pulley model always produces movements that have an accurate dynamic behavior. This is possible because, if the pulleys are properly placed, the oculomotor plant (extraocular muscles, orbital pulleys, and eyeball) in a sense appears commutative to the neural controller. We demonstrate this finding by studying the effect that the pulleys have on the different components of the innervation signal provided by the brain to the extraocular muscles. Because the pulleys make the axes of action of the extraocular muscles dependent on eye orientation, the effect of the innervation signals varies correspondingly as a function of eye orientation. In particular, the Pulse of innervation, which in classical models of the saccadic system encoded eye velocity, here encodes a different signal, which is very close to the derivative of eye orientation. In contrast, the Step of innervation always encodes orientation, whether or not the plant contains pulleys. Thus the Step can be produced by simply integrating the Pulse. Particular care will be given to describing how the pulleys can have this differential effect on the Pulse and the Step. We will show that, if orbital pulleys are properly located, the neural control of saccades can be greatly simplified. Furthermore, the neural implementation of Listing's Law is simplified: eye orientation will lie in Listing's Plane as long as the Pulse is generated in that plane. These results also have implications for the surgical treatment of strabismus. C1 NEI, NIH, Sensorimotor Res Lab, Bethesda, MD 20892 USA. RP Optican, LM (reprint author), NEI, NIH, Sensorimotor Res Lab, Bldg 49,Rm 2A50, Bethesda, MD 20892 USA. NR 68 TC 115 Z9 118 U1 1 U2 1 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 JUN PY 1998 VL 79 IS 6 BP 3197 EP 3215 PG 19 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA ZV958 UT WOS:000074359400031 PM 9636119 ER PT J AU Clark, VP Maisog, JM Haxby, JV AF Clark, VP Maisog, JM Haxby, JV TI fMRI study of face perception and memory using random stimulus sequences SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID POSITRON EMISSION TOMOGRAPHY; HUMAN VISUAL-CORTEX; PET; RETRIEVAL; REGISTRATION; RECOGNITION; ATTENTION; MONKEY; LOCUS; AREA AB A new functional magnetic resonance imaging (fMRI) method was used to investigate the functional neuroanatomy of face perception and memory. Whole-brain fMRI data were acquired while four types of stimuli were presented sequentially in an unpredictable pseudorandom order at a rate of 0.5 Hz. Stimulus types were a single repeated memorized target face, unrepeated novel faces, nonsense scrambled faces, and a blank screen. Random stimulus sequences were designed to generate a functional response to each stimulus type that was uncorrelated with responses to other stimuli. This allowed fMRI responses to each stimulus type to be examined separately using multiple regression. Signal increases were found for all stimuli in ventral posterior cortex. Responses to intact faces extended to more anterior locations of occipitotemporal cortex than did responses to scrambled faces, consistent with previous studies of face perception. Responses evoked by novel faces were in regions of ventral occipitotemporal cortex medial to regions in which significant responses were evoked by the target face. The repeated target face stimulus also evoked activity in widely distributed regions of frontal and parietal cortex. These results demonstrate that cortical hemodynamic responses to interleaved novel and repeated stimuli can be distinguished and measured using fMRI with appropriate stimulus sequences and data analysis methods. This method can now be used to examine the neural systems involved in cognitive tasks that were previously impossible to study using positron emission tomography or fMRI. C1 NIMH, Lab Brain & Cognit, Sect Funct Brain Imaging, NIH, Bethesda, MD 20892 USA. RP Clark, VP (reprint author), Univ Connecticut, Ctr Hlth, Dept Psychiat, MC2017,263 Farmington Ave, Farmington, CT 06030 USA. RI Clark, Vincent/B-3343-2010 OI Clark, Vincent/0000-0002-9151-2102 NR 38 TC 99 Z9 100 U1 2 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUN PY 1998 VL 79 IS 6 BP 3257 EP 3265 PG 9 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA ZV958 UT WOS:000074359400036 PM 9636124 ER PT J AU Bolla, KI Cadet, JL London, ED AF Bolla, KI Cadet, JL London, ED TI The neuropsychiatry of chronic cocaine abuse SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Review ID CEREBRAL BLOOD-FLOW; POSITRON EMISSION TOMOGRAPHY; OBSESSIVE-COMPULSIVE DISORDER; GLUCOSE METABOLIC RATES; PREFRONTAL CORTEX; CEREBROVASCULAR COMPLICATIONS; NEUROPSYCHOLOGICAL DEFICITS; DOPAMINE TRANSPORTER; SUBSTANCE-ABUSE; HUMAN BRAIN AB This review integrates findings from neuropsychological, PET, and MRI studies in human subjects and neurochemical findings in animals to make inferences about neuropsychiatric consequences of chronic abuse of cocaine. It also aims to develop insights into brain-behavioral relationships that may explain the perpetuation of addictive behaviors. Such insights promise to lend to a better understanding of the neuropsychiatry of cocaine abuse and to promote the development of more efficacious treatments. The authors present evidence suggesting that cocaine abusers have specific dysfunction of executive functions (decision making, judgment) and that this behavior is associated with dysfunction of specific prefrontal brain regions, the orbitofrontal cortex, and anterior cingulate gyrus. Suggestions for future research and treatment are also discussed. C1 Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD USA. NIDA, Mol Neuropsychiat Sect, Baltimore, MD USA. NIDA, Brain Imaging Ctr, Baltimore, MD USA. RP Bolla, KI (reprint author), Johns Hopkins Bayview Med Ctr, Dept Neurol, 4940 Eastern Ave, Baltimore, MD 21224 USA. NR 82 TC 98 Z9 100 U1 2 U2 6 PU AMER PSYCHIATRIC ASSOCIATION PI WASHINGTON PA 1400 K ST NW, WASHINGTON, DC 20005 USA SN 0895-0172 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD SUM PY 1998 VL 10 IS 3 BP 280 EP 289 PG 10 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 106GJ UT WOS:000075121300003 PM 9706535 ER PT J AU Levy, ML Cummings, JL Fairbanks, LA Masterman, D Miller, BL Craig, AH Paulsen, JS Litvan, I AF Levy, ML Cummings, JL Fairbanks, LA Masterman, D Miller, BL Craig, AH Paulsen, JS Litvan, I TI Apathy is not depression SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID PROGRESSIVE SUPRANUCLEAR PALSY; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; POSITRON EMISSION; DIAGNOSIS; DEMENTIA; RELIABILITY; CRITERIA; VALIDITY; SCALE AB If depression is associated with apathy, then they should be expressed together in different dementia syndromes and should co-occur at varying levels of disease severity. The authors performed a cross-sectional comparison of neuropsychiatric symptoms in 30 Alzheimer's disease, 28 frontotemporal dementia, 40 Parkinson's disease, 34 Huntington's disease, and 22 progressive supranuclear palsy patients, using a standardized rating scale (the Neuropsychiatric Inventory). Apathy did not correlate with depression in the combined sample; apathy (r = -0.40, P<0.0001), but not depression, correlated with lower cognitive function as measured by the Mini-Mental State Examination. The relationship of apathy to depression also varied across diagnostic groups. Apathy is a specific neuropsychiatric syndrome that is distinct from depression. Distinguishing these two syndromes has therapeutic implications. C1 Univ Calif Los Angeles, Sch Med, Reed Neurol Res Ctr, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. W Los Angeles Vet Affairs Med Ctr, Psychiat Serv, Los Angeles, CA 90073 USA. Harbor Univ Calif Los Angeles Med Ctr, Los Angeles, CA USA. Univ Iowa, Coll Med, Dept Psychiat, Iowa City, IA 52242 USA. NINDS, Bethesda, MD 20892 USA. RP Cummings, JL (reprint author), Univ Calif Los Angeles, Sch Med, Reed Neurol Res Ctr, Dept Psychiat & Biobehav Sci, 710 Westwood Pl, Los Angeles, CA 90095 USA. OI Litvan, Irene/0000-0002-3485-3445 FU NIA NIH HHS [AG10123] NR 37 TC 333 Z9 343 U1 2 U2 7 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD SUM PY 1998 VL 10 IS 3 BP 314 EP 319 PG 6 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 106GJ UT WOS:000075121300007 PM 9706539 ER PT J AU Veeranna Amin, ND Ahn, NG Jaffe, H Winters, CA Grant, P Pant, HC AF Veeranna Amin, ND Ahn, NG Jaffe, H Winters, CA Grant, P Pant, HC TI Mitogen-activated protein kinases (Erk1,2) phosphorylate Lys-Ser-Pro (KSP) repeats in neurofilament proteins NF-H and NF-M SO JOURNAL OF NEUROSCIENCE LA English DT Article DE MAPK; neurofilaments; cytoskeleton; phosphorylation; neuron; rat ID GLYCOGEN-SYNTHASE KINASE-3; CYCLIN-DEPENDENT KINASE-5; GANGLION-CELL NEURONS; ALZHEIMER-LIKE STATE; MAP KINASE; BOVINE BRAIN; SPINAL-CORD; MAMMALIAN NEUROFILAMENTS; INTERMEDIATE FILAMENTS; HIPPOCAMPAL-NEURONS AB Mammalian neurofilament proteins, particularly midsized (NF-M) and heavy (NF-H) molecular weight neurofilament proteins, are highly phosphorylated in axons. Neurofilament function depends on the state of phosphorylation of the numerous serine/threonine residues in these proteins. Most phosphorylation occurs in the lys-ser-pro (KSP) repeats in the C-terminal tail domains of NF-H and NF-M. In our previous study, cyclin-dependent kinase 5 (cdk5) was shown to phosphorylate specifically the KSPXK repeats in rat NF-H. Because 80% of the repeats are of the KSPXXXK type, it was of interest to determine which kinase phosphorylates these motifs. Using a synthetic KSPXXXK peptide to screen for a specific kinase, we fractionated rat brain extracts by column chromatography and identified extracellular signal-regulated kinase (Erk2) activated by an upstream activator, the mitogen-activated protein kinase kinase MAPKK (MEK), by Western blot analysis, sequence identification, and inhibition by a specific MEK inhibitor (PD 98059). The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP moths in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. A comparative kinetic study of Erk2 and cdk5 phosphorylation of KSPXK and KSPXXXK peptides revealed that, in contrast to cdk5, which phosphorylated only the KSPXK peptide, Erk2 could phosphorylate both. The preferred substrate for Erk2 was KSPXXXK peptide. The MEK inhibitor PD 98059 also inhibited phosphorylation of NF-H, NF-M, and microtubule associated protein (MAP) in primary rat hippocampal cells and caused a decrease in neurite outgrowth, suggesting that Erk1,2 may play an important role in neurite growth and branching. These data suggest that neuronal Erk1 and Erk2 are capable of phosphorylating serine residues in diverse KSP repeat motifs in NF-M and NF-H. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Univ Colorado, Howard Hughes Med Inst, Dept Chem & Biochem, Boulder, CO 80309 USA. RP Pant, HC (reprint author), NINDS, Neurochem Lab, NIH, Bldg 36,Room 4D20,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 91 TC 36 Z9 37 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 1 PY 1998 VL 18 IS 11 BP 4008 EP 4021 PG 14 WC Neurosciences SC Neurosciences & Neurology GA ZP487 UT WOS:000073758400003 PM 9592082 ER PT J AU Song, S Wang, YM Bak, SY During, MJ Bryan, J Ashe, O Ullrey, DB Trask, LE Grant, FD O'Malley, KL Riedel, H Goldstein, DS Neve, KA LaHoste, GJ Marshall, JF Haycock, JW Neve, RL Geller, AI AF Song, S Wang, YM Bak, SY During, MJ Bryan, J Ashe, O Ullrey, DB Trask, LE Grant, FD O'Malley, KL Riedel, H Goldstein, DS Neve, KA LaHoste, GJ Marshall, JF Haycock, JW Neve, RL Geller, AI TI Modulation of rat rotational behavior by direct gene transfer of constitutively active protein kinase C into nigrostriatal neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE genetic intervention; herpes simplex virus type 1 vectors; protein kinase C; nigrostriatal neurons; motor behavior; basal ganglia ID SIMPLEX VIRUS TYPE-1; GAMMA-MUTANT MICE; DEFECTIVE HSV-1 VECTORS; NEUROTRANSMITTER RELEASE; TYROSINE-HYDROXYLASE; SUBSTANTIA NIGRA; ESCHERICHIA-COLI; DELETION MUTANT; DOPAMINE; EXPRESSION AB The modulation of motor behavior by protein kinase C (PKC) signaling pathways in nigrostriatal neurons was examined by using a genetic intervention approach. Herpes simplex virus type 1 (HSV-1) vectors that encode a catalytic domain of rat PKC beta II (Pkc Delta) were developed. Pkc Delta exhibited a constitutively active protein kinase activity with a substrate specificity similar to that of rat brain PKC. As demonstrated in cultured sympathetic neurons, Pkc Delta caused a long-lasting, activation-dependent increase in neurotransmitter release. In the rat brain, microinjection of HSV-1 vectors that contain the tyrosine hydroxylase promoter targeted expression to dopaminergic nigrostriatal neurons. Expression of pkc Delta in a small percentage of nigrostriatal neurons (similar to 0.1-2%) was sufficient to produce a long-term (greater than or equal to 1 month) change in apomorphine-induced rotational behavior. Nigrostriatal neurons were the only catecholaminergic neurons that contained Pkc Delta, and the amount of rotational behavior was correlated with the number of affected nigrostriatal neurons. The change in apomorphine-induced rotational behavior was blocked by a dopamine receptor antagonist (fluphenazine). D-2-like dopamine receptor density was increased in those regions of the striatum innervated by the affected nigrostriatal neurons. Therefore, this strategy enabled the demonstration that a PKC pathway or PKC pathways in nigrostriatal neurons modulate apomorphine-induced rotational behavior, and altered dopaminergic transmission from nigrostriatal neurons appears to be the affected neuronal physiology responsible for the change in rotational behavior. C1 Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. Yale Univ, Sch Med, Dept Surg, New Haven, CT 06510 USA. Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. NINDS, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. Vet Affairs Med Ctr, Res Serv, Portland, OR 97201 USA. Univ Calif Irvine, Dept Psychobiol, Irvine, CA 92689 USA. Louisiana State Univ, Med Ctr, Dept Biochem, New Orleans, LA 70119 USA. McLean Hosp, Mol Neurogenet Lab, Belmont, MA 02178 USA. Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. RP Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. RI Geller, Alfred/C-6469-2012 FU NICHD NIH HHS [HD24236]; NIMH NIH HHS [MH00967]; NINDS NIH HHS [NS25143] NR 71 TC 33 Z9 34 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 1 PY 1998 VL 18 IS 11 BP 4119 EP 4132 PG 14 WC Neurosciences SC Neurosciences & Neurology GA ZP487 UT WOS:000073758400013 PM 9592092 ER PT J AU Okabe, S Collin, C Auerbach, JM Meiri, N Bengzon, J Kennedy, MB Segal, M McKay, RDG AF Okabe, S Collin, C Auerbach, JM Meiri, N Bengzon, J Kennedy, MB Segal, M McKay, RDG TI Hippocampal synaptic plasticity in mice overexpressing an embryonic subunit of the NMDA receptor SO JOURNAL OF NEUROSCIENCE LA English DT Article DE hippocampus; NMDA receptor; long-term potentiation; long-term depression; water maze; transgenic mice ID LONG-TERM POTENTIATION; GAMMA-MUTANT MICE; II CAM KINASE; VISUAL-CORTEX; AREA CA1; AUTOPHOSPHORYLATION; INDUCTION; BLOCKADE; BRAIN; LTP AB The effects of changing NMDA receptor subunit composition on synaptic plasticity in the hippocampus were analyzed by creating transgenic mice overexpressing NR2D, a predominantly embryonic NMDA receptor subunit. NMDA-evoked currents in the transgenic mice had smaller amplitudes and slower kinetics, The transgenics also displayed age-dependent deficits in synaptic plasticity in area CA1 of the hippocampus. Long-term depression was selectively impaired in juvenile mice when NR2D overexpression was moderate. In mature mice, overexpression of NR2D was associated with a reduction of both NR2B and Ca2+-independent activity of Ca2+- and calmodulin-dependent protein kinase II. These biochemical changes were correlated with a marked impairment of NMDA-dependent long-term potentiation, but spatial behavior was normal in these mice. These results show that the developmental regulation of NMDA receptor subunit composition alters the frequency at which modification of synaptic responses occur after afferent stimulation. C1 NINDS, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. NINDS, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. CALTECH, Div Biol, Pasadena, CA 91125 USA. Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. RP McKay, RDG (reprint author), NINDS, NIH, Mol Biol Lab, Bldg 36,Room 5A29,36 Convent Dr,MSC 4092, Bethesda, MD 20892 USA. NR 40 TC 74 Z9 79 U1 2 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 1 PY 1998 VL 18 IS 11 BP 4177 EP 4188 PG 12 WC Neurosciences SC Neurosciences & Neurology GA ZP487 UT WOS:000073758400018 PM 9592097 ER PT J AU Bac, P Maurois, P Dupont, C Pages, N Stables, JP Gressens, P Evrard, P Vamecq, J AF Bac, P Maurois, P Dupont, C Pages, N Stables, JP Gressens, P Evrard, P Vamecq, J TI Magnesium deficiency-dependent audiogenic seizures (MDDASs) in adult mice: A nutritional model for discriminatory screening of anticonvulsant drugs and original assessment of neuroprotection properties SO JOURNAL OF NEUROSCIENCE LA English DT Article DE antiepileptic drugs; phenytoin; carbamazepine; phenobarbital; ethosuximide; valproic acid; diazepam; nutrition; magnesium deficiency; anticonvulsants; audiogenic seizures; electroshock; MES; pentylenetetrazol; bicuculline; neuroprotectors; picrotoxin; thieno-triazolodiazepine; benzodiazepine; hefrazepine; melatonin; ibotenate; PAF; anti-PAF; WEB2170; GABA; NMDA receptor; discriminatory screening; seizure test; GABA; NMDA receptor; discriminatory screening; seizure test ID PLATELET-ACTIVATING-FACTOR; EPILEPSY-PRONE RATS; PONTINE RETICULAR-FORMATION; INFERIOR COLLICULUS PLAYS; EXCITANT AMINO-ACID; ETHANOL WITHDRAWAL; RECEPTOR-BINDING; NEUROETHOLOGICAL EVALUATION; CEREBRAL-ISCHEMIA; NOISE EXPOSURE AB A great many animal models for audiogenic seizures have been described. The extent to which these models may provide insight into neuroscience fields such as abnormal locomotor behavior (wild running), seizures and anticonvulsants, and neuroinsults and neuroprotectors is examined here by our study of magnesium deficiency-dependent audiogenic seizures (MDDASs) in adult mice. MDDASs were induced in all of the eight tested adult murine strains and are presented as a sequence of four successive components (latency, wild running, convulsion, and recovery phase periods). Compared with several classic seizure tests, the nutritional MDDAS model responded to low doses of prototype antiepileptic drugs (AEDs), including phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), valproic acid (VPA), ethosuximide (ESM), and diazepam (DZP). Modulation by AEDs of the four components of MDDAS indicated that this seizure test was discriminatory, distinguishing between phenytoinergic (PHT, CBZ), GABAergic (PB, VPA, DZP), and ethosuximide (ESM) compounds. Suitability of the MDDAS test for evaluation of neuroprotective compounds was also examined: it showed partial (melatonin) and complete (WEB2170, an anti-PAF agent) reduction of recovery phase by non-anticonvulsant doses of test compounds. These neuroprotective responses were compared with neuroprotective potentials determined in a model of neonatal cerebral injury induced by focal injection of ibotenate (a glutamate analog). WEB2170 and melatonin reduced the size of lesions in white matter, but only WEB2170 protected cortical plate against ibotenate-induced lesions. In addition to the original neuroprotective behavior of WEB2170, studies on the neuroprotectors also supported GABAergic anticonvulsant activity of melatonin in the MDDAS test. C1 INSERM, U42, Ctr Etud & Rech Technol Ind Alimentaires, F-59651 Villeneuve Dascq, France. Univ Paris 11, Fac Pharm, Pharmacol Lab, F-92290 Chatenay Malabry, France. Fac Pharm, Toxicol Lab, F-67401 Strasbourg, France. NINDS, Preclin Pharmacol Sect, Epilepsy Branch, Div Convuls Dev & Neuromuscular Disorders,NIH, Bethesda, MD 20892 USA. Hop Robert Debre, Lab Neurol Dev, F-75019 Paris, France. Hop Robert Debre, Serv Neurol Pediat, F-75019 Paris, France. Univ Paris 07, Fac Med Xavier Bichat, F-75019 Paris, France. Ctr Hosp Reg & Univ Lille, INSERM, Lab Ext, Ctr Etud & Rech Technol Ind Alimentaires, F-59651 Villeneuve Dascq, France. RP Vamecq, J (reprint author), INSERM, U42, Ctr Etud & Rech Technol Ind Alimentaires, 369 Rue Jules Guesde, BP 39, F-59651 Villeneuve Dascq, France. NR 71 TC 49 Z9 49 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 1 PY 1998 VL 18 IS 11 BP 4363 EP 4373 PG 11 WC Neurosciences SC Neurosciences & Neurology GA ZP487 UT WOS:000073758400034 PM 9592113 ER PT J AU Nichols, AM Ruffner, TW Sommer, MA Wurtz, RH AF Nichols, AM Ruffner, TW Sommer, MA Wurtz, RH TI A screw microdrive for adjustable chronic unit recording in monkeys SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE monkey; single unit recording; chronic recording; grid system; microdrive; screwdrive ID HIPPOCAMPAL AB A screw microdrive is described that attaches to the grid system used for recording single neurons from brains of awake behaving monkeys. Multiple screwdrives can be mounted on a grid over a single cranial opening. This method allows many electrodes to be implanted chronically in the brain and adjusted as needed to maintain isolation. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. RP Sommer, MA (reprint author), NEI, Sensorimotor Res Lab, Bldg 49,Room 2A50, Bethesda, MD 20892 USA. NR 3 TC 15 Z9 15 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 JUN 1 PY 1998 VL 81 IS 1-2 BP 185 EP 188 DI 10.1016/S0165-0270(98)00036-3 PG 4 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA ZX857 UT WOS:000074562400022 PM 9696324 ER PT J AU Xu, S Jordan, EK Brocke, S Bulte, JWM Quigley, L Tresser, N Ostuni, JL Yang, YH McFarland, HF Frank, JA AF Xu, S Jordan, EK Brocke, S Bulte, JWM Quigley, L Tresser, N Ostuni, JL Yang, YH McFarland, HF Frank, JA TI Study of relapsing remitting experimental allergic encephalomyelitis SJL mouse model using MION-46L enhanced in vivo MRI: Early histopathological correlation SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE EAE mouse; in vivo MRI; contrast agent enhanced; MOIN-46L iron oxide ID MULTIPLE-SCLEROSIS; PARTICLES AB MION-46L, a superparamagnetic iron oxide contrast agent, was investigated for its ability to increase the sensitivity of in vivo 3D MRI in the detection of brain lesions in a chronic experimental allergic encephalomyelitis (crEAE) mouse model. Lesion conspicuity on postcontrast 3D MRI was dramatically enhanced as compared to precontrast images corresponding to areas of inflammatory and demyelinating lesions. MION-46L could be detected on Prussian blue iron stain in the vascular endothelium, the perivascular space, and in macrophages within perivascular cuffs and areas of inflammation and demyelination, By taking advantage of the MION-46L induced macroscopic susceptibility effect, acute early lesions measuring only 100 mu m in diameter could be detected. MION-46L enhanced MRI may be used to 1) provide a unique sensitivity in EAE lesion detection and correlate imaging to histopathology; 2) help to understand EAE lesion development and its underlying pathophysiology; and 3) eventually assist in preclinical screening of new experimental therapies directed at patients with multiple sclerosis (MS). (C) 1998 Wiley-Liss, Inc. dagger. C1 NIH, Lab Diagnost Radiol Res, CC, Bethesda, MD 20892 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Frank, JA (reprint author), NIH, Lab Diagnost Radiol Res, CC, Bldg 10,B1N256,10 Ctr Dr MSC 1074, Bethesda, MD 20892 USA. EM jafrank@helix.nih.gov RI Bulte, Jeff/A-3240-2008 OI Bulte, Jeff/0000-0003-1202-1610 NR 27 TC 62 Z9 64 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 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUN 1 PY 1998 VL 52 IS 5 BP 549 EP 558 DI 10.1002/(SICI)1097-4547(19980601)52:5<549::AID-JNR7>3.0.CO;2-C PG 10 WC Neurosciences SC Neurosciences & Neurology GA ZQ760 UT WOS:000073900300007 PM 9632311 ER PT J AU Williamson, LC Neale, EA AF Williamson, LC Neale, EA TI Syntaxin and 25-kDa synaptosomal-associated protein: Differential effects of botulinum neurotoxins C1 and A on neuronal survival SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE SNARES; fusion proteins; synaptic; clostridial ID SPINAL-CORD CULTURES; N-TYPE; NEUROTRANSMITTER RELEASE; CALCIUM CHANNELS; TETANUS TOXIN; AXONAL GROWTH; SYNAPTIC TRANSMISSION; SEROTYPE-A; IN-VITRO; SNAP-25 AB The Clostridium botulinum neurotoxins (BoNTs) A and C1 cleave specific proteins required for neuroexocytosis. We demonstrated that, in intact neurons, BoNT A cleaves 25-kDa synaptosomal-associated protein (SNAP-25), and BoNT C1 cleaves both syntaxin and SNAP-25 (Williamson et al,: Mol Biol Cell 6:61a, 1995; J Biol Chem 271:7694-7699, 1996), Here, we compare the actions of BoNT A and BoNT C1 on mature and developing mouse spinal cord neurons in cell culture and demonstrate that BoNT C1 is severely neurotoxic. In mature cultures, synaptic terminals become enlarged shortly after BoNT C1 exposure, and, subsequently, axons, dendrites, and cell bodies degenerate, Electron microscopy confirms that early degenerative changes occur in synaptic terminals when the somatic cytoplasm appears normal. In newly plated cultures, few neurons survive exposure to BoNT C1, Whereas both BoNT A and BoNT C1 cleave SNAP-25, BoNT A has no adverse effect on neurite outgrowth, synaptogenesis, or neuron survival, This cytotoxicity is unique to BoNT C1, is specific to neurons, and is initiated at the synaptic terminal, suggesting either a novel role for syntaxin or additional actions of BoNT C1, The neurodegeneration induced by BoNT C1 may be significant in terms of its efficacy for the clinical treatment of dystonia and spasticity. (C) 1998 Wiley-Liss, Inc. dagger. C1 NICHHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Neale, EA (reprint author), NICHHD, Dev Neurobiol Lab, NIH, Bldg 49,Room 5A38, Bethesda, MD 20892 USA. NR 45 TC 36 Z9 37 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUN 1 PY 1998 VL 52 IS 5 BP 569 EP 583 DI 10.1002/(SICI)1097-4547(19980601)52:5<569::AID-JNR9>3.0.CO;2-A PG 15 WC Neurosciences SC Neurosciences & Neurology GA ZQ760 UT WOS:000073900300009 PM 9632313 ER PT J AU Ward, S Donovan, M Max, MB AF Ward, S Donovan, M Max, MB TI A survey of the nature and perceived impact of quality improvement activities in pain management SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article; Proceedings Paper CT 15th Scientific Meeting of the American-Pain-Society CY NOV, 1996 CL WASHINGTON, D.C. SP Amer Pain Soc DE QA standards; pain; outcomes ID PATIENT SATISFACTION; ASSURANCE STANDARDS; OUTCOMES AB We surveyed members of the American Pain Society (APS) to determine if they were engaged in quality assurance or improvement (QA/I) activities. If so, we queried them about the characteristics of these activities and their perceptions of whether their data appear to show improvements, decrements, or no change in pain outcomes. Of the 222 respondents from at least 180 institutions, 201 (91%) reported that their institutions had a continuous improvement program. One hundred forty-three respondents reported having data on at least one of six pain outcomes at two points in time. The majority reported that their data revealed improvements in outcomes. A large number; however, had not collected data on important outcomes, such as pain intensity and patient functioning. Many APS members are collecting longitudinal data, and interpreting the data as revealing improvements in outcomes. There is a need for rigorously controlled assessment of the effects of QA/I programs on pain outcomes. J Pain Symptom Manage 1998;15:365-373. (C) U.S. Cancer Pain Relief Committee, 1998. C1 Univ Wisconsin, Sch Nursing, Madison, WI 53792 USA. Kaiser Permanente, Clackamas, OR USA. NIDR, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD 20892 USA. RP Ward, S (reprint author), Univ Wisconsin, Sch Nursing, K6-348,600 Highland Ave, Madison, WI 53792 USA. NR 13 TC 12 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD JUN PY 1998 VL 15 IS 6 BP 365 EP 373 DI 10.1016/S0885-3924(98)00004-9 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA ZZ078 UT WOS:000074693500006 PM 9670637 ER PT J AU Giuliano, M Mastrantonio, P Giammanco, A Piscitelli, A Salmaso, S Wassilak, SGF AF Giuliano, M Mastrantonio, P Giammanco, A Piscitelli, A Salmaso, S Wassilak, SGF TI Antibody responses and persistence in the two years after immunization with two acellular vaccines and one whole-cell vaccine against pertussis SO JOURNAL OF PEDIATRICS LA English DT Article ID BORDETELLA-PERTUSSIS; ACCELERATED IMMUNIZATION; IMMUNOGENICITY; DIPHTHERIA; TETANUS; BOOSTER; TRIAL; TOXIN; MICE AB Objective: To evaluate the persistence of specific antibodies induced by primary immunization with three doses of two three-component acellular vaccines against pertussis with an observed efficacy of 84%, and one whole-cell vaccine with an observed efficacy of 36%. Study design: Serum samples were collected from a subsample of 1572 children from the Italian double-blind, placebo-controlled, randomized trial Of vaccines used in 15,601 children at three time points: before administration of the first dose of vaccine, and 1 month and approximately 15 months after administration of the third dose. Further evaluation included pooled cross-sectional analysis of serum specimens associated with episodes of cough (which were not laboratory confirmed as pertussis infection) occurring among the entire population enrolled in the trial. Results: With both acellular vaccines there was a fast and steep decrease in geometric mean antibody titers to pertussis toxin, filamentous hemagglutinin, and pertactin after vaccination. Mean titers were close to the limit of detection 15 months after primary immunization. The immunogenicity of the whole-cell study vaccine was poor 1 month after the third dose, and no antibody was detected in nearly all children 15 months after whole-cell vaccination. Conclusions: Although the study acellular pertussis vaccines induced a strong primary specific antibody response in almost all recipients, the duration of the response was limited. Sustained high-level production of antibody to the antigens tested does not account for the observed efficacy of acellular pertussis vaccines. C1 Ist Super Sanita, Lab Bacteriol & Med Mycol, I-00161 Rome, Italy. Ist Super Sanita, Epidemiol & Biostat Lab, I-00161 Rome, Italy. Univ Palermo, Dept Hyg & Microbiol, I-90133 Palermo, Italy. NIAID, NIH, Bethesda, MD 20892 USA. RP Giuliano, M (reprint author), Ist Super Sanita, Lab Bacteriol & Med Mycol, Viale Regina Elena 299, I-00161 Rome, Italy. FU NIAID NIH HHS [N01-AI-25138] NR 23 TC 74 Z9 75 U1 0 U2 1 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 JUN PY 1998 VL 132 IS 6 BP 983 EP 988 DI 10.1016/S0022-3476(98)70395-6 PG 6 WC Pediatrics SC Pediatrics GA ZT243 UT WOS:000074065100015 PM 9627590 ER PT J AU McCrae, RR Stone, SV Fagan, PJ Costa, PT AF McCrae, RR Stone, SV Fagan, PJ Costa, PT TI Identifying causes of disagreement between self-reports and spouse ratings of personality SO JOURNAL OF PERSONALITY LA English DT Article; Proceedings Paper CT 104th Annual Conference of the American-Psychological-Association CY AUG 09-13, 1996 CL TORONTO, CANADA SP Amer Psychol Assoc, Div 10 Psychol & Arts, Amer Psychol Assoc ID SOCIAL COGNITION; 5-FACTOR MODEL; K-CORRECTION; JUDGMENT; ACCURACY; ACQUAINTANCESHIP; DEFINITIONS; PERCEPTION; AGREEMENT; VALIDITY AB Self-reports and spouse ratings of personality traits typically show less-than-perfect agreement, but powerful moderators of agreement have not yet been identified. In Study 1, 47 married couples completed the Revised NEO Personality Inventory to describe themselves and their spouses. Extent of agreement was not consistently moderated by response sets; the age, intelligence, or education of the respondent; or the length or quality of the relationship. In Study 2 these couples were interviewed about reasons for substantial disagreements, and an audiotape was content-analyzed. Sixteen reasons were reliably coded, including idiosyncratic understanding of items, reference to different time frames or roles, and unavailability of covert experience to the spouse. Faking good, assumed similarity, and other variables prominent in the psychometric literature were relatively unimportant. Findings (1) suggest that attempts to improve the validity of self-reports and ratings may need to be refocused and (2) underscore the desirability of routinely obtaining multiple sources of information on personality. C1 NIA, Gerontol Res Ctr, Personal Stress & Coping Sect, NIH, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Baltimore, MD USA. RP McCrae, RR (reprint author), NIA, Gerontol Res Ctr, Personal Stress & Coping Sect, NIH, 4940 Eastern Ave, Baltimore, MD 21224 USA. OI Costa, Paul/0000-0003-4375-1712 NR 47 TC 88 Z9 89 U1 1 U2 12 PU BLACKWELL PUBLISHERS PI MALDEN PA 350 MAIN STREET, STE 6, MALDEN, MA 02148 USA SN 0022-3506 J9 J PERS JI J. Pers. PD JUN PY 1998 VL 66 IS 3 BP 285 EP 313 DI 10.1111/1467-6494.00013 PG 29 WC Psychology, Social SC Psychology GA ZP567 UT WOS:000073766400001 PM 9615420 ER PT J AU Jang, KL McCrae, RR Angleitner, A Riemann, R Livesley, WJ AF Jang, KL McCrae, RR Angleitner, A Riemann, R Livesley, WJ TI Heritability of facet-level traits in a cross-cultural twin sample: Support for a hierarchical model of personality SO JOURNAL OF PERSONALITY AND SOCIAL PSYCHOLOGY LA English DT Article ID GENETIC-ANALYSIS; 5-FACTOR MODEL; INTELLIGENCE; EXPERIENCE; INVENTORY; OPENNESS; CHILDREN; FAMILY AB The common variance among personality traits can be summarized in the factors of the five-factor model, which are known to be heritable. This study examined heritability of the residual specific variance in facet-level traits from the Revised NEO Personality Inventory. Analyses of raw and residual facet scales across Canadian (183 monozygotic [MZ] and 175 dizogotic [DZ] pairs) and German (435 MZ and 205 DZ pairs) twin samples showed genetic and environmental influences of the same type and magnitude across the 2 samples for most facets. Additive genetic effects accounted for 25% to 65% of the reliable specific variance. Results provide strong support for hierarchical models of personality that posit a large number of narrow traits in addition to a few broader trait factors or domains. Facet-level traits are not simply exemplars of the broad factors they define; they are discrete constructs with their own heritable and thus biological basis. C1 Univ British Columbia, Dept Psychiat, Vancouver, BC V6T 2A1, Canada. NIA, Personal Stress & Coping Sect, Gerontol Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Bielefeld, Dept Psychol, D-4800 Bielefeld, Germany. RP Jang, KL (reprint author), Univ British Columbia, Dept Psychiat, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada. EM kjang@unixg.ubc.ca NR 52 TC 293 Z9 294 U1 4 U2 24 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-3514 J9 J PERS SOC PSYCHOL JI J. Pers. Soc. Psychol. PD JUN PY 1998 VL 74 IS 6 BP 1556 EP 1565 DI 10.1037/0022-3514.74.6.1556 PG 10 WC Psychology, Social SC Psychology GA ZV666 UT WOS:000074328700011 PM 9654759 ER PT J AU Gu, J Zhang, QY Genter, MB Lipinskas, TW Negishi, M Nebert, DW Ding, XX AF Gu, J Zhang, QY Genter, MB Lipinskas, TW Negishi, M Nebert, DW Ding, XX TI Purification and characterization of heterologously expressed mouse CYP2A5 and CYP2G1: Role in metabolic activation of acetaminophen and 2,6-dichlorobenzonitrile in mouse olfactory mucosal microsomes SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID RABBIT NASAL MICROSOMES; HUMAN LIVER-MICROSOMES; COUMARIN 7-HYDROXYLASE; REACTIVE METABOLITE; CYTOCHROME-P-450; TOXICITY; RAT; DICHLOBENIL; P450; ENZYMES AB The metabolic activation of two known olfactory mucosal (OM) toxicants, acetaminophen (AP) and 2,6-dichlorobenzonitrile (DCBN), was examined with mouse liver and OM microsomes and purified, heterologously expressed mouse CYP2A5 and CYP2G1. In reconstituted systems, both isoforms were active in metabolizing DCBN and AP to metabolites that formed protein adducts. The formation of DCBN- or AP-protein adducts and other AP metabolites, including 3-hydroxy-AP and, in the presence of glutathione, AP-glutathione conjugate, was also detected in OM microsomal reactions and to a much greater extent than in liver microsomes. Evidence was obtained that CYP2A5 and CYP2G1 play major roles in mouse OM microsomal metabolic activation of DCBN and AP. Immunoblot analysis indicated that CYP2A5 and CYP2G1 are abundant P450 isoforms in OM microsomes. OM microsomal AP and DCBN metabolic activation was inhibited by 5- and 8-methoxsalen, which inhibit both CYP2A5 and CYP2G1, and by an inhibitory anti-CYP2A5 antibody that also inhibits CYP2G1. In addition, the roles of CYP1A2 and CYP2EI in the OM bioactivation of AP and DCBN were ruled out by comparing activities of acetone-treated mice or Cyp1a2(-/-) mice with those of control mice. Thus, CYP2A5 and CYP2G1 may both contribute to the known OM-selective toxicity of AP and DCBN. Further analysis of the kinetics of AP and DCBN metabolism by the purified P450s suggested that CYP2A5 may play a greater role in OM microsomal metabolism of AP, whereas their relative roles in DCBN metabolism may be dose dependent, with CYP2G1 playing more important roles at low substrate concentrations. C1 New York State Dept Hlth, Wadsworth Ctr Labs & Res, Div Environm Dis Prevent, Lab Human Toxicol & Mol Epidemiol, Albany, NY 12201 USA. Univ Cincinnati, Med Ctr, Dept Environm Hlth, Cincinnati, OH 45267 USA. Univ Cincinnati, Med Ctr, Ctr Environm Genet, Cincinnati, OH 45267 USA. Univ Cincinnati, Med Ctr, Dept Cellular & Mol Physiol, Cincinnati, OH 45267 USA. NIEHS, Reprod & Dev Toxicol Lab, Pharmacogenet Sect, Res Triangle Pk, NC 27709 USA. SUNY Albany, Sch Publ Hlth, Albany, NY USA. RP Ding, XX (reprint author), New York State Dept Hlth, Wadsworth Ctr Labs & Res, Div Environm Dis Prevent, Lab Human Toxicol & Mol Epidemiol, Box 509, Albany, NY 12201 USA. EM xding@wadsworth.org FU NIA NIH HHS [AG13837]; NIEHS NIH HHS [ES06321, ES07462] NR 40 TC 69 Z9 70 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN PY 1998 VL 285 IS 3 BP 1287 EP 1295 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ZT825 UT WOS:000074131400044 PM 9618435 ER PT J AU Tapia, JA Ferris, HA Jensen, RT Garcia, LJ AF Tapia, JA Ferris, HA Jensen, RT Garcia, LJ TI Cholecystokinin (CCK) causes tyrosine phosphorylation of PYK2/CAK beta in pancreatic acinar cells by both calcium-dependent and -independent pathways SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Meeting Abstract C1 Univ Extremadura, Dept Physiol, Caceres 10071, Spain. NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RI Tapia, Jose/C-5181-2008 OI Tapia, Jose/0000-0002-3614-6867 NR 3 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JUN PY 1998 VL 509P SI SI BP 11P EP 12P PG 2 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA ZZ634 UT WOS:000074750300013 ER PT J AU Kostenis, E Zeng, FY Wess, J AF Kostenis, E Zeng, FY Wess, J TI Structure-function analysis of muscarinic acetylcholine receptors SO JOURNAL OF PHYSIOLOGY-PARIS LA English DT Article DE muscarinic receptors; mutagenesis studies; receptor-G protein coupling; receptor structure; cysteine mutagenesis ID PROTEIN-COUPLED RECEPTORS; RANDOM SATURATION MUTAGENESIS; TRANSMEMBRANE HELICES; SELECTIVITY; ACTIVATION; RHODOPSIN; IDENTIFICATION; SPECIFICITY; G-ALPHA(Q); FAMILY AB The structural basis underlying the G protein coupling selectivity of different muscarinic receptor subtypes was analyzed by using a combined molecular genetic/biochemical approach. These studies led to the identification of key residues on the receptors as well as the associated G proteins that are critically involved in determining proper receptor/G protein recognition. Mutational analysis of the m3 muscarinic receptor showed that most native cysteine residues are not required for productive receptor/G protein coupling. The putative extracellular disulfide bond was found to be essential for efficient trafficking of the receptor protein to the cell surface but not for receptor-mediated G protein activation. ((C)Elsevier, Paris). C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bldg 8A,Room B1A-05, Bethesda, MD 20892 USA. NR 22 TC 4 Z9 5 U1 5 U2 7 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 0928-4257 J9 J PHYSIOLOGY-PARIS JI J. Physiol.-Paris PD JUN-AUG PY 1998 VL 92 IS 3-4 BP 265 EP 268 DI 10.1016/S0928-4257(98)80030-2 PG 4 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 120VR UT WOS:000075978500022 PM 9789820 ER PT J AU Canto, MT Kawaguchi, Y Horowitz, AM AF Canto, MT Kawaguchi, Y Horowitz, AM TI Coverage and quality of oral cancer information in the popular press: 1987-98 SO JOURNAL OF PUBLIC HEALTH DENTISTRY LA English DT Article DE oral cancer; prevention; public; knowledge; magazines; newspapers ID MAGAZINES; WOMENS AB Objectives: National data show a lack of knowledge and misinformation about oral cancer and its early detection among the general public. A major source of health information is the popular press. For that reason this study reviewed coverage and quality of news items on the topic of oral cancer in the popular press. In addition, the number and types of tobacco advertisements in women and men's magazines were recorded for a one-year period. Methods: Articles from magazines and newspapers were retrieved from the Magazine Index (1987 to April 1998), Newspaper Abstract (1989 to April 1998) and the Health & Wellness (1987 to April 1998) databases. The articles were analyzed both for adequacy of content and information. Results: A total of 50 articles and news items including oral cancer were identified and analyzed, 18 from newspapers and 32 from magazines. Ninety-four-percent of the articles mentioned at least one risk factor for oral cancer. More than half of the articles (56%) identified spit tobacco (chewing tobacco or snuff) as the major risk factor for oral cancer, while far fewer mentioned either cigarettes (32%) or cigars (12%). Over 50 percent of the articles did not mention warning signs for oral cancers. Fourteen percent suggested clinical oral cancer examinations by a health professional only 8 percent advised the use of self-examination. A total of 417 tobacco advertisements (482 pages) were found among 22 magazines for the one-year period. They included 410 cigarette ads, seven cigar ads, and no spit tobacco ads. Conclusions: This study demonstrates the lack of coverage about oral cancer in the popular press in the past decade and provides a partial explanation of the public's lack of knowledge and misinformation about oral cancers. C1 NIDR, NIH, Bethesda, MD 20892 USA. RP Canto, MT (reprint author), 1528 Ingram Terrace, Silver Spring, MD 20906 USA. NR 25 TC 19 Z9 19 U1 1 U2 2 PU AAPHD NATIONAL OFFICE PI PORTLAND PA 3760 SW LYLE COURT, PORTLAND, OR 97221 USA SN 0022-4006 J9 J PUBLIC HEALTH DENT JI J. Public Health Dent. PD SUM PY 1998 VL 58 IS 3 BP 241 EP 247 DI 10.1111/j.1752-7325.1998.tb03000.x PG 7 WC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health SC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health GA 176QT UT WOS:000079163800009 PM 10101701 ER PT J AU Bicout, DJ Szabo, A AF Bicout, DJ Szabo, A TI On the Wang-Uhlenbeck problem in discrete velocity space SO JOURNAL OF STATISTICAL PHYSICS LA English DT Article DE first passage times; persistent random walk; Kramers equation ID TELEGRAPHERS EQUATION AB The arguably simplest model for dynamics in phase space is the one where the velocity can jump between only two discrete values, +/- v, with rate constant k. For this model, which is the continuous-space version of a persistent random walk, analytic expressions are found for the first passage lime distributions to the origin. Since the evolution equation of this model can be regarded as the two-state finite-difference approximation in velocity space of the Kramers-Klein equation, this work constitutes a solution of the simplest version of the Wang-Uhlenbeck problem. Formal solution (in Laplace space) of generalizations where the velocity can assume an arbitrary number of discrete states that mimic the Maxwell distribution is also provided. C1 NIDDKD, Chem Phys Lab, Bethesda, MD 20892 USA. RP NIDDKD, Chem Phys Lab, Bldg 2, Bethesda, MD 20892 USA. EM bicout@speck.niddk.nih.gov RI Szabo, Attila/H-3867-2012 NR 12 TC 4 Z9 4 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0022-4715 EI 1572-9613 J9 J STAT PHYS JI J. Stat. Phys. PD JUN PY 1998 VL 91 IS 5-6 BP 1047 EP 1054 DI 10.1023/A:1023088118307 PG 8 WC Physics, Mathematical SC Physics GA 101ED UT WOS:000074855900010 ER PT J AU Slavkin, HC AF Slavkin, HC TI The National Institute of Dental Research celebrates its golden anniversary SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article ID UNITED-STATES; DENTITION; CARIES C1 NIDR, NIH, Bethesda, MD 20892 USA. RP Slavkin, HC (reprint author), NIDR, NIH, 31 Ctr Dr,Bldg 31C,Room 2C39, Bethesda, MD 20892 USA. NR 11 TC 2 Z9 2 U1 0 U2 0 PU AMER DENTAL ASSN PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD JUN PY 1998 VL 129 IS 6 BP 694 EP 701 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA ZR689 UT WOS:000074003900017 PM 9631609 ER PT J AU Birkedal-Hansen, H AF Birkedal-Hansen, H TI Fifty years of dental, oral and craniofacial research - The National Institute of Dental Research's Division of Intramural Research SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article C1 NIDR, NIH, Bethesda, MD 20892 USA. RP Birkedal-Hansen, H (reprint author), NIDR, NIH, Bldg 30,Room 132,30 Convent Dr, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU AMER DENTAL ASSN PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD JUN PY 1998 VL 129 IS 6 BP 702 EP 710 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA ZR689 UT WOS:000074003900018 PM 9631610 ER PT J AU Winn, DM Diehl, SR Horowitz, AM Gutkind, S Sandberg, AL Kleinman, DV AF Winn, DM Diehl, SR Horowitz, AM Gutkind, S Sandberg, AL Kleinman, DV TI Scientific progress in understanding oral and pharyngeal cancers SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article ID SQUAMOUS-CELL CARCINOMA; SMOKING; GENE AB Oral and pharyngeal cancers result from a complex interaction between genetic susceptibility and behavioral factors. Improved understanding of the underlying genetic events has led to insights about how oral and pharyngeal cancers develop and suggests promising new treatments. Tobacco and alcohol consumption are associated with most oral and pharyngeal cancers. Dental professionals' efforts to modify their patients' tobacco and alcohol use and to detect oral lesions at an early stage, together with scientific advances, will help reduce the impact of these cancers. C1 NIDR, Risk Factors & Mol Epidemiol Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. NIDR, Off Sci Policy & Anal, NIH, Bethesda, MD 20892 USA. RP Winn, DM (reprint author), NIDR, Risk Factors & Mol Epidemiol Branch, Div Intramural Res, NIH, Natcher Bldg,Room 4AS-19F,45 Ctr Dr, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009 NR 34 TC 10 Z9 10 U1 0 U2 0 PU AMER DENTAL ASSN PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD JUN PY 1998 VL 129 IS 6 BP 713 EP 718 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA ZR689 UT WOS:000074003900019 PM 9631611 ER PT J AU Fox, PC Brennan, M Pillemer, S Radfar, L Yamano, S Baum, BJ AF Fox, PC Brennan, M Pillemer, S Radfar, L Yamano, S Baum, BJ TI Sjogren's syndrome: A model SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article ID SALIVARY-GLAND HYPOFUNCTION; GASTROINTESTINAL SYSTEMS; ORAL PILOCARPINE; DOUBLE-BLIND; NECK-CANCER; XEROSTOMIA; TASTE; PERFORMANCE; BIOPSY; HEAD AB The diagnosis and treatment of Sjogren's syndrome, which poses many severe complications, should be of critical interest to dentists, who are often the first practitioners to detect symptoms. Dentistry is an integral part of health care delivery for patients with this condition. Management of Sjogren's syndrome can be seen as a model for the expanded scope of dental care in the future. C1 NIDR, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. NR 42 TC 17 Z9 19 U1 0 U2 1 PU AMER DENTAL ASSN PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD JUN PY 1998 VL 129 IS 6 BP 719 EP 728 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA ZR689 UT WOS:000074003900020 PM 9631612 ER PT J AU Rogan, WJ Ware, JH AF Rogan, WJ Ware, JH TI Comment: Problems with using auxiliary information to correct for omitted variables when estimating the effect of lead on IQ SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Editorial Material C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Rogan, WJ (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD JUN PY 1998 VL 93 IS 442 BP 513 EP 514 PG 2 WC Statistics & Probability SC Mathematics GA ZR930 UT WOS:000074030600009 ER PT J AU Kirschner-Hermanns, R Scherr, PA Branch, LG Wetle, T Resnick, NM AF Kirschner-Hermanns, R Scherr, PA Branch, LG Wetle, T Resnick, NM TI Accuracy of survey questions for geriatric urinary incontinence SO JOURNAL OF UROLOGY LA English DT Article DE epidemiology; urinary incontinence; aging; questionnaires; data collection ID ELDERLY WOMEN; PREVALENCE; SYMPTOMS; FEMALE; DYSFUNCTION; PATIENT; SURGERY AB Purpose: Risk factors, natural history, consequences, therapeutic responses and costs are all likely related to type of urinary incontinence, for example stress or urge. Yet few epidemiologic type specific data are available and only 1 study has been validated urodynamically. We compare the accuracy of a typical questionnaire used in a large epidemiologic study with the criterion standard of multichannel video urodynamic testing. Materials and Methods: The questionnaire was administered before urodynamic testing to 132 subjects 65 years old or older, of whom 80% were women, all were mobile and none was severely demented. Responses to questionnaire items were compared to the criterion standard, singly and in combination, using a total of 4 a priori and post hoc strategies, including a computerized regression tree program. Results: Overall, no analytic strategy correctly classified more than 67% of patients and none accurately classified even a single type of incontinence, including stress incontinence. Conclusions: Short questionnaires commonly used in epidemiologic studies correlated poorly with video urodynamic testing in incontinent older adults. Previously published information regarding prevalence of the types of incontinence should be reviewed in the light of these data. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Gerontol Div, Boston, MA 02115 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. Duke Univ, Ctr Aging, Durham, NC USA. NIA, Bethesda, MD 20892 USA. RP Kirschner-Hermanns, R (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Gerontol Div, Boston, MA 02115 USA. RI Kirschner-Hermanns, Ruth/F-1025-2014 OI Kirschner-Hermanns, Ruth/0000-0001-6332-916X FU NIA NIH HHS [AG04390]; NIDDK NIH HHS [R01-DK49482] NR 32 TC 34 Z9 34 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUN PY 1998 VL 159 IS 6 BP 1903 EP 1908 DI 10.1016/S0022-5347(01)63191-4 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA ZM868 UT WOS:000073584400033 PM 9598484 ER PT J AU Holodniy, M Anderson, D Wright, D Sharma, O Cohn, J Alexander, N Stratton, P Reichelderferd, P AF Holodniy, M Anderson, D Wright, D Sharma, O Cohn, J Alexander, N Stratton, P Reichelderferd, P CA DATRI 005 Study Team TI HIV quantitation in spiked vaginocervical secretions: lack of non-specific inhibitory factors SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE HIV-1 quantitation; vaginocervical secretions; assay variation; menstrual phases ID HUMAN-IMMUNODEFICIENCY-VIRUS; CERVICOVAGINAL SECRETIONS; CERVICAL SECRETIONS; TYPE-1 RNA; VAGINAL SECRETIONS; GENITAL SECRETIONS; MENSTRUAL-CYCLE; INFECTED WOMEN; PLASMA; RISK AB The objective of this study was to assess the effect of menstrual phase on the ability to quantitate HIV-1 in vaginocervical secretions (VCS) through reconstruction experiments with HIV seronegative VCS collected throughout the menstrual cycle. Measurement of HIV-1 inoculated into both fresh and frozen VCS;was undertaken by quantitative micro co-culture, p24 antigen assay and polymerase chain reaction (PCR) for both HIV-1 RNA and pro-viral DNA. Two laboratories carried out these assays over a range of viral concentrations; The study involved a randomized factorial design and the factors were: (1) diluents (phases of the menstrual cycle and controls); (2) laboratories: (3) stock concentrations; and (4) frozen versus fresh VCS samples. Each assay was assessed independently using a random effects analysis of variance (ANOVA) model. No statistical differences due to menstrual cycle were seen in the assay results of p24 antigen (P = 0.08), PBMC culture(P = 0.74), plasma culture (P = 0.13), cell-free RNA (P = 0.44), cell-associated RNA (P = 0.58) and cell-associated DNA (P = 0.43). inter-laboratory differences were statistically significant for cell-free RNA (P < 0.001), cell-associated DNA (P < 0.001) and p24 (P < 0,001). It is concluded that VCS obtained throughout the menstrual cycle from HIV-uninfected women lacks intrinsic inhibitory factors which could limit detection and quantification by antigen, culture or nucleic acid-based technologies for HIV-1 in VCS throughout the menstrual cycle. Using a standardized collection procedure, we suggest that variation in HIV quantity over time, when reported in VCS of infected women, should be attributed to HIV-associated biologic factors, rather than non-specific or other technical factors. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Palo Alto Vet Affairs Hlth Care Syst, Ctr AIDS Res, Palo Alto, CA 94304 USA. Harvard Univ, Fearing Lab Reprod Med, Boston, MA 02115 USA. Westat Inc, Rockville, MD 20850 USA. NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. Wayne State Univ, Detroit, MI 48201 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Reichelderferd, P (reprint author), Div Aids, 6003 Execut Blvd, Rockville, MD 20892 USA. FU NIAID NIH HHS [N01-AI-35157, N01-AI-35172, AI-52314] NR 43 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD JUN PY 1998 VL 72 IS 2 BP 185 EP 195 DI 10.1016/S0166-0934(98)00021-4 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA ZZ993 UT WOS:000074790000007 PM 9694326 ER PT J AU Smith, RH Kotin, RM AF Smith, RH Kotin, RM TI The Rep52 gene product of adeno-associated virus is a DNA helicase with 3 '-to-5 ' polarity SO JOURNAL OF VIROLOGY LA English DT Article ID SITE-SPECIFIC INTEGRATION; REPLICATION IN-VITRO; ADENOASSOCIATED VIRUS; ESCHERICHIA-COLI; TERMINAL REPEATS; FUSION PROTEIN; BINDING MOTIF; WILD-TYPE; AAV DNA; SEQUENCE AB The rep gene of adeno-associated virus type 2 encodes four overlapping proteins from two separate promoters, termed P-5 and P-19. The P-5-promoted Rep proteins, Rep78 and Rep68, are essential for viral DNA replication, and a wealth of data concerning the biochemical activities of these proteins has been reported. In contrast, data concerning the biochemical functions of the P-19-promoted Rep proteins, Rep52 and Rep40, are lacking. Here, we describe enzymatic activities associated with a bacterially expressed maltose-binding protein (MBP)-Rep52 fusion protein. Purified MBP-Rep52 possesses 3'-to-5' DNA helicase activity that is strictly dependent upon the presence of nucleoside triphosphate and divalent cation cofactors. In addition, MBP-Rep52 demonstrates a constitutive ATPase activity that is active in the absence of DNA effector molecules. An MBP-Rep52 chimera bearing a lysine-to-histidine substitution at position 116 (K116H) within a consensus helicase- and ATPase-associated motif (motif I or Walker A site) was deficient For both DNA helicase and ATPase activities. In contrast to a Rep78 A-site mutant protein bearing a corresponding amino acid substitution at position 340 (K340H), the MBP-Rep52 A-site mutant protein failed to exhibit a trans-dominant negative effect when it was mixed with wild-type MBP-Rep52 or MBP-Rep78 in vitro. This lack of harts dominance, coupled with the results of coimmunoprecipitation and gel filtration chromatography experiments reported here, suggests that the ability of Rep52 to engage in multimeric interactions may differ from that of Rep78 or -68. C1 NHLBI, Mol Hematol Branch, Bethesda, MD 20892 USA. RP Kotin, RM (reprint author), NHLBI, Mol Hematol Branch, Bldg 10,Rm 7D18,10 Ctr Dr,MSC 1654, Bethesda, MD 20892 USA. RI kotin, robert/B-8954-2008 NR 51 TC 67 Z9 69 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 JUN PY 1998 VL 72 IS 6 BP 4874 EP 4881 PG 8 WC Virology SC Virology GA ZM029 UT WOS:000073497600038 PM 9573254 ER PT J AU Leverett, BD Farrell, KB Eiden, MV Wilson, CA AF Leverett, BD Farrell, KB Eiden, MV Wilson, CA TI Entry of amphotropic murine leukemia virus is influenced by residues in the putative second extracellular domain of its receptor, Pit2 SO JOURNAL OF VIROLOGY LA English DT Article ID A AVIAN-LEUKOSIS; RETROVIRUS RECEPTOR; CELLULAR RECEPTOR; SARCOMA-VIRUSES; INFECTION; PROTEIN; CELLS; TRANSPORTER; BINDING; FAMILY AB Human cells express distinct but related receptors for the gibbon ape leukemia virus (GALV) and the amphotropic murine leukemia virus (A-MuLV), termed Pit1 and Pit2, respectively. Pit1 is not able to function as a receptor for A-MuLV infection, while Pit2 does not confer susceptibility to GALV. Previous studies of chimeric receptors constructed by interchanging regions of Pit1 and Pit2 failed to clarify the determinants unique to Pit2 which correlate with A-MuLV: receptor function. In order to identify which regions of Pit2 are involved in A-MuLV receptor function, we exchanged the putative second and third extracellular domains of Pit1, either individually or together,,vith the corresponding regions of Pit2, Our functional characterization of these receptors indicates a role for the putative second extracellular domain (domain II) in A-MuLV infection. We further investigated the influence of domain LT with respect to A-MuLV: receptor function by performing site-specific mutagenesis within this region of Pit2, Many of the mutations had little or no effect on receptor function. However, the substitution of serine for methionine at position 138 (S138M) in a Pit1 chimera containing domain II of Pit2 resulted in a 1,000-fold reduction in A-MuLV receptor function, Additional mutations made within domain II of the nonfunctional S138M mutant restored receptor function to nearly wild-type efficiency: The high degree of tolerance for mutations as well as the compensatory effect of particular substitutions observed within domain II suggests that an element of secondary structure within this region plays a critical role in the interaction of the receptor with A-MuLV. C1 US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Bethesda, MD 20892 USA. NIMH, Lab Cellular & Mol Regulat, NIH, Bethesda, MD USA. RP Wilson, CA (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, HFM-530,8800 Rockville Pike, Bethesda, MD 20892 USA. EM wilsonc@A1.cber.fda.gov NR 26 TC 15 Z9 15 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 1998 VL 72 IS 6 BP 4956 EP 4961 PG 6 WC Virology SC Virology GA ZM029 UT WOS:000073497600048 PM 9573264 ER PT J AU Muralidhar, S Pumfery, AM Hassani, M Sadaie, MR Azumi, N Kishishita, M Brady, JN Doniger, J Medveczky, P Rosenthal, LJ AF Muralidhar, S Pumfery, AM Hassani, M Sadaie, MR Azumi, N Kishishita, M Brady, JN Doniger, J Medveczky, P Rosenthal, LJ TI Identification of kaposin (open reading frame k12) as a human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) transforming gene SO JOURNAL OF VIROLOGY LA English DT Article ID INDUCED MALIGNANT TRANSFORMATION; SIMPLEX VIRUS TYPE-2; BOVINE PAPILLOMAVIRUS; DNA-SEQUENCES; GROWTH-FACTOR; ONCOPROTEIN BINDS; CELLS; AIDS; PROTEIN; KSHV AB The recently identified human herpesvirus 8 (HHV-8, or Kaposi's sarcoma-associated herpesvirus) has been implicated in the etiology of both Kaposi's sarcoma (KS) and primary effusion (body cavity-based) lymphoma (PEL) (Y. Chang et al., Science 266:1865-1869, 1994; P. S. Moore et al., J, Virol. 70:549-558, 1996). An important feature of the association of HHV-8 with these malignancies is the expression of an abundant, latency-associated 0.7-kb transcript, T0.7 (W. Zhong et al., Proc. Natl. Acad. Sci. USA 93:6641-6616, 1996). T0.7 is found in all stages in nearly all KS tumors of different epidemiologic origin, including AIDS-associated, African endemic, and classical KS (K. A. Staskus et al., J. Virol. 71:715-719, 1997), as well as in a body cavity-based lymphoma-derived cell line, BCBL-1, that is latently infected with HHV-8 (R. Renne et al., Nat, Med. 2:342-346, 1996). T0.7 encodes a unique HHV-8 open reading frame, K12, also known as kaposin. In this study, we report that the kaposin gene induced tumorigenic transformation. Constructs with kaposin expressed either from its endogenous promoter or from a heterologous promoter induced focal transformation upon transfection into Rat-3 cells. All transformed Rat-3 cell lines containing kaposin sequences produced high-grade, highly vascular, undifferentiated sarcomas upon subcutaneous injection of athymic nu/nu mice, Tumor-derived cell lines expressed kaposin mRNA, suggesting a role in the maintenance of the transformed phenotype. Furthermore, kaposin protein was detected in transformed and tumor-derived cells by immunofluorescence and localized to the cytoplasm. More importantly, expression of kaposin protein was also detected in the PEL cell Lines BCBL-1 and KS-l. These findings demonstrate the oncogenic potential of kaposin and suggest its possible role in the development of KS and other HHV-8-associated malignancies. C1 Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Pathol, Washington, DC 20007 USA. NCI, Mol Virol Lab, Bethesda, MD 20892 USA. Univ S Florida, Dept Med Microbiol & Immunol, Tampa, FL 33612 USA. RP Rosenthal, LJ (reprint author), Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, 3900 Reservoir Rd NW, Washington, DC 20007 USA. EM rosenthl@gunet.georgetown.edu RI Medveczky, Peter/A-6846-2012 FU NCI NIH HHS [P30 CA51008-09, CA 60577, P30 CA051008] NR 76 TC 162 Z9 172 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 1998 VL 72 IS 6 BP 4980 EP 4988 PG 9 WC Virology SC Virology GA ZM029 UT WOS:000073497600051 PM 9573267 ER PT J AU Mikovits, JA Taub, DD Turcovski-Corrales, SM Ruscetti, FW AF Mikovits, JA Taub, DD Turcovski-Corrales, SM Ruscetti, FW TI Similar levels of human immunodeficiency virus type 1 replication in human T(H)1 and T(H)2 clones SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-INFECTED INDIVIDUALS; PROGRAMMED CELL-DEATH; T-CELLS; ASYMPTOMATIC INDIVIDUALS; CYTOKINE PRODUCTION; TH2 SUBSETS; APOPTOSIS; VIRIONS; HELPER; LYMPHOCYTES AB Studies on the development and function of CD4(+) T(H)1 and T(H)2 cells during the progression to AIDS may increase the understanding of AIDS pathogenesis, The preferential replication of human immunodeficiency virus (HIV) in either T(H)1 or T(H)2 cells could alter the delicate balance of the immune response. T(H)1 (gamma interferon [IFN-gamma] positive, interleukin-3 [IL-4] and IL-5 negative) and T(H)2 (IFN-gamma negative, IL-4 and IL-5 positive) clones, developed from several healthy donors, pedigreed by reverse transcriptase PCR (RT-PCR) and enzyme linked immunosorbent assay have similar levels of cell surface expression of CD4 and several chemokine receptor cofactors necessary for viral entry, After activation by specific antigens and infection with T-cell-tropic strains of HIV type 1 (HIV-1), T(H)1 and T(H)2 clones showed similar levels of viral entry and reverse transcription. At days 3 through 14 postinfection, HIV replicated to similar levels in several T(H)1 and T(H)2 clones as measured by release of HIV p24 and total number of copies of gag RNA/total cell RNA as measured by RT-PCR, When values were normalized for viable cell number in three clones of each type, there was up to twofold more HIV RNA in T(H)1 than T(H)2 cells. In addition, several primary monocytotropic HIV-1 strains were able to replicate to similar levels in T(H)1 and T(H)2 cells. These studies suggest that the importance of T(H)1 and T(H)2 subsets in AIDS pathogenesis transcends clonal differences in their ability to support HIV replication. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Leukocyte Biol, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC, Frederick, MD 21702 USA. NIA, Program Immunol, Baltimore, MD 21224 USA. RP Ruscetti, FW (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Leukocyte Biol, Bldg 567,Rm 254, Frederick, MD 21702 USA. NR 64 TC 17 Z9 17 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 1998 VL 72 IS 6 BP 5231 EP 5238 PG 8 WC Virology SC Virology GA ZM029 UT WOS:000073497600080 PM 9573296 ER PT J AU Eisner, E Castro, N Taylor, M AF Eisner, E Castro, N Taylor, M TI Beyond the controversy: Qualitative research on mammography and the national cancer institute's new mammography screening recommendations SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 NCI, Off Canc Commun, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1059-7115 J9 J WOMENS HEALTH JI J. Womens Health PD JUN PY 1998 VL 7 IS 5 BP 631 EP 631 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA ZW759 UT WOS:000074445500071 ER PT J AU Williams, JK AF Williams, JK TI Women with HIV/AIDS: A neglected patient population SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 NIH, HIV Counseling Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1059-7115 J9 J WOMENS HEALTH JI J. Womens Health PD JUN PY 1998 VL 7 IS 5 BP 634 EP 634 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA ZW759 UT WOS:000074445500084 ER PT J AU Biesecker, BB AF Biesecker, BB TI Future directions in genetic counseling: Practical and ethical considerations SO KENNEDY INSTITUTE OF ETHICS JOURNAL LA English DT Article ID OVARIAN-CANCER; ATTITUDES; FAMILIES; BREAST AB The accelerated discovery of gene mutations that lead to increased risk of disease has led to the rapid development of predictive genetic tests. These tests improve the accuracy of assigning risk, but at a time when intervention or prevention strategies are largely unproved. In coming years, however, data will become increasingly available to guide treatment of genetic diseases. Eventually genetic testing will be performed for common diseases as well as for rare genetic conditions. This will challenge genetic counseling practice. The ethical principles that now guide this practice take into account the personal nature of test decision making, the need to respect individual self-determination, and the importance of client confidentiality. Certain of these principles may have to be modified as genetic testing becomes more widespread in order to meet the changing needs of clients and society. This paper offers recommendations to ensure that genetic counselors will take a leading role in the future delivery of ethical genetic services. C1 NIH, Genet Counseling Res & Training Program, Med Genet Branch, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. RP Biesecker, BB (reprint author), NIH, Genet Counseling Res & Training Program, Med Genet Branch, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. NR 45 TC 29 Z9 29 U1 0 U2 9 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 1054-6863 J9 KENNEDY INST ETHIC J JI Kennedy Inst. Ethics J. PD JUN PY 1998 VL 8 IS 2 BP 145 EP 160 DI 10.1353/ken.1998.0009 PG 16 WC Ethics; Philosophy; Social Issues SC Social Sciences - Other Topics; Philosophy; Social Issues GA ZV827 UT WOS:000074345300004 PM 11657426 ER PT J AU Juengst, ET AF Juengst, ET TI Groups as gatekeepers to genomic research: Conceptually confusing, morally hazardous, and practically useless SO KENNEDY INSTITUTE OF ETHICS JOURNAL LA English DT Article AB Some argue that human groups have a stake in the outcome of population-genomics research and that the decision to participate in such research should therefore be subject to group permission. It is not possible, however, to obtain prior group permission, because the actual human groups under study, human demes, are unidentifiable before research begins. Moreover, they lack moral standing. If identifiable social groups with moral standing are used as proxies for demes, group approval could be sought, but at the expense of unfairly exposing these surrogates to risks from which prior group approval is powerless to protect them. Unless population genomics can proceed without targeting socially defined groups, or can find other ways of protecting them, it may fall to individuals to protect the interests of the groups they care about, and to scientists to warn their subjects of the need to do so. C1 Case Western Reserve Univ, Sch Med, Cleveland, OH 44106 USA. NIH, Eth Legal & Social Implicat Branch, Natl Ctr Human Genome Res, Bethesda, MD USA. RP Juengst, ET (reprint author), Case Western Reserve Univ, Sch Med, Cleveland, OH 44106 USA. OI Juengst, Eric/0000-0002-8374-5774 NR 31 TC 54 Z9 55 U1 0 U2 2 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 1054-6863 J9 KENNEDY INST ETHIC J JI Kennedy Inst. Ethics J. PD JUN PY 1998 VL 8 IS 2 BP 183 EP 200 DI 10.1353/ken.1998.0010 PG 18 WC Ethics; Philosophy; Social Issues SC Social Sciences - Other Topics; Philosophy; Social Issues GA ZV827 UT WOS:000074345300007 PM 11657428 ER PT J AU Tardif, S Jaquish, C Layne, D Bales, K Power, M Power, R Oftedal, O AF Tardif, S Jaquish, C Layne, D Bales, K Power, M Power, R Oftedal, O TI Growth variation in common marmoset monkeys (Callitrix jacchus) fed a purified diet: Relation to care-giving and weaning behaviors SO LABORATORY ANIMAL SCIENCE LA English DT Article ID CALLITHRIX-JACCHUS; MATERNAL-CARE; SURVIVAL; PRIMATES AB Significant relations were observed between select infant-care and weaning behaviors and growth in body weight in common marmoset monkeys (Callithrix jacchus). The patterns of these relations suggest that earlier occurrence of developmental milestones, such as cessation of transport (being off carriers) and weaning to solid food, were associated with slower growth duping the subsequent period. In contrast, more frequent nursing bouts during the period in which weaning was initiated were associated with higher growth rates. In the case of being off carriers, these effects did not carry over to older ages, suggesting that any deficits in growth were temporary. In the case of earlier; more frequent consumption of solid food, there was some suggestion that there were longer-term effects, followed by catch-up growth. The knee-to-heel length of subjects was not related to the measured behaviors. There was no relation between early weaning to solid food and leanness at day 75, suggesting that, although this behavior was affecting overall weight, it did not affect relative gains of fat versus lean mass, There were, however, significant correlations between cessation of transport or frequency of nursing bouts during the weaning period and leanness, with earlier cessation of transport and less frequent nursing associated with leaner infants, after weaning. Our results differed from those of a previous study that found a relation between linear growth and abuse in this species, with abuse defined as physical injury by other members of the group. We found no differences in growth between abused and nonabused infants. However, abused infants had lower birth weight. C1 Kent State Univ, Dept Biol Sci, Kent, OH 44242 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Zool, College Pk, MD 20742 USA. Smithsonian Inst, Natl Zool Pk, Dept Zool Res, Washington, DC 20008 USA. RP Tardif, S (reprint author), Kent State Univ, Dept Biol Sci, POB 5190,Cunningham Hall, Kent, OH 44242 USA. FU NCRR NIH HHS [R01-RR02022] NR 33 TC 28 Z9 28 U1 1 U2 7 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI CORDOVA PA 70 TIMBERCREEK DR, SUITE 5, CORDOVA, TN 38018 USA SN 0023-6764 J9 LAB ANIM SCI JI Lab. Anim. Sci. PD JUN PY 1998 VL 48 IS 3 BP 264 EP 269 PG 6 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 123ZZ UT WOS:000076157000010 PM 10090026 ER PT J AU Kingsbury, GA Waldmann, TA Junghans, RP AF Kingsbury, GA Waldmann, TA Junghans, RP TI Examination of a role for idiotypy in the disease remission of a long-term survivor adult T cell leukemia treated with anti-Tac antibody SO LEUKEMIA LA English DT Article DE human; anti-idiotype antibodies; ATL; immunotherapy ID VIRUS TYPE-I; INTERLEUKIN-2 RECEPTOR; MONOCLONAL-ANTIBODY; IMMUNE-RESPONSE; IMMUNOGLOBULIN LIBRARIES; IMMUNOLOGICAL MEMORY; HUMANIZED ANTIBODY; IMMUNOTHERAPY; THERAPY; CHAIN AB The alpha chain of the interleukin 2 receptor (IL2R alpha; Tac) was targeted in clinical trials with adult T cell leukemia using murine anti-Tac antibody. Of 19 patients, a single individual achieved a durable complete remission. The mechanism of this action by murine anti-Tac has not been defined. We examined the hypothesis that the maintenance of the long-term response after treatment might be related to induction of a network of anti-idiotypic antibodies, as proposed in other tumor settings. In contrast to anti-Tac non-responders, the patient was found to have produced a human anti-mouse antibody (HAMA) response, and specifically an anti-idiotypic (Ab2) response, that was readily detectable by standard assays 4 years after treatment. Using phage display antibody libraries, this response was shown to be monoclonal, consisting of a single IgG1,kappa antibody of moderate affinity. No evidence was found for anti-anti-idiotypic (Ab3) antibodies with reactivity for sTac, which might alternatively have maintained an autogenic human anti-Tac antibody response. An area of limited homology was noted between the Ab2 antibody and the IL2R in the domain of IL2 binding, but no binding of Ab2 to IL2 could be shown that might have reduced endogenous ligand (IL2) concentrations. Similarly, no anti-anti-idiotypic (T3) T cell response was detected. Thus, we are unable to confirm features of idiotypy that could suggest a role in maintaining an anti-tumor response by anti-Tac antibody therapy. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Biotherapeut Dev Lab, Boston, MA 02115 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Junghans, RP (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Biotherapeut Dev Lab, Boston, MA 02115 USA. NR 50 TC 5 Z9 5 U1 1 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD JUN PY 1998 VL 12 IS 6 BP 982 EP 991 DI 10.1038/sj.leu.2401048 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA ZU377 UT WOS:000074191000021 PM 9639430 ER PT J AU Quintanilla-Martinez, L Lome-Maldonado, C Ott, G Gschwendtner, A Gredler, E Angeles-Angeles, A Reyes, E Fend, F AF Quintanilla-Martinez, L Lome-Maldonado, C Ott, G Gschwendtner, A Gredler, E Angeles-Angeles, A Reyes, E Fend, F TI Primary intestinal non-Hodgkin's lymphoma and Epstein-Barr virus: High frequency of EBV-infection in T-cell lymphomas of Mexican origin SO LEUKEMIA & LYMPHOMA LA English DT Article DE intestinal lymphoma; EBV infection; EB virus; T-cell lymphomas; Mexican origin; B-cell lymphoma ID LATENT MEMBRANE-PROTEIN; REED-STERNBERG CELLS; POLYMERASE CHAIN-REACTION; LOWER RESPIRATORY-TRACT; NASOPHARYNGEAL CARCINOMA; VIRAL GENOMES; LYMPHOPROLIFERATIVE DISORDERS; MALIGNANT-LYMPHOMAS; MIDLINE GRANULOMA; BURKITTS-LYMPHOMA AB Epstein-Barr virus is universally associated with endemic Burkitt's lymphoma (BL) and undifferentiated nasopharyngeal carcinoma and can be detected in a significant proportion of cases of Hodgkin's disease (HD) and peripheral T-cell lymphoma, but only rarely in sporadic B-NHL. The frequency of EBV-positivity in certain neoplasms shows important geographic variations. Both HD and sporadic BL from Latin America have shown higher rates of EBV-association than cases from Western countries. In T-NHL, the frequency of EBV-positivity is influenced by the site of the primary tumor and the phenotype of the neoplastic cells. Nasal and nasal-type T-NHL, which show a T/NK-cell phenotype with expression of CD56 are virtually always EBV-associated, whereas only a proportion of nodal, gastrointestinal and pulmonary T-NHL are EBV-infected. A recent investigation of primary intestinal lymphomas of Mexican origin demonstrated EBV-positivity in all examined cases of T-NHL and BL and a proportion of other B-NHLs. The presence of EBV was independent of the presence or absence of enteropathy. Two of 6 cases studied showed CD56 expression. The high rate of EBV-positivity independent of histologic subtype is in contrast to the low to intermediate rates of EBV-positivity found in cases of intestinal T-NHL from Western countries and indicates that geographic differences in the frequency of EBV-association of lymphoid neoplasms might also extend to a fraction of peripheral T-cell lymphomas. C1 Inst Nacl Nutr Salvador Zubiran, Dept Pathol, Mexico City 14000, DF, Mexico. RP Fend, F (reprint author), NCI, NIH, Bldg 10,Room 2N110, Bethesda, MD 20892 USA. NR 82 TC 18 Z9 19 U1 2 U2 2 PU HARWOOD ACAD PUBL GMBH PI READING PA C/O STBS LTD, PO BOX 90, READING, BERKS, ENGLAND RG1 8JL SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD JUN PY 1998 VL 30 IS 1-2 BP 111 EP + PG 14 WC Oncology; Hematology SC Oncology; Hematology GA ZX229 UT WOS:000074493000011 PM 9669681 ER PT J AU Basser, PJ Pierpaoli, C AF Basser, PJ Pierpaoli, C TI A simplified method to measure the diffusion tensor from seven MR images SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; diffusion; tensor; anisotropy ID HUMAN BRAIN; MAGNETIC-RESONANCE; SPIN-ECHO; SPECTROSCOPY; ANISOTROPY; GRADIENTS AB Analytical expressions of the diffusion tensor of water, (D) under bar, and of scalar invariants derived from it, are given in terms of the intensities of seven diffusion-weighted images (DWIs). These formulas simplify the post-processing steps required in diffusion tensor imaging, including estimating (D) under bar in each voxel (from the set of b-matrices and their corresponding DWIs), and then computing its eigenvalues, eigenvectors, and scalar invariants. In a study conducted using artifact-free DWIs with high diffusion weighting (b(max) similar to 900 s/mm(2)), maps of Trace((D) under bar) and the Relative and Lattice Anisotropy indices calculated analytically and by multivariate linear regression showed excellent agreement in brain parenchyma of a healthy living cat. However, the quality of the analytically computed maps degraded markedly as diffusion weighting was reduced. Although diffusion tensor MRI with seven DWIs may be useful for clinical applications where rapid scanning and data processing are required, it does not provide estimates of the uncertainty of the measured imaging parameters, rendering it susceptible to noise and systematic artifacts. Therefore, care should be taken when using this technique in radiological applications. C1 NICHD, NIH, STBB, Bethesda, MD 20892 USA. NINDS, Neuroimaging Branch, NIH, Bethesda, MD 20892 USA. RP Basser, PJ (reprint author), NICHD, NIH, STBB, Bldg 13,Room 3N-17,13 S Dr, Bethesda, MD 20892 USA. RI Pierpaoli, Carlo/E-1672-2011; Basser, Peter/H-5477-2011 NR 37 TC 429 Z9 438 U1 3 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn.Reson.Med. PD JUN PY 1998 VL 39 IS 6 BP 928 EP 934 DI 10.1002/mrm.1910390610 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ZP499 UT WOS:000073759600010 PM 9621916 ER PT J AU Klett, CPR Zimonjic, DB Keck, CL Bonner, TI AF Klett, CPR Zimonjic, DB Keck, CL Bonner, TI TI Localization of the rat M1 muscarinic receptor gene to chromosome 1q43-51 SO MAMMALIAN GENOME LA English DT Article ID IDENTIFICATION; HYPERTENSION; ASSIGNMENT C1 Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. NIMH, Genet Sect, Bethesda, MD 20892 USA. RP Klett, CPR (reprint author), Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. NR 19 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD JUN PY 1998 VL 9 IS 6 BP 476 EP 478 DI 10.1007/s003359900801 PG 3 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA ZN865 UT WOS:000073691200014 PM 9585439 ER PT J AU Horton, WE Feng, LX Adams, C AF Horton, WE Feng, LX Adams, C TI Chondrocyte apoptosis in development, aging and disease SO MATRIX BIOLOGY LA English DT Review ID PROGRAMMED CELL-DEATH; DNA FRAGMENTATION; HYPERTROPHIC CHONDROCYTES; BONE-FORMATION; GROWTH-PLATE; DIFFERENTIATION; CARTILAGE; EXPRESSION; HEDGEHOG; CULTURE AB There is increasing evidence that chondrocyte apoptosis plays an important role in cartilage development, aging and disease. A variety of morphological and biochemical studies have identified apoptotic chondrocytes in both growth plate and articular cartilage of a variety of species. In addition, there is an ever increasing list of diverse stimuli that can induce chondrocyte apoptosis in vitro. A feedback loop regulating chondrocyte apoptosis in the growth plate has been described that includes Indian Hedgehog, parathyroid hormone-related protein and Bcl-2. The molecular mechanism regulating apoptosis in articular cartilage is still under investigation. Future studies should elucidate more fully how abnormal regulation of chondrocyte apoptosis may contribute to the development of chondrodysplasias and chondrosarcomas. Also, it will be of importance to define the relationship between chondrocyte apoptosis and the regulation of chondrocyte-specific gene expression. C1 NIA, Gerontol Res Ctr, Biol Chem Lab, NIH, Baltimore, MD 21224 USA. RP Horton, WE (reprint author), NIA, Gerontol Res Ctr, Biol Chem Lab, NIH, Mail Locat 12,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Adams, Christopher/0000-0003-2100-4417 NR 53 TC 92 Z9 95 U1 1 U2 4 PU GUSTAV FISCHER VERLAG PI JENA PA VILLENGANG 2, D-07745 JENA, GERMANY SN 0945-053X J9 MATRIX BIOL JI Matrix Biol. PD JUN PY 1998 VL 17 IS 2 BP 107 EP 115 DI 10.1016/S0945-053X(98)90024-5 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZY825 UT WOS:000074664500002 PM 9694591 ER PT J AU Adams, CS Horton, WH AF Adams, CS Horton, WH TI Increased apoptosis of articular chondrocytes in a Bcl-2 knockout transgenic mouse line SO MATRIX BIOLOGY LA English DT Meeting Abstract C1 NIA, Gerontol Res Ctr, Biol Chem Lab, NIH, Baltimore, MD 21224 USA. OI Adams, Christopher/0000-0003-2100-4417 NR 0 TC 0 Z9 0 U1 0 U2 1 PU GUSTAV FISCHER VERLAG PI JENA PA VILLENGANG 2, D-07745 JENA, GERMANY SN 0945-053X J9 MATRIX BIOL JI Matrix Biol. PD JUN PY 1998 VL 17 IS 2 BP 154 EP 155 DI 10.1016/S0945-053X(98)90032-4 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZY825 UT WOS:000074664500011 ER PT J AU Dawson, PA Marini, JC AF Dawson, PA Marini, JC TI Ribozyme suppression of mutant type T collagen mRNA in cultured OI fibroblasts: Development of gene therapy for dominant disorders SO MATRIX BIOLOGY LA English DT Meeting Abstract C1 NICHD, Heritable Disorders Branch, Bethesda, MD USA. RI Dawson, Paul/B-1268-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU GUSTAV FISCHER VERLAG PI JENA PA VILLENGANG 2, D-07745 JENA, GERMANY SN 0945-053X J9 MATRIX BIOL JI Matrix Biol. PD JUN PY 1998 VL 17 IS 2 BP 158 EP 158 DI 10.1016/S0945-053X(98)90041-5 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZY825 UT WOS:000074664500020 ER PT J AU Forlino, A Porter, FD Marini, JC AF Forlino, A Porter, FD Marini, JC TI Use of the cre/lox recombination system to create the first knock-in murine model for osteogenesis imperfecta SO MATRIX BIOLOGY LA English DT Meeting Abstract C1 NICHD, Heritable Disorders Branch, Bethesda, MD USA. RI Forlino, Antonella/H-5385-2015 OI Forlino, Antonella/0000-0002-6385-1182 NR 0 TC 0 Z9 0 U1 0 U2 0 PU GUSTAV FISCHER VERLAG PI JENA PA VILLENGANG 2, D-07745 JENA, GERMANY SN 0945-053X J9 MATRIX BIOL JI Matrix Biol. PD JUN PY 1998 VL 17 IS 2 BP 164 EP 164 DI 10.1016/S0945-053X(98)90055-5 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZY825 UT WOS:000074664500034 ER PT J AU Nyska, A Leininger, JR Maronpot, RR Haseman, JK Hailey, JR AF Nyska, A Leininger, JR Maronpot, RR Haseman, JK Hailey, JR TI Effect of individual versus group caging on the incidence of pituitary and Leydig cell tumors in F344 rats: proposed mechanism SO MEDICAL HYPOTHESES LA English DT Article ID TESTICULAR 11-BETA-HYDROXYSTEROID DEHYDROGENASE; GONADOTROPIN-RELEASING HORMONE; PLASMA TESTOSTERONE LEVELS; MALE RHESUS; STRESS; STEROIDOGENESIS; SUPPRESSION; CORTISOL AB Recently, an increase in pituitary tumor (pars distalis adenoma) incidence, and decrease in testicular interstitial cell tumor incidence, has been noted in F344 rats, in 2 year National Toxicology Program dermal and inhalation studies. One of the factors that may have contributed to this correlation is the difference in housing protocols. Rats in inhalation and dermal toxicity studies are singly caged, in contrast to other types of studies in which rats are group-caged, such as dosed-feed, dosed-water, or gavage studies. We propose that stress, related to individual caging, particularly among males, directly impairs testosterone synthesis and produces Leydig cell atrophy which leads to a feedback increase in the synthesis of luteinizing hormone by the anterior pituitary. This is followed by anterior pituitary cell functional hypertrophy, hyperplasia, and eventually neoplasia. It is known that individual caging of male rats produces a stress response associated with increased serum corticosteroids. The testicular interstitial cells (Leydig cells) have specific receptors for the glucocorticoid hormones. The Leydig cell enzyme 11-beta-hydroxysteroid dehydrogenase (11-beta-HSD) inactivates gluococorticoids; however, prolonged stress depletes this enzyme, enabling the gluococorticoids to impair steroidogenesis and eventually to lead to compensatory pituitary proliferations, including neoplasms. C1 NIEHS, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. RP Leininger, JR (reprint author), NIEHS, Natl Toxicol Program, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 23 TC 22 Z9 22 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0306-9877 J9 MED HYPOTHESES JI Med. Hypotheses PD JUN PY 1998 VL 50 IS 6 BP 525 EP 529 DI 10.1016/S0306-9877(98)90276-6 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA ZX659 UT WOS:000074541100015 PM 9710329 ER PT J AU Hospenthal, DR Kwon-Chung, KJ Bennett, JE AF Hospenthal, DR Kwon-Chung, KJ Bennett, JE TI Concentrations of airborne Aspergillus compared to the incidence of invasive aspergillosis: lack of correlation SO MEDICAL MYCOLOGY LA English DT Article; Proceedings Paper CT XIIIth Congress of the International-Society-of-Human-and-Animal-Mycology CY JUN, 1997 CL SALSOMAGGIORE TERME, ITALY SP Int Soc Human & Anim Mycol DE Aspergillus; aspergillosis; epidemiology; nosocomial AB Air sampling of the rooms and corridors of the oncology wards of the hospital was carried out over a 54-week period to assess the concentration of viable Aspergillus conidia. A. fumigatus and A. flavus were recovered at a mean of 1.83 cfu m(-3) air sampled. Individual samplings yielded concentrations of up to 11.6 cfu m(-3). Other Aspergillus spp. were recovered at a mean of 2.38 cfu m(-3) (maximum 32.6 cfu m(-3)). Concentration was not correlated with season or hospital ward. Review of autopsy results showed an average of 6.6 cases of aspergillosis annually over a 22-year period. No seasonal variation in case incidence was found. Six cases of invasive aspergillosis were diagnosed on the three cancer wards during the air-sampling period, but no association was seen linking these cases with changes in recovery of airborne Aspergillus. A seasonal pattern was not observed in the overall incidence of aspergillosis cases nor concentrations of airborne conidia. C1 NIAID, Clin Mycol Sect, LCI, NIH, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Infect Dis Serv, Washington, DC 20307 USA. RP Hospenthal, DR (reprint author), NIAID, Clin Mycol Sect, LCI, NIH, Bldg 10,Room 11C304,10 Ctr Dr,MSC 1882, Bethesda, MD 20892 USA. EM dhospenthal@atlas.niaid.nih.gov NR 23 TC 94 Z9 99 U1 1 U2 3 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1369-3786 J9 MED MYCOL JI Med. Mycol. PD JUN PY 1998 VL 36 IS 3 BP 165 EP 168 DI 10.1046/j.1365-280X.1998.00147.x PG 4 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 105XL UT WOS:000075100600005 PM 9776829 ER PT J AU Rimer, BK Glassman, B AF Rimer, BK Glassman, B TI Tailoring communications for primary care settings SO METHODS OF INFORMATION IN MEDICINE LA English DT Article; Proceedings Paper CT International-Health-Evaluation-Association Conference on Persons, Providers, and Settings CY 1996 CL VICTORIA, CANADA SP Int Hlth Evaluat Assoc DE tailored print communications; primary care; new-media; cancer screening ID SMOKING CESSATION; MESSAGES; MAMMOGRAPHY AB In more and more medical settings, physicians have less and less ti me to be effective communicators. To be effective, they need accurate, current information about their patients. Tailored health communications can facilitate positive patient-provider communications and foster behavioral changes conducive to health. Tailored communications (TCs) are produced for an individual based on information about that person. The focus of this report is on tailored print communications (TPCs). TPCs also enhance the process of evaluation, because they require a database and the collection of patient-specific information. We present a Tailoring Model for Primary Care that describes the steps involved in creating TPCs. We also provide examples from three ongoing studies in which TPCs are being used in order to illustrate the kinds of variables used for tailoring the products that are developed and how evaluation is conducted. TPCs offer opportunities to expand the reach of health professionals and to give personalized, individualized massages in an era of shrinking professional contact time. C1 Duke Univ, Med Ctr, Durham, NC 27710 USA. NCI, Bethesda, MD 20892 USA. RP Rimer, BK (reprint author), Duke Univ, Med Ctr, Trent Dr,Hanes House,2nd Floor,Box 2949 DUMC, Durham, NC 27710 USA. EM br79a@nih.gov FU NCI NIH HHS [1P50CA68438-02, 1R01CA59734-04, 1R01CA63782-04] NR 22 TC 34 Z9 35 U1 0 U2 3 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0026-1270 J9 METHOD INFORM MED JI Methods Inf. Med. PD JUN PY 1998 VL 37 IS 2 BP 171 EP 177 PG 7 WC Computer Science, Information Systems; Health Care Sciences & Services; Medical Informatics SC Computer Science; Health Care Sciences & Services; Medical Informatics GA ZW543 UT WOS:000074421500013 PM 9656660 ER PT J AU Tardieux, I Baines, I Mossakowska, M Ward, GE AF Tardieux, I Baines, I Mossakowska, M Ward, GE TI Actin-binding proteins of invasive malaria parasites and the regulation of actin polymerization by a complex of 32/34-kDa proteins associated with heat shock protein 70kDa SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Plasmodium knowlesi; actin-binding proteins; cytoskeleton; heat shock protein 70kDa; affinity chromatography ID PLASMODIUM-FALCIPARUM; CAPPING PROTEIN; F-ACTIN; TOXOPLASMA-GONDII; MAMMALIAN-CELLS; COGNATE PROTEIN; DICTYOSTELIUM; LOCALIZATION; CYTOSKELETON; GENE AB Movement of the malaria parasite into a host erythrocyte during invasion is thought to involve polymerization of parasite actin. We have used F-actin affinity chromatography to isolate actin-binding proteins from Plasmodium knowlesi merozoites, in an attempt to identify proteins responsible for regulating parasite actin polymerization during invasion. Five major proteins, of molecular masses 75, 70, 48, 40 and 34 kDa, were reproducibly eluted from the F-actin columns. The 70-kDa actin-binding protein was identified by tryptic peptide microsequencing as heat shock protein-70 kDa (HSC70); this identification was confirmed by Western blotting with anti-HSC70 antibody, and binding of the protein to ATP-agarose. A doublet of 32/34-kDa proteins coeluted with parasite HSC70 from the F-actin and ATP-agarose columns; a complex of these three proteins was also observed by gel filtration chromatography. Highly enriched fractions containing the Plasmodium HSC70/32/34 complex inhibited the polymerization of rabbit skeletal muscle actin, in vitro. This capping activity was calcium-independent, and abrogated by phosphatidylinositol 4,5-bisphosphate. The average length of the actin filaments polymerized in presence of the HSC70/32/34-kDa complex was significantly shorter than in the absence of the complex, consistent with a capping activity. The capping or uncapping of actin filament ends by the HSC70/32/34-kDa complex during invasion could provide a mechanism for localized actin filament growth and movement of the parasite into the host cell. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIAID, NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. NHLBI, NIH, Cell Biol Lab, Bethesda, MD 20892 USA. RP Tardieux, I (reprint author), Inst Pasteur, BBMI, 28 Rue Dr Roux, F-75724 Paris 15, France. RI Tardieux, Isabelle/G-4733-2014 NR 51 TC 34 Z9 37 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD JUN 1 PY 1998 VL 93 IS 2 BP 295 EP 308 DI 10.1016/S0166-6851(98)00044-9 PG 14 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA ZX664 UT WOS:000074541600012 PM 9662713 ER PT J AU Otrin, VR Kuraoka, I Nardo, T McLenigan, M Eker, APM Stefanini, M Levine, AS Wood, RD AF Otrin, VR Kuraoka, I Nardo, T McLenigan, M Eker, APM Stefanini, M Levine, AS Wood, RD TI Relationship of the xeroderma pigmentosum group E DNA repair defect to the chromatin and DNA binding proteins UV-DDB and replication protein A SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NUCLEOTIDE-EXCISION-REPAIR; COMPLEMENTATION GROUP-E; GROUP-E CELLS; DAMAGED DNA; PRIMATE CELLS; PHOTOPRODUCTS; PURIFICATION; COMPLEX; LIGHT; TRICHOTHIODYSTROPHY AB Cells from complementation groups A through G of the heritable sun-sensitive disorder xeroderma pigmentosum (XP) show defects in nucleotide excision repair of damaged DNA, Proteins representing groups A, B, C, D, F, and G are subunits of the core recognition and incision machinery of repair. XP group E (XP-E) is the mildest form of the disorder, and cells generally show about 50% of the normal repair level, We investigated two protein factors previously implicated in the XP-E defect, UV-damaged DNA binding protein (UV-DDB) and replication protein A (RPA), Three newly identified XP-E cell lines (XP23PV, XP25PV, and a line formerly classified as an XP variant) were defective in UV-DDB binding activity but had levels of RPA in the normal range. The XP-E cell extracts did not display a significant nucleotide excision repair defect in vitro, with either UV-irradiated DNA or a uniquely placed cisplatin lesion used as a substrate. Purified UV-DDB protein did not stimulate repair of naked DNA by DDB- XP-E cell extracts, but microinjection of the protein into DDB- XP-E cells could partially correct the repair defect. RPA stimulated repair in normal, XP-E, or complemented extracts from other XP groups, and so the effect of RPA was not specific for XP-E cell extracts. These data strengthen the connection between XP-E and UV-DDB, Coupled with previous results, the findings suggest that UV-DDB has a role in the repair of DNA in chromatin. C1 NICHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. CNR, Ist Genet Biochim & Evoluzionist, I-27100 Pavia, Italy. Imperial Canc Res Fund, Clare Hall Labs, S Mimms EN6 3LD, Herts, England. Erasmus Univ, Dept Cell Biol & Genet, NL-3000 DR Rotterdam, Netherlands. RP Levine, AS (reprint author), NICHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bldg 6,Rm 1A15, Bethesda, MD 20892 USA. RI Wood, Richard/E-7855-2011 OI Wood, Richard/0000-0002-9495-6892 NR 48 TC 54 Z9 55 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 1998 VL 18 IS 6 BP 3182 EP 3190 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZN267 UT WOS:000073628800009 ER PT J AU Fan, H Goodier, JL Chamberlain, JR Engelke, DR Maraia, RJ AF Fan, H Goodier, JL Chamberlain, JR Engelke, DR Maraia, RJ TI 5 ' processing of tRNA precursors can be modulated by the human La antigen phosphoprotein SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RNA-POLYMERASE-III; 5S RIBOSOMAL-RNA; 2 FUNCTIONAL COMPONENTS; TERMINATION FACTOR LA; TRANSCRIPTION TERMINATION; ESCHERICHIA-COLI; LUPUS ANTIBODIES; AUTOANTIGEN LA; RIBONUCLEASE-P; CAP STRUCTURE AB Eukaryotic precursor (pre)-tRNAs are processed at both ends prior to maturation. Pre-tRNAs and other nascent transcripts synthesized by RNA polymerase III are bound at their 3' ends at the sequence motif UUUOH [3' oligo(U)] by the La antigen, a conserved phosphoprotein whose role in RNA processing has been associated previously with 3'-end maturation only. We show that in addition to its role in tRNA 3'-end maturation, human La protein can also modulate 5' processing of pre-tRNAs. Both the La antigen's N-terminal RNA-binding domain and its C-terminal basic region are required for attenuation of pre-tRNA 5' processing. RNA binding and nuclease protection assays with a variety of pre-tRNA substrates and mutant La proteins indicate that 5' protection is a highly selective activity of La. This activity is dependent on 3' oligo(U) in the pre-tRNA for interaction with the N-terminal RNA binding domain of La and interaction of the C-terminal basic region of La with the 5' triphosphate end of nascent pre-tRNA. Phosphorylation of La is known to occur on serine 366, adjacent to the C-terminal basic region. We show that this modification interferes with the La antigen's ability to protect pre-tRNA(i)(Met) from 5' processing either by HeLa extract or purified RNase P but that it does not affect interaction with the 3' end of pre-tRNA. These findings provide the first evidence to indicate that tRNA 5'-end maturation may be regulated in eukaryotes. Implications of triphosphate recognition is discussed as is a role for La phosphoprotein in controlling transcriptional and posttranscriptional events in the biogenesis of polymerase III transcripts. C1 NICHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Univ Michigan, Cellular & Mol Biol Program, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA. RP Maraia, RJ (reprint author), NICHD, Lab Mol Growth Regulat, NIH, Bldg 6,Room 416,9000 Rockville Pike, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [T32 GM07315, T32 GM007315, GM34869, R01 GM034869] NR 45 TC 82 Z9 88 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 1998 VL 18 IS 6 BP 3201 EP 3211 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZN267 UT WOS:000073628800011 PM 9584161 ER PT J AU Kobayashi, T Rein, T DePamphilis, ML AF Kobayashi, T Rein, T DePamphilis, ML TI Identification of primary initiation sites for DNA replication in the hamster dihydrofolate reductase gene initiation zone SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RIBOSOMAL-RNA GENES; POLYMERASE CHAIN-REACTION; CHO CELLS; MIMOSINE ARRESTS; POLYOMA-VIRUS; ORIGIN; DOMAIN; CHROMOSOMES; XENOPUS; LOCUS AB Mammalian replication origins appear paradoxical. While some studies conclude that initiation occurs bidirectionally from specific loci, others conclude that initiation occurs at many sites distributed throughout large DNA regions, To clarify this issue, the relative number of early replication bubbles was determined at 26 sites in a 110-kb locus containing the dihydrofolate reductase (DHFR)-encoding gene in CHO cells; 19 sites were located within an 11-kb sequence containing ori-beta. The ratio of similar to 0.8-kb nascent DNA strands to nonreplicated DNA at each site was quantified by competitive PCR. Nascent DNA was defined either as DNA that was labeled by incorporation of bromodeoxyuridine in vivo or as RNA-primed DNA that was resistant to lambda-exonuclease. Two primary initiation sites were identified within the 12-kb region, where two-dimensional gel electrophoresis previously detected a high frequency of replication bubbles. A sharp peak of nascent DNA occurred at the ori-beta origin of bidirectional replication where initiation events were 12 times more frequent than at distal sequences. A second peak occurred 5 kb downstream at a previously unrecognized origin (ori-beta'), Thus, the DHFR gene initiation zone contains at least three primary initiation sites (ori-beta, ori-beta', and ori-gamma), suggesting that initiation zones in mammals, like those in fission yeast, consist of multiple replication origins. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP DePamphilis, ML (reprint author), NICHHD, NIH, Bldg 6,Rm 416, Bethesda, MD 20892 USA. NR 64 TC 108 Z9 110 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 1998 VL 18 IS 6 BP 3266 EP 3277 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZN267 UT WOS:000073628800017 PM 9584167 ER PT J AU Bohen, SP AF Bohen, SP TI Genetic and biochemical analysis of p23 and ansamycin antibiotics in the function of Hsp90-dependent signaling proteins SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID HEAT-SHOCK PROTEIN; CELL GLUCOCORTICOID RECEPTOR; HUMAN PROGESTERONE-RECEPTOR; STEROID-RECEPTOR; SACCHAROMYCES-CEREVISIAE; RETICULOCYTE LYSATE; TYROSINE KINASE; HSP90 MUTANTS; YEAST; BINDING AB The ubiquitous molecular chaperone Hsp90 acts in concert with a cohort of associated proteins to facilitate the functional maturation of a number of cellular signaling proteins, such as steroid hormone receptors and oncogene tyrosine kinases, The Hsp90-associated protein p23 is required for the assembly of functional steroid aporeceptor complexes in cell lysates, and Hsp90-binding ansamycin antibiotics disrupt the activity of Hsp90-dependent signaling proteins in cultured mammalian cells and prevent the association of p23 with Hsp90-receptor heterocomplexes; these observations have led to the hypotheses that p23 is required for the maturation of Hsp90 target proteins and that ansamycin antibiotics abrogate the activity of such proteins by disrupting the interaction of p23 with Hsp90, In this study, I demonstrate that ansamycin antibiotics disrupt the function of Hsp90 target proteins expressed in yeast cells; prevent the assembly of Sba1, a yeast p23-like protein, into steroid receptor-Hsp90 complexes; and result in the assembly of receptor-Hsp90 complexes that are defective for ligand binding. To assess the role of p23 in Hsp90 target protein function, I show that the activity of Hsp90 target proteins is unaffected by deletion of SBA1. Interestingly, steroid receptor activity in cells lacking Sba1 displays increased sensitivity to ansamycin antibiotics, and this phenotype is rescued by the expression of human p23 in yeast cells. These findings indicate that Hsp90-dependent signaling proteins can achieve a functional conformation in vivo in the absence of p23. Furthermore, while the presence of p23 decreases the sensitivity of Hsp90-dependent processes to ansamycin treatment, ansamycin antibiotics disrupt signaling through some mechanism other than altering the Hsp90-p23 interaction. C1 Natl Canc Inst, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. EM bohens@itsa.ucsf.edu NR 69 TC 83 Z9 85 U1 0 U2 1 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 JUN PY 1998 VL 18 IS 6 BP 3330 EP 3339 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZN267 UT WOS:000073628800023 PM 9584173 ER PT J AU Srivastava, RK Srivastava, AR Korsmeyer, SJ Nesterova, M Cho-Chung, YS Longo, DL AF Srivastava, RK Srivastava, AR Korsmeyer, SJ Nesterova, M Cho-Chung, YS Longo, DL TI Involvement of microtubules in the regulation of Bcl2 phosphorylation and apoptosis through cyclic AMP-dependent protein kinase SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PROGRAMMED CELL-DEATH; TAXOL-INDUCED APOPTOSIS; POLY(ADP-RIBOSE) POLYMERASE; CANCER CELLS; LEUKEMIA; ACTIVATION; GENE; DIFFERENTIATION; SUPPRESSION; INHIBITION AB The Bcl2 family of proteins plays a significant role in regulation of apoptosis. In this study, the microtubule-damaging drugs paclitaxel, vincristine, and vinblastine induced Bcl2 hyperphosphorylation and apoptosis in MCF-7 and MDA-MB-231 cells and reduced Bcl2-Bax dimerization. Paclitaxel or vincristine induced increased expression of Bax, while overexpression of Bcl2 in these cell lines counteracted the effects of low doses of these drugs. In addition, paclitaxel- and vincristine-induced activation of cyclic AMP (cAMP)-dependent protein kinase (protein kinase A [PKA]) induced Bcl2 hyperphosphorylation and apoptosis, which were blocked by the PKA inhibitor Rp diastereomers of cAMP (Rp-cAMP). This finding suggests that activation of PKA due to microtubule damage is an important event in Bcl2 hyperphosphorylation and induction of apoptosis. These microtubule-damaging drugs caused growth arrest in G(2)-M phase of the cell cycle and had no effect on p53 induction, suggesting that hyperphosphorylation mediated inactivation of Bcl2 and apoptosis without the involvement of p53. By comparison, the DNA-damaging drugs methotrexate and doxorubicin had no effect on Bcl2 hyperphosphorylation but induced p53 expression. Interestingly, paclitaxel or vincristine induced activation of caspase 3 and cleavage of poly(ADP-ribose) polymerase downstream of Bcl2 hyperphosphorylation. These data suggest that there may be a signaling cascade induced by agents that disrupt or damage the cytoskeleton that is distinct from (i.e., p53 independent), but perhaps related to (i.e., involves kinase activation and leads to apoptosis), the cellular response to DNA damage. C1 NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. Greater Baltimore Med Ctr, Baltimore, MD 21204 USA. Washington Univ, Sch Med, St Louis, MO 63110 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Srivastava, RK (reprint author), NIA, Immunol Lab, NIH, 5600 Nathan Shock Dr,Box 28, Baltimore, MD 21224 USA. EM rakeshs@vax.grc.nia.nih.gov NR 48 TC 317 Z9 325 U1 2 U2 9 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 JUN PY 1998 VL 18 IS 6 BP 3509 EP 3517 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZN267 UT WOS:000073628800041 PM 9584191 ER PT J AU Neuveut, C Low, KG Maldarelli, F Schmitt, I Majone, F Grassmann, R Jeang, KT AF Neuveut, C Low, KG Maldarelli, F Schmitt, I Majone, F Grassmann, R Jeang, KT TI Human T-cell leukemia virus type 1 Tax and cell cycle progression: Role of cyclin D-cdk and p110Rb SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RETINOBLASTOMA GENE-PRODUCT; DEPENDENT KINASE INHIBITORS; LONG TERMINAL REPEATS; HTLV-1 TAX; MAMMALIAN-CELLS; E7 PROTEIN; TRANSCRIPTIONAL ACTIVATOR; MYOGENIC DIFFERENTIATION; MOLECULAR-CLONING; SUPPRESSOR GENES AB Human T cell leukemia virus type 1 is etiologically linked to the development of adult T-cell leukemia and various human neuropathies. The Tax protein of human T-cell leukemia virus type I has been implicated in cellular transformation. Like other oncoproteins, such as Myc, Jun, and Fos, Tax is a transcriptional activator. How it mechanistically dysregulates the cell cycle is unclear. Previously, it was suggested that Tax affects cell-phase transition by forming a direct protein-protein complex with p16(INK4a), thereby inactivating an inhibitor of G(1)-to-S-phase progression. Here we show that, in T cells deleted for p16(INK4a), Tax can compel an egress of cells from G(0)/G(1) into S despite the absence of serum. We also show that in undifferentiated myocytes, expression of Tax represses cellular differentiation. In both settings, Tax expression was found to increase cyclin D-cdk activity and to enhance pRb phosphorylation. In T cells, a Tax-associated increase in steady state E2F2 protein was also documented. In searching for a molecular explanation for these observations, we found that Tax forms a protein-protein complex with cyclin D3, whereas a point-mutated and transcriptionally inert Tax mutant failed to form such a complex. Interestingly, expression of wild-type Tax protein in cells was also correlated with the induction of a novel hyperphosphorylated cyclin D3 protein. Taken together, these findings suggest that Tax might directly influence cyclin D-cdk activity and function, perhaps by a route independent of cdk inhibitors such as p16(INK4a). C1 NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. CUNY Mt Sinai Sch Med, Inst Gene Therapy & Mol Med, New York, NY 10029 USA. Univ Padua, Dipartimento Biol, Padova, Italy. Univ Erlangen Nurnberg, Inst Klin & Mol Virol, D-8520 Erlangen, Germany. RP Jeang, KT (reprint author), NIAID, Mol Microbiol Lab, Bldg 4,302,900 Rockville Pike, Bethesda, MD 20892 USA. RI Jeang, Kuan-Teh/A-2424-2008 NR 92 TC 150 Z9 152 U1 0 U2 1 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 JUN PY 1998 VL 18 IS 6 BP 3620 EP 3632 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZN267 UT WOS:000073628800053 PM 9584203 ER PT J AU Fragoso, G Pennie, WD John, S Hager, GL AF Fragoso, G Pennie, WD John, S Hager, GL TI The position and length of the steroid-dependent hypersensitive region in the mouse mammary tumor virus long terminal repeat are invariant despite multiple nucleosome B frames SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANSCRIPTION ELONGATION COMPLEX; HORMONE REGULATORY ELEMENT; TISSUE-SPECIFIC FACTORS; YEAST SWI/SNF COMPLEX; BREAST-CANCER CELLS; CIS-ACTING ELEMENT; GLUCOCORTICOID RECEPTOR; CHROMATIN STRUCTURE; IN-VIVO; MMTV PROMOTER AB Stimulation of the mouse mammary tumor virus with steroids results in the generation of a DNase I-hypersensitive region (HSR) spanning the hormone responsive element (HRE) in the long terminal repeat. Restriction enzymes were used to characterize the accessibility of various sites within the HSR of mouse mammary tumor virus long terminal repeat-reporter constructions in four different cell lines. The glucocorticoid-dependent HSR was found to span minimally 187 bases, a stretch of DNA longer than that associated with histones in the core particle. Although the 5'-most receptor binding site within the HRE is downstream of -190, hypersensitive sites were found further upstream to at least -295. The relationship in the accessibility between pairs of sites in the vicinity of the HSR was further examined in one cell line by a two-enzyme restriction access assay. In the uninduced state, the accessibilities at these sites were found to be independent of each other. In contrast, when stimulated with hormone, the accessibilities at these sites were observed to become linked. That is, once a distinct promoter was activated, all of the sites within the HSR of that molecule became accessible. The HSR formed along an invariant stretch of DNA sequence despite the multiplicity of nucleosome frames in the nucleosome B region, where the I-IRE is located, The results indicate that the macroscopic length of the HSR does not arise from core length-remodeling events in molecules containing Nuc-B in alternative positions. C1 NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bldg 41,Rm B602,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA. NR 88 TC 56 Z9 56 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 JUN PY 1998 VL 18 IS 6 BP 3633 EP 3644 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZN267 UT WOS:000073628800054 PM 9584204 ER PT J AU Krasnoselskaya, I Huang, J Jones, T Dezan, C Mortin, MA AF Krasnoselskaya, I Huang, J Jones, T Dezan, C Mortin, MA TI Selection and analysis of rare second-site suppressors of Drosophila RNA polymerase II mutation SO MOLECULAR AND GENERAL GENETICS LA English DT Article DE adaptive mutation; Drosophila melanogaster; mutagenesis; RNA polymerase II; suppressor selection ID ESCHERICHIA-COLI; ADAPTIVE MUTATION; DNA-POLYMERASE; 3-DIMENSIONAL STRUCTURE; 2ND-LARGEST SUBUNIT; MELANOGASTER; LOCUS; RESOLUTION; GENE AB We used a mutagenesis and selection procedure in Drosophila melanogaster to recover rare allele-specific suppressor mutations. More than 11 million flies mutant for one of five recessive-lethal mutations in the two largest subunits of RNA polymerase II were selected for additional mutations that restored viability. Forty one suppressor mutations were recovered. At least 16 are extragenic, identifying a minimum of three loci, two of which do not map near genes known to encode subunits of RNA polymerase II. At most, 25 are intragenic, 4 reverting the initial altered nucleotide back to wild type. Sequence analysis of interacting mutations in the two largest subunits identified a discrete domain in each subunit. These domains might be contact points for the subunits. Finally, our selections were large enough to allow recovery of multiple independent changes in the same nucleotides yet mutations in other equally likely targets were not recovered. The mutations recovered are not random and might provide insights into possible mechanisms for mutagenesis in eukaryotes. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Mortin, MA (reprint author), NCI, Biochem Lab, NIH, Bldg 37,Rm 4D-25,37 Convent Dr, Bethesda, MD 20892 USA. RI Mortin, Mark/B-4251-2008 NR 35 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0026-8925 J9 MOL GEN GENET JI Mol. Gen. Genet. PD JUN PY 1998 VL 258 IS 5 BP 457 EP 465 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 100FN UT WOS:000074805400002 PM 9669327 ER PT J AU Horikawa, I Oshimura, M Barrett, JC AF Horikawa, I Oshimura, M Barrett, JC TI Repression of the telomerase catalytic subunit by a gene on human chromosome 3 that induces cellular senescence SO MOLECULAR CARCINOGENESIS LA English DT Article DE chromosome transfer; telomerase activity; telomerase components; telomere shortening; renal cell carcinoma ID HUMAN-CELLS; IDENTIFICATION; IMMORTALITY; FIBROBLASTS; EXPRESSION; INHIBITOR; CANCER AB The cellular senescence program is controlled by multiple genetic pathways, one of which involves the regulation of telomerase and telomere shortening. The introduction of a normal human chromosome 3 into the human renal cell carcinoma cell line RCC23 caused repression of telomerase activity, progressive shortening of telomeres, and restoration of the cellular senescence program. We attributed the repression of telomerase activity to the marked downregulation of the gene encoding the catalytic subunit of telomerase (hEST2/hTRT) but not another protein component (TP1/TLP1) or the RNA component of telomerase. These results suggest that a senescence-inducing gene on chromosome 3 controls hEST2/hTRT gene expression either directly or indirectly and support the notion that hEST2/hTRT is the major determinant of telomerase enzymatic activity in human cells. Mol. Carcinog. 22:65-72, 1998. (C) 1998 Wiley-Liss, Inc.dagger C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Tottori Univ, Sch Life Sci, Dept Mol & Cell Genet, Yonago, Tottori, Japan. RP Barrett, JC (reprint author), NIEHS, Mol Carcinogenesis Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 33 TC 64 Z9 65 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 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD JUN PY 1998 VL 22 IS 2 BP 65 EP 72 DI 10.1002/(SICI)1098-2744(199806)22:2<65::AID-MC1>3.0.CO;2-J PG 8 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA ZX063 UT WOS:000074465400001 PM 9655250 ER PT J AU Romagnolo, D Annab, LA Thompson, TE Risinger, JI Terry, LA Barrett, JC Afshari, CA AF Romagnolo, D Annab, LA Thompson, TE Risinger, JI Terry, LA Barrett, JC Afshari, CA TI Estrogen upregulation of BRCA1 expression with no effect on localization SO MOLECULAR CARCINOGENESIS LA English DT Article DE Hormone; breast cancer; ovarian cancer; BRCA1 ID CANCER SUSCEPTIBILITY GENE; OVARIAN-CANCER; HUMAN BREAST; TRANSCRIPTIONAL ACTIVATION; CELLS; MUTATIONS; GROWTH; TUMOR; FAMILIES; RNA AB Alterations in the expression of the breast and ovarian cancer susceptibility gene BRCA1 may contribute to the development of mammary and ovarian neoplasia. The sex-steroid estrogen modulates cell proliferation of normal and neoplastic breast and ovarian epithelial cells, but the role of estrogen regulation on the expression of BRCA1 remains to be defined. In this study, estrogen-regulated BRCA1 expression was examined in breast and ovarian cancer cells. Estrogen stimulated the proliferation of estrogen receptor (ER)-positive breast MCF-7, C7-MCF-7, and ovarian BG-1 cells as well as the expression of the estrogen-inducible pS2 gene. This was concomitant with upregulation of BRCA1 mRNA (2.5- to 5.0-fold) and a 3- to 10-fold induction of BRCA1 protein (230 kDa). Cell fractionation studies localized the BRCA1 protein to the nucleus in both unstimulated and estrogen-stimulated cells. The antiestrogen ICI-182780 inhibited estrogen-induced cell proliferation, BRCA1 mRNA induction, and BRCA1 protein expression in ER-positive cells. Conversely, estrogen did not influence expression of BRCA1 in HBL-100 cells that lacked the estrogen receptor, although the constitutive levels of BRCA1 mRNA (but not protein) in these cells were 5- to 30-fold higher than in other breast and ovarian cancer cells. Secretion of the BRCA1 protein into the cell medium did not account for the discrepancy between the mRNA and protein levels in HBL-100 cells. Proliferation of HBL-100 cells was not affected by either estrogen or ICI-182780. Taken together, these data support a role for the steroid estrogen and the involvement of the estrogen receptor pathway in the modulation of expression of BRCA1.We therefore propose that stimulation of cell proliferation may be a prerequisite for upregulation of BRCA1 in breast and ovarian cancer cells. n/lol. Carcinog. 22:102-109, 1998. (C) 1998 Wiley-Liss, Inc.dagger C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Afshari, CA (reprint author), NIEHS, Mol Carcinogenesis Lab, POB 12233,MD2-04, Res Triangle Pk, NC 27709 USA. NR 46 TC 45 Z9 45 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD JUN PY 1998 VL 22 IS 2 BP 102 EP 109 DI 10.1002/(SICI)1098-2744(199806)22:2<102::AID-MC5>3.0.CO;2-O PG 8 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA ZX063 UT WOS:000074465400005 PM 9655254 ER PT J AU Paull, TT Gellert, M AF Paull, TT Gellert, M TI The 3 ' to 5 ' exonuclease activity of Mre11 facilitates repair of DNA double-strand breaks SO MOLECULAR CELL LA English DT Article ID ESCHERICHIA-COLI K-12; END-JOINING REPAIR; SACCHAROMYCES-CEREVISIAE; NONHOMOLOGOUS RECOMBINATION; ILLEGITIMATE RECOMBINATION; MEIOTIC RECOMBINATION; MAMMALIAN-CELLS; WILD-TYPE; MUTATIONS; RAD50 AB MRE11 and RAD50 are known to be required for nonhomologous joining of DNA ends in vivo. We have investigated the enzymatic activities of the purified proteins and found that Mre11 by itself has 3' to 5' exonuclease activity that is increased when Mre11 is in a complex with Rad50. Mre11 also exhibits endonuclease activity, as shown by the asymmetric opening of DNA hairpin loops. In conjunction with a DNA ligase, Mre11 promotes the joining of noncomplementary ends in vitro by utilizing short homologies near the ends of the DNA fragments. Sequence identities of 1-5 base pairs are present at all of these junctions, and their diversity is consistent with the products of nonhomologous end-joining observed in vivo. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gellert, M (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 58 TC 551 Z9 565 U1 1 U2 15 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell. PD JUN PY 1998 VL 1 IS 7 BP 969 EP 979 DI 10.1016/S1097-2765(00)80097-0 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZW235 UT WOS:000074389200004 PM 9651580 ER PT J AU Hiom, K Gellert, M AF Hiom, K Gellert, M TI Assembly of a 12/23 paired signal complex: A critical control point in V(D)J recombination SO MOLECULAR CELL LA English DT Article ID DNA STRAND TRANSFER; STRUCTURE REQUIREMENTS; MOUSE THYMOCYTES; RAG2 PROTEINS; 2 STEPS; CLEAVAGE; INITIATION; MECHANISM; SEQUENCE; REARRANGEMENT AB The 12/23 rule requires that V(D)J recombination only occurs between recombination signals with 12 and 23 base pair spacers. We show that the 12/23 rule is established prior to DNA cleavage, by the formation of a synaptic complex containing both 12-spacer and 23-spacer signals. The RAG1 and RAG2 proteins, as well as the DNA bending protein HMG1, are needed for efficient formation of this complex. We show further that the synaptic complex is the functional complex for coupled cleavage. After cleavage, all four broken DNA ends remain associated with the RAG proteins in a postcleavage synaptic complex, whose existence helps to explain the known role of RAG1 and RAG2 in the subsequent end-joining events that complete V(D)J recombination. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gellert, M (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RI Hiom, Kevin/B-4374-2009 NR 25 TC 180 Z9 180 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell. PD JUN PY 1998 VL 1 IS 7 BP 1011 EP 1019 DI 10.1016/S1097-2765(00)80101-X PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZW235 UT WOS:000074389200008 PM 9651584 ER PT J AU Cooksey, RC Morlock, GP Holloway, BP Mazurek, GH Abaddi, S Jackson, LK Buzard, GS Crawford, JT AF Cooksey, RC Morlock, GP Holloway, BP Mazurek, GH Abaddi, S Jackson, LK Buzard, GS Crawford, JT TI Comparison of two nonradioactive, single-strand conformation polymorphism electrophoretic methods for identification of rpoB mutations in rifampin-resistant isolates of Mycobacterium tuberculosis SO MOLECULAR DIAGNOSIS LA English DT Article DE rifampin resistance; Mycobacterium tuberculosis; single-strand conformation polymorphism electrophoresis ID GENOTYPIC DETECTION; GENE; SPECIMENS; ASSAY; PCR AB Background: Diverse mutations in an 81 bp region of the rpoB gene are found in similar to 95% of rifampin-resistant (RIP) Mycobacterium tuberculosis isolates. Various methods to detect these mutations have been evaluated for their usefulness as rapid screens for rifampin resistance, Methods and Results: Two nonradioactive variations of single-strand conformation polymorphism (SSCP) electrophoresis were optimized and evaluated for their ability to distinguish nine rpoB mutations present in a collection of 51 RIFr M. tuberculosis isolates. One of the methods used polymerase chain reaction products (128 bp) encompassing the 81 bp region of the rpoB gene, which were denatured in the presence of methyl mercury hydroxide, subjected to polyacrylamide gel electrophoresis (PAGE) and detected by staining with ethidium bromide. For the second method, fluorogenically labeled primers were used to generate products that were electrophoresed in an ABI Model 310 Genetic Analyzer equipped with a 3% GeneScan Polymer Column (Applied Biosystems Inc; Foster City, CA). Mobility shifts for all nine mutations were clearly discernible from the wildtype pattern by methods when tested in blind analyses. When an additional 30 isolates were tested by both SSCF methods in a blinded fashion, correlations with RIF susceptibility testing were complete for susceptible and homogeneously resistant isolates. Among three isolates with heterogeneously resistant populations, however, two were correctly identified by fluorescent SSCP compared with one by the PAGE SSCP method. Subpopulations of the His(526)-->TYr rpoB mutant, which is frequently encountered among RIFr strains, could be detected using templates prepared from mixtures of broth cultures with a susceptible strain. Conclusions: SSCP electrophoresis is useful for rapid screening for RIF resistance in susceptible and fully resistant isolates of M. tuberculosis. However, conventional susceptibility testing is still necessary for two reasons: (1) <100% of RIFr strains have mutations in the 81 bp hotspot rpoB genomic region, and (2) SSCP may not offer sufficient sensitivity to detect clinically important emergent mutant subpopulations, especially those present as <10% of the total population in a sam pie. Whereas PAGE SSCP is less costly than fluorescent SSCP, the latter method is somewhat easier to perform and generates quantitative data. C1 Ctr Dis Control & Prevent, Div AIDS STD & TB Lab Res, Natl Ctr Infect Dis, Atlanta, GA 30333 USA. Ctr Dis Control & Prevent, Natl Ctr HIV STD & TB Prevent, Atlanta, GA 30333 USA. Xavier Univ, Coll Pharm, New Orleans, LA 70125 USA. NCI, Frederick Canc Res & Dev Ctr, ESAIC Frederick, Frederick, MD USA. Suez Canal Univ, Sch Med, Ismailia, Egypt. RP Cooksey, RC (reprint author), Ctr Dis Control & Prevent, Div AIDS STD & TB Lab Res, Natl Ctr Infect Dis, Mailstop F08, Atlanta, GA 30333 USA. NR 16 TC 15 Z9 15 U1 0 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1084-8592 J9 MOL DIAGN JI Mol. Diagn. PD JUN PY 1998 VL 3 IS 2 BP 73 EP 80 DI 10.1016/S1084-8592(98)80055-6 PG 8 WC Biotechnology & Applied Microbiology; Medical Laboratory Technology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Medical Laboratory Technology; Research & Experimental Medicine GA ZY535 UT WOS:000074631800003 ER PT J AU Shotelersuk, V Hazelwood, S Larson, D Iwata, F Kaiser-Kupfer, MI Kuehl, E Bernardini, I Gahl, WA AF Shotelersuk, V Hazelwood, S Larson, D Iwata, F Kaiser-Kupfer, MI Kuehl, E Bernardini, I Gahl, WA TI Three new mutations in a gene causing Hermansky-Pudlak syndrome: Clinical correlations SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE albinism; mutation analysis; autosomal recessive; platelet dense bodies; storage pool deficiency ID STORAGE POOL DEFICIENCY; GRANULOMATOUS COLITIS; POPULATION; DISORDER AB Hermansky-Pudlak syndrome (HPS) consists of oculocutaneous albinism, a platelet storage pool deficiency, and ceroid lipofuscinosis. HPS is common in northwest Puerto Rico, where affected individuals are homozygous for a 16-bp duplication in the gene HPS. Two other homozygous frameshift mutations in HPS were previously identified among non-Puerto Rican patients, Eighteen non-Puerto Rican HPS families were studied and HPS mutations in three of them identified. One mutation, T322insC, has been previously described, However, three additional mutations, E133X, T322delC, and S396delC, have not been reported. Two families exhibited compound heterozygosity for these mutations, although most previously reported HPS patients have been homozygous for a particular mutation. All the newly described mutations were associated with decreased or undetectable levels of HPS RNA by Northern blot analysis of fibroblasts, and all had significant pigment dilution, To date, all mutations in HPS result in a truncated protein, suggesting that the C-terminal portion of the HPS protein is functionally important. (C) 1998 Academic Press. C1 NICHHD, Sect Human Biochem Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. NEI, Ophthalm Genet & Clin Serv Branch, NIH, Bethesda, MD 20892 USA. RP Shotelersuk, V (reprint author), NICHHD, Sect Human Biochem Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. NR 26 TC 40 Z9 40 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUN PY 1998 VL 64 IS 2 BP 99 EP 107 DI 10.1006/mgme.1998.2679 PG 9 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 112XP UT WOS:000075520300002 PM 9705234 ER PT J AU Chu, CC Paul, WE AF Chu, CC Paul, WE TI Expressed genes in interleukin-4 treated B cells identified by cDNA representational difference analysis SO MOLECULAR IMMUNOLOGY LA English DT Article DE cDNA; representational difference analysis; subtraction; interleukin-4; B lymphocytes ID POLYMERASE CHAIN-REACTION; MONOCLONAL-ANTIBODIES; LYMPHOCYTE SUBSETS; DNA REARRANGEMENT; MESSENGER-RNA; GROWTH-FACTOR; T-CELLS; CLONING; TRANSCRIPTS; PROTEIN AB Interleukin-4 (IL-4) stimulates B cell growth and differentiation, such as inducing mature B cells to switch to IgG1 and IgE production. To further characterize IL-4 effects on B cells, we used a sensitive PCR-based subtraction approach to isolate genes expressed in IL-4 treated cells. Our approach combined an adaptation of the genomic representational difference analysis (RDA) method to cDNA analysis with a physical separation method (magnetic bead depletion). This cDNA RDA technique allowed us to perform subtraction on the relatively small number of highly, characterized, purified B cells that can be conveniently prepared. In stimulated B cells from cDNA from LPS + IL-4 stimulated B cells. Two rounds of subtraction resulted in greater than 100-fold enhancement of expected IL-4-induced C gamma 1 cDNA. At that point, we cloned this subtraction library and analysed 154 randomly picked clones for sequence similarities. From these clones, 37 individual genes were obtained. Most of these genes (30) could be functionally identified by sequence similarity. These included genes encoding C gamma 1 (1), cytoskeletal components (4) and products involved in DNA replication (3). metabolism (5), signal transduction (4), transcription (4), translation (6) and transport (3). Only 7 genes had no similarity to known sequences in the GenBank, EMBL or Swiss Prot databases. One unknown gene (designated Fig1 for IL-Four Induced Gene 1) and one gene with homology to the human transcription factor E4BP4 were confirmed by Northern blot analysis to be induced 10-20-fold by IL-4 treatment. This list of expressed genes in LPS + IL-4 treated B cells may shed further insight on the action and mechanism of IL-4 stimulation of cells. (C) 1998 Elsevier Science Ltd. All rights reserved. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Chu, CC (reprint author), N Shore Univ Hosp, Dept Med, Div Rheumatol & Allergy Clin Immunol, 350 Community Dr, Manhasset, NY 11030 USA. EM cchu@nshs.edu NR 60 TC 30 Z9 47 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD JUN PY 1998 VL 35 IS 8 BP 487 EP 502 DI 10.1016/S0161-5890(98)00031-5 PG 16 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 130FR UT WOS:000076509700007 PM 9798653 ER PT J AU Smith, MW Chapman, RW Powers, DA AF Smith, MW Chapman, RW Powers, DA TI Mitochondrial DNA analysis of Atlantic Coast, Chesapeake Bay, and Delaware Bay populations of the teleost Fundulus heteroclitus indicates temporally unstable distributions over geologic time SO MOLECULAR MARINE BIOLOGY AND BIOTECHNOLOGY LA English DT Article ID DEHYDROGENASE LDH-B4 ALLOZYMES; BIOCHEMICAL GENETICS; GEOGRAPHICAL VARIATION; SPATIAL VARIATION; ALLELIC ISOZYMES; HYBRID ZONES; FREQUENCIES; ADAPTATION; FISH; LOCI AB The estuarine teleost Fundulus heteroclitus exhibits some of the most remarkable genetic and morphologic transitions of any species along the Atlantic coast of the United States. Abrupt changes in gene frequencies at a variety of allelic isozymes have been identified at or near the Hudson River, and these changes are mirrored in morphologic characters. Analysis of mitochondrial DNA variation of four Atlantic coast populations identified two major mtDNA haplotype assemblages with a transition zone somewhere along the coast of New Jersey, but the concordance of patterns of mtDNA distributions and those evident in other genetic and morphologic features is unclear owing to the limited number of populations examined. In this study we extend the analysis of mtDNA variation to include 740 individual F. heteroclitus from 29 populations along the Atlantic coast and within the Chesapeake and Delaware Bays. The intent was to define more clearly the transition zone from southern to northern populations in reference to those already identified in allelic isozymes and morphologic characters. In addition, this study examined the distribution of mtDNA variation within two major estuaries (Chesapeake Bay and Delaware Bay) to determine if glacial relect populations of the northern form might still inhabit the upper reaches of these systems. The results indicate an abrupt transition in mtDNA haplotype frequencies in northern New Jersey, which is somewhat south of the transition zone indicated by allelic isozymes and morphologic features. The northern mtDNA haplotypes were also detected in the upper reaches of Chesapeake and Delaware Bays, but the frequency distribution was more clinal than that identified along the coast. On the basis of these data, we suggest that a single ancestral contact zone previously existed at least as far south as the mouth of the Chesapeake Bay prior to the last glaciation and that this zone has been unstable during the past several hundred thousand years. C1 Stanford Univ, Dept Biol Sci, Hopkins Marine Stn, Pacific Grove, CA 93950 USA. NCI, Genet Epidemiol Lab, SAIC, Frederick Lab Genom Divers, Frederick, MD 21702 USA. Marine Resources Res Inst, S Carolina Dept Nat Resources, Charleston, SC 29412 USA. RP Powers, DA (reprint author), Stanford Univ, Dept Biol Sci, Hopkins Marine Stn, Pacific Grove, CA 93950 USA. RI Smith, Michael/B-5341-2012 NR 50 TC 25 Z9 25 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1053-6426 J9 MOL MAR BIOL BIOTECH JI Mol. Mar. Biol. Biotechnol. PD JUN PY 1998 VL 7 IS 2 BP 79 EP 87 PG 9 WC Biotechnology & Applied Microbiology; Marine & Freshwater Biology SC Biotechnology & Applied Microbiology; Marine & Freshwater Biology GA ZR136 UT WOS:000073940400001 ER PT J AU Bera, TK Kennedy, PE Berger, EA Barbas, CF Pastan, I AF Bera, TK Kennedy, PE Berger, EA Barbas, CF Pastan, I TI Specific killing of HIV-infected lymphocytes by a recombinant immunotoxin directed against the HIV-1 envelope glycoprotein SO MOLECULAR MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; PSEUDOMONAS EXOTOXIN; CD4-PSEUDOMONAS EXOTOXIN; A-CHAIN; TYPE-1; CELLS; NEUTRALIZATION; PROTEIN; CANCER AB Background: 3B3 is a high-affinity anti-gp120 antibody that neutralizes a wide range of primary and laboratory isolates of HIV-1. The parental antibody was isolated from a combinatorial phage display library constructed from bone marrow RNA of an HIV-infected individual. We have generated a highly active immunotoxin using the 3B3 single-chain Fv (scFv) which can specifically kill lymphocytes infected by HIV-1. Materials and Methods: We used recombinant DNA technology to clone the Fv fragment of 3B3 and produce a single-chain Fv (scFv). 3B3 scFv was then fused to a truncated version of Pseudomonas exotoxin A (PE38), giving rise to a recombinant immunotoxin 3B3(Fv)PE38 that was expressed in E, coli and purified to near homogeneity. Results: 3B3(Fv)-PE38 binds with the same affinity as the parental Fab antibody to the MN strain of gp120. The immunotoxin specifically kills a gp120-expressing transfected cell line and a chronically HN-infected lymphocytic cell line. The immunotoxin is very stable at 37 degrees C, retaining 80% of its original activity after 24 hr. Conclusions: Potent immunotoxins such as 3B3(Fv)PE38 could be utilized in combination with multidrug cocktails that limit viral replication to help reduce viral reservoirs in patients with AIDS. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Scripps Res Inst, Dept Mol Biol, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Room 4E16,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI37470] NR 27 TC 30 Z9 31 U1 1 U2 2 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD JUN PY 1998 VL 4 IS 6 BP 384 EP 391 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA ZX873 UT WOS:000074564000003 PM 10780881 ER PT J AU Kubbutat, MHG Vousden, KH AF Kubbutat, MHG Vousden, KH TI Keeping an old friend under control: regulation of p53 stability SO MOLECULAR MEDICINE TODAY LA English DT Review ID BREAST-CANCER; DNA-DAMAGE; PROTEIN; CHECKPOINT; EXPRESSION; GENE; SARCOMAS; MUTATION; BINDING; CELLS AB The tumor suppressor protein p53 plays a pivotal role in protection against the development of cancer and is inactivated in many human malignancies. p53 is thought to prevent accumulation of genomic alterations by hindering cell proliferation in response to genotoxic stress, and two of the principal functions of p53 are the induction of cell-cycle arrest and the activation of apoptotic cell death. Because p53 is an extremely efficient inhibitor of cell growth, keeping p53 function under control in normal cells is critical. One of the principal mechanisms by which cells achieve this is by regulating the p53 protein level, although the ability of the protein to adopt active and latent forms and its cellular localization also contribute to the regulation of its function. Here, we summarize recently identified mechanisms that regulate the stability of the p53 protein and discuss the potentially immense clinical relevance of these observations in developing therapeutical approaches that aim to restore p53 function in human tumors. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Kubbutat, MHG (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, W 7th St, Frederick, MD 21702 USA. NR 50 TC 80 Z9 81 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 JUN PY 1998 VL 4 IS 6 BP 250 EP 256 DI 10.1016/S1357-4310(98)01260-X PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA ZV826 UT WOS:000074345200010 PM 9679243 ER PT J AU Bannantine, JP Rockey, DD Hackstadt, T AF Bannantine, JP Rockey, DD Hackstadt, T TI Tandem genes of Chlamydia psittaci that encode proteins localized to the inclusion membrane SO MOLECULAR MICROBIOLOGY LA English DT Article ID INFECTED-CELLS; PARASITOPHOROUS VACUOLES; LEGIONELLA-PNEUMOPHILA; ELECTRON-MICROSCOPY; COXIELLA-BURNETII; TRACHOMATIS; PHAGOSOME; ANTIGENS; PATHWAY; CLONING AB Chlamydiae are obligate intracellular bacteria that replicate within a non-acidified vacuole, termed an inclusion. To identify chlamydial proteins that are unique to the intracellular phase of the life cycle, a lambda expression library of Chlamydia psittaci DNA was differentially screened with convalescent antisera from infected guinea pigs and antisera directed at formalin-fixed purified chlamydial elementary bodies (EBs). One library clone was identified that harboured two open reading frames (ORFs) with coding potential for similar-sized proteins of approximate to 20 kDa. These proteins were subsequently termed IncB and IncC. Sequencing of the cloned insert revealed a strong Escherichia coli-like promoter sequence immediately upstream of incS and a 36nt intergenic region between the ORFs. Sequence analysis of the region upstream of incB and incC revealed two ORFs that had strong homologies to an amino acid transporter and a sodium-dependent transporter. Immunoblotting with antisera directed at IncB or IncC demonstrated that these proteins are present in C. psiffaci-infected HeLa cells but are absent or below the level of detection in purified EBs. Reverse transcriptase-polymerase chain reactions provided evidence that incB and incC are transcribed in an operon, Immunofluorescence microscopy demonstrated that IncB and IncC are each localized to the inclusion membrane of infected cells. No primary sequence similarity is evident between IncA, IncB or IncC, but each contains a large hydrophobic domain of similar size and character as in IncA. Analysis of the recently completed C. trachomatis serovar D genome database has revealed C. trachomatis ORFs encoding homologues to incS and incC, indicating that these genes are conserved among the chlamydiae. C1 Oregon State Univ, Dept Microbiol, Corvallis, OR 97331 USA. NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Rockey, DD (reprint author), Oregon State Univ, Dept Microbiol, Corvallis, OR 97331 USA. OI Bannantine, John/0000-0002-5692-7898 NR 31 TC 60 Z9 63 U1 0 U2 2 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUN PY 1998 VL 28 IS 5 BP 1017 EP 1026 DI 10.1046/j.1365-2958.1998.00867.x PG 10 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA ZU803 UT WOS:000074236500014 PM 9663687 ER PT J AU Britton, RA Powell, BS Dasgupta, S Sun, Q Margolin, W Lupski, JR Court, DL AF Britton, RA Powell, BS Dasgupta, S Sun, Q Margolin, W Lupski, JR Court, DL TI Cell cycle arrest in era GTPase mutants: a potential growth rate-regulated checkpoint in Escherichia coli (vol 27, pg 739, 1998) SO MOLECULAR MICROBIOLOGY LA English DT Correction C1 Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Baylor Coll Med, Program Mol & Cell Biol, Houston, TX 77030 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Lab Gene Regulat & Chromosome Biol, Frederick, MD 21702 USA. Univ Texas, Sch Med, Dept Microbiol & Mol Genet, Houston, TX 77030 USA. Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. RP Court, DL (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. NR 1 TC 3 Z9 3 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUN PY 1998 VL 28 IS 6 BP 1391 EP 1393 PG 3 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA ZW772 UT WOS:000074446800031 ER PT J AU Hansen, AJ Lee, YH Sterneck, E Gonzalez, FJ MacKenzie, PI AF Hansen, AJ Lee, YH Sterneck, E Gonzalez, FJ MacKenzie, PI TI C/EBP alpha is a regulator of the UDP glucuronosyltransferase UGT2B1 gene SO MOLECULAR PHARMACOLOGY LA English DT Article ID ALPHA-1-ACID GLYCOPROTEIN GENE; BINDING PROTEIN-ALPHA; SYNERGISTICALLY ACTIVATE; GLUCOCORTICOID RECEPTOR; NUCLEAR FACTOR; ALBUMIN GENE; EXPRESSION; TRANSCRIPTION; FAMILY; SEQUENCE AB The rat UDP glucuronosyltransferase, UGT2B1, is expressed in the liver where it glucuronidates steroids, environmental toxins, and carcinogens. A region between -88 and -111 base pairs upstream from the UGT2B1 gene transcription start site contains a CCAAT enhancer binding protein (C/EBP)-like element and was previously shown by Dnase I footprint analysis to bind to proteins in both rat liver and human hepatoma (HepG2) cell nuclear extracts. In this study, the importance of this region in the regulation of the UGT2B1 gene was assessed by functional and DNA binding assays. Varying lengths of the UGT2B1 gene promoter, with and without the C/EBP-like element, were fused to the chloramphenicol acetyltransferase reporter gene and transfected into HepG2 cells. Transcriptional activity of the UGT2B1 promoter construct containing the C/EBP-like element was strongly elevated in the presence of a cotransfected C/EBP alpha expression vector. In contrast, no change was observed when an expression vector encoding C/EBP beta was cotransfected with the UGT2B1 promoter constructs. Introduction of point mutations into the C/EBP-like element prevented any C/EBP alpha-mediated increase in chloramphenicol acetyltransferase activity. Gel shift analyses demonstrated that the C/EBP-like element binds a complex of nuclear proteins present in both HepG2 cells and rat liver. The presence of C/EBP alpha in this complex was confirmed by supershift analysis with antiserum to this factor. These data strongly suggest that the liver-enriched factor C/EBP alpha binds to, and activates, the UGT2B1 gene promoter. The importance of C/EBP alpha in the regulation of the homologous mouse UGT2B1 gene was also assessed in vivo. Transcripts homologous to UGT2B1 were detected in the livers of mice containing intact c/ebp alpha and c/ebp beta genes and in mice containing a homozygous null mutation in the c/ebp beta gene. In contrast, these transcripts were not detected in mice with a disrupted hepatic c/ebp alpha gene. These data extend the findings with the rat UGT2B1 gene promoter and establish that C/EBP alpha, but not C/EBP beta, is an essential transcriptional regulator of the homologous UGT2B1 gene in the mouse. C1 Flinders Univ S Australia, Sch Med, Flinders Med Ctr, Dept Clin Pharmacol, Bedford Pk, SA 5042, Australia. Acad Sinica, Inst Mol Biol, Taipei, Taiwan. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. NCI, Lab Metab, NIH, Bethesda, MD 20891 USA. RP MacKenzie, PI (reprint author), Flinders Univ S Australia, Sch Med, Flinders Med Ctr, Dept Clin Pharmacol, Bedford Pk, SA 5042, Australia. NR 35 TC 25 Z9 25 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUN PY 1998 VL 53 IS 6 BP 1027 EP 1033 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ZU233 UT WOS:000074175700008 PM 9614204 ER PT J AU Wilson, SH AF Wilson, SH TI Mammalian base excision repair and DNA polymerase beta SO MUTATION RESEARCH-DNA REPAIR LA English DT Review DE abasic site; base excision repair; DNA repair; DNA polymerase beta; apurinic/apyrimidinic site; DNA polymerase delta; DNA polymerase epsilon ID APURINIC APYRIMIDINIC ENDONUCLEASES; COLI EXONUCLEASE-III; ESCHERICHIA-COLI; STRUCTURAL BASIS; CRYSTAL-STRUCTURE; CROSS-LINKING; REVERSE-TRANSCRIPTASE; CATALYTIC DOMAIN; TEMPLATE-PRIMER; APEX NUCLEASE C1 NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov NR 95 TC 236 Z9 241 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0921-8777 J9 MUTAT RES-DNA REPAIR JI Mutat. Res.-DNA Repair PD JUN PY 1998 VL 407 IS 3 BP 203 EP 215 DI 10.1016/S0921-8777(98)00002-0 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA ZV211 UT WOS:000074281500001 PM 9653447 ER PT J AU Jones, PL Veenstra, GJC Wade, PA Vermaak, D Kass, SU Landsberger, N Strouboulis, J Wolffe, AP AF Jones, PL Veenstra, GJC Wade, PA Vermaak, D Kass, SU Landsberger, N Strouboulis, J Wolffe, AP TI Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription SO NATURE GENETICS LA English DT Article ID CHROMATIN STRUCTURE; GENE; ISLAND AB CpG methylation in vertebrates correlates with alterations in chromatin structure and gene silencing(1-4). Differences in DNA-methylation status are associated with imprinting phenomena and carcinogenesis(5-10). In Xenopus laevis oocytes, DNA methylation dominantly silences transcription through the assembly of a repressive nucleosomal array(11). Methylated DNA assembled into chromatin binds the transcriptional repressor MeCP2 which cofractionates with Sin3 and histone deacetylase. Silencing conferred by MeCP2 and methylated DNA can be relieved by inhibition of histone deacetylase, facilitating the remodeling of chromatin and transcriptional activation. These results establish a direct causal relationship between DNA methylation-dependent transcriptional silencing and the modification of chromatin. C1 NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. Janssen Res Fdn, Dept Expt Mol Biol, B-2340 Beerse, Belgium. Univ Varese, Dipartimento Biol Strutturale & Funz, I-2100 Varese, Italy. RP Wolffe, AP (reprint author), NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RI Veenstra, Gert Jan C./D-4963-2012; Ain, Kenneth/A-5179-2012; OI Veenstra, Gert Jan C./0000-0002-7787-4940; Ain, Kenneth/0000-0002-2668-934X; Landsberger, Nicoletta/0000-0003-0820-3155 NR 30 TC 1660 Z9 1705 U1 6 U2 87 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUN PY 1998 VL 19 IS 2 BP 187 EP 191 DI 10.1038/561 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA ZQ468 UT WOS:000073865100030 PM 9620779 ER PT J AU Ivanova, AV Bonaduce, MJ Ivanov, SV Klar, AJS AF Ivanova, AV Bonaduce, MJ Ivanov, SV Klar, AJS TI The chromo and SET domains of the Clr4 protein are essential for silencing in fission yeast SO NATURE GENETICS LA English DT Article ID POLYMERASE CHAIN-REACTION; SCHIZOSACCHAROMYCES-POMBE; DROSOPHILA; GENE; MUTATIONS; DISRUPT; REGION AB Heritable inactivation of specific regions of the genome is a widespread, possibly universal phenomenon for gene regulation in eukaryotes. Self-perpetuating, clonally inherited chromatin structure has been proposed as the explanation for such phenomena as position-effect variegation(1,2) (PEV) and control of segment determination and differentiation in flies(3), X-chromosome inactivation and parental imprinting in mammals(4,5), gene silencing by paramutation in maize(6) and silencing of the mating-type loci in yeasts(7,8). We have now found that the clr4 gene, which is essential for silencing of centromeres(9) and the mating-type loci in Schizosaccharomyces pombe(8,10), encodes a protein with high homology to the product of Su(var)3-9, a gene affecting PEV in Drosophila(1). Like Su(var)3-9p, Clr4p contains SET and chrome domains, motifs found in proteins that modulate chromatin structure. Site-directed mutations in the conserved residues of the chrome domain confirm that it is required for proper silencing and directional switching of the mating type, like SET domain. Surprisingly, RNA differential display experiments demonstrated that clr4(+) can mediate transcriptional activation of certain other loci. These results show that clr4 plays a critical role in silencing at mating-type loci and centromeres through the organization of repressive chromatin structure and demonstrate a new, activator function for Clr4p. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RP NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. EM klar@ncifcrf.gov NR 30 TC 126 Z9 129 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JUN PY 1998 VL 19 IS 2 BP 192 EP 195 DI 10.1038/566 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA ZQ468 UT WOS:000073865100031 PM 9620780 ER PT J AU Chang, MCJ Jones, CR AF Chang, MCJ Jones, CR TI Chronic lithium treatment decreases brain phospholipase A(2) activity SO NEUROCHEMICAL RESEARCH LA English DT Article DE lithium; phospholipase A(2); arachidonate; brain; phospholipids; phosphatidylcholine ID PROTEIN-KINASE-C; ARACHIDONIC-ACID; PROSTAGLANDIN-BIOSYNTHESIS; PSYCHOTROPIC-DRUGS; BOVINE BRAIN; GTP-BINDING; RAT; ACTIVATION; CELLS; SCHIZOPHRENIA AB Chronic lithium administration decreases the turnover of arachidonic acid (AA) in several brain phospholipids. This suggests that lithium may attenuate phospholipase A(2) (PLA(2)) activity in brain. We now report effects of chronic lithium treatment on PLA(2) activity in postnuclear supernatant from rat brain: Enzyme activity was determined by two assay methods, radiometric and fluorometric, and measured the release of the fatty acid on the second acyl position (sn2) from choline and ethanolamine phospholipids. PLA(2) activity in brain postnuclear supernatant from rats chronically treated with lithium in the diet was significantly decreased (20-50%) when compared with controls. In vehicle or lithium-treated rats, PLA(2) activity was not significantly augmented or attenuated by the addition of calcium chelators, divalent cations or LiCl supplementation (1.0 mM) to postnuclear supernatant. These results suggest that a major therapeutic effect of lithium is to attenuate brain PLA(2) activity involved in signal transduction. C1 NIA, Bethesda, MD 20892 USA. RP Chang, MCJ (reprint author), NIA, NIH Bldg 10,Rm 6C103,10 Ctr MSC 1582, Bethesda, MD 20892 USA. EM mcjchang@box-m.nih.gov NR 44 TC 66 Z9 68 U1 0 U2 1 PU PLENUM PUBL CORP PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD JUN PY 1998 VL 23 IS 6 BP 887 EP 892 DI 10.1023/A:1022415113421 PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA ZH531 UT WOS:000073120400009 PM 9572678 ER PT J AU Ibanez, V Pietrini, P Alexander, GE Furey, ML Teichberg, D Rajapakse, JC Rapoport, SI Schapiro, MB Horwitz, B AF Ibanez, V Pietrini, P Alexander, GE Furey, ML Teichberg, D Rajapakse, JC Rapoport, SI Schapiro, MB Horwitz, B TI Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer's disease SO NEUROLOGY LA English DT Article ID POSITRON EMISSION TOMOGRAPHY; CEREBRAL BLOOD-FLOW; AUTOMATED ALGORITHM; ENERGY-METABOLISM; DEMENTIA; PET; BRAIN; PATTERNS; VOLUME; MRI AB Objective: To determine whether the hypometabolism observed in PET images of patients with Alzheimer's disease (AD) is due entirely to brain atrophy. Background: Reduced brain glucose metabolism in AD patients measured using PET has been reported by numerous authors. Actual glucose metabolic values in AD may be reduced artificially because of brain atrophy, which accentuates the partial volume effect (PVE) on data collected by PET. Methods: Using segmented MR images, we corrected regional cerebral metabolic rates for glucose for PVEs to evaluate the effect of atrophy on uncorrected values for brain metabolism in AD patients and healthy control subjects. Results: Global glucose metabolism was reduced significantly before and after correction in AD patients compared with controls. Before PVE correction, glucose metabolic values in patients were lower than in control subjects in the inferior parietal, frontal, and lateral temporal cortex; in the posterior cingulate; and in the precuneus. These reductions remained significantly lower after PVE correction, although in the posterior cingulate the difference in metabolism between AD patients and control subjects lessened. Regional glucose metabolism of these areas with PVE correction was lower in moderately-severely demented patients than in mildly demented patients. Conclusion: Reduced glucose metabolism measured by PET in AD is not simply an artifact due to an increase in CSF space induced by atrophy, but reflects a true metabolic reduction per gram of tissue. C1 NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. Div Neuropsychiat, Neuroimaging Unit, Geneva, Switzerland. Univ Pisa, Dept Human & Environm Sci, I-56100 Pisa, Italy. RP Horwitz, B (reprint author), Bldg 10,Room 6C414,MSC 1588,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Rajapakse, Jagath/B-8485-2008; Furey, Maura/H-5273-2013 OI Rajapakse, Jagath/0000-0001-7944-1658; NR 63 TC 243 Z9 248 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN PY 1998 VL 50 IS 6 BP 1585 EP 1593 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA ZU712 UT WOS:000074226700013 PM 9633698 ER PT J AU Santacruz, P Uttl, B Litvan, I Grafman, J AF Santacruz, P Uttl, B Litvan, I Grafman, J TI Progressive supranuclear palsy - A survey of the disease course SO NEUROLOGY LA English DT Article ID STEELE-RICHARDSON-OLSZEWSKI; NATURAL-HISTORY; PREVALENCE; CRITERIA AB Background: The most accurate knowledge about progressive supranuclear palsy (PSP) comes from small sample studies that preclude precise estimation of the proportion of PSP patients affected with various symptoms and the examination of factors predicting survival time. Objective: To describe the course of PSP in a large clinically diagnosed sample of PSP patients and to identify factors predicting survival time. Methods: We surveyed the caregivers of 318 living and 119 deceased patients with progressive supranuclear palsy. The main outcome measures were a principal symptom severity questionnaire and a signs and symptoms questionnaire. Results: The estimated age of PSP symptom onset depends critically on how symptom onset is defined, with estimates differing by as much as 1.5 years. Men and women were represented equally (51.6% versus 48.4%) in the living sample, but men formed 61.8% of the deceased sample. Men were diagnosed later than women following symptom onset (33.4 versus 24.1 months) and died earlier following the diagnosis (37.0 versus 47.6 months). Motor and visual symptoms appeared first, followed by emotional and personality problems, cognitive impairment, and sleep changes. Whereas motor symptoms eventually affected almost every patient, emotional/personality and cognitive symptoms did not. The early onset, presence of falls, slowness, and inability to move eyes downward early in the development of the disease predicted survival time. Conclusion: PSP is a rapidly progressive disease dominated by motor symptoms, and it affects men more frequently than women. C1 NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. NINDS, Henry M Jackson Fdn, NIH, Bethesda, MD 20892 USA. NINDS, Neuropharmacol Unit, NIH, Bethesda, MD 20892 USA. NINDS, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bldg 10,Room 5S-209,10 Ctr Dr,MSC 1440, Bethesda, MD 20892 USA. OI Grafman, Jordan H./0000-0001-8645-4457; Litvan, Irene/0000-0002-3485-3445 NR 18 TC 63 Z9 66 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN PY 1998 VL 50 IS 6 BP 1637 EP 1647 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA ZU712 UT WOS:000074226700020 PM 9633705 ER PT J AU DeBaun, MR Schatz, J Siegel, MJ Koby, M Craft, S Resar, L Chu, JY Launius, G Dadash-Zadeh, M Lee, RB Noetzel, M AF DeBaun, MR Schatz, J Siegel, MJ Koby, M Craft, S Resar, L Chu, JY Launius, G Dadash-Zadeh, M Lee, RB Noetzel, M TI Cognitive screening examinations for silent cerebral infarcts in sickle cell disease SO NEUROLOGY LA English DT Article ID CHILDREN; HISTORY; STROKE AB Objective: In children with sickle cell disease (SCD), silent cerebral infarcts are the most frequent cause of neurologic injury. We determined the sensitivity and specificity of selective neurocognitive measures when separating children with silent cerebral infarcts and SCD from sibling controls. Additionally, we tested the validity of the same cognitive measures to identify patients with overt strokes. Methods: We examined performance on a neuropsychologic battery containing measures of attention/executive, spatial, language, memory, and motor functioning for seven children with SCD and silent cerebral infarct, 21 children with SCD and overt stroke, and 17 normal siblings. Diagnosis of cerebral infarct was based on results of MRI. Results: Measures from the attention and executive domains were the most useful for identifying children with silent cerebral infarct. The Test of Variables of Attention was the most robust measure and yielded a sensitivity rate of 86% and a specificity rate of 81%. This measure also showed a sensitivity rate of 95% in identifying overt stroke. Conclusions: Brief cognitive screening measures, if properly constructed, may be an effective means of identifying children with silent cerebral infarct. Future prospective studies should be pursued to assess the utility of cognitive screening for silent cerebral infarcts in SCD. C1 Washington Univ, Sch Med, Dept Pediat, Div Pediat Hematol Oncol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. Washington Univ, Dept Psychol, St Louis, MO 63110 USA. NIH, Dept Radiol, Bethesda, MD 20892 USA. Univ Washington, GRECC, Seattle Amer Lake Vet Affairs Med Ctr, Seattle, WA 98195 USA. Sinai Hosp, Baltimore, MD 21215 USA. St Louis Univ, Dept Pediat, Div Hematol Oncol, St Louis, MO 63103 USA. St Louis Univ, Dept Radiol, Div Pediat Radiol, St Louis, MO 63103 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Div Hematol Oncol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. RP DeBaun, MR (reprint author), Washington Univ, Sch Med, Dept Pediat, Div Pediat Hematol Oncol, 1 Childrens Pl,Campus Box 8116, St Louis, MO 63110 USA. NR 19 TC 79 Z9 79 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN PY 1998 VL 50 IS 6 BP 1678 EP 1682 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA ZU712 UT WOS:000074226700025 PM 9633710 ER PT J AU Crutchfield, KE Patronas, NJ Dambrosia, JM Frei, KP Banerjee, TK Barton, NW Schiffmann, R AF Crutchfield, KE Patronas, NJ Dambrosia, JM Frei, KP Banerjee, TK Barton, NW Schiffmann, R TI Quantitative analysis of cerebral vasculopathy in patients with Fabry disease SO NEUROLOGY LA English DT Article ID COMPLICATIONS; INVOLVEMENT; DEFICIENCY; STROKE AB Objective: This study's purpose was to obtain a quantitative natural history of the cerebrovascular involvement in Fabry disease. Background: Fabry disease is an X-linked recessive disorder due to ol-galactosidase A deficiency. Progressive accumulation of ceramidetrihexoside within the intima and media of cerebral blood vessels causes ischemic lesions in the majority of affected patients. Determination of the natural history of the cerebral vasculopathy in Fabry disease is important to assess the effects of therapeutic intervention in this disorder. Methods: A longitudinal MRI study of 50 patients who had a total of 129 MRI scans was performed. The burden of cerebrovascular disease was determined using direct linear measurement. Results: On T2-weighted MRI scans, 32% of the patients had no lesions (mean age, 33 years), 16% had gray matter lesions only (mean age, 36 years), 26% had lesions in white matter only (mean age, 43 years), and 26% had lesions in white and gray matter (mean age, 47 years). Disease burden increased with age, but no patient younger than 26 had lesions on MRI. All patients older than 54 had cerebrovascular involvement. The distribution of MRI-detectable lesions was typical of a small-vessel disease. Only 37.5% of patients with cerebral lesions had neurologic symptoms. Conclusion: These findings provide a predictable outcome measure to assess the effect of molecular interventions on the cerebrovascular circulation in Fabry disease. C1 NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. NINDS, Biometry Branch, NIH, Bethesda, MD 20892 USA. RP Schiffmann, R (reprint author), NINDS, Dev & Metab Neurol Branch, NIH, Bldg 10,Room 3D03,10 Ctr Dr,MSC 1260, Bethesda, MD 20892 USA. NR 22 TC 123 Z9 127 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN PY 1998 VL 50 IS 6 BP 1746 EP 1749 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA ZU712 UT WOS:000074226700036 PM 9633721 ER PT J AU Higley, J Hasert, M Suomi, S Linnoila, M AF Higley, J Hasert, M Suomi, S Linnoila, M TI The serotonin reuptake inhibitor sertraline reduces excessive alcohol consumption in nonhuman primates: Effect of stress SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE alcoholism and alcohol abuse; primate; sertraline; serotonin; aggression; stress ID 5-HYDROXYINDOLEACETIC ACID CONCENTRATIONS; CEREBROSPINAL-FLUID MONOAMINE; DIMINISHED SOCIAL COMPETENCE; IMPULSE CONTROL DISORDERS; MONKEYS MACACA-MULATTA; RHESUS-MONKEYS; HEALTHY-VOLUNTEERS; VIOLENT OFFENDERS; SEVERE AGGRESSION; FEEDING-BEHAVIOR AB Many monkeys that ave reared without adult influence, with only peers, voluntarily consume alcohol in amounts producing intoxication on a relatively regular basis. Using a cross-over design, eight adolescent, peer-reared rhesus monkeys were allowed unfettered access to an 8.4% ethanol solution and treated with 20 mg/kg/24 h of sertraline during three phases: home-cage, social separation, and reunion with cage-mates. Although there was no immediate effect, sertraline reduced alcohol consumption beginning the second week of home-cage treatment, but only in subjects that consumed large amounts of alcohol. Initially, the social separation stress caused the sertraline-treated subjects' alcohol consumption rates to return to baseline levels, but when the stress was repeated, alcohol consumption fell below baseline and placebo levels. Sertraline treatment was ineffective in reducing consumption during the stressful period of home-cage reunion, a period characterized by high levels of aggressive behavior. Behaviorally, sertraline reduced aggression and anxiety-like self-directed behaviors. Our findings provide evidence that sertraline may be an effective pharmacological treatment for excessive alcohol consumption and aggression. On the other hand, stress during treatment may reduce sertraline's effectiveness as a treatment for excessive alcohol consumption. C1 NIAAA, Clin Studies Lab, DICBR, Sect Neurochem & Neuroendocrinol,Primate Unit, Poolesville, MD 20837 USA. NICHD, Comparat Ethol Lab, Poolesville, MD USA. RP Higley, J (reprint author), NIAAA, Clin Studies Lab, DICBR, Sect Neurochem & Neuroendocrinol,Primate Unit, Poolesville, MD 20837 USA. RI McCarthy, Jodie/B-5760-2012 NR 72 TC 43 Z9 43 U1 3 U2 4 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 JUN PY 1998 VL 18 IS 6 BP 431 EP 443 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA ZJ086 UT WOS:000073178100002 PM 9571652 ER PT J AU Nawashiro, H Messing, A Azzam, N Brenner, M AF Nawashiro, H Messing, A Azzam, N Brenner, M TI Mice lacking GFAP are hypersensitive to traumatic cerebrospinal injury SO NEUROREPORT LA English DT Article DE astrocytes ultrastructure; glial fibrillary acidic protein deficiency; glial fibrillary acidic protein genetics; hemorrhage; sequence deletion; spinal cord injuries; transgenic mice; traumatic brain injury ID BRAIN INJURY; INTERMEDIATE FILAMENTS; RAT; ARCHITECTURE; INCREASES; RECEPTORS; DEVELOP AB GLIAL fibrillary acidic protein (GFAP) is an intermediate filament protein expressed primarily in astrocytes. We have tested whether GFAP protects against mechanical stress by inducing percussive head injury in GFAP-null mice with a weight drop device. When mice were positioned on a foam bed which allowed head movement at impact, all 14 wild-type mice tested survived, but 12 of 15 GFAP-null mice died within a few minutes. The cause of death appeared to be upper cervical spinal cord injury resulting in respiratory arrest. When the foam bed was replaced by a firm support, both GFAP-null and wild-type mice survived. These results indicate that mice lacking GFAP are hypersensitive to cervical spinal cord injury caused by sudden acceleration of the head. (C) 1998 Rapid Science Ltd. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. Univ Wisconsin, Sch Vet Med, Madison, WI 53706 USA. RP Brenner, M (reprint author), NINDS, Stroke Branch, NIH, Bldg 36,Room 4A03,6 Convent Dr,MSC 4128, Bethesda, MD 20892 USA. FU NINDS NIH HHS [NS-22475] NR 23 TC 65 Z9 66 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUN 1 PY 1998 VL 9 IS 8 BP 1691 EP 1696 DI 10.1097/00001756-199806010-00004 PG 6 WC Neurosciences SC Neurosciences & Neurology GA ZU455 UT WOS:000074198700004 PM 9665584 ER PT J AU De Vries, TJ Cools, AR Shippenberg, TS AF De Vries, TJ Cools, AR Shippenberg, TS TI Infusion of a D-1 receptor agonist into the nucleus accumbens enhances cocaine-induced behavioural sensitization SO NEUROREPORT LA English DT Article DE behavioural sensitization; cocaine; D-1 receptors; locomotor activity; nucleus accumbens ID VENTRAL TEGMENTAL AREA; RAT STRIATUM; REPEATED STIMULATION; DOPAMINE-RECEPTORS; AMPHETAMINE; SENSITIVITY; EXPRESSION; ADDICTION; SKF-38393; MORPHINE AB THE present study was designed to evaluate the effect of dopamine (DA) D-1receptor activation in the nucleus accumbens (NAC) on the locomotor sensitizing effects of repeated intra-accumbens (intra-NAC) infusions of cocaine. Repeated infusion of cocaine (10 mu g/0.5 mu l daily for 2 days) resulted in an enhanced locomotor response to a subsequent intra-NAC and systemic (i.p.) challenging dose of the psychostimulant. Pretreatment with the selective D-l agonist SK&F82958 (1.0 mu g) markedly enhanced the sensitizing effects of both intra-NAC and systemic cocaine. The effect of SK&F82958 was completely blocked by systemic administration of the D-1antagonist SCH23390 (0.1 mg/kg, i.p.). These data give further support to the idea that activation of D-1 receptors plays an important role in the induction of locomotor sensitization and show that the NAC may, in fact, be an anatomical locus of initiation of behavioural sensitization. (C) 1998 Rapid Science Ltd. C1 Free Univ Amsterdam, Dept Pharmacol, Neurosci Res Inst, NL-1081 BT Amsterdam, Netherlands. Univ Nijmegen, Nijmegen Inst Neurosci, Dept Psychoneuropharmacol, NL-6500 HB Nijmegen, Netherlands. NIDA, Integrat Neurosci Unit, Behav Pharmacol Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP De Vries, TJ (reprint author), Free Univ Amsterdam, Dept Pharmacol, Neurosci Res Inst, Boechorststr 7, NL-1081 BT Amsterdam, Netherlands. RI De Vries, Taco/B-2831-2014; OI De Vries, Taco/0000-0002-0340-4946 NR 25 TC 27 Z9 27 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUN 1 PY 1998 VL 9 IS 8 BP 1763 EP 1768 DI 10.1097/00001756-199806010-00017 PG 6 WC Neurosciences SC Neurosciences & Neurology GA ZU455 UT WOS:000074198700017 PM 9665597 ER PT J AU Li, Q Luyo, D Maatteson, DM Chan, CC AF Li, Q Luyo, D Maatteson, DM Chan, CC TI Suppressive effect of antiflammin-2 on compound 48/80-induced conjunctivitis - Role of phospholipase A(2)s and inducible nitric oxide synthase SO OCULAR IMMUNOLOGY AND INFLAMMATION LA English DT Article DE antiflammin; phospholipase A(2); corticosteroids; allergic conjunctivitis; inducible nitric oxide synthase (iNOS) ID PLATELET-ACTIVATING-FACTOR; UTEROGLOBIN; RELEASE AB Phospholipase A(2)s (PLA(2)s) are a family of esterases that initiate the arachidonic acid cascade, which results in the production of numerous inflammatory mediators. We investigated the expression of Group I and II PLA(2) proteins and Group II mRNA in normal conjunctivae and in the conjunctivae of mice with compound 48/80-induced conjunctivitis. Conjunctivitis was induced in C57BL/6 mice by topical instillation of compound 48/80 (C48/80). Mice were then treated with corticosteroid (Pred Forte), antiflammin-2 (AF(2), a synthetic peptide that inhibits PLA(2)), or a placebo (Dacriose, an isotonic, buffered, sterile eye irrigating solution). Low levels of PLA(2)s were detected on the epithelium of normal conjunctivae. One hr after C48/80 instillation, the expression of PLA(2)s appeared and increased in the substantia propria, peaked at 6 hr, and returned to baseline 72 hr later. Compared to the placebo, the conjunctivitis was moderate in the AF(2)-treated group and mild in Pred Forte-treated group. The expression of PLA(2)s was suppressed in mice treated with Pred Forte and AF(2), iNOS mRNA was also diminished in the AF(2)- and Pred Forte-treated groups. The mechanisms by which anti-allergic medications suppress conjunctivitis may involve the inhibition of PLA(2)s and iNOS. C1 NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Cornea Serv, Wilmer Ophthalmol Inst, Baltimore, MD USA. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, Bldg 10,Rm 10N103,10 Ctr Dr, Bethesda, MD 20892 USA. EM ccc@helix.nih.gov NR 23 TC 5 Z9 6 U1 0 U2 0 PU AEOLUS PRESS PI BUREN PA PO BOX 740, 4116 ZJ BUREN, NETHERLANDS SN 0927-3948 J9 OCUL IMMUNOL INFLAMM JI Ocul. Immunol. Inflamm. PD JUN PY 1998 VL 6 IS 2 BP 65 EP 73 DI 10.1076/ocii.6.2.65.4048 PG 9 WC Ophthalmology SC Ophthalmology GA 108BC UT WOS:000075245300001 PM 9689636 ER PT J AU Conley, BA Smiley, JK Cheson, BD AF Conley, BA Smiley, JK Cheson, BD TI Clinical trials of multimodality approaches for advanced esophageal cancer SO ONCOLOGY-NEW YORK LA English DT Article ID CARCINOMA; THERAPY C1 NCI, Bethesda, MD 20892 USA. RP Conley, BA (reprint author), NCI, Bethesda, MD 20892 USA. NR 21 TC 1 Z9 1 U1 0 U2 0 PU P R R INC PI HUNTINGTON PA 17 PROSPECT ST, HUNTINGTON, NY 11743 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD JUN PY 1998 VL 12 IS 6 BP 856 EP + PG 4 WC Oncology SC Oncology GA ZX680 UT WOS:000074543200015 PM 9644685 ER PT J AU Little, RF Pluda, JM Feigal, E Yarchoan, R AF Little, RF Pluda, JM Feigal, E Yarchoan, R TI The challenge of designing clinical trials for AIDS-related Kaposi's sarcoma SO ONCOLOGY-NEW YORK LA English DT Article ID ACQUIRED IMMUNODEFICIENCY SYNDROME; IMMUNE-DEFICIENCY-SYNDROME; LONG-TERM CULTURE; LIPOSOMAL DAUNORUBICIN; PERIPHERAL-BLOOD; HOMOSEXUAL MEN; SPINDLE CELLS; DNA-SEQUENCES; HERPESVIRUS; DOXORUBICIN AB Kaposi's sarcoma (KS) is a frequent cause of morbidity and mortality in patients with human immunodeficiency virus (HIV) infection. Several characteristics of KS pose challenges for the conduct of clinical trials. Kaposi's sarcoma patients often have multiple, irregularly shaped lesions, making accurate assessment of tumor size difficult. The lesions may have varying degrees of nodularity. Involvement of the lung or other visceral organs often consists of multiple irregular lesions. Conventional oncology staging systems cannot be applied effectively to KS because there is no clear primary lesion. Kaposi's sarcoma is affected by the status of the underlying HIV infection, and there are reports of KS lesions regressing in response to effective antiretroviral therapy. A system for staging and response assessment irt KS, developed by the AIDS Clinical Trials Group (ACTG), has proven to be a useful tool for the conduct of trials in KS. A newer system that also attempts to assess patient benefit in response to therapy is now being developed by the National Cancer Institute, FDA, and AIDS Malignancy Consortium. These tools, as well as careful methodology in the conduct of clinical trials, should help optimize the clinical development and evaluation of new therapies for KS. C1 NCI, HIV & AIDS Malignancy Branch, Div Clin Sci, Bethesda, MD 20892 USA. NCI, Invest Drug Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Little, RF (reprint author), NCI, HIV & AIDS Malignancy Branch, Div Clin Sci, Bethesda, MD 20892 USA. NR 75 TC 5 Z9 5 U1 0 U2 0 PU P R R INC PI HUNTINGTON PA 17 PROSPECT ST, HUNTINGTON, NY 11743 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD JUN PY 1998 VL 12 IS 6 BP 871 EP + PG 10 WC Oncology SC Oncology GA ZX680 UT WOS:000074543200018 PM 9644686 ER PT J AU Dougherty, ER Chen, YD AF Dougherty, ER Chen, YD TI Logical structural filters SO OPTICAL ENGINEERING LA English DT Article DE adaptive filter; granulometry; opening; optimal filter; morphology ID MORPHOLOGY AB Binary granulometric filters are formed from unions of parameterized openings, a point passing the filter if and only if a translate of at least one structuring element fits in the image and contains the point. A granulometry induces a reconstructive granulometry by passing any image component not eliminated by the granulometry. As historically studied in the context of Matheron's granulometric theory, reconstructive granulometries appear as unions of reconstructive parameterized openings. The theory is extended to a much wider class of filters: a logical structural filter (LSF) is termed as a union of intersections of both reconstructive and complementary reconstructive openings. A reconstructive opening passes a component ii and only if at least one translate of the structuring element fits inside; a complementary reconstructive opening passes a component if and only if no translate of the structuring element fits inside. The original reconstructive granulometries form the special class of disjunctive LSFs. Complement-free LSFs form granulometries in a slightly more general sense; LSFs containing complements are not increasing and therefore not openings. Along with the relevant algebraic representations for LSFs, the theories of optimal and adaptive granulometric filters are extended to LSFs, a systematic formulation of adaptive transitions is given, transition probabilities for adaptation are found, and two applications to biological imaging are presented. (C) 1998 Society of Photo-Optical Instrumentation Engineers. [S0091-3286(98)00506-6]. C1 Texas A&M Univ, Texas Ctr Appl Technol, Dept Elect Engn, College Stn, TX 77843 USA. NIH, Natl Ctr Human Genome Res, Canc Genet Lab, Bethesda, MD 20892 USA. RP Dougherty, ER (reprint author), Texas A&M Univ, Texas Ctr Appl Technol, Dept Elect Engn, College Stn, TX 77843 USA. NR 15 TC 4 Z9 4 U1 0 U2 0 PU SPIE - INTERNATIONAL SOCIETY FOR OPTICAL ENGINEERING PI BELLINGHAM PA POB 10, BELLINGHAM, WA 98227-0010 USA SN 0091-3286 J9 OPT ENG JI Opt. Eng. PD JUN PY 1998 VL 37 IS 6 BP 1668 EP 1676 DI 10.1117/1.601900 PG 9 WC Optics SC Optics GA ZT109 UT WOS:000074049300002 ER PT J AU Machelska, H Stein, C AF Machelska, H Stein, C TI Peripheral nociceptive integration SO PAIN FORUM LA English DT Editorial Material ID CORTICOTROPIN-RELEASING FACTOR; INFLAMED TISSUE; OPIOID RECEPTORS; IMMUNE CELLS; SUBSTANCE-P; INFLAMMATION; ANTINOCICEPTION; MECHANISMS; RAT; LOCALIZATION C1 Johns Hopkins Univ, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21218 USA. Natl Inst Drug Abuse, Div Intramural Res, Behav Pharmacol & Genet Sect, NIH, Baltimore, MD USA. Univ Klinikum Benjamin Franklin, Klin Anaesthesiol & Operat Intensivmed, Berlin, Germany. NR 23 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1058-9139 J9 PAIN FORUM JI Pain Forum PD SUM PY 1998 VL 7 IS 2 BP 87 EP 89 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA ZY915 UT WOS:000074675400005 ER PT J AU Tian, JH Good, MF Hirunpetcharat, C Kumar, S Ling, IT Jackson, D Cooper, J Lukszo, J Coligan, J Ahlers, J Saul, A Berzofsky, JA Holder, AA Miller, LH Kaslow, DC AF Tian, JH Good, MF Hirunpetcharat, C Kumar, S Ling, IT Jackson, D Cooper, J Lukszo, J Coligan, J Ahlers, J Saul, A Berzofsky, JA Holder, AA Miller, LH Kaslow, DC TI Definition of T cell epitopes within the 19 kDa carboxylterminal fragment of Plasmodium yoelii merozoite surface protein 1 (MSP1(19)) and their role in immunity to malaria SO PARASITE IMMUNOLOGY LA English DT Article DE vaccine; MSP1(19); T cell epitopes; malaria; helper T cells ID PROTECTIVE MONOCLONAL-ANTIBODY; TERMINAL FRAGMENT; AOTUS MONKEYS; RODENT MALARIA; LYMPHOCYTES-T; MICE; ANTIGEN; RECOMBINANT; FALCIPARUM; INFECTION AB MSP1(19) is one of the leading malaria vaccine candidates. However the mechanism of protection is not clear. To determine whether MSP1(19)-specific effector T cells can control parasitaemia, we analysed the specificity of T cells induced following immunization with recombinant forms of P. yoelii MSP1(19) and asked whether they could protect mice. There was no evidence that effector T cells were capable of protecting since: (1) immunization of mice with yMSP1(19), but not defined epitopes, was able to induce protection; and (2) long term MSP1(19)-specific CD4(+) T cell lines were incapable of adoptively transferring protection In contrast, priming mice with the T cell epitopes resulted in a rapid anamnestic antibody response to MSP1(19) after either challenge with MSP1(19) or parasite. Thus, MSP1(19) contains multiple T cell epitopes but such epitopes are the targets of helper T cells for antibody response but not of identified effector T cells capable of controlling parasitaemia. C1 PO Royal Brisbane Hosp, Queensland Inst Med Res, Brisbane, Qld 4029, Australia. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Mol Struct Lab, NIH, Bethesda, MD 20892 USA. Natl Inst Med Res, Div Parasitol, London NW7 1AA, England. NCI, Mol Immunogenet & Vaccine Res Sect, NIH, Bethesda, MD 20892 USA. Univ Melbourne, Dept Microbiol, Parkville, Vic 3052, Australia. RP Good, MF (reprint author), PO Royal Brisbane Hosp, Queensland Inst Med Res, Brisbane, Qld 4029, Australia. RI Holder, Anthony/A-7554-2013; Saul, Allan/I-6968-2013; OI Holder, Anthony/0000-0002-8490-6058; Saul, Allan/0000-0003-0665-4091; Jackson, David/0000-0001-7255-270X FU Medical Research Council [MC_U117532067] NR 36 TC 29 Z9 30 U1 0 U2 0 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 JUN PY 1998 VL 20 IS 6 BP 263 EP 278 DI 10.1046/j.1365-3024.1998.00138.x PG 16 WC Immunology; Parasitology SC Immunology; Parasitology GA 223DW UT WOS:000081826000002 PM 9651928 ER PT J AU Rowe, JA Newbold, CI Moulds, JM Miller, LH AF Rowe, JA Newbold, CI Moulds, JM Miller, LH TI Do C2b-CRI interactions contribute to rosette formation by Plasmodium falciparum? Reply SO PARASITOLOGY TODAY LA English DT Letter ID INFECTED ERYTHROCYTES; EXPRESSION; SURFACE; ANTIGEN C1 Inst Mol Med, Mol Parasitol Grp, Oxford OX3 9DS, England. Univ Texas, Sch Med, Div Rheumatol & Clin Immunogenet, Houston, TX 77030 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Rowe, JA (reprint author), Inst Mol Med, Mol Parasitol Grp, Oxford OX3 9DS, England. NR 9 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0169-4758 J9 PARASITOL TODAY JI Parasitol. Today PD JUN PY 1998 VL 14 IS 6 BP 250 EP 250 DI 10.1016/S0169-4758(98)01253-8 PG 1 WC Parasitology SC Parasitology GA ZQ374 UT WOS:000073854800013 PM 17040770 ER PT J AU Willy, MEP Hoover, DR Halsey, NA Maloney, EM Pate, EJ Wiktor, SZ Blattner, WA Manns, A AF Willy, MEP Hoover, DR Halsey, NA Maloney, EM Pate, EJ Wiktor, SZ Blattner, WA Manns, A TI Relationship between unsupplemented vitamin A serum concentrations and measles vaccine response in Jamaican children SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE vitamin A; measles; vaccine C1 Warren G Magnuson Clin Ctr, Hosp Epidemiol Serv, Bethesda, MD 20892 USA. NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21218 USA. Johns Hopkins Univ, Dept Int Hlth, Baltimore, MD 21218 USA. Univ W Indies, Dept Pediat, Jamaica, W Ind Assoc St. RP Willy, MEP (reprint author), Warren G Magnuson Clin Ctr, Hosp Epidemiol Serv, Room 4A21,10 Ctr Dr, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CP-40548] NR 11 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD JUN PY 1998 VL 17 IS 6 BP 526 EP 528 DI 10.1097/00006454-199806000-00021 PG 3 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA ZU297 UT WOS:000074182600020 PM 9655550 ER PT J AU Etzel, RA Balk, SJ Bearer, CF Miller, MD Shannon, MW Shea, KM Falk, H Goldman, LR Miller, RW Rogan, W Coven, B Harvey, B Simon, P AF Etzel, RA Balk, SJ Bearer, CF Miller, MD Shannon, MW Shea, KM Falk, H Goldman, LR Miller, RW Rogan, W Coven, B Harvey, B Simon, P CA Comm Environm Hlth TI Screening for elevated blood lead levels SO PEDIATRICS LA English DT Article ID PORT-PIRIE COHORT; ENVIRONMENTAL EXPOSURE; RISK ASSESSMENT; CHILDREN; PREVALENCE; POPULATION; QUESTIONNAIRE; INTELLIGENCE; PERFORMANCE; BEHAVIOR AB Although recent data continue to demonstrate a decline in the prevalence of elevated blood lead levels (BLLs) in children, lead remains a common, preventable, environmental health threat. Because recent epidemiologic data have shown that lead exposure is still common in certain communities in the United States, the Centers for Disease Control and Prevention recently issued new guidelines endorsing universal screening in areas with greater than or equal to 27% of housing built before 1950 and in populations in which the percentage of 1- and 2-year-olds with elevated BLLs is greater than or equal to 12%. For children living in other areas, the Centers for Disease Control and Prevention recommends targeted screening based on risk-assessment during specified pediatric visits. In this statement, The American Academy of Pediatrics supports these new guidelines and provides an update on screening for elevated BLLs. The American Academy of Pediatrics recommends that pediatricians continue to provide anticipatory guidance to parents in an effort to prevent lead exposure (primary prevention). Additionally, pediatricians should increase their efforts to screen children at risk for lead exposure to find those with elevated BLLs (secondary prevention). C1 Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. US EPA, Washington, DC 20460 USA. NCI, Bethesda, MD 20892 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Etzel, RA (reprint author), Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. RI Goldman, Lynn/D-5372-2012; OI Miller, Mark/0000-0002-9301-0093 NR 48 TC 90 Z9 92 U1 0 U2 4 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 JUN PY 1998 VL 101 IS 6 BP 1072 EP 1078 PG 7 WC Pediatrics SC Pediatrics GA ZR055 UT WOS:000073931100021 ER PT J AU Harmar, AJ Arimura, A Gozes, I Journot, L Laburthe, M Pisegna, JR Rawlings, SR Robberecht, P Said, SI Sreedharan, SP Wank, SA Waschek, JA AF Harmar, AJ Arimura, A Gozes, I Journot, L Laburthe, M Pisegna, JR Rawlings, SR Robberecht, P Said, SI Sreedharan, SP Wank, SA Waschek, JA TI International Union of Pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide SO PHARMACOLOGICAL REVIEWS LA English DT Review ID DIFFERENTIAL SIGNAL-TRANSDUCTION; IN-SITU HYBRIDIZATION; MOLECULAR-CLONING; FUNCTIONAL EXPRESSION; PACAP RECEPTOR; MESSENGER-RNA; SPLICE VARIANTS; BINDING-SITES; VIP RECEPTOR; RAT-BRAIN C1 Royal Edinburgh & Associated Hosp, MRC, Brain Metab Unit, Edinburgh, Midlothian, Scotland. Tulane Univ, Med Ctr, US Japan Biomed Res Labs, Belle Chasse, LA USA. Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, Ramat Aviv, Israel. CCIPE, CNRS, UPR 9023, F-34094 Montpellier, France. Univ Paris 07, INSERM, U410, Paris, France. Univ Calif Los Angeles, W Los Angeles Vet Affairs Med Ctr, UCAL DDRC, CURE VA, Los Angeles, CA USA. Life Sci Resources, Cambridge, England. Free Univ Brussels, Lab Chim Biol & Nutr, Brussels, Belgium. SUNY Stony Brook, Sch Med, Stony Brook, NY 11794 USA. Univ Calif San Francisco, Dept Med, Div Allergy & Immunol, San Francisco, CA 94143 USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Mental Retardat Res Ctr, Los Angeles, CA 90024 USA. NIDDK, Digest Dis Branch, NIH, Bethesda, MD USA. RP Univ Edinburgh, Dept Pharmacol, MRC, Brain Metab Unit, 1 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland. EM Tony.Harmar@ed.ac.uk RI LABURTHE, Marc/C-1875-2012; OI Harmar, Anthony/0000-0002-3838-9264 NR 82 TC 613 Z9 630 U1 0 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 EI 1521-0081 J9 PHARMACOL REV JI Pharmacol. Rev. PD JUN PY 1998 VL 50 IS 2 BP 265 EP 270 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ZW733 UT WOS:000074442300003 PM 9647867 ER PT J AU Bagossi, P Cheng, YSE Oroszlan, S Tozser, J AF Bagossi, P Cheng, YSE Oroszlan, S Tozser, J TI Comparison of the specificity of homo- and heterodimeric linked HIV-1 and HIV-2 proteinase dimers SO PROTEIN ENGINEERING LA English DT Article DE linked HIV proteinase dimers; heterodimers; oligo-peptide substrates; enzyme kinetics; substrate specificity ID HUMAN-IMMUNODEFICIENCY-VIRUS; MOLECULAR-DYNAMICS SIMULATIONS; STATE ANALOG INHIBITORS; CRYSTAL-STRUCTURE; CRYSTALLOGRAPHIC STRUCTURE; SUBSTRATE-SPECIFICITY; TYPE-2 PROTEASE; TETHERED DIMER; CLEAVAGE SITES; ACTIVE-SITE AB The specificity of linked homo- and heterodimeric HIV-1 and HIV-2 proteinases was characterized by using oligopeptide substrates, For two substrates the k(cat)/K-m values for the heterodimers were the mean values for those of the homodimers, suggesting that these substrates could productively bind into the heterodimers in both directions, However, for two other substrates the k(cat)/K-m values for the heterodimers were higher than those of the homodimers, suggesting that these substrates could productively bind into the enzymes in a preferable direction. However, the mode of binding does not seem to depend on the sequential position of the subunits, The studied linked homo- and heterodimers may represent intermediate stages in the evolution of bilobal aspartic proteinases. As divergence in sequence of the two halves of such a proteinase increases, the possibility of bidirectional binding is likely lost at the expense of the optimized side-chain subsite interactions. The differences in observed and calculated k(cat)/K-m values revealed dependence of the substrate specificity at one subsite of the enzyme from the next residue in sequence of substrate. These findings were also supported by molecular modeling studies. C1 Debrecen Univ Med, Sch Med, Dept Biochem & Mol Biol, H-4012 Debrecen, Hungary. Dupont Merck Pharmaceut Co, Expt Stn, Wilmington, DE 19803 USA. NCI, Mol Virol & Carcinogenesis Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Tozser, J (reprint author), Debrecen Univ Med, Sch Med, Dept Biochem & Mol Biol, POB 6, H-4012 Debrecen, Hungary. RI Tozser, Jozsef/A-7840-2008; OI Tozser, Jozsef/0000-0003-0274-0056; Tozser, Jozsef/0000-0001-5076-8729 NR 44 TC 9 Z9 10 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 JUN PY 1998 VL 11 IS 6 BP 439 EP 445 DI 10.1093/protein/11.6.439 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 109CE UT WOS:000075303000005 PM 9725622 ER PT J AU Villoutreix, BO Hardig, Y Wallqvist, A Covell, DG de Frutos, PG Dahlback, B AF Villoutreix, BO Hardig, Y Wallqvist, A Covell, DG de Frutos, PG Dahlback, B TI Structural investigation of C4b-binding protein by molecular modeling: Localization of putative binding sites SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE complement control protein; protein modeling; blood coagulation; C4b-binding protein ID AMYLOID-P COMPONENT; HUMAN-COMPLEMENT SYSTEM; BETA-CHAIN; S-BINDING; REGULATORY COMPONENT; ALPHA-CHAIN; LIGAND-BINDING; STREPTOCOCCUS-PYOGENES; CLASSICAL PATHWAY; CDNA STRUCTURE AB C4b-binding protein (C4BP) contributes to the regulation of the classical pathway of the complement system and plays an important role in blood coagulation. The main human C4BP isoform is composed of one beta-chain and seven alpha-chains essentially built from three and eight complement control protein (CCP) modules, respectively, followed by a nonrepeat carboxy-terminal region involved in polymerization of the chains. C4BP is known to interact with heparin, C4b, complement factor I, serum amyloid P component, streptococcal Arp and Sir proteins, and factor VII/VIIIa via its alpha-chains and with protein S through its beta-chain. The principal aim of the present study was to localize regions of C4BP involved in the interaction with C4b, Arp, and heparin. For this purpose, a computer model of the 8 CCP modules of C4BP alpha-chain was constructed, taking into account data from previous electron microscopy (EM) studies. This structure was investigated in the context of known and/or new experimental data. Analysis of the alpha-chain model, together with monoclonal antibody studies and heparin binding experiments, suggests that a patch of positively charged residues, at the interface between the first and second CCP modules, plays an important role in the interaction between C4BP and C4b/Arp/Sir/heparin. Putative binding sites, secondary-structure prediction for the central core, and an overall reevaluation of the size of the C4BP molecule are also presented. An understanding of these intermolecular interactions should contribute to the rational design of potential therapeutic agents aiming at interfering specifically some of these protein-protein interactions. (C) 1998 Wiley-Liss, Inc. C1 Univ Lund Hosp, Dept Clin Chem, Wallenberg Lab, S-20502 Malmo, Sweden. Rutgers State Univ, Dept Chem, Piscataway, NJ USA. Sci Applicat Int Corp, NCI, Frederick Canc Res & Dev Ctr, Frederick, MD USA. RP Villoutreix, BO (reprint author), Univ Lund Hosp, Dept Clin Chem, Wallenberg Lab, S-20502 Malmo, Sweden. EM bruno.villoutreix@klkemi.mas.lu.se RI Garcia de Frutos, Pablo/B-8594-2011; OI Garcia de Frutos, Pablo/0000-0003-1547-1190; wallqvist, anders/0000-0002-9775-7469 NR 84 TC 45 Z9 45 U1 0 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-3585 J9 PROTEINS JI Proteins PD JUN 1 PY 1998 VL 31 IS 4 BP 391 EP 405 DI 10.1002/(SICI)1097-0134(19980601)31:4<391::AID-PROT6>3.0.CO;2-L PG 15 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZT567 UT WOS:000074100800006 PM 9626699 ER PT J AU Lin, SL Xu, D Li, AJ Nussinov, R AF Lin, SL Xu, D Li, AJ Nussinov, R TI Electrostatics, allostery, and activity of the yeast chorismate mutase SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE chorismate mutase; activity; allosteric; electrostatics ID CRYSTAL-STRUCTURE; PROGRAM; ENERGY; STATE AB The predicted active site of chorismate mutase of baker's yeast Saccharomyces cerevisiae has been studied by continuum electrostatics, molecular surface/volume calculations, and molecular modeling. Our study shows that despite being subject to an allosteric transition, the enzyme's active-site pocket neither decreased in volume nor deformed significantly in shape between the active R state and the inactive T state. We find that the polar atmosphere in the pocket is responsible for the enzyme's affinity, A single amino acid, Glu23, can adequately account for the atmospheric variation. This residue swings into the active-site pocket from the R state to the T state, In the R state, Glu23 on helix H2 doubly pairs with Arg204 and Lys208 of H11, which is packed against H2, In the T state, a slide occurs between H11 and H2 such that Glu23 can no longer interact with Lys208 and competes with Asp24 for interacting with Arg204, Consequently, Glu23 is found in the T state to couple with Arg157, an active-site residue critical to substrate binding. The tandem sliding of H11 in both monomers profoundly changes the interactions in the dimer interface. The loop between H11 and H12 demonstrates the largest conformational change. Hence, we establish a connection between the allosteric transition and the activity of the enzyme. The conformational change in the transition is suggested to propagate into the active-site pocket via a series of polar interactions that result in polarity reversal in the active-site pocket, which regulates the enzyme's activity. (C) 1998 Wiley-Liss, Inc. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC, IRSP,Lab Expt & Computat Biol, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, Bldg 469,Room 151, Frederick, MD 21702 USA. EM ruthn@ncifcrf.gov FU NCI NIH HHS [1-CO-74102] NR 19 TC 6 Z9 6 U1 2 U2 8 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 JUN 1 PY 1998 VL 31 IS 4 BP 445 EP 452 DI 10.1002/(SICI)1097-0134(19980601)31:4<445::AID-PROT10>3.0.CO;2-F PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZT567 UT WOS:000074100800010 PM 9626703 ER PT J AU Long, JM Mellem, JE Kesner, RP AF Long, JM Mellem, JE Kesner, RP TI The effects of parietal cortex lesions on an object spatial location paired-associate task in rats SO PSYCHOBIOLOGY LA English DT Article ID HEAD-DIRECTION CELLS; POSTERIOR PARIETAL; BILATERAL LESIONS; HIPPOCAMPAL; INFORMATION; ATTENTION AB The present experiment was conducted in order to test the hypotheses (1) that the posterior parietal cortex (PPC) serves as a neural system that is critical for binding spatial location and object information in long-term memory and (2) that even restricted lesions of the PPC would result in similar deficits. Long-Evans rats were given either a large or a small PPC lesion or a control surgery under Nembutal anesthesia. After a 1-week recovery period, the rats were tested on either an object or a spatial location go/no-go successive discrimination task. After reaching criterion (a minimum of a 5 sec difference between reward and nonreward trials), they were trained on the other discrimination. After reaching criterion on the second discrimination, all of the rats were trained on a successive discrimination go/no-go task in which they had to remember which object/spatial location pairs had been associated with reward. As compared with controls, neither the small nor the large PPC lesion impaired object or spatial location discrimination. In the paired-associate object/spatial location task, both large and small PPC lesioned rats were impaired, relative to controls. These data suggest that the rodent PPC is not involved in object or spatial location discrimination but rather is involved in discrimination and long-term memory for the combination of object and spatial location information. C1 Univ Utah, Dept Psychol, Salt Lake City, UT 84112 USA. NIA, NIH, Baltimore, MD 21224 USA. RP Kesner, RP (reprint author), Univ Utah, Dept Psychol, Salt Lake City, UT 84112 USA. NR 24 TC 14 Z9 15 U1 0 U2 0 PU PSYCHONOMIC SOC INC PI AUSTIN PA 1710 FORTVIEW RD, AUSTIN, TX 78704 USA SN 0889-6313 J9 PSYCHOBIOLOGY JI Psychobiology PD JUN PY 1998 VL 26 IS 2 BP 128 EP 133 PG 6 WC Psychology; Psychology, Multidisciplinary SC Psychology GA ZY396 UT WOS:000074617100006 ER PT J AU Kesner, RP Long, JM AF Kesner, RP Long, JM TI Parietal cortex and a spatial cognitive map SO PSYCHOBIOLOGY LA English DT Article ID HEAD-DIRECTION CELLS; RAT POSTERIOR CORTEX; 14-UNIT T-MAZE; HIPPOCAMPAL-FORMATION; DOUBLE DISSOCIATION; ENTORHINAL CORTEX; BILATERAL LESIONS; MEMORY; ATTENTION; NEGLECT AB A framework is proposed, based on the assumption that the posterior parietal cortex stores longterm memory information in the form of a spatial cognitive map, reflecting the operation of perceptual representations of relations among spatial features and landmarks as well as the operation of attentional processes to bind spatial features and landmarks and to selectively attend to the critical features that form spatial cognitive maps. Evidence in support of this assumption, based on an analysis of specific properties of neural systems that store long-term memory information, is presented. C1 Univ Utah, Dept Psychol, Salt Lake City, UT 84112 USA. NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Kesner, RP (reprint author), Univ Utah, Dept Psychol, Salt Lake City, UT 84112 USA. NR 52 TC 7 Z9 7 U1 0 U2 1 PU PSYCHONOMIC SOC INC PI AUSTIN PA 1710 FORTVIEW RD, AUSTIN, TX 78704 USA SN 0889-6313 J9 PSYCHOBIOLOGY JI Psychobiology PD JUN PY 1998 VL 26 IS 2 BP 162 EP 166 PG 5 WC Psychology; Psychology, Multidisciplinary SC Psychology GA ZY396 UT WOS:000074617100010 ER PT J AU Panlilio, LV Goldberg, SR Gilman, JP Jufer, R Cone, EJ Schindler, CW AF Panlilio, LV Goldberg, SR Gilman, JP Jufer, R Cone, EJ Schindler, CW TI Effects of delivery rate and non-contingent infusion of cocaine on cocaine self-administration in rhesus monkeys SO PSYCHOPHARMACOLOGY LA English DT Article DE substitution therapy; self-administration; cocaine; rhesus monkey ID DRUG-THERAPY; BEHAVIOR; ABUSE AB The goal of this study was to determine whether slowly infused, response-independent cocaine would reduce cocaine self-administration in an animal model of drug abuse. Seven male rhesus monkeys self-administered IV cocaine on a fixed-ratio 30 schedule (5-min time-out). With unit dose (0.056 mg/kg per infusion for one monkey and 0.032 mg/kg per infusion for the rest) and infusion volume (0.5 mi) held constant, the rate of delivery was manipulated (0.125, 0.1875, 0.375, 0.75 and 3 ml/min, with infusions lasting 240, 160, 80, 40, and 10 s, respectively). Response rates increased monotonically as a function of delivery rate. Responding for cocaine at the slowest delivery rate did not differ from saline. The effects of infusing additional cocaine (starting 30 min prior to the session) at this non-reinforcing rate (0.125 ml/min) were then determined. Delivery rate of the self-administered infusion was manipulated as before. Non-contingent cocaine significantly increased responding for cocaine (at the fastest delivery rate) and for saline. While non-contingent cocaine reduced responding for cocaine in two of the seven monkeys, it also significantly reduced responding in three monkeys that responded for food on the same schedule. Plasma levels of cocaine delivered at rates of 0.125 and 3 ml/min were compared in five other monkeys. While a higher peak was reached with the faster infusion, levels did not differ after 5 min. Thus, when an infusion became available (after the fi-min time-out) in the self-administration experiments, plasma levels should not have differed regardless of the delivery rate. These results suggest that a low-dose, slow-delivery treatment with cocaine might prime or reinstate drug seeking rather than decrease it. C1 NIDA, Preclin Pharmacol Lab, Behav Pharmacol & Genet Sect, Div Intramural Res, Baltimore, MD 21224 USA. NIDA, Chem & Drug Metab Sect, Clin Pharmacol Branch, Div Intramural Res, Baltimore, MD 21224 USA. RP Panlilio, LV (reprint author), NIDA, Preclin Pharmacol Lab, Behav Pharmacol & Genet Sect, Div Intramural Res, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 17 TC 60 Z9 60 U1 0 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 JUN PY 1998 VL 137 IS 3 BP 253 EP 258 DI 10.1007/s002130050618 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA ZX234 UT WOS:000074493600007 PM 9683003 ER PT J AU DeVries, AC Pert, A AF DeVries, AC Pert, A TI Conditioned increases in anxiogenic-like behavior following exposure to contextual stimuli associated with cocaine are mediated by corticotropin releasing factor SO PSYCHOPHARMACOLOGY LA English DT Article DE anxiety; elevated plus-maze; classical conditioning; drug abuse; CRF antagonist ID ELEVATED PLUS-MAZE; FACTOR ANTAGONIST; ANIMAL-MODEL; WITHDRAWAL; RATS; ANXIETY; SECRETION; RESPONSES; ABUSE; CRF AB Although cocaine is a powerful reinforcer, it has been reported to produce anxiety in humans and anxiogenic-like behavior in animals. The goal of this study was three-fold: (1) to determine the doses of cocaine that induce anxiogenic-like behavior in the elevated plus-maze in rats, (2) to determine if cocaine-associated contextual cues are capable of eliciting anxiogenic-like behavior in the absence of the drug, and (3) to identify possible mechanisms through which cocaine-associated cues affect behavior in the elevated plus-maze. Measurement of the amount of time that the animals spend exploring the open arms of the maze provides a sensitive index of anxiogenic-like behavior in rats. In experiment 1, rats were injected with 10 mg/kg, 20 mg/kg, or 30 mg/kg cocaine HCl or saline for 6 days. On day 6, the rats were tested in the elevated plus-maze 25 min after injection with cocaine or saline. The animals chronically treated with the three doses of cocaine exhibited a dose-dependent increase in anxiogenic-like behavior in the elevated plus-maze, compared to the saline-treated group. In experiment 2, cocaine-induced (30 mg/kg) conditioning was achieved using a simple contextual design. On the final day of the experiment (day 6), after 5 days of conditioning, the rats were exposed for 25 min to the cocaine-associated contextual cues, then placed in the elevated plus-maze. Animals that had been exposed to cocaine-associated contextual cues prior to being placed in the elevated plus-maze exhibited a significant increase.in anxiogenic-like behavior compared to the control groups. However, pretreatment of the rats with the CRF antagonist, proportional to-helical CRF9-41, (1 mu g, ICV), on the test day, prior to exposure to cocaine-associated contextual cues, attenuated the subsequent anxiogenic-like behavioral response in the elevated plus-maze (experiment 3). The results suggest that contextual cues associated with repeated treatment with 30 mg/kg cocaine are capable of eliciting anxiogenic-like behavior in the absence of the drug and that CRF mediates the expression of anxiogenic-like behaviors in the elevated plus-maze following exposure to cocaine-associated cues. The conditioned anxiogenic action elicited by cocaine-associated cues may have relevance for understanding the complex addictive nature of this drug and some of the clinical phenomena related to its use. C1 NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. RP DeVries, AC (reprint author), Johns Hopkins Hosp, Dept Anesthesiol, CCM, 600 N Wolfe St,Bialcock 1404, Baltimore, MD 21287 USA. NR 50 TC 59 Z9 60 U1 2 U2 3 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUN PY 1998 VL 137 IS 4 BP 333 EP 340 DI 10.1007/s002130050627 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA ZY406 UT WOS:000074618100004 PM 9676892 ER PT J AU Schneider, AB Lubin, J Ron, E Abrahams, C Stovall, M Goel, A Shore-Freedman, E Gierlowski, TC AF Schneider, AB Lubin, J Ron, E Abrahams, C Stovall, M Goel, A Shore-Freedman, E Gierlowski, TC TI Salivary gland tumors after childhood radiation treatment for benign conditions of the head and neck: Dose-response relationships SO RADIATION RESEARCH LA English DT Article ID ATOMIC-BOMB SURVIVORS; THYROID-CANCER; PAROTID-GLAND; IRRADIATION; RISK; EXPOSURE; NODULES AB We have investigated the dose-response relationships for the incidence of salivary gland tumors in a cohort of 2945 individuals who were irradiated as children between 1939-1962. Most of the patients were treated to reduce the size of their tonsils and adenoids. The mean dose to the salivary glands (+/-SD) was 4.2 +/- 1.7 Gy. Eighty-nine patients developed 91 salivary gland neoplasms; 22 had single malignancies, 64 had single benign neoplasms, 2 developed two separate benign neoplasms, and 1 developed a single neoplasm but did not have surgery. The majority (81 of 89) of the patients developed neoplasms in the parotid glands. Mucoepidermoid carcinomas were the most common malignancy and mixed (pleomorphic) adenomas were the most common benign neoplasm. For all salivary gland tumors, the excess relative risk per gray (ERR/Gy) was 0.82; however, the 95% confidence interval was wide (0.04, upper bound indeterminate). The trend was determined principally by benign tumors, as there was no dose-response relationship for salivary gland cancer, although there were too few cases to draw definitive conclusions. Overall, our study provides support for an association between salivary gland tumors and radiation exposure, Although most salivary gland tumors are benign and are usually readily detected, they may cause morbidity, and people who have been irradiated in the area should be monitored for their occurrence. (C) 1998 by Radiation Research Society. C1 Univ Illinois, Coll Med, Sect Endocrinol & Metab, Chicago, IL 60612 USA. NCI, Biostat Branch, Rockville, MD 20892 USA. NCI, Radiat Epidemiol Branch, Rockville, MD 20892 USA. Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. Univ Texas, MD Anderson Cancer Ctr, Dept Radiat Phys, Houston, TX 77030 USA. Michael Reese Hosp & Med Ctr, Div Endocrinol, Chicago, IL 60616 USA. RP Schneider, AB (reprint author), Univ Illinois, Coll Med, Sect Endocrinol & Metab, Chicago, IL 60612 USA. OI Shore-Freedman, Eileen/0000-0001-6194-1814 FU NCI NIH HHS [CA-21518, N01-CP-85604, N01-CP-95614] NR 28 TC 42 Z9 42 U1 0 U2 1 PU RADIATION RESEARCH SOC PI OAK BROOK PA 2021 SPRING RD, STE 600, OAK BROOK, IL 60521 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD JUN PY 1998 VL 149 IS 6 BP 625 EP 630 DI 10.2307/3579909 PG 6 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA ZQ060 UT WOS:000073817400011 PM 9611101 ER PT J AU Rose, PM Stoklosa, K Gray, SA AF Rose, PM Stoklosa, K Gray, SA TI A focus group approach to assessing technostress at the reference desk SO REFERENCE & USER SERVICES QUARTERLY LA English DT Article AB As in many academic libraries, reference desk service at the Health Sciences Library of the State University of New York at Buffalo involves an increasing number and complexity of: automated systems. As such, expectations of those who staff the reference desk to have technical facility have increased along with expression of anxiety about staffing the desk. To test the assumption that technology is the cause of this anxiety, the investigators conducted a focus group with segments of the reference desk staff who seemed to experience the most strain. This qualitative study resulted in the identification of technological and other factors that contribute to the anxiety and makes recommendations to resolve such stress. C1 SUNY Buffalo, Hlth Sci Lib, Reference & Educ Serv Dept, Buffalo, NY 14260 USA. NIH Lib, Bethesda, MD USA. RP Rose, PM (reprint author), SUNY Buffalo, Hlth Sci Lib, Reference & Educ Serv Dept, Buffalo, NY 14260 USA. NR 14 TC 2 Z9 2 U1 1 U2 2 PU AMER LIBRARY ASSOC PI CHICAGO PA 50 E HURON ST, CHICAGO, IL 60611 USA SN 1094-9054 J9 REF USER SERV Q JI Ref. User Serv. Q. PD SUM PY 1998 VL 37 IS 4 BP 311 EP 317 PG 7 WC Information Science & Library Science SC Information Science & Library Science GA 176KF UT WOS:000079149700003 ER PT J AU Hanbauer, I Galdzicki, Z Rapoport, SI Scortegagna, M AF Hanbauer, I Galdzicki, Z Rapoport, SI Scortegagna, M TI Evidence of increased oxidative stress in hippocampal primary cultures of trisomy 16 mouse. Studies on metallothionein-I/II SO RESTORATIVE NEUROLOGY AND NEUROSCIENCE LA English DT Article DE trisomy 16 mouse; oxidative stress; metallothionein; antioxidant response; hydrogen peroxide; ionotropic; metabotropic glutamate receptor ID ANTIOXIDANT RESPONSE ELEMENT; HYDROGEN-PEROXIDE; DOWNS-SYNDROME; GLUTATHIONE-PEROXIDASE; SUPEROXIDE-DISMUTASE; BINDING-ACTIVITY; FREE-RADICALS; CELL-LINE; I GENE; DISEASE AB In the trisomy 16 mouse che increased gene dosage of SOD-1 increases H2O2 production that results in increased oxidative stress. We report here that in hippocampal primary cultures, metallothionein (MT)-I/II immunoreactivity was present mainly in glial fibrillary acidic protein-immunolabeled cells. Western blot analysis showed a two-fold higher level of MT-I/II in trisomy 16 mice then in euploid Littermates. In contrast, the immunoreactivity of glutamine synthetase, another glia-expressed protein, was similar in hippocampal cultures of trisomy 16 mouse and euploid littermates. Oxyblot analysis of hippocampal cultures showed that the carbonyl content in several protein bands was higher in trisomy 16 mice than in euploid littermates giving evidence for increased oxidative stress in trisomy 16 mouse cultures. To evaluate the responsiveness of MT-I/II to agents that increase the level of reactive oxygen species in cells we measured the effect of H2O2, kainic acid, (+/-)ACPD, and beta-amyloid peptide 1-42. Western blot analysis documented that in hippocampal cultures of euploid littermates MT-I/II was maximally increased by 50 mu M H2O2, 100 mu M kainic acid, 10 mu M (+/-)ACPD, or 1.0 mM beta-amyloid peptide 1-42, whereas in those of trisomy 16 mice no further increase above the elevated level was observed. Our data suggest that in the trisomy 16 mouse the production of reactive oxygen species may have shifted the intracellular redox environment that could have altered the susceptibility of MT-I/II transcription. The possibility that transcription factors whose activation may be essential to initiate MT-I/II transcription get oxidized has yet to be examined. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Hanbauer, I (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10,Room 7N-312, Bethesda, MD 20892 USA. NR 37 TC 2 Z9 2 U1 0 U2 0 PU IOS PRESS PI AMSTERDAM PA VAN DIEMENSTRAAT 94, 1013 CN AMSTERDAM, NETHERLANDS SN 0922-6028 J9 RESTOR NEUROL NEUROS JI Restor. Neurol. Neurosci. PD JUN PY 1998 VL 12 IS 2-3 BP 87 EP 93 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 150NV UT WOS:000077672100006 PM 12671302 ER PT J AU Scortegagna, M Chikhale, E Hanbauer, I AF Scortegagna, M Chikhale, E Hanbauer, I TI Lead exposure increases oxidative stress in serum deprived E14 mesencephalic cultures. Role of metallothionein and glutathione SO RESTORATIVE NEUROLOGY AND NEUROSCIENCE LA English DT Article DE primary cultures; lend; glutathione; metallothionein; serum deprivation; oxidative stress ID GLUTAMINE-SYNTHETASE; TRANSCRIPTION FACTOR; ASTROCYTE CULTURES; SUBSTANTIA-NIGRA; BRAIN-AREAS; GLIAL-CELLS; RAT; TOXICITY; NEURONS; CADMIUM AB E14 mesencephalic cultures grown 6 days in Neurobasal Medium containing 10% horse serum consist of differentiated neurons and astroglia. In these cultures, glutathione and metallothionein-I/II are enriched in astrocytes and play an important role in heavy metal scavenging and oxidative stress response. A 24 h exposure to 25 mu M Pb, in serum-containing medium, elevated the glutathione content by more than twofold and increased the metallothionein VII-immunolabeled protein band. In contrast, exposure to 3 to 25 mu M Pb in serum-free medium increased Pb uptake by cells 2 to 4-times above the levels found in 10% serum-containing medium, reduced the glutathione level and obliterated the metallothionein-I/II protein band. The rapid decrease of metallothionein-I/II and glutathione levels in serum-free medium implies that their regulation may depend on a serum factor operative in inducing immediate early genes. Exposure to 6 mu M Pb in serum-free or in B27-supplemented medium increased the carbonyl content of several protein bands above control levels indicating that under conditions that curtail metallothionein induction Pb exposure causes increased oxidative stress. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Hanbauer, I (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10,Room 7N-312, Bethesda, MD 20892 USA. NR 30 TC 9 Z9 9 U1 0 U2 0 PU IOS PRESS PI AMSTERDAM PA VAN DIEMENSTRAAT 94, 1013 CN AMSTERDAM, NETHERLANDS SN 0922-6028 J9 RESTOR NEUROL NEUROS JI Restor. Neurol. Neurosci. PD JUN PY 1998 VL 12 IS 2-3 BP 95 EP 101 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 150NV UT WOS:000077672100007 PM 12671303 ER PT J AU Jin, AJ Mudd, CP Gershfeld, NL Fukada, K AF Jin, AJ Mudd, CP Gershfeld, NL Fukada, K TI Ultrasensitive excitation/relaxation calorimeter for simultaneous measurement of thermal conductivity and heat capacity in fluids SO REVIEW OF SCIENTIFIC INSTRUMENTS LA English DT Article ID TEMPERATURE; WATER; PRESSURE; DIFFUSIVITY; LIQUID AB An ultrasensitive heat conduction microcalorimeter for fluids with a novel method of data analysis is described. The instrument measures the thermal conductivity (lambda) and heat capacity (C-p) simultaneously on the same sample with a resolution of 1 part in 10(5) for each of these properties. Baseline and sample filling errors are below the instrument resolution. The accuracies for lambda and C-p are approximately 1 part in 10(4), limited primarily by the uncertainty in the properties of the standards used for calibration. The instrument operates essentially isothermally, and is capable of automated temperature stepping between 5 and 55 degrees C. [S0034-6748(98)03106-2]. C1 NIAMS, Phys Biol Lab, NIH, Bethesda, MD 20892 USA. C&E Engn Serv, Charlottesville, VA 22911 USA. RP Jin, AJ (reprint author), NIAMS, Phys Biol Lab, NIH, Bldg 6,Rm 408, Bethesda, MD 20892 USA. OI Jin, Albert/0000-0003-3826-1081 NR 26 TC 2 Z9 2 U1 0 U2 2 PU AMER INST PHYSICS PI WOODBURY PA CIRCULATION FULFILLMENT DIV, 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2999 USA SN 0034-6748 J9 REV SCI INSTRUM JI Rev. Sci. Instrum. PD JUN PY 1998 VL 69 IS 6 BP 2439 EP 2451 DI 10.1063/1.1148972 PG 13 WC Instruments & Instrumentation; Physics, Applied SC Instruments & Instrumentation; Physics GA 108RK UT WOS:000075279100035 ER PT J AU Berger, EA AF Berger, EA TI Introduction: HIV co-receptors solve old questions and raise many new ones SO SEMINARS IN IMMUNOLOGY LA English DT Editorial Material ID CD8(+) T-CELLS; CHEMOKINE RECEPTORS; FUSION COFACTORS; INFECTION; RESISTANCE; ENTRY; IDENTIFICATION; MIP-1-ALPHA; PROGRESSION; INDIVIDUALS C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Berger, EA (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 20 TC 9 Z9 9 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD JUN PY 1998 VL 10 IS 3 BP 165 EP 168 DI 10.1006/smim.1998.0126 PG 4 WC Immunology SC Immunology GA 131NG UT WOS:000076581700001 PM 9653042 ER PT J AU Pease, JE Murphy, PM AF Pease, JE Murphy, PM TI Microbial corruption of the chemokine system: An expanding paradigm SO SEMINARS IN IMMUNOLOGY LA English DT Review DE chemokine; HIV; AIDS; malaria; herpesvirus; poxvirus ID PROTEIN-COUPLED RECEPTOR; SARCOMA-ASSOCIATED HERPESVIRUS; DUFFY-NEGATIVE INDIVIDUALS; RED-BLOOD-CELLS; HUMAN CYTOMEGALOVIRUS; HIV-1 INFECTION; KAPOSIS-SARCOMA; PLASMODIUM-VIVAX; SEQUENCE-ANALYSIS; ANTIGEN RECEPTOR AB The chemokine signaling system includes more than 40 secreted pro-inflammatory peptides and 12 G protein-coupled receptors that together orchestrate specific leukocyte trafficking in the mammalian immune system, ideally for antimicrobial defense and tissue repair processes. Paradoxically and perversely, some chemokines and chemokine receptors are also promicrobial factors and facilitate infectious disease, the result of either exploitation or subversion by specific microbes. Two modes of exploitation are known: usage of cellular chemokine receptors for cell entry by intracellular pathogens, including HN, and usage of virally-encoded chemokine receptors for host cell proliferation. Likewise, two modes of subversion are known: virally-encoded chemokine antagonists and virally-encoded chemokine scavengers. Understanding how microbes turn, the tables on the chemokine system may point to new methods to prevent or treat infection, or, more generally, to treat inappropriate chemokine mediated inflammation. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Natl Heart & Lung Inst, Imperial Coll Sch Med, Dept Appl Pharmacol, London SW3 6LY, England. RP Pease, JE (reprint author), Natl Heart & Lung Inst, Imperial Coll Sch Med, Dept Appl Pharmacol, Dovehouse St, London SW3 6LY, England. NR 80 TC 39 Z9 39 U1 0 U2 2 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD JUN PY 1998 VL 10 IS 3 BP 169 EP 178 DI 10.1006/smim.1998.0129 PG 10 WC Immunology SC Immunology GA 131NG UT WOS:000076581700002 PM 9653043 ER PT J AU Daly, M Obrams, GI AF Daly, M Obrams, GI TI Epidemiology and risk assessment for ovarian cancer SO SEMINARS IN ONCOLOGY LA English DT Review ID STATES CASE-CONTROL; UNITED-STATES; COLLABORATIVE ANALYSIS; FAMILIAL BREAST; SUSCEPTIBILITY GENE; WHITE WOMEN; FOLLOW-UP; BRCA1; MUTATION; TALC C1 Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. NCI, Bethesda, MD 20892 USA. RP Daly, M (reprint author), Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. NR 90 TC 86 Z9 94 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 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD JUN PY 1998 VL 25 IS 3 BP 255 EP 264 PG 10 WC Oncology SC Oncology GA ZT936 UT WOS:000074143000004 PM 9633839 ER PT J AU Muntaner, C Wolyniec, P McGrath, J Pulver, AE AF Muntaner, C Wolyniec, P McGrath, J Pulver, AE TI Arrest among psychotic inpatients: assessing the relationship to diagnosis, gender, number of admissions, and social class SO SOCIAL PSYCHIATRY AND PSYCHIATRIC EPIDEMIOLOGY LA English DT Article ID MENTALLY-ILL; PSYCHIATRIC-DISORDERS; UNITED-STATES; VIOLENCE; SCHIZOPHRENIA; BEHAVIOR; HEALTH; CONSEQUENCES; ILLNESS; CRIME AB The present study of psychotic patients investigates the relationship of specific psychotic diagnoses (i.e., psychoactive-substance-induced psychosis, schizophrenia, bipolar disorder, other DSM-III Axis I psychotic disorders), social class, gender, and number of admissions to the rate of arrest in the community. All admissions with psychotic symptoms to hospitals providing inpatient psychiatric services in the Baltimore area were surveyed during a 6-year period. Study participants were assessed using a modified version of the Diagnostic Interview Schedule. During the course of the interview, patients were asked whether they had ever been arrested as a juvenile or as an adult. After adjusting for age, gender? number of admissions, and social class, we found that patients admitted for psychoactive-substance-induced psychosis were more likely to report having been arrested than patients with other psychotic diagnoses. Patients with schizophrenia were not more likely to have an history of arrest than patients with other psychotic disorders. Number of admissions and social class were independent predictors of history of arrest. The relationship between psychotic diagnosis and history of arrest was modified by gender. Psychotic patients with substance-induced diagnosis who were male were more likely to report a prior arrest in the community than their female counterparts. Our results suggest that type of psychotic diagnosis and social class, in addition to gender and number of admissions, are important predictors of differences in arrest-rate histories among psychotic patients. Gender appears to be an effect modifier of the relationship between psychotic diagnosis and history of arrest. C1 NIMH, Sect Socio Environm Studies, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. W Virginia Univ, Sch Med, Prevent Res Ctr, Morgantown, WV 26506 USA. W Virginia Univ, Sch Med, Inst Occupat & Environm Hlth, Morgantown, WV 26506 USA. RP Muntaner, C (reprint author), NIMH, Sect Socio Environm Studies, Bethesda, MD 20892 USA. RI Muntaner, C/A-5043-2010 FU NIMH NIH HHS [R01MH35712] NR 60 TC 13 Z9 13 U1 1 U2 3 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PLATZ DER DEUTSCHEN EINHEIT 25, D-64293 DARMSTADT, GERMANY SN 0933-7954 J9 SOC PSYCH PSYCH EPID JI Soc. Psychiatry Psychiatr. Epidemiol. PD JUN PY 1998 VL 33 IS 6 BP 274 EP 282 DI 10.1007/s001270050055 PG 9 WC Psychiatry SC Psychiatry GA ZR315 UT WOS:000073961800006 PM 9640096 ER PT J AU Midhet, F Becker, S Berendes, HW AF Midhet, F Becker, S Berendes, HW TI Contextual determinants of maternal mortality in rural Pakistan SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE maternal mortality; rural Pakistan; contextual analysis; health services indicators ID HEALTH PROMOTION AB Maternal mortality is high in Pakistan, particularly in the rural areas which have poor access to health services. We investigated the risk factors associated with maternal mortality in sixteen rural districts of Balochistan and the North-West Frontier (NWFP) provinces of Pakistan. We designed a nested case-control study comprising 261 cases (maternal deaths reported during last five years) and 9135 controls (women who survived a pregnancy during last five years). Using contextual analysis, we estimated the interactions between the biological risk factors of maternal mortality and the district-level indicators of health services. Women under 19 or over 39 yr of age, those having their first birth, and those having a previous history of fetal loss were at greater risk of maternal death. Staffing patterns of peripheral health facilities in the district and accessibility of essential obstetric care (EOC) were significantly associated with maternal mortality. These indicators also modified the effects of the biological risk factors of maternal mortality. For example, nulliparous women living in the under-served districts were at greater risk than those living in the better-served districts. Our results are consistent with several studies which have pointed out the role of health services in the causation of maternal mortality. Many such studies have implicated distance to hospital (an indicator of access to EOC) and lack of prenatal care as major determinants of maternal mortality. We conclude that better staffing of peripheral health facilities and improved access to EOC could reduce the risk of maternal mortality among women in rural Balochistan and the NWFP. (C) 1998 Elsevier Science Ltd. All rights reserved. C1 NICHHD, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Populat Dynam, Baltimore, MD 21205 USA. RP Midhet, F (reprint author), NICHHD, 6100 Execut Blvd,Room 7B05, Bethesda, MD 20892 USA. NR 42 TC 28 Z9 33 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD JUN PY 1998 VL 46 IS 12 BP 1587 EP 1598 DI 10.1016/S0277-9536(97)10137-X PG 12 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA ZV757 UT WOS:000074338100006 PM 9672397 ER PT J AU Dawkins, FW Delapenha, RA Frezza, EE Green, WR Hardy, C Frederick, WRJ Manns, A AF Dawkins, FW Delapenha, RA Frezza, EE Green, WR Hardy, C Frederick, WRJ Manns, A TI HIV-1-associated Kaposi's sarcoma in a predominantly black population at an inner city hospital SO SOUTHERN MEDICAL JOURNAL LA English DT Article ID DNA-SEQUENCES; AIDS; INFECTION AB Background. Kaposi's sarcoma (KS) associated with human immunodeficiency virus type 1 (HIV-1) is the most common malignancy in patients with AIDS. It has been most commonly reported in white homosexual men, though a few cases have been reported in blacks,. Methods. We conducted a retrospective analysis of all HIV-1 seropositive patients with biopsy-proven KS seen at Howard University Hospital between February 1985 and June 1995. Results. Of the 73 patients identified, 66 (90%), 4 were white, 2 were Hispanic, and 1 was of unidentified race. The median age was 32 years. Forty-eight (66%) were homosexual or bisexual men, and 10 (14%) were homosexual or bisexual with a history of intravenous drug use (IDU). A history of IDU or blood transfusion was the only risk factor in 7 (9%) and 2 (3%), respectively. The other 6 (8)% were heterosexual. The median survival was 2.2 years. A CD4 count <200 and the presence of an opportunistic infection were associated with shortened survival. Conclusions. The predominant risk factor for HIV-1-associated KS was homosexual or bisexual activity. Only a few women with KS were identified, and they also reported sexual transmission from male bisexuals and/or drug users. Poor survival was associated with CD4 <200, stage III and IV KS at presentation, and opportunistic infections. C1 Howard Univ, Coll Med, Dept Med, Washington, DC USA. Howard Univ, Coll Med, Dept Pathol, Washington, DC USA. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Dawkins, FW (reprint author), Howard Univ Hosp, Div Hematol Oncol, 2041 Georgia Ave NW, Washington, DC 20060 USA. NR 14 TC 1 Z9 1 U1 0 U2 0 PU SOUTHERN MEDICAL ASSN PI BIRMINGHAM PA 35 LAKESHORE DR PO BOX 190088, BIRMINGHAM, AL 35219 USA SN 0038-4348 J9 SOUTHERN MED J JI South.Med.J. PD JUN PY 1998 VL 91 IS 6 BP 546 EP 549 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA ZT601 UT WOS:000074104200007 PM 9634116 ER PT J AU Breier, A Adler, CM Weisenfeld, N Su, TP Elman, I Picken, L Malhotra, AK Pickar, D AF Breier, A Adler, CM Weisenfeld, N Su, TP Elman, I Picken, L Malhotra, AK Pickar, D TI Effects of NMDA antagonism on striatal dopamine release in healthy subjects: Application of a novel PET approach SO SYNAPSE LA English DT Article DE NMDA; glutamate; dopamine; C-11-raclopride; positron emission tomography; schizophrenia ID POSITRON EMISSION TOMOGRAPHY; CEREBRAL GLUCOSE-UTILIZATION; PREFRONTAL CORTEX; C-11 RACLOPRIDE; SCHIZOPHRENIC BRAINS; GLUTAMIC-ACID; AMINO-ACIDS; RAT-BRAIN; RECEPTOR; KETAMINE AB Agents that antagonize the glutamatergic N-methyl-d-aspartate (NMDA) receptor, such as phenylcyclidine (PCP) and ketamine, produce a behavioral state in healthy volunteers that resembles some aspects of schizophrenia. A dysfunction in NMDA-dopaminergic interactions has been proposed as a mechanism for these behavioral effects. In this study, we examined the effects of ketamine on striatal dopamine release in healthy human subjects with a novel C-11-raclopride/PET displacement paradigm and compared these effects to administration of saline and the direct-acting dopamine agonist amphetamine. We found that the percent decreases (mean +/- SD) in specific C-11-raclopride binding from baseline for ketamine (11.2 +/- 8.9) was greater than for saline (1.9 +/- 3.7) (t = 2.4, df = 13, P = 0.003) indicating that ketamine caused increases in striatal synaptic dopamine concentrations. Ketamine-related binding changes were not significantly different than the decreases in percent change (mean +/- SD) in specific C-11-raclopride binding caused by amphetamine (15.5 +/- 6.2) (t = 1.3, df = 19, P = 0.21). Ketamine-induced changes in C-11-raclopride-specific binding were significantly correlated with induction of schizophrenia-like symptoms. The implications of this brain imaging method for studies of schizophrenia and the mechanism of action of antipsychotic drugs are discussed. (C) 1998 Wiley-Liss, Inc.dagger C1 NIMH, Expt Therapeut Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Breier, A (reprint author), Eli Lilly & Co, Lilly Corp Ctr, Drop Code 0538, Indianapolis, IN 46285 USA. EM Breier_Alan@Lilly.com NR 58 TC 150 Z9 151 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 0887-4476 J9 SYNAPSE JI Synapse PD JUN PY 1998 VL 29 IS 2 BP 142 EP 147 DI 10.1002/(SICI)1098-2396(199806)29:2<142::AID-SYN5>3.0.CO;2-7 PG 6 WC Neurosciences SC Neurosciences & Neurology GA ZK687 UT WOS:000073351100005 PM 9593104 ER PT J AU Passaro, KT Little, RE Savitz, DA Noss, J AF Passaro, KT Little, RE Savitz, DA Noss, J CA ALSPAC Study Team TI Effect of paternal alcohol consumption before conception on infant birth weight SO TERATOLOGY LA English DT Article ID PREGNANCY; ASSOCIATION; INFECTION; DRINKING; ETHANOL; MICE AB Previous studies of paternal drinking and fetal growth in both animals and humans have produced conflicting results. We evaluated the association between paternal drinking before conception and infant birth weight in a cohort of 9,845 liveborn singleton infants born to couples who participated in the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC). ALSPAC is a population-based cohort study in which women and their partners completed several self-administered questionnaires over the course of pregnancy. Of participating male partners, 20% were reportedly daily drinkers before conception, and 8% were considered moderately heavy or very heavy drinkers. Because maternal drinking is highly correlated with paternal drinking, the analyses were stratified by maternal drinking in early pregnancy. We also adjusted for confounders and known predictors of birth weight. For all three maternal drinking strata, all adjusted mean differences in birth weight across levels of paternal drinking were similar, and all had confidence intervals that included zero. These findings persisted even after adjustment for other covariates and after stratification by parental smoking, race, and education. The size of the ALSPAC cohort, the large number of heavy drinkers, and the availability of data from the fathers themselves support the conclusion that paternal drinking before conception is not an important predictor of infant birth weight in humans. (C) 1998 Wiley-Liss,Inc. C1 Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. WESTAT Corp, Durham, NC 27701 USA. Univ Bristol, Bristol, Avon, England. RP Passaro, KT (reprint author), NC Dept Hlth & Human Serv, Off Epidemiol, POB 29605, Raleigh, NC 27626 USA. EM kristi_passaro@mail.ehnr.state.nc.us FU FDA HHS [GENBANK/RO3AAO9758-01]; Wellcome Trust NR 23 TC 19 Z9 21 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 0040-3709 J9 TERATOLOGY JI Teratology PD JUN PY 1998 VL 57 IS 6 BP 294 EP 301 DI 10.1002/(SICI)1096-9926(199806)57:6<294::AID-TERA2>3.0.CO;2-X PG 8 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA ZY306 UT WOS:000074606900002 PM 9664637 ER PT J AU Steiner, LL Cavalli, A Zimmerman, PA Boatin, BA Titanji, VPK Bradley, JE Lucius, R Nutman, TB Begovich, AB AF Steiner, LL Cavalli, A Zimmerman, PA Boatin, BA Titanji, VPK Bradley, JE Lucius, R Nutman, TB Begovich, AB TI Three new DP alleles identified in sub-Saharan Africa: DPB1*7401, DPA1*02013, and DPA1*0302 SO TISSUE ANTIGENS LA English DT Article DE class II; HLA-DPA1; HLA-DPB1; sequence-specific oligonucleotide probe; sub-Saharan Africa AB HLA-DP genotyping of over 400 individuals from sub-Saharan Africa identified three new DP alleles: DPB1*7401, DPA1*02013, and DPA1*0302. DNA sequencing confirmed that DPB1*7401, found in one individual, is a novel combination of previously described sequence motifs in the six variable regions of DPB1, DPA1*02013, found in one individual, is identical to DPA1*02012 except for two silent substitutions, a T to C transition in codon 37, and an A to G transition in codon 38. DPA1*0302, identified in seven individuals, is identical to DPA1*0301 except for a C to T transition at the second position of codon 66. The identification of these novel alleles brings the total number of reported DPB1 alleles to 77 and DPA1 alleles to 11. C1 Roche Mol Syst Inc, Dept Human Genet, Alameda, CA 94501 USA. Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. Roche Mol Syst Inc, Dept Core Res, Alameda, CA 94501 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Onchocerciasis Control Program, Ouagadougou, Burkina Faso. Univ Buea, Buea, Cameroon. Univ Salford, Dept Biol Sci, Salford M5 4WT, Lancs, England. Humboldt Univ, Berlin, Germany. RP Begovich, AB (reprint author), Roche Mol Syst Inc, Dept Human Genet, 1145 Atlant Ave, Alameda, CA 94501 USA. EM Ann.Begovich@Roche.com OI Bradley, Janette/0000-0003-3973-7977 FU NIAID NIH HHS [AI29042] NR 8 TC 4 Z9 6 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD JUN PY 1998 VL 51 IS 6 BP 653 EP 657 DI 10.1111/j.1399-0039.1998.tb03009.x PG 5 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA ZY723 UT WOS:000074652900010 PM 9694359 ER PT J AU Purchase, IFH Botham, PA Bruner, LH Flint, OP Frazier, JM Stokes, WS AF Purchase, IFH Botham, PA Bruner, LH Flint, OP Frazier, JM Stokes, WS TI Workshop overview: Scientific and regulatory challenges for the reduction, refinement, and replacement of animals in toxicity testing SO TOXICOLOGICAL SCIENCES LA English DT Article ID HUMAN LIVER SLICES; PRECISION-CUT LIVER; IN-VITRO; EYE IRRITATION; LUNG SLICES; RAT-LIVER; SKIN CORROSIVITY; TOXICOLOGY; VALIDATION; METABOLISM AB Public concern for animal welfare has been expressed through legislative control of animal use for experimental purposes since the first legislation was introduced in 1876 in the United Kingdom. Legislative control of animal use has been introduced in virtually every developed country, with major initiatives in Europe (1986) and the United States (1966 and 1985). Advances in scientific thinking resulted in the development of the concept of the three Rs-refinement, reduction, and replacement-by Russell and Burch in 1959, The field has expanded substantially since, with specialist scientific journals dedicated to alternatives, World Congresses organized to discuss the scientific and philosophical issues, and European and U.S. validation organizations being launched. Current scientific attention is focused on validation of alternative methods. The underlying scientific principles of chemical toxicity are complicated and insufficiently understood for alternative methods for all toxicity endpoints of importance in protecting human health to be available. Important lessons have been learned about how to validate methods, including the need to have prediction models available before the validation is undertaken, the need to understand the variability of the animal-based data which is to be used as the validation standard, and the need to have well-managed validation programs. Future progress will depend on the development of novel methods, which can now be validated through international collaborative efforts. (C) 1998 Society of Toxicology. C1 Zeneca Ltd, Cent Toxicol Lab, Macclesfield SK10 4TJ, Cheshire, England. Procter & Gamble Co, Hlth & Beauty Care Europe, Staines TW18 3AZ, Middx, England. Bristol Myers Squibb Co, Expt Pathol, E Syracuse, NY 13057 USA. USAF, Armstrong Lab, L AL HSC OET, Wright Patterson AFB, OH 45433 USA. NIEHS, NTP Interagcy Ctr Evaluat Alternat Toxicol Method, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Purchase, IFH (reprint author), Zeneca Ltd, Cent Toxicol Lab, Alderley Pk, Macclesfield SK10 4TJ, Cheshire, England. NR 57 TC 15 Z9 16 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUN PY 1998 VL 43 IS 2 BP 86 EP 101 DI 10.1093/toxsci/43.2.86 PG 16 WC Toxicology SC Toxicology GA 108PR UT WOS:000075275100002 PM 9710950 ER PT J AU Stroncek, DF Shankar, R Litz, C Clement, L AF Stroncek, DF Shankar, R Litz, C Clement, L TI The expression of the NB1 antigen on myeloid precursors and neutrophils from children and umbilical cords SO TRANSFUSION MEDICINE LA English DT Article DE myeloid antigens; NB1 antigen; neutrophil antigens; neutrophils; umbilical cord blood ID MONOCLONAL-ANTIBODIES; MATURATION AB The neutrophil-specific antigen NB1 is expressed by neutrophils from 97% of healthy adults. However, membrane expression of this molecule is unique in that it is found on only a subpopulation of neutrophils present in NB1-positive adults. We have investigated the ontogeny of NBI antigen expression by haematopoietic progenitor cells to determine the stage and pattern of antigen expression during granulocytic cell differentiation. In addition, we examined whether the ontogeny and frequency of granulocytic cells expressing the NB1 antigen might vary in subjects according to age. A monoclonal antibody (MoAb) specific for NB1 (1B5) and flow cytometry was used to assess the frequency and characteristics of the NBI-positive cells found in umbilical cord blood (n = 11), children (n = 37), healthy adults (n = 46) and patients with chronic myelogenous leukaemia (n = 8). We also used flow cytometry to isolate NB1-positive and NBI-negative bone marrow and peripheral blood cells from various tissue sources. The separated subpopulations were then analysed by Wright stain and light microscopy. The size of the NB1-positive neutrophil subpopulation in 46 healthy adults (56 +/- 19%) was identical to that found for neutrophils from 36 children ranging in age from 8 months to 18 years (56 +/- 11%). In contrast, expression of the NBI antigen by the neutrophils present in umbilical cord blood (91 +/- 3%, n = 11) was significantly greater than that in adults (P < 0.002) or children (P < 0.002). We also examined the size of the NB1-positive subpopulation among neutrophils from eight patients with chronic myelogenous leukaemia (CML). The NB1-positive subset in CML subjects (29.5 +/- 22.4%) was significantly less that in healthy adults (P < 0.02) or children (P < 0.02). Marrow cells from eight adults were similarly separated and analysed. We found that 69 +/- 17% of segmented and band forms of neutrophils, 70 +/- 2% of metamyelocytes and 61 +/- 23% of myelocytes were NB1-positive. In fetal bone marrow, 86 +/- 9% of the segmented and band forms, 82 +/- 10% of the metamyelocytes and 3 +/- 4% of myelocytes were NB1-positive. In conclusion, neutrophil-specific antigen NBI is first expressed at the myelocyte stage of myeloid differentitation. In adult bone marrow, the percentages of myelocytes, metamyelocytes and segmented or band cells that expressed this antigen were similar and comparable in magnitude to the frequency of NB1-positive neutrophils found in the circulation. Although the size of the NB1-positive neutrophil subpopulation was the same in healthy adults and children, it was significantly increased in umbilical cord blood, and in fetal marrow cells. C1 Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. Childrens Mercy Hosp, Dept Pediat, Sect Allergy & Immunol, Kansas City, MO 64108 USA. RP Stroncek, DF (reprint author), NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, 10 Ctr Dr,MSC,1184,Bldg 10,Room 1C711, Bethesda, MD 20892 USA. NR 12 TC 19 Z9 19 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0958-7578 J9 TRANSFUSION MED JI Transfus. Med. PD JUN PY 1998 VL 8 IS 2 BP 119 EP 123 PG 5 WC Hematology SC Hematology GA ZW085 UT WOS:000074372400007 PM 9675788 ER PT J AU Small, PLC Waterman, SR AF Small, PLC Waterman, SR TI Acid stress, anaerobiosis and gadCB lessons from Lactococcus lactis and Escherichia coli SO TRENDS IN MICROBIOLOGY LA English DT Editorial Material ID GLUTAMATE-DECARBOXYLASE; SHIGELLA-FLEXNERI; RESISTANCE; GENES; BACTERIA C1 NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Hammersmith Hosp, Imperial Coll, Dept Infect Dis & Bacteriol, London W12 0NN, England. RP Small, PLC (reprint author), NIAID, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 12 TC 76 Z9 82 U1 2 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0966-842X J9 TRENDS MICROBIOL JI Trends Microbiol. PD JUN PY 1998 VL 6 IS 6 BP 214 EP 216 DI 10.1016/S0966-842X(98)01285-2 PG 3 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA ZV338 UT WOS:000074294600003 PM 9675796 ER PT J AU Oram, MW Foldiak, P Perrett, DI Sengpiel, F AF Oram, MW Foldiak, P Perrett, DI Sengpiel, F TI The 'Ideal Homunculus': decoding neural population signals SO TRENDS IN NEUROSCIENCES LA English DT Review ID ACCESSORY OPTIC-SYSTEM; PRIMATE MOTOR CORTEX; FREE ARM MOVEMENTS; TRAJECTORY FORMATION; NEURONAL POPULATION; 3-DIMENSIONAL SPACE; TERMINAL NUCLEUS; TEMPORAL CORTEX; CELL DISCHARGE; VISUAL TARGETS AB Information processing in the nervous system involves the activity of large populations of neurons. It is possible, however, to interpret the activity of relatively small numbers of cells in terms of meaningful aspects of the environment. 'Bayesian inference' provides a systematic and effective method of combining information from multiple cells to accomplish this. It is not a model of a neural mechanism (neither are alternative methods, such as the population vector approach) but a tool for analysing neural signals. It does not require difficult assumptions about the nature of the dimensions underlying cell selectivity, about the distribution and tuning of cell responses or about the way in which information is transmitted and processed. It can be applied to any parameter of neural activity (for example, firing rate or temporal pattern). In this review we demonstrate the power of Bayesian analysis using examples of visual responses of neurons in primary visual and temporal cortices. We show that interaction between correlation in mean responses to different stimuli (signal) and correlation in response variability within stimuli (noise) can lead to marked improvement of stimulus discrimination using population responses. C1 Univ St Andrews, Sch Psychol, St Andrews KY16 9JU, Fife, Scotland. Max Planck Inst Neurobiol, D-82152 Munchen, Germany. RP Oram, MW (reprint author), NIMH, NIH, Bethesda, MD 20892 USA. RI Sengpiel, Frank/A-4682-2010; Oram, Michael/A-2558-2010; Foldiak, Peter/I-4987-2012 OI Sengpiel, Frank/0000-0002-7060-1851; Foldiak, Peter/0000-0001-7407-5804 NR 52 TC 154 Z9 154 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD JUN PY 1998 VL 21 IS 6 BP 259 EP 265 DI 10.1016/S0166-2236(97)01216-2 PG 7 WC Neurosciences SC Neurosciences & Neurology GA ZQ302 UT WOS:000073844400011 PM 9641539 ER PT J AU Pletneva, MA Sosnovtsev, SV Sosnovtseva, SA Green, KY AF Pletneva, MA Sosnovtsev, SV Sosnovtseva, SA Green, KY TI Characterization of a recombinant human calicivirus capsid protein expressed in mammalian cells SO VIRUS RESEARCH LA English DT Article DE human calicivirus; calicivirus capsid; calicivirus; Hawaii virus; Hawaii virus capsid; MVA/T7 system ID IMMUNE ELECTRON-MICROSCOPY; MOLECULAR CHARACTERIZATION; HEMORRHAGIC-DISEASE; GENOME ORGANIZATION; FELINE CALICIVIRUS; VIRUS; SEQUENCE; RNA; GASTROENTERITIS; PARTICLES AB The capsid protein of the Hawaii strain of human calicivirus was expressed in the transient MVA/bacteriophage T7 polymerase hybrid expression system in order to examine its processing in mammalian cells. Selected amino acid modifications (an insertion, deletion, and substitution) at the predicted amino terminus of the capsid protein as well as the presence or absence of the ORF3 gene were examined for their effect on capsid expression. The protein was expressed efficiently in cell lines derived from three different species, with most of the expressed protein remaining localized within the cells. There was no evidence for N-linked glycosylation or myristylation of the 57 kDa capsid protein. Hawaii virus-like particles (HV VLPs), efficiently produced in the baculovirus expression system, were not observed in this expression system under the conditions in this study. (C) 1998 Published by Elsevier Science B.V. All rights reserved. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Green, KY (reprint author), NIAID, Infect Dis Lab, NIH, 9000 Rockville Pike,Bldg 7,Room 137, Bethesda, MD 20892 USA. NR 21 TC 12 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD JUN PY 1998 VL 55 IS 2 BP 129 EP 141 DI 10.1016/S0168-1702(98)00045-8 PG 13 WC Virology SC Virology GA 110GZ UT WOS:000075374200002 PM 9725666 ER PT J AU Mei, Q Gurunathan, S Masur, H Kovacs, JA AF Mei, Q Gurunathan, S Masur, H Kovacs, JA TI Failure of co-trimoxazole in Pneumocystis carinii infection and mutations in dihydropteroate synthase gene SO LANCET LA English DT Article C1 NIAID, Dept Crit Care Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Kovacs, JA (reprint author), NIAID, Dept Crit Care Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. NR 5 TC 80 Z9 81 U1 0 U2 0 PU LANCET LTD PI LONDON PA 42 BEDFORD SQUARE, LONDON WC1B 3SL, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAY 30 PY 1998 VL 351 IS 9116 BP 1631 EP 1632 DI 10.1016/S0140-6736(05)77687-X PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA ZR900 UT WOS:000074026600015 PM 9620722 ER PT J AU Anzala, AO Ball, TB Rostron, T O'Brien, SJ Plummer, FA Rowland-Jones, SL AF Anzala, AO Ball, TB Rostron, T O'Brien, SJ Plummer, FA Rowland-Jones, SL CA Univ Nairoby Collaboration HIV Res TI CCR2-64I allele and genotype association with delayed AIDS progression in African women SO LANCET LA English DT Article C1 John Radcliffe Hosp, Inst Mol Med, Mol Immunol Grp, Oxford OX3 9DU, England. NCI, Lab Genom Divers, Frederick, MD 21701 USA. Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. RP Rowland-Jones, SL (reprint author), John Radcliffe Hosp, Inst Mol Med, Mol Immunol Grp, Oxford OX3 9DU, England. NR 5 TC 75 Z9 78 U1 0 U2 0 PU LANCET LTD PI LONDON PA 42 BEDFORD SQUARE, LONDON WC1B 3SL, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAY 30 PY 1998 VL 351 IS 9116 BP 1632 EP 1633 DI 10.1016/S0140-6736(05)77688-1 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA ZR900 UT WOS:000074026600016 PM 9620723 ER PT J AU Longini, IM Sagatelian, K Rida, WN Halloran, ME AF Longini, IM Sagatelian, K Rida, WN Halloran, ME TI Optimal vaccine trial design when estimating vaccine efficacy for susceptibility and infectiousness from multiple populations SO STATISTICS IN MEDICINE LA English DT Article ID MALARIA VACCINES; HIV-INFECTION; DISEASES; MODELS; INFERENCE; IMMUNITY AB Vaccination can have important indirect effects on the spread of an infectious agent by reducing the level of infectiousness of vaccinees who become infected. To estimate the effect of vaccination on infectiousness, one typically requires data on the contacts between susceptible and infected vaccinated and unvaccinated people. As an alternative, we propose a trial design that involves multiple independent and interchangeable populations. By varying the fraction of susceptible people vaccinated across populations, we obtain an estimate of the reduction in infectiousness that depends only on incidence data from the vaccine and control groups of the multiple populations. One can also obtain from these data an estimate of the reduction of susceptibility to infection, We propose a vaccination strategy that is a trade-off between optimal estimation of vaccine efficacy for susceptibility and of vaccine efficacy for infectiousness. We show that the optimal choice depends on the anticipated efficacy of the vaccine as well as the basic reproduction number of the underlying infectious disease process. Smaller vaccination fractions appear desirable when vaccine efficacy is likely high and the basic reproduction number is not large. This strategy avoids the potential for too few infections to occur to estimate vaccine efficacy parameters reliably. (C) 1998 John Wiley & Sons, Ltd. C1 Emory Univ, Rollins Sch Publ Hlth, Dept Biostat, Atlanta, GA 30322 USA. NIAID, Div Aids, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Longini, IM (reprint author), Emory Univ, Rollins Sch Publ Hlth, Dept Biostat, 1518 Clifton Rd NE, Atlanta, GA 30322 USA. FU NIAID NIH HHS [1-R01-AI32042, 1-R29-AI31057] NR 27 TC 40 Z9 40 U1 1 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD MAY 30 PY 1998 VL 17 IS 10 BP 1121 EP 1136 DI 10.1002/(SICI)1097-0258(19980530)17:10<1121::AID-SIM824>3.0.CO;2-E PG 16 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 ZN014 UT WOS:000073599200003 PM 9618773 ER PT J AU Delporte, C Hoque, ATMS Kulakusky, JA Braddon, VR Goldsmith, CM Wellner, RB Baum, BJ AF Delporte, C Hoque, ATMS Kulakusky, JA Braddon, VR Goldsmith, CM Wellner, RB Baum, BJ TI Relationship between adenovirus-mediated aquaporin expression and fluid movement across epithelial cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID GENE-THERAPY; WATER; TRANSPORT AB AdhAQP1, a recombinant adenovirus encoding the human water channel aquaporin 1 (AQP1), has been shown to be useful for gene therapy of salivary glands rendered hypofunctional following irradiation. Here we utilized AdhAQP1 to examine the relationship between AQP1 expression and fluid movement across a polarized salivary epithelial cell monolayer. In response to a 440 to 340 mosm gradient, net fluid movement across cells infected with AdhAQP1 was similar to 10-fold that seen in uninfected cells or cells infected with a control virus. At a multiplicity of infection (MOI) of 5, fluid movement was linear for 15-30 min. Increasing the osmotic gradient resulted in a proportional increase in fluid movement. At low virus MOIs (0.1-1.0), fluid movement was markedly enhanced relative to that seen at higher MOIs (similar to 5-10), where the level of AQP1 expression and number of cells transduced were considerably greater. We conclude that significant, osmotically-obliged fluid movement in a salivary cell monolayer with low basal water permeability does not require high levels of AQP1 expression. (C) 1998 Academic Press. C1 NIDR, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), NIDR, Gene Therapy & Therapeut Branch, NIH, Bldg 10,Room 1N113,10 Ctr Dr,MSC 1190, Bethesda, MD 20892 USA. NR 17 TC 29 Z9 30 U1 1 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 MAY 29 PY 1998 VL 246 IS 3 BP 584 EP 588 DI 10.1006/bbrc.1998.8668 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZT218 UT WOS:000074061900004 PM 9618254 ER PT J AU Weber, DJ McFadden, PN Caughey, B AF Weber, DJ McFadden, PN Caughey, B TI Measurement of altered aspartyl residues in the scrapie associated form of prion protein SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE L-isoaspartyl; D-aspartyl; prion; scrapie; methyltransferase ID CARBOXYL METHYLTRANSFERASE; RACEMIZATION; DISEASE; POLYPEPTIDES; PEPTIDES; ACID AB In transmissible spongiform encephalopathies (TSE), the endogenous protease-sensitive prion protein (PrP-sen) of the host is converted to a pathologic form (PrP-res) that has greatly enhanced proteinase K resistance, insolubility, and beta sheet content, To investigate the possibility that alterations at aspartyl or asparaginyl residues in the form of D-aspartate and/or L-isoaspartate could play a role in either the formation or stabilization of PrP-res in TSE-infected animals, we assayed for the presence of these abnormal residues in PrP-res, Protein D-aspartyl/L-isoaspartyl carboxyl methyltransferase (PIMT) was used to methylate and radiolabel altered aspartyl residues, which were detected in PrP-res, but at low levels (0.5 mole%). The scarcity of D-aspartyl and/or L-isoaspartyl groups in PrP-res suggests that this modification is unlikely to be primarily responsible for the differences between PrP-res and PrP-sen. However, it remains possible that such modifications in substoichiometric numbers of PrP molecules could help to initiate the PrP-res formation or stabilize PrP-res polymers in vivo. (C) 1998 Academic Press. C1 NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. Oregon State Univ, Dept Biochem & Biophys, Corvallis, OR 97333 USA. RP Caughey, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. NR 25 TC 23 Z9 23 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 29 PY 1998 VL 246 IS 3 BP 606 EP 608 DI 10.1006/bbrc.1998.8672 PG 3 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZT218 UT WOS:000074061900008 PM 9618258 ER PT J AU Wolford, JK Bogardus, C Prochazka, M AF Wolford, JK Bogardus, C Prochazka, M TI Polymorphism in the 3 ' untranslated region of MTG8 is associated with obesity in Pima Indian males SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID ACUTE MYELOID-LEUKEMIA; FUSION TRANSCRIPT; DIABETES-MELLITUS; GENE; PATHOGENESIS; DISEASE; LINKAGE; ETO AB Obesity has a genetic component and predisposes for the development of type 2 diabetes mellitus. One approach to identifying new candidate genes for obesity is to explore potential regulatory factors expressed in fat tissue that may play a role in adipocyte development or metabolic control. Because we found relatively abundant mRNA levels of the putative transcription factor MTG8 in human adipose tissue, a polymorphic microsatellite marker in the 3' untranslated region of this gene was genotyped in 281 Pima Indians, a population with one of the highest reported rates of obesity. We detected a male-specific association with age-adjusted percentage body fat (p = 0.0002), body mass index (p = 0.01), waist circumference (p = 0.008), and thigh circumference (p = 0.02). Comparative analysis of all 13 MTG8 exons in 30 Pimas did not reveal any genetic variants which could explain the association with obesity in males. (C) 1998 Academic Press. C1 NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. RP Wolford, JK (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, 4212 N 16Th St, Phoenix, AZ 85016 USA. NR 16 TC 16 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 29 PY 1998 VL 246 IS 3 BP 624 EP 626 DI 10.1006/bbrc.1998.8683 PG 3 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZT218 UT WOS:000074061900012 PM 9618262 ER PT J AU Kutty, G Kutty, RK Samuel, W Duncan, T Jaworski, C Wiggert, B AF Kutty, G Kutty, RK Samuel, W Duncan, T Jaworski, C Wiggert, B TI Identification of a new member of transforming growth factor-beta superfamily in Drosophila: The first invertebrate activin gene SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID DEVELOPMENTAL EXPRESSION; MOLECULAR-CLONING; RECEPTOR; FAMILY; SEQUENCE; PROTEIN; SAXOPHONE; PREDICTS; MESODERM; INHIBIN AB Activins, a subgroup of the transforming growth factor-beta (TGP-beta) superfamily, have been extensively studied in vertebrates for their roles in growth and development. However, activins are not thought to be expressed in invertebrates. The identification of the first invertebrate activin gene is reported here. A genomic clone representing 102 F region of the Drosophila chromosome 4 is found to encode a putative activin beta. The predicted protein sequence has a multibasic protease site that would generate a mature C-terminal peptide containing 113 amino acids showing >60% similarity to the vertebrate activin beta(B) (inhibin beta(B)) sequences. A TGF-beta family signature as well as all 9 cysteine residues conserved in the vertebrate activins are also present in this mature peptide sequence. Northern blot and RT-PCR analyses indicated that the activin beta gene is expressed in embryo, larva and adult stages of Drosophila. (C) 1998 Academic Press. C1 NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kutty, RK (reprint author), NEI, Retinal Cell & Mol Biol Lab, NIH, Bldg 6,Room 338,6 Ctr Dr, Bethesda, MD 20892 USA. NR 37 TC 32 Z9 35 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 MAY 29 PY 1998 VL 246 IS 3 BP 644 EP 649 DI 10.1006/bbrc.1998.8678 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZT218 UT WOS:000074061900016 PM 9618266 ER PT J AU Woodhouse, EC Amanatullah, DF Schetz, JA Liotta, LA Stracke, ML Clair, T AF Woodhouse, EC Amanatullah, DF Schetz, JA Liotta, LA Stracke, ML Clair, T TI Adenosine receptor mediates motility in human melanoma cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE adenosine receptor; adenosine; chemotaxis; melanoma ID PURINE NUCLEOSIDE; HUMAN NEUTROPHILS; TUMOR-CELLS; CHEMOTAXIS; EXPRESSION; HAPTOTAXIS; MOLECULES; MIGRATION; BRAIN; A1 AB Cell motility is an essential component of tumor progression and metastasis. A number of factors, both autocrine and paracrine, have been found to influence cell motility. In the present study, adenosine and adenine nucleotides directly stimulated chemotaxis of A2058 melanoma cells in the absence of exogenous factors. Three adenosine receptor agonists stimulated motility in the melanoma cells and two adenosine receptor antagonists strongly inhibited the chemotactic response to both adenosine and AMP. The chemotactic stimulation by adenosine and AMP was pertussis toxin sensitive. Otherwise unresponsive Chinese hamster ovary cells which were transfected with the adenosine A(1) receptor cDNA acquired the direct, pertussis toxin sensitive, chemotactic response to adenosine, and this response was inhibited by adenosine receptor antagonists. These findings demonstrate that adenosine and adenine nucleotides are capable of stimulating chemotaxis of tumor cells mediated through an adenosine receptor, probably of the A(1) subtype, The possibility of antimetastatic therapies based on inhibition of adenosine receptor activity is raised. (C) 1998 Academic Press. C1 NCI, Pathol Lab, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NINDS, Mol Pharmacol Sect, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Woodhouse, EC (reprint author), NCI, Pathol Lab, Div Clin Sci, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 25 TC 39 Z9 41 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 MAY 29 PY 1998 VL 246 IS 3 BP 888 EP 894 DI 10.1006/bbrc.1998.8714 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZT218 UT WOS:000074061900057 PM 9618307 ER PT J AU Ramsey, WJ Caplen, NJ Li, Q Higginbotham, JN Shah, M Blaese, RM AF Ramsey, WJ Caplen, NJ Li, Q Higginbotham, JN Shah, M Blaese, RM TI Adenovirus vectors as transcomplementing templates for the production of replication defective retroviral vectors SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID LEUKEMIA-VIRUS; GENE-TRANSFER; MEDIATED TRANSFER; HUMAN SERUM; CELLS; EXPRESSION AB We have generated an adenovirus containing a retroviral vector sequence encoding the neomycin phosphotransferase (neo) gene (AV-LXSN). AV-LXSN transduction of retroviral packaging cell lines led to production of LXSN retroviral vector with alternative viral envelopes; exposure of target cells to retroviral containing supernatants confirmed envelope specific tropism. Retroviral titers (G418(R) cfu/ml) were comparable to those produced by standard techniques. Retrovirus could be detected in supernatants within 24 hours of AV-LXSN transduction and persisted as long as 120 hours. Southern blot analysis of DNA purified from populations of G418(R) cells showed the presence of a single neo containing restriction fragment of the appropriate size that could only be generated by reverse transcription of LXSN to produce LXSN provirus. This adeno-retroviral chimeric vector system could simplify the generation and testing of different retroviral vectors, particularly where assessment of vectors with alternative envelopes carrying novel targeting ligands is required. (C) 1998 Academic Press. C1 NIH, Natl Human Genome Res Inst, Clin Gene Therapy Branch, Bethesda, MD 20892 USA. RP Ramsey, WJ (reprint author), NIH, Natl Human Genome Res Inst, Clin Gene Therapy Branch, 10 Ctr Dr,10C103, Bethesda, MD 20892 USA. RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 NR 30 TC 26 Z9 26 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 MAY 29 PY 1998 VL 246 IS 3 BP 912 EP 919 DI 10.1006/bbrc.1998.8726 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZT218 UT WOS:000074061900061 PM 9618311 ER PT J AU Jourd'heuil, D Mai, CT Laroux, FS Wink, DA Grisham, MB AF Jourd'heuil, D Mai, CT Laroux, FS Wink, DA Grisham, MB TI The reaction of S-nitrosoglutathione with superoxide (vol 244, pg 525, 1998) SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Correction DE nitrosothiols; superoxide; nitric oxide; peroxynitrite; dinitrogen tretroxide; glutathione; nitrosoglutathione; superoxide dismutase; dihydrorhodamine; 2,3-diaminonaphthalene ID NITRIC-OXIDE; NITROSO-GLUTATHIONE; PLATELET ACTIVATION; INHIBITION; OXIDATION; INVITRO AB The nitric oxide (NO)-dependent S-nitrosation of thiols to generate S-nitrosothiols has been proposed as an important pathway for the metabolism of NO in vivo. Although it has been suggested that these S-nitrosated compounds are resistant to decomposition by reactive oxygen metabolites (ROMs), very little information is available regarding the interaction between S-nitrosothiols and ROMs. We found that S-nitrosoglutathione (GSNO) rapidly reacted with O-2(-) to generate glutathione disulfide and equimolar quantities of nitrite and nitrate. The reaction was second order with respect of GSNO and first order with respect of O-2(-) with a rate equation of -d[GSNO]/dt = 2k(3)[GSNO](2)[O-2(-)], where k(3) = 3 - 6 X 10(8) M-2 s(-1). In addition, the reaction of GSNO with O-2(-) generated a strong oxidant as an intermediate capable of oxidizing dihydrorhodamine in the absence of the apparent generation of NO, We conclude that O-2(-) may act as a physiological modulator of S-nitrosation reactions by directly promoting the decomposition of S-nitrosothiols. (C) 1998 Academic Press. C1 Louisiana State Univ, Med Ctr, Dept Mol & Cellular Physiol, Shreveport, LA 71130 USA. NCI, Bethesda, MD 20892 USA. RP Jourd'heuil, D (reprint author), Louisiana State Univ, Med Ctr, Dept Mol & Cellular Physiol, Shreveport, LA 71130 USA. NR 27 TC 1 Z9 1 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 29 PY 1998 VL 246 IS 3 BP 926 EP 932 DI 10.1006/bbrc.1998.8700 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZT218 UT WOS:000074061900065 ER PT J AU Cai, T Yu, P Monga, SPS Mishra, B Mishra, L AF Cai, T Yu, P Monga, SPS Mishra, B Mishra, L TI Identification of mouse itih-4 encoding a glycoprotein with two EF-hand motifs from early embryonic liver SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE gene; cloning; glycoprotein; calcium; embryo development; liver ID ALPHA-INHIBITOR FAMILY; PROTEINS; CDNA AB An essential feature of cell differentiation is the specificity of signal transduction events from extracellular cues, which are considered to be conferred by scaffold, anchoring and adaptor proteins. Our aim was to identify important scaffolding proteins required for liver development. Utilizing subtraction hybridization of embryonic liver cDNA libraries, here we report the full length cDNA sequence for mouse itih-4 (Inter-alpha-trypsin inhibitor H4). Itih-4 encodes a 942 amino acid protein containing two EF-hand (helix-loop-helix) motifs with an unique short loop, with a potential calcium-binding function. Itih-4 is expressed as a strong 3.1-kb transcript in liver, to a lesser extent in lung and heart tissue. RT-PCR demonstrates itih-4 mRNAs abundantly in liver, less in heart and brain, during mid-embryonic gestation. These results suggest that itih-4 is a potential regulator for extracellular matrix proteins and plays a role during early embryonic liver development. (C) 1998 Elsevier Science B.V. All rights reserved. C1 DVAMC, Lab Dev Mol Biol, Washington, DC USA. Temple Univ, Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19122 USA. Natl Human Genome Res Inst, Clin Gene Therapy Branch, NIH, Bethesda, MD USA. RP Mishra, L (reprint author), Dept Vet Affairs, 151-A,50 Irving St NW, Washington, DC 20422 USA. NR 14 TC 8 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD MAY 29 PY 1998 VL 1398 IS 1 BP 32 EP 37 DI 10.1016/S0167-4781(98)00049-9 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZU066 UT WOS:000074157800005 PM 9602042 ER PT J AU Gaborik, Z Mihalik, B Jayadev, S Jagadeesh, G Catt, KJ Hunyady, L AF Gaborik, Z Mihalik, B Jayadev, S Jagadeesh, G Catt, KJ Hunyady, L TI Requirement of membrane-proximal amino acids in the carboxyl-terminal tail for expression of the rat AT(1a) angiotensin receptor SO FEBS LETTERS LA English DT Article DE AT(1) angiotensin receptor; carboxyl-terminal tail; inositol phosphate; receptor expression; Ca2+ mobilizing hormone ID AGONIST-INDUCED INTERNALIZATION; PROTEIN-COUPLED RECEPTORS; SIGNAL-TRANSDUCTION; II RECEPTOR; HORMONE RECEPTOR; C-TERMINUS; DESENSITIZATION; BINDING; REGIONS; MUTAGENESIS AB A series of deletion mutants was created to analyze the function of the membrane-proximal region of the cytoplasmic tail of the rat type 1a (AT(1a)) angiotensin receptor, In transiently transfected COS-7 cells, the truncated mutant receptors showed a progressive decrease in surface expression, with no major change in binding affinity for the peptide antagonist, [Sar(1),Ile(8)]angiotensin II, In parallel with the decrease in receptor expression, a progressive decrease in angiotensin II-induced inositol phosphate responses was observed, Alanine substitutions in the region 307-311 identified the highly conserved phenylalanine(309) and adjacent lysine residues as significant determinants of AT(1a) receptor expression. (C) 1998 Federation of European Biochemical Societies. C1 Semmelweis Univ Med, Dept Physiol, H-1444 Budapest, Hungary. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Drug Evaluat & Res, Div Cardiorenal Prod, Rockville, MD 20857 USA. RP Hunyady, L (reprint author), Semmelweis Univ Med, Dept Physiol, 8,POB 259, H-1444 Budapest, Hungary. NR 38 TC 28 Z9 28 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD MAY 29 PY 1998 VL 428 IS 3 BP 147 EP 151 DI 10.1016/S0014-5793(98)00511-0 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA ZT975 UT WOS:000074148000005 PM 9654124 ER PT J AU Ji, BT Chow, WH Yang, G McLaughlin, JK Zheng, W Shu, XO Jin, F Gao, RN Gao, YT Fraumeni, JF AF Ji, BT Chow, WH Yang, G McLaughlin, JK Zheng, W Shu, XO Jin, F Gao, RN Gao, YT Fraumeni, JF TI Dietary habits and stomach cancer in Shanghai, China SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID GASTRIC-CANCER; RISK; CARDIA AB Stomach cancer remains the second leading cancer in incidence in Shanghai, China, despite its decline over the past 2 decades. To clarify risk factors for this common malignancy, we conducted a population-based case-control study in Shanghai, China. Included in the study were 1,124 stomach cancer patients (age 20-69) newly diagnosed in 1988-1989 and 1,451 controls randomly selected among Shanghai residents. Usual adult dietary intake was assessed using a comprehensive food frequency questionnaire. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models. Risks of stomach cancer were inversely associated with high consumption of several food groups, including fresh vegetables and fruits, poultry, eggs, plant oil, and some nutrients, such as protein, fat, fiber and antioxidant vitamins. By contrast, risks increased with increasing consumption of dietary carbohydrates, with odds ratios (ORs) of 1.5 (95% confidence interval [CI] 1.1-2.1) and 1.9 (95% CI 1.3-2.9) in the highest quartile of intake among men (p for trend = 0.02) and women (p = 0.0007), respectively. Similar increases in risk were associated with frequent intake of noodles and bread in both men (p = 0.07) and women (p = 0.05) after further adjustment for fiber consumption. In addition, elevated risks were associated with frequent consumption of preserved, salty. or fried foods, and hot soup/porridge, and with irregular meals, speed eating and binge eating. No major differences in risk were seen according to subsite (cardia vs. non-cardia). Our findings add to the evidence that diet plays a major role in stomach cancer risk and suggest the need for further evaluation of risks associated with carbohydrates and starchy foods as well as the mechanisms involved. (C) 1998 Wiley-Liss, Inc. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. Zhejiang Med Univ, Zhejiang Canc Inst, Hangzhou, Peoples R China. Int Epidemiol Inst, Rockville, MD USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. Univ Minnesota, Div Pediat Epidemiol Clin Res, Minneapolis, MN USA. Stat Canada, Hlth Stat Div, Hlth Status Sect, Ottawa, ON, Canada. RP Ji, BT (reprint author), NCI, 6130 Executive Blvd,EPN 415, Rockville, MD 20852 USA. NR 29 TC 105 Z9 111 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAY 29 PY 1998 VL 76 IS 5 BP 659 EP 664 DI 10.1002/(SICI)1097-0215(19980529)76:5<659::AID-IJC8>3.0.CO;2-P PG 6 WC Oncology SC Oncology GA ZP648 UT WOS:000073774500008 PM 9610722 ER PT J AU Klee, CB Ren, H Wang, XT AF Klee, CB Ren, H Wang, XT TI Regulation of the calmodulin-stimulated protein phosphatase, calcineurin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID IMMUNOPHILIN-IMMUNOSUPPRESSANT COMPLEXES; CYCLOPHILIN-CYCLOSPORINE-A; CHANNEL RYANODINE RECEPTOR; B-SUBUNIT; BINDING DOMAIN; DEPHOSPHORYLATION; IDENTIFICATION; BRAIN; INHIBITION; ACTIVATION C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Klee, CB (reprint author), NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. EM ckl@helix.nih.gov NR 95 TC 636 Z9 661 U1 2 U2 20 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 MAY 29 PY 1998 VL 273 IS 22 BP 13367 EP 13370 DI 10.1074/jbc.273.22.13367 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZQ947 UT WOS:000073919100001 PM 9593662 ER PT J AU Williams, SC Du, Y Schwartz, RC Weiler, SR Ortiz, M Keller, JR Johnson, PF AF Williams, SC Du, Y Schwartz, RC Weiler, SR Ortiz, M Keller, JR Johnson, PF TI C/EBP epsilon is a myeloid-specific activator of cytokine, chemokine, and macrophage-colony-stimulating factor receptor genes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; TRANSCRIPTION-FACTOR; FAMILY MEMBERS; NUCLEAR FACTOR; GROWTH-FACTOR; CELL-LINE; EXPRESSION; INTERLEUKIN-6; BINDING; NF-IL6 AB C/EBP epsilon is a member of the CCAAT/enhancer binding protein family of basic region/leucine zipper transcriptional activators. The C/EBP epsilon protein is highly conserved between rodents and humans, and its domain structure is very similar to C/EBP alpha, In mice C/EBP epsilon mRNA is only detected in hematopoietic tissues, including embryonic liver and adult bone marrow and spleen. Within the hematopoietic system, C/EBP epsilon is expressed primarily in myeloid cells, including promyelocytes, myelomonocytes, and their differentiated progeny. To identify potential functions of C/EBP epsilon, cell lines overexpressing the C/EBP epsilon protein were generated in the P388 lymphoblastic cell line. In contrast to the parental cell line, C/EBPE-expressing cell lines displayed lipopolysaccharide-inducible expression of the interleukin-6 and monocyte chemoattractant protein 1 (MCP-1) genes as well as elevated basal expression of the MIP-1 alpha and MIP-1 beta chemokine genes. In the EML-C1 hematopoietic stem cell line, C/EBP epsilon mRNA levels increased as the cells progressed along the myeloid lineage, just preceding activation of the gene encoding the receptor for macrophage-colony-stimulating factor (M-CSFR). M-CSFR expression was stimulated in C/EBP epsilon-expressing P388 cell lines, when compared with either the parental P388 cells or P388 cell lines expressing either C/EBP alpha or C/EBP beta, These results suggest that C/EBP epsilon may be an important regulator of differentiation of a subset of myeloid cell types and may also participate in the regulation of cytokine gene expression in mature cells. C1 Texas Tech Univ, Hlth Sci Ctr, Dept Biochem & Cell Biol, Lubbock, TX 79430 USA. Michigan State Univ, Dept Microbiol, E Lansing, MI 48824 USA. Sci Applicat Int Corp, Lab Leukocyte Biol, Div Basic Sci, Frederick, MD 21702 USA. Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Basic Res Program, Adv Biosci Labs, Frederick, MD 21702 USA. RP Williams, SC (reprint author), Texas Tech Univ, Hlth Sci Ctr, Dept Biochem & Cell Biol, 3601 4th St, Lubbock, TX 79430 USA. EM cbbscw@ttuhsc.edu RI Johnson, Peter/A-1940-2012 OI Johnson, Peter/0000-0002-4145-4725 NR 43 TC 57 Z9 58 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 MAY 29 PY 1998 VL 273 IS 22 BP 13493 EP 13501 DI 10.1074/jbc.273.22.13493 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZQ947 UT WOS:000073919100023 PM 9593684 ER PT J AU Ryan, RR Weber, HC Hou, W Sainz, E Mantey, SA Battey, JF Coy, DH Jensen, RT AF Ryan, RR Weber, HC Hou, W Sainz, E Mantey, SA Battey, JF Coy, DH Jensen, RT TI Ability of various bombesin receptor agonists and antagonists to alter intracellular signaling of the human orphan receptor BRS-3 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SWISS 3T3 CELLS; GASTRIN-RELEASING PEPTIDE; PROTEIN-KINASE-C; NEUROMEDIN-B RECEPTORS; STIMULATE TYROSINE PHOSPHORYLATION; NUCLEOTIDE-BINDING PROTEINS; LUNG-CARCINOMA CELLS; SMOOTH-MUSCLE CELLS; ADENYLATE-CYCLASE; ANGIOTENSIN-II AB Bombesin (Bn) receptor subtype 3 (BRS-3) is an orphan receptor that is a predicted member of the hepta-helical G-protein receptor family and so named because it shares a 50% amino acid homology with receptors for the mammalian bombesin-like peptides neuromedin B (NMB) and gastrin-releasing peptide. In a recent targeted disruption study, in which BRS-3-deficient mice were generated, the mice developed obesity, diabetes, and hypertension. To date, BRS-3's natural ligand remains unknown, its pharmacology unclear, and cellular basis of action undetermined. Furthermore, there are few tissues or cell lines found that express sufficient levels of BRS-3 protein for study. To define the intracellular signaling properties of BRS-3, we examined the ability of [D-Phe(6),beta-Ala(11),Phe(13),Nle(14)]Bn-(6-14), a newly discovered peptide with high affinity for BRS-3, and various Bn receptor agonists and antagonists to alter cellular function in hBRS-3-transfected BALB 3T3 cells and hBRS-3-transfected NCI-H1299 non-small cell lung cancer cells, which natively express very low levels of hBRS-3. This ligand stimulated a 4-9-fold increase in [H-3]inositol phosphate formation in both cell lines under conditions where it caused no stimulation in untransfected cells and also stimulated an increase in [H-3]IP1, [H-3]IP2, and H-3]IP3. The elevation of [H-3]IP was concentration dependent, with an EC50 of 20-35 nM in both cell lines. [D-Phe(6),beta-Ala(11),Phe(13),Nle(14)]Bn-(6-14) stimulated a 2-3-fold increase in [Ca2+](i), a 3-fold increase in tyrosine phosphorylation of p125(FAK) with an EC50 of 0.2-0.7 nm, but failed to either stimulate increases in cyclic AMP or inhibit forskolin-stimulated increases. None of nine naturally occurring Bn peptides or three synthetic Bn analogues reported to activate hBRS-3 did so with high affinity. No high affinity Bn receptor antagonists had high affinity for the hBRS-3 receptor, although two low affinity antagonists for gastrin-releasing peptide and NMB receptors, [D-Arg(1),n-Trp(7,9),Leu(11)]substance P and [D.Pro(4),D-Trp(7,9,10)]substance P-(4-11), inhibited hBRS-3 receptor activation. The NMB receptor-specific antagonist D-Nal,Cys,Tyr,D-Trp,Lys,Val, Cys,Nal-NH2 inhibited hBRS-3 receptor activation in a competitive fashion (K-i = 0.5 mu M) Stimulation of p125(FAK) tyrosine phosphorylation by hBRS-3 activation was not inhibited by the protein kinase C inhibitor, GF109203X, or thapsigargin, alone or in combination. These results show that hBRS-3 receptor activation increases phospholipase C activity, which causes generation of inositol phosphates and changes in [Ca2+](i) and is also coupled to tyrosine kinase activation, but is not coupled to adenylate cyclase activation or inhibition. hBRS-3 receptor activation results in tyrosine phosphorylation of p125(FAK) and it is not dependent on activation of either limb of the phospholipase C cascade. Although the natural ligand is not a known bombesin-related peptide, the availability of [D-Phe(6),beta-Ala(11),Phe(13),Nle(14)]Bn-(6-14), which functions as a high affinity agonist in conjunction with hBRS-3-transfected cell lines and the recognition of three classes of receptor antagonists including one with affinity of 0. 5 mu M, should provide important tools to assist in the identification of its natural ligand, the development of more potent selective receptor antagonists and agonists, and further exploration of the signaling properties of the hBRS-3 receptor. C1 NIDDK, NIH, Digest Dis Branch, Bethesda, MD 20892 USA. NIDCD, NIH, Rockville, MD 20892 USA. Tulane Univ, Med Ctr, Peptide Res Labs, New Orleans, LA 70112 USA. RP Jensen, RT (reprint author), NIDDK, NIH, Digest Dis Branch, Bldg 10,Rm 9C-103,10 Ctr Dr,MSC 1804, Bethesda, MD 20892 USA. NR 91 TC 55 Z9 57 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 MAY 29 PY 1998 VL 273 IS 22 BP 13613 EP 13624 DI 10.1074/jbc.273.22.13613 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZQ947 UT WOS:000073919100038 PM 9593699 ER PT J AU Kultz, D Madhany, S Burg, MB AF Kultz, D Madhany, S Burg, MB TI Hyperosmolality causes growth arrest of murine kidney cells - Induction of GADD45 and GADD153 by osmosensing via stress-activated protein kinase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-DAMAGING AGENTS; MAMMALIAN-CELLS; OSMOTIC-STRESS; GENE; PATHWAY; INHIBITOR; TRANSCRIPTION; IRRADIATION; EXPRESSION; ELEMENT AB Murine kidney cells of the inner medullary collecting duct (mIMCD) were exposed to either isosmotic (300 mosmol/kg) or hyperosmotic medium (isosmotic medium + 150 mM NaCl) after seeding. We determined cell numbers, total nucleic acid, DNA, and RNA contents in both groups every day for a total period of 7 days, Based on all 4 parameters it was evident that growth of mIMCD3 cells is arrested for similar to 18 h following onset of hyperosmolality, However, none of the parameters measured indicated cell death because of hyperosmolality, Growth curves of hyperosmotic samples were shifted compared with isosmotic samples showing a gap of 18 h but had the same shape otherwise. We demonstrated that at 24 and 48 h after onset of hyperosmolality, but not in isosmotic controls, growth arrest and DNA damage-inducible (GADD) proteins GADD45 and GADD153 are strongly induced. This result is consistent with growth arrest observed in hyperosmotic medium. We tested if mitogen-and stress-activated protein kinase (SAPK) cascades are involved in osmosignaling that leads to GADD45 and GADD153 induction. Using phosphospecific antibodies we showed that extracellular signal-regulated kinases 1 and 2 (ERK), SAPK1 (JNK), and SAPK2 (p38) are hyperosmotically activated in mIMCD cells. Hyperosmotic GADD45 induction was significantly decreased by 37.5% following inhibition of the SAPK2 pathway, whereas it was significantly increased (65.2%) after inhibition of the ERK pathway. We observed similar, although less pronounced effects of SAPK2 and ERK inhibition on hyperosmotic GADD153 induction. In conclusion, we demonstrate that mIMCD cells arrest growth following hyperosmotic shock, that this causes strong induction of GADD45 and GADD153, that GADD induction is partially dependent on osmosignaling via SAPK2 and ERK, and that SAPK2 and ERK pathways have opposite effects on GADD expression. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Kultz, D (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, 10 Ctr Dr,MSC 1603,Bldg 10,Rm 6N260, Bethesda, MD 20892 USA. EM kultzd@gwgate.nhlbi.nih.gov NR 44 TC 172 Z9 172 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 MAY 29 PY 1998 VL 273 IS 22 BP 13645 EP 13651 DI 10.1074/jbc.273.22.13645 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZQ947 UT WOS:000073919100042 PM 9593703 ER PT J AU Candi, E Melino, G Lahm, A Ceci, R Rossi, A Kim, IG Ciani, B Steinert, PM AF Candi, E Melino, G Lahm, A Ceci, R Rossi, A Kim, IG Ciani, B Steinert, PM TI Transglutaminase 1 mutations in lamellar ichthyosis - Loss of activity due to failure of activation by proteolytic processing SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CORNIFIED CELL-ENVELOPE; COAGULATION-FACTOR-XIII; CROSS-LINKING ENZYMES; KERATINOCYTE TRANSGLUTAMINASE; EPIDERMAL-KERATINOCYTES; RECESSIVE ICHTHYOSIS; EXPRESSION; DIFFERENTIATION; PROTEIN; GENE AB Lamellar ichthyosis is a congenital recessive skin disorder characterized by generalized scaling and hyperkeratosis. It is caused by mutations in the TGM1 gene that encodes the transglutaminase 1 (TGase 1) enzyme, which is critical for the assembly of the cornified cell envelope in terminally differentiating keratinocytes. TGase 1 is a complex enzyme existing as both cytosolic and membrane-bound forms. Moreover, TGase 1 is proteolytically processed, and the major functionally active form consists of a membrane-bound 67/33/10-kDa complex with a myristoylated and palmitoylated amino-terminal 10-kDa membrane anchorage fragment. To understand better how point mutations, deletions, and truncations found in lamellar ichthyosis disease affect the structure and function of TGase 1, we have expressed in baculovirus and keratinocytes a number of reported TGase 1 mutants. The structural implications of these mutations were examined using a homology-derived three-dimensional model of TGase 1 generated from the known x-ray structure of the related coagulation factor XIIIa enzyme. The present studies demonstrate that loss of TGase 1 activity is not restricted to mutations that directly affect the enzymatic activity. We report a new class of mutations that impair the subsequent post-synthetic processing of the protein into its highly active functional forms. C1 NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Roma Tor Vergata, Ist Ricovero & Cura Carattere Sci, Ist Dermopat Immacolata, I-00133 Rome, Italy. Univ Roma Tor Vergata, Biochem Lab, I-00133 Rome, Italy. Univ Aquila, I-00133 Rome, Italy. Ist Ric Biol Mol P Angeletti, Dept Biol & Chem Computat, I-00040 Pomezia, Italy. Seoul Natl Univ, Dept Biochem, Seoul 449900, South Korea. RP Steinert, PM (reprint author), NIAMS, Skin Biol Lab, NIH, Bldg 6,Rm 425, Bethesda, MD 20892 USA. EM pemast@helix.nih.gov RI Ciani, Barbara/A-1679-2012; OI Ciani, Barbara/0000-0001-7223-4154; Ceci, Roberta/0000-0002-8900-8839 FU Telethon [E.0413] NR 46 TC 59 Z9 64 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 MAY 29 PY 1998 VL 273 IS 22 BP 13693 EP 13702 DI 10.1074/jbc.273.22.13693 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZQ947 UT WOS:000073919100049 PM 9593710 ER PT J AU Jenkins, AL Nannizzi-Alaimo, L Silver, D Sellers, JR Ginsberg, MH Law, DA Phillips, DR AF Jenkins, AL Nannizzi-Alaimo, L Silver, D Sellers, JR Ginsberg, MH Law, DA Phillips, DR TI Tyrosine phosphorylation of the beta(3) cytoplasmic domain mediates integrin-cytoskeletal interactions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GLYCOPROTEIN-IIB-IIIA; HUMAN-PLATELETS; SIGNAL-TRANSDUCTION; GLANZMANNS THROMBASTHENIA; MONOCLONAL-ANTIBODIES; FIBRONECTIN RECEPTOR; CELL-ADHESION; GPIIB-IIIA; SUBUNIT; PROTEIN AB Tyrosine phosphorylation of the beta(3) subunit of the major platelet integrin alpha(IIb)beta(3) has been shown to occur during thrombin-induced platelet aggregation (1), We now show that a wide variety of platelet stimuli induced beta(3) tyrosine phosphorylation, but that this phosphorylation occurred only following platelet aggregation. Several lines of evidence suggest that the beta(3) cytoplasmic domain tyrosine residues and/or their phosphorylation function to mediate interactions between beta(3) integrins and cytoskeletal proteins. First, phospho-beta(3) was retained preferentially in a Triton X-100 insoluble cytoskeletal fraction of thrombin aggregated platelets. Second, in vitro experiments show that the cytoskeletal protein, myosin, associated in a phosphotyrosine-dependent manner with a diphosphorylated peptide corresponding to residues 740-762 of beta(3), Third, mutation of both tyrosines in the beta(3) cytoplasmic domain to phenylalanines markedly reduced beta(3)-dependent fibrin clot retraction. Thus, our data indicate that platelet aggregation is both necessary and sufficient for beta(3) tyrosine phosphorylation, and this phosphorylation results in the physical linkage of alpha(IIb)beta(3) to the cytoskeleton. We hypothesize that this linkage may involve direct binding of the phosphorylated integrin to the contractile protein myosin in order to mediate transmission of force to the fibrin clot during the process of clot retraction. C1 COR Therapeut Inc, San Francisco, CA 94080 USA. NHLBI, NIH, Sect Cellular & Mol Motil, Mol Cardiol Lab, Bethesda, MD 20892 USA. Scripps Res Inst, La Jolla, CA 92037 USA. RP Phillips, DR (reprint author), COR Therapeut Inc, 256 E Grand Ave, San Francisco, CA 94080 USA. EM david_phillips@corr.com FU NHLBI NIH HHS [HL 48728] NR 48 TC 103 Z9 106 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 MAY 29 PY 1998 VL 273 IS 22 BP 13878 EP 13885 DI 10.1074/jbc.273.22.13878 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZQ947 UT WOS:000073919100073 PM 9593734 ER PT J AU Xu, M Dittmar, KD Giannoukos, G Pratt, WB Simons, SS AF Xu, M Dittmar, KD Giannoukos, G Pratt, WB Simons, SS TI Binding of hsp90 to the glucocorticoid receptor requires a specific 7-amino acid sequence at the amino terminus of the hormone-binding domain SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAT-SHOCK PROTEIN; DNA-BINDING; FUNCTIONAL HETEROCOMPLEX; EXPRESSION; 90-KDA; REGION; SYSTEM; CDNA; RECONSTITUTION; COMPLEXES AB The glucocorticoid receptor (GR) HBD must be bound to the protein chaperone hsp90 in order to acquire the high affinity steroid binding conformation. Despite this crucial role of hsp90, its binding site in GR remains poorly defined. Large portions of the GR HBD have been implicated and no similarity has been established between steroid receptor HBDs and the catalytic domains of the protein kinases (e,g. pp60(src), Raf) that also form stable heterocomplexes with hsp90, Thus, it has been thought that some general property of the proteins, such as exposure of hydrophobic residues in partially denatured regions, determines the assembly of stable hsp90 heterocomplexes, In this work, we have studied fusion proteins containing glutathione S-transferase (GST) and very short amino-terminal truncations just before and at the beginning of the rat GR HBD that are otherwise intact to the carboxyl terminus. Overexpression in COS cells of the chimeras GST537C and GST547C was found to yield receptors that were bound to hsp90 and had wild-type steroid binding affinity. However, removal of 7 more amino acids to form GST554C resulted in a fusion protein that did not bind either hsp90 or steroid. Additional mutations revealed that the role of these 7 amino acids was neither to provide a spacer between protein domains nor to expose a protein surface by introducing a bend in the conserved alpha-helix. Instead, these observations support a model in which the sequence of the 7 amino acids directly or indirectly affects hsp90 binding to the GR HBD. Thus, a region of GB that has not been thought to be relevant for hsp90 binding is now seen to be of critical importance, and these data argue strongly against the commonly accepted model of receptor-hsp90 heterocomplex assembly in which the chaperone initially interacts nonspecifically with hydrophobic regions of the partially denatured HBD and subsequently assists its folding to the steroid binding confirmation. C1 Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. NIDDK, Steroid Hormones Sect, LMCB, NIH, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), Univ Michigan, Sch Med, Dept Pharmacol, Med Sci Res Bldg 3, Ann Arbor, MI 48109 USA. EM steroids@helix.nih.gov FU NIDDK NIH HHS [DK31573]; NIGMS NIH HHS [GM07767] NR 41 TC 47 Z9 48 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 MAY 29 PY 1998 VL 273 IS 22 BP 13918 EP 13924 DI 10.1074/jbc.273.22.13918 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZQ947 UT WOS:000073919100079 PM 9593740 ER PT J AU Matsuda, K Matsuda, S Ito, Y AF Matsuda, K Matsuda, S Ito, Y TI Toroidal coil counter-current chromatography - Achievement of high resolution by optimizing flow-rate, rotation speed, sample volume and tube length SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE counter-current chromatography; optimization; toroidal coil centrifuge; amino acids ID THROUGH CENTRIFUGE; SEALS AB This paper deals with optimization of a new seal-free compact toroidal coil centrifuge to achieve high resolution in analytical counter-current chromatography (CCC). Toroidal coil CCC (hydrostatic motion) has advantages compared with high-speed CCC (efficiently mixing solution with planetary motion) in the separation of protein or easily emulsified samples. A toroidal coil separation column of 0.4 mm I.D. PTFE tubing was accommodated around the periphery of the cylindrical centrifuge bowl. Using a two-phase solvent system composed of chloroform-acetic acid-0.1 M hydrochloric acid (2:2,1, v/v/v) and a set of dinitrophenyl-amino acids as test samples, a series of experiments was performed with parameters such as the column length, sample volume, flow-rate, elution mode of the mobile phase and rotation speed. The highest efficiency, over 10 000 theoretical plates, was achieved with a 100 m long coiled tube and an 11 ml total capacity at a flow-rate of 0.01 ml/min at 800 rpm. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Ito, Y (reprint author), NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. NR 10 TC 19 Z9 19 U1 0 U2 4 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 MAY 29 PY 1998 VL 808 IS 1-2 BP 95 EP 104 DI 10.1016/S0021-9673(98)00114-9 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA ZT892 UT WOS:000074138500010 PM 9652111 ER PT J AU Shibusawa, Y Kihira, S Ito, Y AF Shibusawa, Y Kihira, S Ito, Y TI One-step purification of proteins from chicken egg white using counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY B LA English DT Article DE counter-current chromatography; aqueous polymer two-phase system; proteins ID COIL PLANET CENTRIFUGE; STATIONARY PHASE; LIPOPROTEINS; SEPARATION; RETENTION; SYSTEMS AB Proteins present in chicken egg white are separated by counter-current chromatography (CCC) in one step using a cross-axis coil planet centrifuge (X-axis CPC). The separation was performed with an aqueous polymer two-phase system composed of 16% (w/w) poly(ethylene glycol) 1000 and 12.5% (w/ w) dibasic potassium phosphate by eluting the lower phase at a flow-rate of 1.0 ml/min. From about 20 g of the crude egg white solution, lysozyme, ovalbumin, and ovotransferrin were resolved within 5.5 h. Each component was identified by 12% SDS gel electrophoresis with Coomassie brilliant blue staining. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Tokyo Univ Pharm & Life Sci, Sch Pharm, Dept Analyt Chem, Hachioji, Tokyo 1920392, Japan. NHLBI, NIH, Biophys Chem Lab, Bethesda, MD 20892 USA. RP Shibusawa, Y (reprint author), Tokyo Univ Pharm & Life Sci, Sch Pharm, Dept Analyt Chem, 1432-1 Horinouchi, Hachioji, Tokyo 1920392, Japan. NR 12 TC 28 Z9 29 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-4347 J9 J CHROMATOGR B JI J. Chromatogr. B PD MAY 29 PY 1998 VL 709 IS 2 BP 301 EP 305 DI 10.1016/S0378-4347(98)00071-1 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA ZR938 UT WOS:000074031400016 PM 9657228 ER PT J AU Pace, CN Hebert, EJ Shaw, KL Schell, D Both, V Krajcikova, D Sevcik, J Wilson, KS Dauter, Z Hartley, RW Grimsley, GR AF Pace, CN Hebert, EJ Shaw, KL Schell, D Both, V Krajcikova, D Sevcik, J Wilson, KS Dauter, Z Hartley, RW Grimsley, GR TI Conformational stability and thermodynamics of folding of ribonucleases Sa, Sa2 and Sa3 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Review DE ribonucleases; protein folding; protein stability; thermal denaturation; disulfide bonds ID GUANIDINE-HYDROCHLORIDE DENATURATION; LINEAR EXTRAPOLATION METHOD; HEAT-CAPACITY CHANGES; PROTEIN STABILITY; DISULFIDE BONDS; STREPTOMYCES-AUREOFACIENS; MICROBIAL RIBONUCLEASES; CHEMICAL DENATURATION; ALPHA-CHYMOTRYPSIN; ACID DENATURATION AB Ribonucleases Sa, Sa2, and Sa3 are three small, extracellular enzymes produced by different strains of Streptomyces nureofaciens with amino acid sequences that are 50% identical. We have studied the unfolding of these enzymes by heat and urea to determine the conformational stability and its dependence on temperature, pH, NaCl, and the disulfide bond. All three of the Sa ribonucleases unfold reversibly by a two-state mechanism with melting temperatures, T-m, at pH 7 of 48.4 degrees C (Sa), 41.1 degrees C (Sa2), and 47.2 degrees C (Sa3). The T-m values are increased in the presence of 0.5 M NaCl by 4.0 deg. C (Sa), 0.1 deg. C (Sa2), and 7.2 deg. C (Sa3). The T-m values are decreased by 20.0 deg. C (Sa), 31.5 deg. C (Sa2), and 27.0 deg. C (Sa3) when the single disulfide bond in the molecules is reduced. We compare these results with similar studies on two Other members of the microbial ribonuclease family, RNase T-1 and RNase Ba (barnase), and with a member of the mammalian ribonuclease family, RNase A. At pH 7 and 25 degrees C, the conformational stabilities of the ribonucleases are (kcal/mol): 2.9 (Sa2), 5.6 (Sa3), 6.1 (Sa), 6.6 (T-1), 8.7 (Ba), and 9.2 (A). Our analysis of the stabilizing forces suggests that the hydrophobic effect contributes from 90 to 110 kcal/mol and that hydrogen bonding contributes from 70 to 105 kcal/mol to the stability of these ribonucleases. Thus, we think that the hydrophobic effect and hydrogen bonding make large but comparable contributions to the conformational stability of these proteins. (C) 1998 Academic Press Limited. C1 Texas A&M Univ, Dept Med Biochem & Genet, College Stn, TX 77843 USA. Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA. Texas A&M Univ, Ctr Macromol Design, College Stn, TX 77843 USA. Slovak Acad Sci, Inst Mol Biol, Bratislava 84251, Slovakia. Univ York, Dept Chem, York YO1 5DD, N Yorkshire, England. NIH, Cellular & Dev Biol Lab, Bethesda, MD 20892 USA. RP Pace, CN (reprint author), Texas A&M Univ, Dept Med Biochem & Genet, College Stn, TX 77843 USA. OI Krajcikova, Daniela/0000-0002-4024-2384 FU NIGMS NIH HHS [GM 37039] NR 110 TC 123 Z9 125 U1 0 U2 11 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 MAY 29 PY 1998 VL 279 IS 1 BP 271 EP 286 DI 10.1006/jmbi.1998.1760 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZT248 UT WOS:000074065600022 PM 9636716 ER PT J AU Kassiou, M Scheffel, UA Ravert, HT Mathews, WB Musachio, JL London, ED Dannals, RF AF Kassiou, M Scheffel, UA Ravert, HT Mathews, WB Musachio, JL London, ED Dannals, RF TI Pharmacological evaluation of [C-11]A-84543: An enantioselective ligand for in vivo studies of neuronal nicotinic acetylcholine receptors SO LIFE SCIENCES LA English DT Article DE [C-11]A-84543; nAChR radiotracer; brain; enantiomer ID IN-VIVO; BINDING-SITES; HUMAN BRAIN; EPIBATIDINE; DIVERSITY; DEMENTIA; AGONIST AB [C-11]A-84543, 3-[(1-[C-11]methyl-2(S)-pyrrolidinyl)methoxy]pyridine is a specific and enantioselective neuronal nicotinic acetylcholine receptor (nAChR) radiotracer. The in vivo biodistribution of this radiotracer in mice showed high brain uptake and a distribution consistent with the density of nAChRs. Highest uptake was observed in the thalamus (9.6 %ID/g), cortex (9.9 %ID/g), superior colliculus (7.6 %ID/g) and hippocampus (7.6 %ID/g) at 5 min followed by clearance. As a measure of specificity, the thalamus/cerebellar ratio reached a maximum of 2.3 at 30 min post-injection. Radioactivity in the thalamus and superior colliculus was reduced by 33% by pre-administration of unlabeled A-84543. The nAChR agonists (-)nicotine, cytisine, and (+) epibatidine reduced the radioactivity due to [C-11]A-84543 in the superior colliculus by 41%, 38%, and 27%, respectively, while lobeline, which also interacts with central nAChRs, produced a 24% inhibition. The noncompetitive nAChR ligand, mecamylamine displayed no inhibitory effect on [C-11]A-84543 accumulation in any brain region. Ketanserin (5-HT2/5-HT2C), scopolamine (mAChR antagonist), (+)butaclamol (DA receptor antagonist), and haloperidol (D-2/sigma) also displayed no inhibitory effect in any brain region studied. With the pharmacologically less active enantiomer, 3-[(1-[C-11]methyl-2(R)-pyrrolidinyl)methoxy] pyridine, high brain uptake was also observed, but with a low thalamus/cerebellar ratio of 1.4 at 30 min post-injection. [C-11]A-84543 displays enantioselectivity for nAChRs and may deserve further investigation asa possible PET radiotracer. (C) 1998 Elsevier Science Inc. C1 Natl Inst Drug Abuse, Brain Imaging Sect, Div Intramural Res, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Div Nucl Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Div Radiat Hlth Sci, Baltimore, MD 21205 USA. RP Kassiou, M (reprint author), Royal Prince Alfred Hosp, Dept PET & Nucl Med, Missenden Rd, Camperdown, NSW 2050, Australia. NR 17 TC 23 Z9 23 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD MAY 29 PY 1998 VL 63 IS 1 BP PL13 EP PL18 DI 10.1016/S0024-3205(98)00240-9 PG 6 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA ZR984 UT WOS:000074036000011 PM 9667769 ER PT J AU Probst, FJ Fridell, RA Raphael, Y Saunders, TL Wang, AH Liang, Y Morell, RJ Touchman, JW Lyons, RH Noben-Trauth, K Friedman, TB Camper, SA AF Probst, FJ Fridell, RA Raphael, Y Saunders, TL Wang, AH Liang, Y Morell, RJ Touchman, JW Lyons, RH Noben-Trauth, K Friedman, TB Camper, SA TI Correction of deafness in shaker-2 mice by an unconventional myosin in a BAC transgene SO SCIENCE LA English DT Article ID HAIR-CELLS; MOUSE; GENE; ALIGNMENT; ACTIN AB The shaker-2 mouse mutation, the homolog of human DFNB3, causes deafness and circling behavior. A bacterial artificial chromosome (BAC) transgene from the shaker-2 critical region corrected the vestibular defects, deafness, and inner ear morphology of shaker-2 mice. An unconventional myosin gene, Myo15, was discovered by DNA sequencing of this BAG. Shaker-2 mice were found to have an amino acid substitution at a highly conserved position within the motor domain of this myosin, Auditory hair cells of shaker-2 mice have very short stereocilia and a long actin-containing protrusion extending from their basal end. This histopathology suggests that Myo15 is necessary for actin organization in the hair cells of the cochlea. C1 NIDOCD, NIH, Rockville, MD 20850 USA. Michigan State Univ, Grad Program Genet, E Lansing, MI 48824 USA. Univ Michigan, Kresge Hearing Res Inst, Ann Arbor, MI 48109 USA. Natl Human Genome Res Inst, Bethesda, MD 20892 USA. NIH, Intramural Sequencing Ctr, Rockville, MD 20850 USA. Univ Michigan, DNA Sequencing Core Facil, Ann Arbor, MI 48109 USA. RP Camper, SA (reprint author), Univ Michigan, Dept Human Genet, 4701 MSRB 111,1500 W Med Ctr Dr, Ann Arbor, MI 48109 USA. OI Morell, Robert/0000-0003-1537-7356; Camper, Sally/0000-0001-8556-3379 FU NIDCD NIH HHS [Z01 DC 00035, Z01 DC 00038, Z01 DC 02407] NR 30 TC 274 Z9 286 U1 1 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 MAY 29 PY 1998 VL 280 IS 5368 BP 1444 EP 1447 DI 10.1126/science.280.5368.1444 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZQ591 UT WOS:000073883400058 PM 9603735 ER PT J AU Wang, AH Liang, Y Fridell, RA Probst, FJ Wilcox, ER Touchman, JW Morton, CC Morell, RJ Noben-Trauth, K Camper, SA Friedman, TB AF Wang, AH Liang, Y Fridell, RA Probst, FJ Wilcox, ER Touchman, JW Morton, CC Morell, RJ Noben-Trauth, K Camper, SA Friedman, TB TI Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3 SO SCIENCE LA English DT Article ID GENE; MOUSE AB DFNB3, a locus for nonsyndromic sensorineural recessive deafness, maps to a 3-centimorgan interval on human chromosome 17p11.2, a region that shows conserved synteny with mouse shaker-2. A human unconventional myosin gene, MYO15, was identified by combining functional and positional cloning approaches in searching for shaker-2 and DFNB3. MYO15 has at least 50 exons spanning 36 kilobases. Sequence analyses of these exons in affected individuals from three unrelated DFNB3 families revealed two missense mutations and one nonsense mutation that cosegregated with congenital recessive deafness. C1 NIDOCD, Genet Mol Lab, NIH, Rockville, MD 20850 USA. Michigan State Univ, Grad Program Genet, E Lansing, MI 48824 USA. Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. NIH, Intramural Sequencing Ctr, Rockville, MD 20850 USA. NIH, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Friedman, TB (reprint author), NIDOCD, Genet Mol Lab, NIH, Rockville, MD 20850 USA. OI Morell, Robert/0000-0003-1537-7356; Camper, Sally/0000-0001-8556-3379 FU NIDCD NIH HHS [Z01 DC 00035-01, Z01 DC 00038-01, R01 DC 03402] NR 35 TC 270 Z9 275 U1 1 U2 3 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 MAY 29 PY 1998 VL 280 IS 5368 BP 1447 EP 1451 DI 10.1126/science.280.5368.1447 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZQ591 UT WOS:000073883400059 PM 9603736 ER PT J AU Wolford, JK Prochazka, M AF Wolford, JK Prochazka, M TI Structure and expression of the human MTG8/ETO gene SO GENE LA English DT Article DE exon-intron structure; alternative splicing; tissue-specific gene expression; 8q22 ID ACUTE MYELOID-LEUKEMIA; FUSION TRANSCRIPT; T(8-21) BREAKPOINTS; RESIDUAL DISEASE; PIMA-INDIANS; IDENTIFICATION; PROTEIN; AML1; ETO; CLONING AB Translocations involving the putative proto-oncogene MTG8/ETO on 8q22 are frequently found in acute myeloid leukemia. To date, little is known of the genomic organization of this gene. Here, we report that the MTG8 gene consists of 13 exons distributed over 87 kb of genomic DNA. Two polymorphic microsatellite repeats are described, including one in intron 3 (three alleles; heterozygosity 0.34) and another in the 3UTR (15 alleles; heterozygosity 0.89). Expression of MTG8 was detected in a variety of normal human tissues with the highest mRNA levels occurring in brain and heart. Previously, two mRNA forms produced by the alternative usage of the first exon have been reported. We now describe a novel, abundantly expressed, alternatively spliced transcript resulting from the inclusion of a 155-bp exon (designated 9a) that changes the reading frame and introduces a premature stop codon. Identical alternatively spliced mRNA variants were found to be produced by the highly conserved homologous gene (Cbfa2tl) in the mouse, suggesting an evolutionary significance. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. RP Wolford, JK (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, 4212 N 16th St, Phoenix, AZ 85016 USA. NR 27 TC 46 Z9 51 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 MAY 28 PY 1998 VL 212 IS 1 BP 103 EP 109 DI 10.1016/S0378-1119(98)00141-3 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA ZU025 UT WOS:000074153700013 PM 9661669 ER PT J AU Cragg, GM Newman, DJ Yang, SS AF Cragg, GM Newman, DJ Yang, SS TI Bioprospecting for drugs SO NATURE LA English DT Letter C1 NCI, Nat Prod Branch, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Cragg, GM (reprint author), NCI, Nat Prod Branch, Div Canc Treatment & Diag, POB Box B, Frederick, MD 21702 USA. NR 3 TC 7 Z9 7 U1 1 U2 2 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON, ENGLAND N1 9XW SN 0028-0836 J9 NATURE JI Nature PD MAY 28 PY 1998 VL 393 IS 6683 BP 301 EP 301 DI 10.1038/30586 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZQ593 UT WOS:000073883600016 PM 9620791 ER PT J AU Li, JJ Rhim, JS Schlegel, R Vousden, KH Colburn, NH AF Li, JJ Rhim, JS Schlegel, R Vousden, KH Colburn, NH TI Expression of dominant negative Jun inhibits elevated AP-1 and NF-kappa B transactivation and suppresses anchorage independent growth of HPV immortalized human keratinocytes SO ONCOGENE LA English DT Article DE dominant negative c-Jun; transcription factor; HPV; transformation; human keratinocytes ID HUMAN PAPILLOMAVIRUS TYPE-16; PROMOTER-INDUCED TRANSFORMATION; TRANSGENIC MICE; GENE-PRODUCT; C-JUN; MULTISTAGE CARCINOGENESIS; TRANSCRIPTION FACTORS; RESISTANT VARIANTS; EPIDERMAL-CELLS; JB6 CELLS AB AP-1 transactivation appears to be required for mouse JB6 cell neoplastic transformation induced by the tumor promoter TPA or epidermal growth factor (EGF). Exposure to AP-1 transrepressing retinoids and glucocorticoids and expression of a dominant negative c-jun (TAM67) blocked tumor promoter-induced AP-1 transactivation and neoplastic transformation. The aim of the present study was to extend the inquiry of the role of AP-1 and other transcription factors to human neoplastic progression. Expression of human papilloma-virus (HPV) 16 or 18 E6 and E7 immortalizes human keratinocytes and inhibits serum/calcium-stimulated differentiation. Further transformation by v-fos coexpression renders these keratinocytes tumorigenic in nude mice. We have analysed two series of E6/E7 immortalized human keratinocyte cell lines that show progressing phenotypes ranging from differentiation sensitive to anchorage-independent to tumorigenic in nude mice. We analysed the activities of AP-1 and NF-kappa B which may 'cross-talk'. Both DNA binding and transactivation of AP-1 and NF-kappa B transcription factors showed elevation in the anchorage-independent (16RH) and tumorigenic (18 v-fos) keratinocyte lines compared to the less progressed but immortalized cell lines. HPV E7 was expressed at a constant level shown by quantitative RT-PCR in both the more and the less progressed lines, indicating that E7 is not the factor limiting this progression. Blocked shift/supershift analysis indicates that Fos family member proteins especially Fra-1 and Fra-2 are related to progression and no changes found in the Jun family member proteins although they are present in the AP-1/DNA binding complex. When a dominant negative mutant c-jun driven by a human keratin 14 promoter was cotransfected with AP-1 or NF-kappa B reporters, both AP-1 and NF-kappa B activities were suppressed in the more progressed cell lines 16RH add 18 v-fos but not in the less progressed 16RL or 18 cell lines. Overexpression of the same dominant negative c-jun did not inhibit p53 dependent reporter transactivation, indicating the specificity of inhibition of AP-1 and NF-kappa B transactivation in the HPV-immortalized cells. Stable transfectants of this mutant c-jun in the two more progressed cell lines 16RH and 18 v-fos showed reduced AP-1 and NF-kappa B activation and reduced anchorage-independent growth. Together, these results indicate that activation of AP-1, NF-kappa B or both may contribute to neoplastic progression in HPV immortalized human keratinocytes and that specific targeting of the elevated levels seen in benign or malignant tumors might be effective for prevention or treatment of human cancer. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Biochem Physiol, Frederick, MD 21702 USA. Georgetown Univ, Washington, DC USA. NCI, Frederick Canc Res & Dev Ctr, ABL, Frederick, MD 21702 USA. RP Li, JJ (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Biochem Physiol, Frederick, MD 21702 USA. NR 49 TC 97 Z9 99 U1 0 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 28 PY 1998 VL 16 IS 21 BP 2711 EP 2721 DI 10.1038/sj.onc.1201798 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ZQ013 UT WOS:000073812200002 PM 9652737 ER PT J AU McCormack, SJ Weaver, Z Deming, S Natarajan, G Torri, J Johnson, MD Liyanage, M Ried, T Dickson, RB AF McCormack, SJ Weaver, Z Deming, S Natarajan, G Torri, J Johnson, MD Liyanage, M Ried, T Dickson, RB TI Myc/p53 interactions in transgenic mouse mammary development, tumorigenesis and chromosomal instability SO ONCOGENE LA English DT Article DE c-myc; genomic instability; chromosome 11; mammary development ID WILD-TYPE P53; TUMOR-SUPPRESSOR P53; CELL-CYCLE ARREST; C-MYC; GENE AMPLIFICATION; HUMAN-BREAST; EPITHELIAL-CELLS; MICE; APOPTOSIS; CANCER AB We have examined defects in mammary development and tumorigenesis in a transgenic model expressing the c-myc gene under the MMTV-LTR promoter, The stochastic tumors which arise from hyperplastic ductal and lobular lesions in this model are characterized by high rates both of apoptosis and of chromosomal instability, Since the p53 gene product is thought to be central in the maintenance of genomic integrity, in part due to its ability to induce apoptosis in cells harboring DNA damage, we examined its expression and possible mutation. Initially, we observed that unmutated p53 is strongly expressed in premalignant mammary glands and in mammary tumors derived from the MMTV-c-myc strain. We then mated the MMTV-myc strain to a p53-deficient strain as a means of examining the effect of this lesion on mammary development and tumorigenesis in the context of c-myc overexpression, A lack of both p53 alleles in the presence of c-myc overexpression resulted in a dramatic hyerplastic alteration in mammary gland development, Specifically, in female bitransgenic MMTV-c-myc/p53 null mice (MMTV-myc/p53(-/-)), lobular hyperplasias were observed at almost every ductal end bud as early as 32 days of age, In contrast, only mild ductal and lobular hyperplasias were seen in MMTV-myc mice that contained both p53 alleles (MMTV-myc/p53(+/+)); an intermediate phenotype occurred in mice with a single intact (MMTV-myc/p53(+/-)) p53 allele, Mammary carcinomas arose with a high frequency in MMTV-myc/p53(+/-) mice; the tumors were comparable in frequency, histology and apoptotic index to the tumors in MMTV-myc/p53(+/+) mice, Also, as previously observed (Elson et al,, 1995), lymphomas arose with extremely short latency in MMTV-myc/ p53(-/-) mice, precluding study of the fate of their hyperplastic mammary lesions in situ, The frequency of p53 mutations in MMTV-myc/p53(+/+) and MMTV-myc/ p53+/- mammary tumors and in cell lines derived from these tumors was examined by direct sequencing. No point mutations or deletions in p53 were observed in mammary tumors or cell lines from either genotype, Finally, a detailed chromosomal analysis using multicolor spectral karyotyping (SKY) revealed that there were multiple chromosomal alterations in the c-myc-overexpressing cells that contained either one or two unmutated p53 alleles, Variable ploidy changes, a common translocation of chromosome 11, and other chromosomal aberrations were observed. Our data thus support an interaction between c-Myc and p53 in mammary development, but suggest that loss of p53 is required neither for c-myc-dependent tumorigenesis nor for c-myc-dependent chromosomal instability. C1 Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC 20007 USA. Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. RP Dickson, RB (reprint author), Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC 20007 USA. FU NCI NIH HHS [IP5OCA58185]; NIA NIH HHS [R01AG1496-01] NR 44 TC 68 Z9 71 U1 0 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 28 PY 1998 VL 16 IS 21 BP 2755 EP 2766 DI 10.1038/sj.onc.1201804 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ZQ013 UT WOS:000073812200007 PM 9652742 ER PT J AU Carter, S Auer, KL Reardon, DB Birrer, M Fisher, PB Valerie, K Schmidt-Ullrich, R Mikkelsen, R Dent, P AF Carter, S Auer, KL Reardon, DB Birrer, M Fisher, PB Valerie, K Schmidt-Ullrich, R Mikkelsen, R Dent, P TI Inhibition of the mitogen activated protein (MAP) kinase cascade potentiates cell killing by low dose ionizing radiation in A431 human squamous carcinoma cells SO ONCOGENE LA English DT Article DE MAP kinase; p21(Cip-1); ionizing radiation; cell death ID CYCLIN-DEPENDENT KINASES; GROWTH-FACTOR RECEPTOR; P53-INDEPENDENT PATHWAY; INDUCED APOPTOSIS; EGF RECEPTOR; DNA-DAMAGE; C-JUN; DIFFERENTIATION; STRESS; P21 AB The molecular mechanism(s) by which tumor cells survive after exposure to ionizing radiation are not fully understood. Exposure of A431 cells to low doses of radiation (1Gy) caused prolonged activations of the mitogen activated protein (MAP) kinase and stress activated protein (SAP) kinase pathways, and induced p21(Cip-1/WAF1) via a MAP kinase dependent mechanism. In contrast, higher doses of radiation (6 Gy) caused a much weaker activation of the MAP kinase cascade, but a similar degree of SAP kinase cascade activation. In the presence of MAP kinase blockade by the specific MEK1 inhibitor (PD98059) the basal activity of the SAP kinase pathway was enhanced twofold, and the ability of a 1 Gy radiation exposure to activate the SAP kinase pathway was increased similar to sixfold 60 min after irradiation, In the presence of MAP kinase blockade by PD98059 the ability of a single 1Gy exposure to cause double stranded DNA breaks (TUNEL assay) was enhanced at least threefold over the following 24-48h. The increase in DNA damage within 48 h was also mirrored by a similar decrease in A431 cell growth as judged by MTT assays over the next 4-8 days following radiation exposure. This report demonstrates that the MAP kinase cascade is a key cytoprotective pathway in A431 human squamous carcinoma cells which is activated in response to clinically used doses of ionizng radiation, Inhibition of this pathway potentiates the ability of low dose radiation exposure to induce cell death im vitro. C1 Virginia Commonwealth Univ, Med Coll Virginia, Dept Radiat Oncol, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Immunol & Microbiol, Richmond, VA 23298 USA. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. NIH, Bethesda, MD 20892 USA. RP Dent, P (reprint author), Virginia Commonwealth Univ, Med Coll Virginia, Dept Radiat Oncol, Richmond, VA 23298 USA. FU NCI NIH HHS [CA65896] NR 53 TC 140 Z9 141 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 28 PY 1998 VL 16 IS 21 BP 2787 EP 2796 DI 10.1038/sj.onc.1201802 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ZQ013 UT WOS:000073812200011 PM 9652746 ER PT J AU Contassot, E Murphy, W Angonin, R Pavy, JJ Bittencourt, MC Robinet, R Reynolds, CW Cahn, JY Herve, P Tiberghien, P AF Contassot, E Murphy, W Angonin, R Pavy, JJ Bittencourt, MC Robinet, R Reynolds, CW Cahn, JY Herve, P Tiberghien, P TI In vivo alloreactive potential of ex vivo expanded primary T lymphocytes SO TRANSPLANTATION LA English DT Article ID VERSUS-HOST DISEASE; BONE-MARROW TRANSPLANTATION; CELL DEPLETION; GENE-THERAPY; LEUKEMIA; ENGRAFTMENT; MICE AB Background. We are presently investigating the therapeutic potential of herpes simplex-thymidine kinase-expressing donor T cells in the setting of a T cell-depleted allogeneic bone marrow transplantation, The generation, expansion, and selection of the gene-modified T cells require a 12-day ex vivo culture period in high-dose interleukin (IL)-2 that could significantly alter their in vivo alloreactivity, Methods. We evaluated the alloreactive potential of such cultured cells in a murine allogeneic bone marrow transplantation model. Results. The present studies demonstrate that ex vivo-expanded cultured T cells are capable of strong alloreactivity as evidenced by the occurrence of lethal acute graft-versus-host disease (GVHD). However, GVHD mortality after administration of the cultured T cells occurred later than after the administration of a same number of fresh T cells. Similar kinetics of GVHD-induced mortality between cultured and fresh T cells required a 10-fold increase in the number of cultured T cells, indicating a reduced alloreactive potential of these cells. The addition of a a-day "resting" period in low-dose IL-2 resulted in T cells with enhanced alloreactive potential identical to the alloreactivity observed with fresh T cells. Conclusion. Ex vivo IL-2-expanded T cells are capable of significant in vivo alloreactivity, However, an increase in the number of cultured T cells administered or the introduction of a short resting culture period prior to infusion is necessary in order to achieve in vivo alloreactivity identical to the alloreactivity observed with fresh T cells. C1 CHU Besancon, Serv Anatomopathol, Etablissement Transfus Sanguine Franche Comte, Lab Therapeut Immunomol, F-25000 Besancon, France. CHU Besancon, Serv Radiotherapie Oncol, F-25000 Besancon, France. CHU Besancon, Hematol Serv, F-25000 Besancon, France. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD USA. RP Contassot, E (reprint author), CHU Besancon, Serv Anatomopathol, Etablissement Transfus Sanguine Franche Comte, Lab Therapeut Immunomol, 1 Blvd Fleming, F-25000 Besancon, France. RI Bittencourt, Marcelo/E-9316-2012; OI De Carvalho Bittencourt, Marcelo/0000-0002-2698-2458 NR 22 TC 48 Z9 51 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD MAY 27 PY 1998 VL 65 IS 10 BP 1365 EP 1370 DI 10.1097/00007890-199805270-00014 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA ZR568 UT WOS:000073990700014 PM 9625020 ER PT J AU Maurizi, MR Singh, SK Thompson, MW Kessel, M Ginsburg, A AF Maurizi, MR Singh, SK Thompson, MW Kessel, M Ginsburg, A TI Molecular properties of ClpAP protease of Escherichia coli: ATP-dependent association of ClpA and ClpP SO BIOCHEMISTRY LA English DT Article ID ELECTRON-MICROSCOPY; MUTATIONAL ANALYSIS; DEGRADATION; COMPONENT; SEQUENCE; COMPLEX; ORGANIZATION; PROTEOLYSIS; SPECIFICITY; BACTERIAL AB The ClpAP protease from Escherichia coli consists of the ATP-binding regulatory component, ClpA (subunit M-r 84 165), and the proteolytic component, ClpP (subunit M-r 21 563). Our hydrodynamic studies demonstrate that the predominant forms of these proteins in solution correspond to those observed by electron microscopy. ClpP and proClpP(SA), which in electron micrographs appear to have subunits arranged in rings of seven subunits, were found by ultracentrifugation to have s(20,w) values of 12.2 and 13.2 S and molecular weights of 300 000 and 324 000 +/- 3000, respectively, indicating that the native form of each consists of two such rings. The two intact rings of ClpP were separated in the presence of greater than or equal to 0.1 M sulfate at low temperatures, suggesting that ring-ring contacts are polar in nature and more easily disrupted than subunit contacts within individual rings. Sedimentation equilibrium analysis indicated that ClpA purified without nucleotide exists as an equilibrium mixture of monomers and dimers with K-a = (1.0 +/- 0.2) x 10(5) M-1 and that, upon addition of MgATP or adenosine 5'-O-(3-thiotriphosphate), ClpA subunits associated to a form with M-r 505 000 +/- 5000, consistent with the hexameric structure seen by electron microscopy. Sedimentation velocity and gel-filtration analysis showed that the nucleotide-promoted hexamer of ClpA (s(20,w) = 17.2 S) binds tightly to ClpP producing species with sao,, values of 21 and 27 S (f/f(0) = 1.5 and 1.8, respectively), consistent with electron micrographs of ClpAP that show a single tetradecamer of ClpP associated with either one or two ClpA hexamers [Kessel et al. (1995) J. Mol. Biol. 250, 587-594]. Under assay conditions in the presence of ATP and Mg2+, the apparent dissociation constant of hexameric ClpA and tetradecameric ClpP was similar to 4 +/- 2 nM. By the method of continuous variation, the optimal ratio of ClpA to ClpP in the active complex was 2:1. The specific activities of limiting ClpA and ClpP determined in the presence of an excess of the other component indicated that the second molecule of ClpA provides very little additional activation of ClpP. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Biochem Lab, Sect Prot Chem, NIH, Bethesda, MD 20892 USA. RP Maurizi, MR (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Room 1B09, Bethesda, MD 20892 USA. NR 45 TC 71 Z9 72 U1 1 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 26 PY 1998 VL 37 IS 21 BP 7778 EP 7786 DI 10.1021/bi973093e PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZR717 UT WOS:000074006700015 PM 9601038 ER PT J AU Munoz, V Henry, ER Hofrichter, J Eaton, WA AF Munoz, V Henry, ER Hofrichter, J Eaton, WA TI A statistical mechanical model for beta-hairpin kinetics SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article; Proceedings Paper CT Colloquium on Computational Biomolecular Science CY SEP 11-13, 1997 CL IRVINE, CALIFORNIA SP Natl Acad Sci ID FAST EVENTS; TRANSITION-STATE; PROTEIN; STABILITY; PRINCIPLES; RELAXATION; INHIBITOR; PATHWAYS; DYNAMICS; PEPTIDE AB Understanding the mechanism of protein secondary structure formation is an essential part of the protein-folding puzzle. Here, we describe a simple statistical mechanical model for the formation of a beta-hairpin, the minimal structural element of the antiparallel beta-pleated sheet. The model accurately describes the thermodynamic and kinetic behavior of a 16-residue, beta-hairpin-forming peptide, successfully explaining its two-state behavior and apparent negative activation energy for folding, The model classifies structures according to their backbone conformation, defined by 15 pairs of dihedral angles, and is further simplified by considering only the 120 structures with contiguous stretches of native pairs of backbone dihedral angles. This single sequence approximation is tested by comparison with a more complete model that includes the 2(15) possible conformations and 15 x 2(15) possible kinetic transitions. Finally, we use the model to predict the equilibrium unfolding curves and kinetics for several variants of the beta-hairpin peptide. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Munoz, V (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM vmunoz@helix.nih.gov; eaton@helix.nih.gov RI Henry, Eric/J-3414-2013 OI Henry, Eric/0000-0002-5648-8696 NR 45 TC 319 Z9 320 U1 4 U2 18 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 MAY 26 PY 1998 VL 95 IS 11 BP 5872 EP 5879 DI 10.1073/pnas.95.11.5872 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZQ352 UT WOS:000073852600007 PM 9600886 ER PT J AU Clore, GM Gronenborn, AM AF Clore, GM Gronenborn, AM TI New methods of structure refinement for macromolecular structure determination by NMR SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article; Proceedings Paper CT Colloquium on Computational Biomolecular Science CY SEP 11-13, 1997 CL IRVINE, CALIFORNIA SP Natl Acad Sci DE coupling constants; chemical shifts; conformational database; diffusion anisotropy; dipolar couplings ID NUCLEAR-MAGNETIC-RESONANCE; PROTEIN-STRUCTURE DETERMINATION; RESOLUTION 3-DIMENSIONAL STRUCTURE; PROTON CHEMICAL-SHIFTS; X-RAY STRUCTURES; DISTANCE GEOMETRY; CRYSTAL-STRUCTURES; COUPLING-CONSTANTS; MOLECULAR-DYNAMICS; TRYPSIN-INHIBITOR AB Recent advances in multidimensional NMR methodology have permitted solution structures of proteins in excess of 250 residues to be solved. In this paper, me discuss several methods of structure refinement that promise to increase the accuracy of macromolecular structures determined by NMR. These methods include the use of a conformational database potential and direct refinement against three-bond coupling constants, secondary C-13 shifts, H-1 shifts, T-1/T-2 ratios, and residual dipolar couplings. The latter two measurements provide long range restraints that are not accessible by other solution NMR parameters. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM clore@vger.niddk.nih.gov; gronenborn@vger.niddk.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 63 TC 193 Z9 197 U1 1 U2 14 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 26 PY 1998 VL 95 IS 11 BP 5891 EP 5898 DI 10.1073/pnas.95.11.5891 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZQ352 UT WOS:000073852600010 PM 9600889 ER PT J AU Dobi, A von Agoston, D AF Dobi, A von Agoston, D TI Submillimolar levels of calcium regulates DNA structure at the dinucleotide repeat (TG/AC)(n) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PUTATIVE Z-DNA; GENE-EXPRESSION; FORMING SEQUENCES; OSMIUM-TETROXIDE; BINDING-PROTEIN; ION MICROSCOPY; HUMAN GENOME; B-DNA; CELLS; TRANSCRIPTION AB Submillimolar levels of calcium, similar to the physiological total (bound + free) intranuclear concentration (0.01-1 mM), induced a conformational change within d(TG/AC)(n), one of the frequent dinucleotide repeats of the mammalian genome. This change is calcium-specific, because no other tested cation induced it and it was detected as a concentration-dependent transition from B- to a non-B-DNA conformation expanding from 3' end toward the 5' of the repeat. Genomic footprinting of various rat brain regions revealed the existence of similar non-B-DNA conformation within a d(TG/AC)(28) repeat of the endogenous enkephalin gene only in enkephalin-expressing caudate nucleus and not in the nonexpressing thalamus. Binding assays demonstrated that DNA could bind calcium and can compete with calmodulin for calcium. C1 NICHHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP von Agoston, D (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anat & Cell Biol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM vagoston@helix.nih.gov NR 47 TC 38 Z9 38 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 26 PY 1998 VL 95 IS 11 BP 5981 EP 5986 DI 10.1073/pnas.95.11.5981 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZQ352 UT WOS:000073852600024 PM 9600903 ER PT J AU Tucker, CL Hurley, JH Miller, TR Hurley, JB AF Tucker, CL Hurley, JH Miller, TR Hurley, JB TI Two amino acid substitutions convert a guanylyl cyclase, RetGC-1, into an adenylyl cyclase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID STEREOCHEMICAL COURSE; ACTIVATING PROTEIN; OUTER SEGMENTS; MECHANISM; CLONING; SITE AB Guanylyl cyclases (GCs) and adenylyl cyclases (ACs) have fundamental roles in a wide range of cellular processes. Whereas GCs use GTP as a substrate to form cGMP, ACs catalyze the analogous conversion of ATP to cAMP, Previously, a model based on the structure of adenylate cyclase was used to predict the structure of the nucleotide binding pocket of a membrane guanylyl cyclase, RetGC-1. Based on this model, we replaced specific amino acids in the guanine-binding pocket of GC with their counterparts from AC. A change of two amino acids, E925K together with C995D, is sufficient to completely alter the nucleotide specificity from GTP to ATP. These experiments strongly validate the AC-derived RetGC-1 structural model and functionally confirm the role of these residues in nucleotide discrimination. C1 Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. Univ Washington, Dept Biochem, Seattle, WA 98195 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hurley, JB (reprint author), Univ Washington, Howard Hughes Med Inst, Box 357370, Seattle, WA 98195 USA. RI Tucker, Chandra/F-6842-2011 FU NEI NIH HHS [R01 EY006641, EY06641, F32 EY006641] NR 25 TC 150 Z9 152 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 26 PY 1998 VL 95 IS 11 BP 5993 EP 5997 DI 10.1073/pnas.95.11.5993 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZQ352 UT WOS:000073852600026 PM 9600905 ER PT J AU Grossman, Z Feinberg, MB Paul, WE AF Grossman, Z Feinberg, MB Paul, WE TI Multiple modes of cellular activation and virus transmission in HIV infection: A role for chronically and latently infected cells in sustaining viral replication SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNE-RESPONSES; T-CELLS; LYMPHOCYTE; TYPE-1; TOLERANCE; EXPRESSION; AIDS AB CD4(+) T cell activation, required for virus replication in these cells, occurs in local microenvironmental domains in transient bursts. Thus, although most HIV originates from short-lived virus-producing cells, it is unlikely that chronic infection is generally sustained in rapid continuous cycles of productive infection as has been proposed. Such continuity of productive infection cycles would depend on efficient long-range transmission of HIV from one set of domains to another, in turn requiring the maintenance of sufficiently high concentrations of cell-free virus across lymphoid tissues at all times, By contrast, long-lived cellular sources of HIV maintain the capacity to infect newly activated cells at close range despite the temporal and spatial discontinuities of activation events. Such proximal activation and transmission (PAT) involving chronically and latently infected cells may be responsible for sustained infection, particularly when viral loads are low, Once CD4 cells are productively infected through PAT, they can infect other activated cells in their immediate vicinity. Such events propagate locally but generally do not spread systemically, unlike in the acute phase of the infection, because of the early establishment of protective anergy, Importantly, antiretroviral drug treatment is likely to differentially impact long-range transmission and PAT. C1 NIH, Off AIDS Res, Bethesda, MD 20892 USA. Emory Univ, Sch Med, Atlanta, GA 30322 USA. Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, Tel Aviv, Israel. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Paul, WE (reprint author), NIH, Off AIDS Res, Bldg 10,Room 11N311, Bethesda, MD 20892 USA. EM wepaul@nih.gov RI Grossman, Zvi/A-9643-2008 NR 45 TC 95 Z9 95 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 26 PY 1998 VL 95 IS 11 BP 6314 EP 6319 DI 10.1073/pnas.95.11.6314 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZQ352 UT WOS:000073852600083 PM 9600962 ER PT J AU Damon, I Murphy, PM Moss, B AF Damon, I Murphy, PM Moss, B TI Broad spectrum chemokine antagonistic activity of a human poxvirus chemokine homolog SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MOLLUSCUM CONTAGIOSUM VIRUS; MONOCYTE CHEMOATTRACTANT; HIV-1 ENTRY; RECEPTOR; INTERLEUKIN-8; SELECTIVITY; SEQUENCE; COFACTOR; CLONING; PROTEIN AB A secreted CC chemokine homolog, encoded by the MC148 gene of molluscum contagiosum virus, potently interfered with the chemotaxis of human monocytes, lymphocytes, and neutrophils in response to a large number of CC and CXC chemokines with diverse receptor specificities. Evidence that the viral protein binds to human chemokine receptors was obtained by competition binding and calcium mobilization experiments. The broad spectrum chemokine antagonistic activity of MC148 can explain the prolonged absence of an inflammatory response in skin tumors that harbor replicating molluscum contagiosum virus. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. NR 43 TC 94 Z9 97 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 MAY 26 PY 1998 VL 95 IS 11 BP 6403 EP 6407 DI 10.1073/pnas.95.11.6403 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZQ352 UT WOS:000073852600099 PM 9600978 ER PT J AU Kovbasnjuk, O Leader, JP Weinstein, AM Spring, KR AF Kovbasnjuk, O Leader, JP Weinstein, AM Spring, KR TI Water does not flow across the tight junctions of MDCK cell epithelium SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LATERAL INTERCELLULAR SPACES; TRANSPORT; PH AB Although it has been known for decades that the tight junctions of fluid-transporting epithelia are leaky to ions, it has not been possible to determine directly whether significant transjunctional water movement also occurs. An optical microscopic technique was developed for the direct visualization of the flow velocity profiles within the lateral intercellular spaces of a fluid-absorptive, cultured renal epithelium (MDCK) and used to determine the velocity of the fluid flow across the tight junction. The flow velocity within the lateral intercellular spaces fell to near zero adjacent to the tight junction, showing that significant transjunctional flow did not occur, even when transepithelial fluid movement was augmented by imposition of osmotic gradients. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Univ Otago, Dept Physiol, Dunedin, New Zealand. Cornell Univ, Coll Med, Dept Physiol, New York, NY 10021 USA. RP Kovbasnjuk, O (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bldg 10,Room 6N260,10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. NR 14 TC 55 Z9 57 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 26 PY 1998 VL 95 IS 11 BP 6526 EP 6530 DI 10.1073/pnas.95.11.6526 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZQ352 UT WOS:000073852600121 PM 9601000 ER PT J AU Giugliano, RP Camargo, CA Lloyd-Jones, DM Zagrodsky, JD Alexis, JD Eagle, KA Fuster, V O'Donnell, CJ AF Giugliano, RP Camargo, CA Lloyd-Jones, DM Zagrodsky, JD Alexis, JD Eagle, KA Fuster, V O'Donnell, CJ TI Elderly patients receive less aggressive medical and invasive management of unstable angina - Potential impact of practice guidelines SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; CORONARY-ARTERY DISEASE; RANDOMIZED CLINICAL-TRIALS; DOUBLE-BLIND; UNITED-STATES; THROMBOLYTIC THERAPY; HEART-DISEASE; CARE UNIT; NEW-HAVEN; ASPIRIN AB Background: The Agency for Health Care Policy and Research (AHCPR) released a practice guideline on the diagnosis and management of unstable angina in 1994. Objective: To examine practice variation across the age spectrum in the management of patients hospitalized with unstable angina 2 years before release of the AHCPR guideline. Design: Retrospective cohort. Setting: Urban academic hospital. Patients: All nonreferral patients diagnosed as having unstable angina who were hospitalized directly from the emergency department to the intensive care or telemetry unit between October 1, 1991, and September 30, 1992. Measurements: Percentage of eligible patients receiving medical treatment concordant with 8 important AHCPR guideline recommendations. Results: Half of the 280 patients were older than 66 years; women were older than men on average (70 vs 64 years; P<.001). After excluding those with contraindications to therapy, patients in the oldest quartile (age, 75.20-93.37 years) were less likely than younger patients to receive aspirin (P<.009), P-blockers (P<.04), and referral for cardiac catheterization (P<.001). Overall guideline concordance weighted for the number of eligible patients declined with increasing age (87.4%, 87.4%, 84.0%, and 74.9% for age quartiles 1 to 4, respectively; chi(2), P<.001). Increasing age, the presence of congestive heart failure at presentation, a history of congestive heart failure, previous myocardial infarction, increasing comorbidity, and elevated creatinine concentration were associated with care that was less concordant with AHCPR guideline recommendations; only age and congestive heart failure at presentation remained significant in the multivariate analysis (odds ratios, 1.28 per decade [95% confidence interval, 1.02-1.61] and 3.16 [95% confidence interval, 1.57-6.36], respectively). Conclusions: Older patients were less likely to receive standard therapies for unstable angina before release of the 1994 AHCPR guideline. Patients presenting with congestive heart failure also received care that was more discordant with guideline recommendations. The AHCPR guideline allows identification of patients who receive nonstandard care and, if applied to those patients with the greatest likelihood to benefit, could lead to improved health care delivery. C1 Massachusetts Gen Hosp, Cardiac Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. Univ Michigan, Med Ctr, Div Cardiol, Ann Arbor, MI 48109 USA. Mt Sinai Med Ctr, Cardiovasc Res Inst, New York, NY 10029 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. RP Giugliano, RP (reprint author), Brigham & Womens Hosp, TIMI Study Chairmans Off, 75 Francis St, Boston, MA 02115 USA. EM rgiugliano@rics.bwh.harvard.edu RI Lloyd-Jones, Donald/C-5899-2009; Fuster, Valentin/H-4319-2015 OI Fuster, Valentin/0000-0002-9043-9986 FU NHLBI NIH HHS [HL-03533, HL-07575] NR 69 TC 79 Z9 79 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 MAY 25 PY 1998 VL 158 IS 10 BP 1113 EP 1120 DI 10.1001/archinte.158.10.1113 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA ZP307 UT WOS:000073739200008 PM 9605783 ER PT J AU Gordenin, DA Resnick, MA AF Gordenin, DA Resnick, MA TI Yeast ARMs (DNA at-risk motifs) can reveal sources of genome instability SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Review DE mutation; recombination; repeat; genome stability; mutator ID MICROSATELLITE MUTATOR PHENOTYPE; PROGRESSIVE MYOCLONUS EPILEPSY; DENSITY LIPOPROTEIN RECEPTOR; TRANSPOSON TN5 EXCISION; HORMONE-RELATED PROTEIN; DOUBLE-STRAND BREAKS; MISMATCH REPAIR; SACCHAROMYCES-CEREVISIAE; INVERTED REPEATS; ESCHERICHIA-COLI AB The genomes of all organisms contain an abundance of DNA repeats which are at-risk for causing genetic change. We have used the yeast Saccharomyces cerevisiae to investigate various repeat categories in order to understand their potential for causing genomic instability and the role of DNA metabolism factors. Several types of repeats can increase enormously the likelihood of genetic changes such as mutation or recombination when present either in wild type or mutants defective in replication or repair. Specifically, we have investigated inverted repeats, homonucleotide runs, and short distant repeats and the consequences of various DNA metabolism mutants. Because the at-risk motifs (ARMs) that we characterized are sensitive indicators, we have found that they are useful tools to reveal new genetic factors affecting genome stability as well as to distinguish subtle differences between alleles. (C) 1998 Elsevier Science B,V. All rights reserved. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Gordenin, DA (reprint author), NIEHS, Mol Genet Lab, 101 Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM gordenin@niehs.nih.gov OI Gordenin, Dmitry/0000-0002-8399-1836 NR 109 TC 79 Z9 79 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD MAY 25 PY 1998 VL 400 IS 1-2 SI SI BP 45 EP 58 DI 10.1016/S0027-5107(98)00047-5 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 113JW UT WOS:000075548700006 PM 9685581 ER PT J AU Russell, LB Hunsicker, PR Johnson, DK Shelby, MD AF Russell, LB Hunsicker, PR Johnson, DK Shelby, MD TI Unlike other chemicals, etoposide (a topoisomerase-II inhibitor) produces peak mutagenicity in primary spermatocytes of the mouse SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE topoisomerase-II; germ-cell-stage sensitivity; recombination; etoposide; specific-locus test; dominant mutation; germline mutagenesis; meiotic prophase; spermatocyte; deletion mutant ID MAMMALIAN-CELLS; RECOMBINATION; LOCUS; MICRONUCLEI; INDUCTION; EXPOSURE; MEIOSIS; MICE AB The cancer chemotherapy agent, and topoisomerase-LI inhibitor, etoposide (VP-16) produced both recessive mutations at specific loci and dominants at other loci with peak frequencies in primary spermatocytes, a cell type in which the topo-II gene has been shown to be activated. Etoposide thus differs from all other chemicals whose germ-cell-stage specificity has been analyzed. No effects of etoposide exposure of spermatogonial stem cells (similar to 15,000 offspring scored) were detectable by either mutagenicity or productivity endpoints. The significant mutagenic response that followed exposure of poststem-cell stages (similar to 25,000 offspring scored) showed a clear peak, with three of four specific-locus mutants, and three of four dominant mutants conceived during weeks 4 or 5 (days 22-35) post-injection, a period that also encompassed the dominant-lethal peak. For this period, the induced specific-locus rate (with 95% confidence limits) at a weighted-average exposure of 75.1 mg etop/kg was 59.5 (14.6, 170.9) x 10(-6)/locus. At least 3 of the 4 specific-locus mutations were deletions, paralleling findings with etoposide or analogs in other test systems where a recombinational origin of the deletions has been suggested. Because, unlike other chemicals that induce deletions in male germ cells, etoposide is effective in stages normally associated with recombinational events, it will be of interest to determine whether this chemical can affect meiotic recombination. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Oak Ridge Natl Lab, Div Life Sci, Oak Ridge, TN 37831 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Russell, LB (reprint author), Oak Ridge Natl Lab, Div Life Sci, POB 2008, Oak Ridge, TN 37831 USA. FU NIEHS NIH HHS [1-Y01-ES-50318-00] NR 22 TC 27 Z9 28 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD MAY 25 PY 1998 VL 400 IS 1-2 SI SI BP 279 EP 286 DI 10.1016/S0027-5107(98)00036-0 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 113JW UT WOS:000075548700026 PM 9685680 ER PT J AU Yakovlev, GI Struminskaya, NK Znamenskaya, LV Kipenskaya, LV Leschinskaya, IB Hartley, RW AF Yakovlev, GI Struminskaya, NK Znamenskaya, LV Kipenskaya, LV Leschinskaya, IB Hartley, RW TI Contribution of arginine-82 and arginine-86 to catalysis of RNases from Bacillus intermedius (binase) SO FEBS LETTERS LA English DT Article DE ribonuclease; catalytic property; site-directed mutagenesis ID MICROBIAL RIBONUCLEASES; BARNASE; SITE; 7P; SPECIFICITY; MUTAGENESIS; RESIDUES AB To elucidate the functional role of Arg(82) and Arg(86) in the enzyme activity of binase, the extracellular ribonuclease of Bacillus intermedius, we used site-directed mutagenesis, On cleavage of various substrates the catalytic activity of binase mutant Arg(86)Ala is 2.7 x 10(3)-7.7 x 10(3) times less than that of the native enzyme. The decrease in activity is determined preferentially by the decrease in the molecular rate constant k(cat) with a relatively small change of enzyme-substrate affinity, characterized by K-m, This is the expected result if Arg(86) acts to lower the energy of a transition state of the reaction. The replacement of Arg(82) by Ala causes a 5-19-fold activity decrease, depending on the substrate, We propose that this residue does not have a direct catalytic function in the molecular mechanism of the binase action and that the activity decrease of binase on the replacement of Arg(82) by alanine is mediated by the effect of Arg(82) on the pK of catalytic residues. (C) 1998 Federation of European Biochemical Societies. C1 Russian Acad Sci, VA Engelhardt Mol Biol Inst, Moscow 117984, Russia. Kazan State Univ, Dept Biol, Kazan 420008, Russia. NIDDK, Cellular & Dev Biol Lab, Bethesda, MD 20892 USA. RP Yakovlev, GI (reprint author), Russian Acad Sci, VA Engelhardt Mol Biol Inst, Vavilov Str 32, Moscow 117984, Russia. NR 14 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD MAY 22 PY 1998 VL 428 IS 1-2 BP 57 EP 58 DI 10.1016/S0014-5793(98)00485-2 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA ZR764 UT WOS:000074011400012 PM 9645474 ER PT J AU Richards, OC Ehrenfeld, E AF Richards, OC Ehrenfeld, E TI Effects of poliovirus 3AB protein on 3D polymerase-catalyzed reaction SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GENOME-LINKED PROTEIN; DEPENDENT RNA-POLYMERASE; NEGATIVE-STRAND RNA; ESCHERICHIA-COLI; VIRAL POLYPEPTIDE; POLYURIDYLIC ACID; VPG; PRECURSOR; IDENTIFICATION; INVITRO AB Poliovirus RNA replication requires the activities of a viral RNA-dependent RNA polymerase, 3D(pol), in conjunction with several additional viral and likely cellular proteins. The importance of both the 3A and 3B coding regions has been documented previously by genetic tests, and their biochemical activities have been the subject of several recent investigations. In this study, we examined the previously reported stimulation of 3D-catalyzed RNA synthesis by 3AB, We show that 3AB does not stimulate RNA synthesis on templates that are stably base paired to a primer, indicating that 3AB does not stabilize or otherwise activate 3D(pol) for chain elongation. Similarly, it does not alter the kinetic parameters or binding affinities of 3D for substrates. In the absence of a primer, or in the presence of a primer that does not form a stable hybrid with the template, 3AB increases the utilization of 3'-hydroxyl termini as sites for chain elongation by 3D, and thereby stimulates RNA synthesis, 3AB may interact with and stabilize these sites and/or may recruit 3D(pol) to the site, resulting in stimulation of the initiation of elongation events. We propose that this activity is required for stabilizing weak interactions that occur during nucleotidyl-protein-primed initiation events in the viral RNA replication complex. C1 Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. RP Ehrenfeld, E (reprint author), NIH, Ctr Sci Review, 6701 Rockledge Dr,Bldg 2,Rm 3109,MSC 7776, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI 17386] NR 37 TC 33 Z9 33 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 22 PY 1998 VL 273 IS 21 BP 12832 EP 12840 DI 10.1074/jbc.273.21.12832 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZP588 UT WOS:000073768500022 PM 9582311 ER PT J AU Kimball, SR Fabian, JR Pavitt, GD Hinnebusch, AG Jefferson, LS AF Kimball, SR Fabian, JR Pavitt, GD Hinnebusch, AG Jefferson, LS TI Regulation of guanine nucleotide exchange through phosphorylation of eukaryotic initiation factor eIF2 alpha SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE GCN2; FACTOR-II; TRANSLATIONAL CONTROL; SACCHAROMYCES-CEREVISIAE; CHAIN INITIATION; RAT-LIVER; YEAST; MECHANISM; FACTOR-2-ALPHA; INHIBITION AB The guanine nucleotide exchange activity of eIF2B plays a key regulatory role in the translation initiation phase of protein synthesis. The activity is markedly inhibited when the substrate, i,e, eIF2, is phosphorylated on Ser(51) of its alpha-subunit. Genetic studies in yeast implicate the alpha-, beta-, and delta-subunits of eLF2B in mediating the inhibition by substrate phosphorylation. However, the mechanism involved in the inhibition has not been defined biochemically. In the present study, we have coexpressed the five subunits of rat eIF2B in Sf9 cells using the baculovirus system and have purified the recombinant holoprotein to >90% homogeneity, We have also expressed and purified a four-subunit eIF2B complex lacking the alpha-subunit, Both the five-and four-subunit forms of eIF2B exhibit similar rates of guanine nucleotide exchange activity using unphosphorylated eIF2 as substrate. The five-subunit form is inhibited by preincubation with phosphorylated eIF2 (eIFS(alpha P)) and exhibits little exchange activity when eIF2(alpha P) is used as substrate. In contrast, eIF2B lacking the cu-subunit is insensitive to inhibition by eIF2(alpha P) and is able to exchange guanine nucleotide using eIF2(alpha P) as substrate at a faster rate compared with five-subunit eIF2B, Finally, a double point mutation in the S-subunit of eIF2B has been identified that results in insensitivity to inhibition by eIF2(alpha P) and exhibits little exchange activity when eIFS(alpha P) is used as substrate. The results provide the first direct biochemical evidence that the alpha- and delta-subunits of eIF2B are involved in mediating the effect of substrate phosphorylation. C1 Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. NICHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Kimball, SR (reprint author), Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Cellular & Mol Physiol, POB 850, Hershey, PA 17033 USA. RI Pavitt, Graham/A-1363-2010 OI Pavitt, Graham/0000-0002-8593-2418 FU NIDDK NIH HHS [DK13499, DK15658] NR 25 TC 50 Z9 52 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 MAY 22 PY 1998 VL 273 IS 21 BP 12841 EP 12845 DI 10.1074/jbc.273.21.12841 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZP588 UT WOS:000073768500023 PM 9582312 ER PT J AU Koshimizu, T Tomic, M Koshimizu, M Stojilkovic, SS AF Koshimizu, T Tomic, M Koshimizu, M Stojilkovic, SS TI Identification of amino acid residues contributing to desensitization of the P2X(2) receptor channel SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GATED ION CHANNELS; P-2X RECEPTOR; EXTRACELLULAR ATP; SENSORY NEURONS; BRAIN; MEMBRANE; HORMONE; FAMILY AB The P2X(2) receptor (P2X(2)R) is a member of the ATP-gated ion channels that mediate Ca2+ entry in several tissues, including the brain, adrenal medulla, and pituitary. Alternative usage of cryptic splice sites in the primary P2X(2)R transcript accounts for the existence of several transcript types, one of which (PSX2R) encodes a functional channel. P2X(2-2)R lacks a stretch of cytoplasmic C-terminal amino acids (Val(370)-Gln(438)) and exhibits rapid and complete desensitization, whereas P2X(2)R desensitizes slowly and incompletely, The role of the C terminus in P2X(2)R desensitization was studied by generating several channel mutants and monitoring intracellular free Ca2+ changes in transfected single GT1-7 neurons. Deletion studies indicated that the Arg(371)-Ile(391) segment of the P2XR(2)R is required for sustained Ca2+ influx. To identify the important residues within this segment, three contiguous amino acids were sequentially changed to alanine, Only two of these replacement mutants, at Arg(371)-Thr(372)-pro(373) and Lys(374)-His(375)-Pro(376), had, enhanced rate of desensitization. Single amino acid deletions in the PBX,R C terminus and a series of insertions of wild-type sequences into the corresponding spliced site identified four residues, Pro(373)-Lys(374)-His(375)-Pro(376), required for sustained Ca2+ influx through agonist-occupied wild-type channels. Thus, it is likely that the Pro(373)-Pro(376) sequence of PSX2R represents a functional motif that is critical for the development of the slow desensitization profile observed in these channels. Consequently, deletion of this motif by alternative splicing provides an effective mechanism for generating a channel with controlled Ca2+ influx. C1 NICHD, Endocrinol & Reprod Res Branch, UCS, NIH, Bethesda, MD 20892 USA. RP Stojilkovic, SS (reprint author), NICHD, Endocrinol & Reprod Res Branch, UCS, NIH, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. RI Tomic, Melanija/C-3371-2016; OI Koshimizu, Taka-aki/0000-0001-5292-7535 NR 24 TC 49 Z9 49 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 MAY 22 PY 1998 VL 273 IS 21 BP 12853 EP 12857 DI 10.1074/jbc.273.21.12853 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZP588 UT WOS:000073768500025 PM 9582314 ER PT J AU Deterding, LJ Barr, DP Mason, RP Tomer, KB AF Deterding, LJ Barr, DP Mason, RP Tomer, KB TI Characterization of cytochrome c free radical reactions with peptides by mass spectrometry SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTRAMOLECULAR ELECTRON-TRANSFER; LIPID-PEROXIDATION; HYDROGEN-PEROXIDE; PULSE-RADIOLYSIS; HYDROPEROXIDE; TRYPTOPHAN; REDUCTION; CATALASE; HEART; IONS AB The reactions of horse heart cytochrome c, hydrogen peroxide, and the spin trap 3,5-dibromo-4-nitrosobenzenesulfonic acid with a series of polypeptides were investigated using mass spectrometry. The mass spectra obtained from these reactions revealed that after a free radical has been generated on the heme containing protein horse heart cytochrome c, it can be transferred to other biomolecules. Zn addition, the number of free radicals transferred to the target molecule could be determined. Recipient peptides/proteins that contained a tyrosine and/or tryptophan amino acid residue were most susceptible to free radical transfer. Using tandem mass spectrometry, the location of the 3,5-dibromo-4-nitrosobenzenesulfonic acid radical adduct on the nonapeptide RWIILGLNK was unequivocally determined to be at the tryptophan residue. We also demonstrated that the presence of an antioxidant in the reaction mixture not only inhibits free radical formation on horse heart cytochrome c, but also interferes with the transfer of the free radical, once it has been formed on cytochrome c. C1 NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Deterding, LJ (reprint author), NIEHS, Struct Biol Lab, POB 12233,MD F0-03, Res Triangle Pk, NC 27709 USA. RI Tomer, Kenneth/E-8018-2013 NR 34 TC 47 Z9 47 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 MAY 22 PY 1998 VL 273 IS 21 BP 12863 EP 12869 DI 10.1074/jbc.273.21.12863 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZP588 UT WOS:000073768500027 PM 9582316 ER PT J AU Afonina, E Stauber, R Pavlakis, GN AF Afonina, E Stauber, R Pavlakis, GN TI The human Poly(A)-binding protein 1 shuttles between the nucleus and the cytoplasm SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENDOTHELIAL GROWTH-FACTOR; FACTOR MESSENGER-RNA; POSTTRANSCRIPTIONAL REGULATION; BINDING-PROTEINS; MAMMALIAN NUCLEI; REV PROTEIN; HNRNP A1; YEAST; EXPRESSION AB We have studied the intracellular localization of poly(A)-binding protein 1 (PABP1) by indirect immunofluorescence as well as by tagging with the green fluorescent protein (GFP) in living cells. We show that PABP1 is able to enter the nucleus. Accumulation of PABP1 in the nuclei was observed upon transcription inhibition, suggesting that active transcription is required for PABP1 export. The nuclear import of PABP1 is an energy-dependent process since PABP1 fails to enter the nucleus upon ATP depletion and at low temperature. Transfection of PABP1 or PABP1-GFP resulted in heterogeneity of intracellular distribution of the protein. In the low expressing cells, PABP1 was localized in the cytoplasm, whereas in the high expressors, we observed accumulation of the protein in the nucleus. Nuclear PABP1 observed either after overexpression or after transcription inhibition was found in speckles and colocalized with splicing factor SC35. The ability of PABP1 to shuttle between nucleus and cytoplasm was also shown by heterokaryon formation upon cell fusion. Deletion mutagenesis showed that the minimal part of PABP1 retaining the ability to shuttle consists of the first two RNA-binding domains. This mutant interacted with poly(A) RNA with high affinity and accumulated in the nucleus. Deletion mutants exhibiting reduced RNA binding affinity did not accumulate in the nucleus. PABP1 has been proposed to participate at various steps of mRNA utilization. Our results suggest involvement of PABP1 in nuclear events associated with the formation and transport of mRNP to the cytoplasm and identify a new trafficking pattern for RNA-binding proteins. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Human Retrovirus Sect, Frederick, MD 21702 USA. RP Pavlakis, GN (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Human Retrovirus Sect, POB B,Bldg 535,Rm 210, Frederick, MD 21702 USA. EM pavlakis@ncifcrf.gov OI Stauber, Roland/0000-0002-1341-4523 NR 52 TC 126 Z9 127 U1 0 U2 5 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 MAY 22 PY 1998 VL 273 IS 21 BP 13015 EP 13021 DI 10.1074/jbc.273.21.13015 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZP588 UT WOS:000073768500048 PM 9582337 ER PT J AU Vindevoghel, L Kon, A Lechleider, RJ Uitto, J Roberts, AB Mauviel, A AF Vindevoghel, L Kon, A Lechleider, RJ Uitto, J Roberts, AB Mauviel, A TI Smad-dependent transcriptional activation of human type VII collagen gene (COL7A1) promoter by transforming growth factor-beta SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DYSTROPHIC EPIDERMOLYSIS-BULLOSA; ANCHORING FIBRILS; MAMMALIAN-CELLS; EXPRESSION; IDENTIFICATION; FIBROBLASTS; RESPONSES; PROTEINS; DNA; MAD AB We have previously shown that transforming growth factor-beta (TGF-beta) increases type VII collagen gene (COL7A1) expression in human dermal fibroblasts in culture (Mauviel, A., Lapiere, J.-C., Halcin, C., Evans, C. H., and Uitto, J. (1994) J. Biol. Chem, 269, 25-28), To gain insight into the molecular mechanisms underlying the up-regulation of COL7A1 by this growth factor, we performed transient cell transfections with a series of 5'-deletion promoter/chloramphenicol acetyltransferase reporter gene constructs. We identified a 68-base pair region between nucleotides -524 and -456, relative to the transcription start site, as critical for TGF-beta response. Using electrophoresis mobility shift assays (EMSAs) with an oligonucleotide spanning the region from -524 to -444, we discovered that a TGF-beta-specific protein-DNA complex was formed as early as 11 min after TGF-beta stimulation and persisted for 1 h after addition of the growth factor. Deletion analysis of the TGF-beta-responsive region of the COL7A1 promoter by EMSA identified segment -496/-444 as the minimal fragment capable of binding the TGF-beta-induced complex. Furthermore, two distinct segments, -496/-490 and -453/-444, appeared to be necessary for TGF-beta-induced DNA binding activity, suggesting a bipartite element. Supershift experiments with a pan-Smad antibody unambiguously identified the TGF-beta-induced complex as containing a Smad member. This is the first direct identification of binding of endogenous Smad proteins to regulatory sequences of a human gene. C1 Thomas Jefferson Univ, Jefferson Med Coll, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Biochem & Mol Pharmacol, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Jefferson Inst Mol Med, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Mauviel, A (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Dept Dermatol & Cutaneous Biol, 233 S 10th St,Rm 430, Philadelphia, PA 19107 USA. EM mauviel1@jeflin.tju.edu RI MAUVIEL, Alain/F-6251-2013 FU NIAMS NIH HHS [R01-AR41439, 29-AR43751, T32-AR07651] NR 31 TC 90 Z9 92 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 MAY 22 PY 1998 VL 273 IS 21 BP 13053 EP 13057 DI 10.1074/jbc.273.21.13053 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZP588 UT WOS:000073768500053 PM 9582342 ER PT J AU Remington, KM Bennett, SE Harris, CM Harris, TM Bebenek, K AF Remington, KM Bennett, SE Harris, CM Harris, TM Bebenek, K TI Highly mutagenic bypass synthesis by T7 RNA polymerase of site-specific benzo[a]pyrene diol epoxide-adducted template DNA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DEOXYADENOSINE N-6-AMINO GROUP; DOSE-DEPENDENT DIFFERENCES; REPORTER GENE-EXPRESSION; IN-VITRO REPLICATION; TRANSCRIPTION ELONGATION; ESCHERICHIA-COLI; TRANS ADDITION; V-79 CELLS; STRAND; CARCINOGEN AB We have previously developed an in vitro system that allows quantitative evaluation of the fidelity of transcription during synthesis on a natural template in the presence of all four nucleotides. Here, we have employed this system using a TAA ochre codon reversion assay to examine the fidelity of transcription by T7 RNA polymerase past an adenine residue adducted at the N-6-position with (-)-anti-trans- or (+)-anti-trans-benzo[a]pyrene diol epoxide (BPDE), T7 RNAP was capable of transcribing past either BPDE isomer to generate full-length run-off transcripts, The extent of bypass was found to be 32% for the (-)-anti-trans-isomer and 18% for the (C)-anti-trans-isomer, Transcription past both adducts was highly mutagenic. The reversion frequency of bypass synthesis of the (-)-anti-trans-isomer was elevated 11,000-fold and that of the (+)-anti-trans-isomer 6000-fold, relative to the reversion frequency of transcription on unadducted template. Adenine was misinserted preferentially, followed by guanine, opposite the adenine adducted with either BPDE isomer, Although base substitution errors were by far the most frequent mutation on the adducted template, three- and six-base deletions were also observed. These results suggest that transcriptional errors, particularly with regard to damage bypass, may contribute to the mutational burden of the cell. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. Vanderbilt Univ, Dept Chem, Nashville, TN 37235 USA. Vanderbilt Univ, Ctr Mol Toxicol, Nashville, TN 37235 USA. RP NIEHS, Mol Genet Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM bebenek@niehs.nih.gov FU NIEHS NIH HHS [ES 03755, ES 00267] NR 43 TC 21 Z9 21 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 MAY 22 PY 1998 VL 273 IS 21 BP 13170 EP 13176 DI 10.1074/jbc.273.21.13170 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZP588 UT WOS:000073768500069 PM 9582358 ER PT J AU Chabry, J Caughey, B Chesebro, B AF Chabry, J Caughey, B Chesebro, B TI Specific inhibition of in vitro formation of protease-resistant prion protein by synthetic peptides SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NEUROBLASTOMA-CELLS; PRP 27-30; SCRAPIE; CONVERSION; NEUROTOXICITY; DISEASES; MODEL; FORM AB The transmissible spongiform encephalopathies are characterized by the conversion of the protease-sensitive prion protein (PrPsen) into a protease-resistant isoform (PrPres) associated with the neuropathogenic process in vivo. Recently, PrPres has been shown to be capable of directly inducing the conversion of PrPsen to PrPres in a cell-free in vitro system. In the present experiments, various PrP peptides were studied for their ability to enhance or inhibit this cell-free conversion reaction. None of the synthetic peptides was able to confer protease-resistance to the labeled PrPsen molecules on their own. On the contrary, peptides from the central part of the hamster PrP sequence from 106 to 141 could completely inhibit the conversion induced by preformed PrPres. The presence of residues 119 and 120 from the highly hydrophobic sequence AGAAAAGA (position 113 to 120) was crucial for an efficient inhibitory effect. Fourier transform infrared spectroscopy analysis indicated that inhibitory peptides formed high P-sheet aggregates under the conditions of the conversion reaction, but this was also true of certain peptides that were not inhibitory. Thus, the potential to form P-sheeted aggregates may be necessary, but not sufficient, for peptides to act as inhibitors of PrPres formation, Clearly, the amino acid sequence of the peptide is also important for inhibition. The sequence specificity of the inhibition is consistent with the idea that residues in the vicinity of positions 106-141 of PrPres and/or PrPsen are critically involved in the intermolecular interactions that lead to PrPres formation. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP Chesebro, B (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. RI Chabry, Joelle/O-2101-2016 NR 24 TC 138 Z9 144 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 MAY 22 PY 1998 VL 273 IS 21 BP 13203 EP 13207 DI 10.1074/jbc.273.21.13203 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZP588 UT WOS:000073768500074 PM 9582363 ER PT J AU Vijayakumar, M Wong, KY Schreiber, G Fersht, AR Szabo, A Zhou, HX AF Vijayakumar, M Wong, KY Schreiber, G Fersht, AR Szabo, A Zhou, HX TI Electrostatic enhancement of diffusion-controlled protein-protein association: Comparison of theory and experiment on barnase and barstar SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE protein-protein association; electrostatic rate enhancement; average Boltzmann factor; barnase; barstar ID BROWNIAN DYNAMICS; MACROMOLECULES; COMPLEX; KINETICS; BINDING AB The electrostatic enhancement of the association rate of barnase and barstar is calculated using a transition-state theory like expression and atomic-detail modeling of the protein molecules. This expression predicts that the rate enhancement is simply the average Boltzmann factor in the region of configurational space where association occurs instantaneously in the diffusion-controlled limit. Based on experimental evidence, this "transition state" is defined by configurations in which, relative to the stereospecifically bound complex, the two proteins are shifted apart by similar to 8 Angstrom (so a layer of water can be accommodated in the interface) and the two binding surfaces are rotated away by 0 degrees to 3 degrees. The values of the average Boltzmann factor, calculated by solving the Poisson-Boltzmann equation, for the wild-type complex and 16 complexes with single mutations are found to correlate well with experimental results for the electrostatic rate enhancement. The predicted rate enhancement is found to be somewhat insensitive to the precise definition of the transition state, due to the long-range nature of electrostatic interactions. The experimental ionic strength dependence of the rate enhancement is also reasonably reproduced. (C) 1998 Academic Press Limited. C1 Hong Kong Univ Sci & Technol, Dept Biochem, Kowloon, Hong Kong. Weizmann Inst Sci, Dept Biochem, IL-76100 Rehovot, Israel. MRC Ctr, Cambridge Ctr Prot Engn, Cambridge CB2 2QH, England. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Fersht, AR (reprint author), Hong Kong Univ Sci & Technol, Dept Biochem, Kowloon, Hong Kong. EM hxzhou@einstein.drexel.edu RI Schreiber, Gideon/C-7332-2008; Szabo, Attila/H-3867-2012; Zhou, Huan-Xiang/M-5170-2016 OI Zhou, Huan-Xiang/0000-0001-9020-0302 NR 27 TC 152 Z9 153 U1 3 U2 15 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 MAY 22 PY 1998 VL 278 IS 5 BP 1015 EP 1024 DI 10.1006/jmbi.1998.1747 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZQ726 UT WOS:000073896900009 PM 9600858 ER PT J AU Sanders, JM Griffin, RJ Burka, LT Matthews, HB AF Sanders, JM Griffin, RJ Burka, LT Matthews, HB TI Disposition of 2-methylimidazole in rats SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A LA English DT Article ID 4-METHYLIMIDAZOLE; EXCRETION; TOXICOSIS AB 2-Methylimidazole (2-MI), widely used as a chemical intermediate, is also present in cigarette smoke and may form in food and forage as a result of ammoniation of simple sugars. 2-MI has been shown to be neurotoxic in several animal species and to alter serum levels of T-3, T-4, and thyroid-stimulating hormone (TSH) in the rat, apparently leading to hyperplasia of thyroid follicular cells. In order to better characterize 2-MI-induced toxicity, the disposition of[2-C-14]-2-MI has been investigated following po administration of either 5, 50, or 150 mg/kg to male F344 rats. Excretion data indicated that absorption of 2-MI was both rapid and proportional to dose in the range studied. Approximately 90% of the total dose was eliminated in urine within 24 h. Most of the remaining C-14 was excreted in feces and as expired (CO2)-C-14. Excretion data were similar following iv administration of 5 mg/kg. Little or no enterohepatic circulation of compound occurred since biliary excretion of 2-MI-derived C-14 was negligible. Approximately 70% of the C-14 excreted in urine, following all dosing, consisted of parent compound. High-performance liquid chromatography (HPLC) chromatograms for all treatment groups were similar, indicating that metabolism of 2-MI in rats was not affected by dose or route of administration. C1 NIEHS, Lab Pharmacol & Chem, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Sanders, JM (reprint author), NIEHS, Lab Pharmacol & Chem, Natl Toxicol Program, POB 12233,MD C3-02, Res Triangle Pk, NC 27709 USA. NR 21 TC 10 Z9 10 U1 1 U2 2 PU TAYLOR & FRANCIS LTD PI LONDON PA ONE GUNPOWDER SQUARE, LONDON EC4A 3DE, ENGLAND SN 0098-4108 J9 J TOXICOL ENV HEAL A JI J. TOXICOL. ENV. HEALTH PT A PD MAY 22 PY 1998 VL 54 IS 2 BP 121 EP 132 DI 10.1080/009841098158953 PG 12 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA ZP940 UT WOS:000073803800003 PM 9652548 ER PT J AU Shimada, H Shiao, YH Shibata, MA Waalkes, MP AF Shimada, H Shiao, YH Shibata, MA Waalkes, MP TI Cadmium suppresses apoptosis induced by chromium SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A LA English DT Article ID INDUCED GENOTOXICITY; GENE-EXPRESSION; LIVER-CELLS; DNA-DAMAGE; METALLOTHIONEIN; CARCINOGENESIS; INHIBITION; MECHANISMS; CHROMATE; PROTEINS AB Cadmium and chromium are both well-known human carcinogens, and common exposures to these metals are not infrequent. Recent studies have shown that hexavalent chromium induces apoptosis in Chinese hamster ovary (CHO) cells, suggesting an association of apoptosis with carcinogenesis. In contrast, induction of apoptosis by cadmium has been inconsistently observed. The present study was designed to determine if cadmium could induce apoptosis in CHO cells and if common exposure to cadmium and chromium would modify any apoptotic response. Apoptosis was evaluated by both agarose gel and in situ end-labeling methods. Apoptosis was observed at 48 h after treatment with 300 mu M chromium (Na2CrO4) for 2 h. Cadmium alone at concentrations of 1, 5, or 10 mu M (as CdCl2) did not induce apoptosis in these cells even at times up to ;2 h after treatment. However, when CHO cells were concurrently exposed to cadmium and chromium, chromium-induced apoptosis was markedly suppressed in a cadmium concentration-related fashion. Cadmium did not consistently modify the cytotoxic effects of chromium, and significant increases in metallothionein were not induced by these metal treatments. These findings indicate that cadmium can block chromium-induced apoptosis. The suppression of apoptosis by cadmium may be a significant aspect of its carcinogenic mechanism. C1 NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Off Lab Anim Sci, Frederick, MD 21702 USA. RP Waalkes, MP (reprint author), NIEHS, NCI, POB 12233,111 Alexander Dr,MD F0-09, Res Triangle Pk, NC 27709 USA. NR 31 TC 55 Z9 57 U1 1 U2 2 PU TAYLOR & FRANCIS LTD PI LONDON PA ONE GUNPOWDER SQUARE, LONDON EC4A 3DE, ENGLAND SN 0098-4108 J9 J TOXICOL ENV HEAL A JI J. TOXICOL. ENV. HEALTH PT A PD MAY 22 PY 1998 VL 54 IS 2 BP 159 EP 168 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA ZP940 UT WOS:000073803800006 PM 9652551 ER PT J AU Guan, JA Zhu, XK Tachibana, Y Bastow, KF Brossi, A Hamel, E Lee, KH AF Guan, JA Zhu, XK Tachibana, Y Bastow, KF Brossi, A Hamel, E Lee, KH TI Antitumor agents. 185. Synthesis and biological evaluation of tridemethylthiocolchicine analogues as novel topoisomerase II inhibitors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID THIOCOLCHICINE ANALOGS; COLCHICINE; TUBULIN; DERIVATIVES; PROTEIN AB Several 1,2,3-tridemethyldeacetylthiocolchicine derivatives have been synthesized and evaluated for cytotoxic activity against various human tumor cell lines and for their inhibitory effects on DNA topoisomerases in vitro. Exhaustive demethylation of thiocolchicine analogues completely changes their biological profiles. Instead of displaying antitubulin activity, most target compounds inhibited topoisomerase II activity. Only compounds with a larger side chain, such as 15a, 23a, and 24a, did not interfere with topoisomerase II enzymatic functions. The cytotoxicity of target compounds was reduced by 3 orders of magnitude compared to that of colchicine in most cell lines, The hydrophilicity of phenolic compounds might prevent drug passage through the cell plasma membrane and, thus, be responsible for the relatively weak cytotoxicity. To test this hypothesis, 27-30 were prepared from 16a by protecting all hydroxy groups with esters with an aim to facilitate drug transportation. In vitro cytotoxicity assays indicated that 27 was more potent than its parent compound in all tested tumor cell lines and showed tissue selective cytotoxicity with a significant inhibitory effect against KB cells (IC50 = 2.7 mu g/mL). Therefore, we propose that 27 acts as a prodrug, liberating 16a to exert its antitopoisomerase activity and, finally, to cause cell death. C1 Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Nat Prod Lab, Chapel Hill, NC 27599 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Drug Discovery Res & Dev, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Brossi, A (reprint author), Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Nat Prod Lab, Chapel Hill, NC 27599 USA. FU NCI NIH HHS [CA 54508, CA 17625] NR 23 TC 15 Z9 16 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 21 PY 1998 VL 41 IS 11 BP 1956 EP 1961 DI 10.1021/jm980007f PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA ZQ620 UT WOS:000073886300021 PM 9599244 ER PT J AU Thomas, JB Mascarella, SW Rothman, RB Partilla, JS Xu, H McCullough, KB Dersch, CN Cantrell, BE Zimmerman, DM Carroll, FI AF Thomas, JB Mascarella, SW Rothman, RB Partilla, JS Xu, H McCullough, KB Dersch, CN Cantrell, BE Zimmerman, DM Carroll, FI TI Investigation of the N-substituent conformation governing potency and mu receptor subtype-selectivity in (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HIGH-AFFINITY; BINDING; DISCOVERY; AGONISTS; LIGANDS; AGENTS; SITE AB A study of the binding site requirements associated with the N-substituent of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) derivatives was undertaken using a set of rigid vs flexible N-substituents. The study showed that compounds 7-9 bearing the trans-cinnamyl N-substituent most closely reproduced the potency at the opioid receptor of the flexible N-propylphenyl or N-propylcyclohexyl analogues previously reported. Neither the N-substituted cis-cinnamyl nor the cis-phenylcyclopropylmethyl compounds 10 and 11, respectively, showed high affinity for the opioid receptor. However, the N-trans-phenylcyclopropylmethyl compound 12 closely approximated the affinity of compounds 7-9. Additionally, we found that free rotation of the phenyl ring is necessary for high affinity binding and mu receptor subtype selectivity as the planar N-substituted thianaphthylmethyl and benzofuranylmethyl compounds 13 and 14 had significantly lower binding affinities. Altogether, these findings suggest that the high binding affinity, selectivity, and antagonist potency of N-propylphenyl or N-propylcyclohexyl analogues of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl) (4) are achieved via a conformation wherein the connecting chain of the N-substituents is extended away from piperidine nitrogen with the appended ring system rotated out-of-plane relative to the connecting chain atoms. This conformation is quite similar to that observed in the solid state for 5, as determined by single crystal X-ray analysis. Additionally, it was found that, unlike naltrexone, N-substituents bearing secondary carbons attached directly to the piperidine nitrogen of 4 suffer dramatic losses of potency vs analogues not substituted in this manner. Using a functional assay which measured stimulation or inhibition of [S-35]GTP-gamma-S binding, we show that the trans-cinnamyl analogues of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) retain opioid pure antagonist activity and possess picomolar antagonist potency at the mu receptor. C1 Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NIDA, Addict Res Sect, Clin Psychopharmacol Sect, Baltimore, MD 21224 USA. Eli Lilly & Co, Lilly Res Labs, Lilly Corp Ctr, Indianapolis, IN 46285 USA. RP Carroll, FI (reprint author), Res Triangle Inst, POB 12194, Res Triangle Pk, NC 27709 USA. FU NIDA NIH HHS [DA09045] NR 25 TC 34 Z9 35 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 21 PY 1998 VL 41 IS 11 BP 1980 EP 1990 DI 10.1021/jm980063g PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA ZQ620 UT WOS:000073886300024 PM 9599247 ER PT J AU Agmon-Snir, H Carr, CE Rinzel, J AF Agmon-Snir, H Carr, CE Rinzel, J TI The role of dendrites in auditory coincidence detection SO NATURE LA English DT Article ID INTERAURAL TIME DIFFERENCES; MEDIAL SUPERIOR OLIVE; COCHLEAR NUCLEUS; BRAIN-STEM; NEURONS; CELLS; INFORMATION; MODEL; INTERNEURONS; INTEGRATION AB Coincidence-detector neurons in the auditory brainstem of mammals and birds use interaural time differences to localize sounds(1,2). Each neuron receives many narrow-band inputs from both ears and compares the time of arrival of the inputs with an accuracy of 10-100 mu s (refs 3-6). Neurons that receive low-frequency auditory inputs (up to about 2 kHz) have bipolar dendrites, and each dendrite receives inputs from only one ear(7,8). Using a simple model that mimics the essence of the known electrophysiology and geometry of these cells, we show here that dendrites improve the coincidence-detection properties of the cells. The biophysical mechanism for this improvement is based on the nonlinear summation of excitatory inputs in each of the dendrites and the use of each dendrite as a current sink for inputs to the other dendrite. This is a rare casein which the contribution of dendrites to the known computation of a neuron may be understood. Our results show that, in these neurons, the cell morphology and the spatial distribution of the inputs enrich the computational power of these neurons beyond that expected from 'point neurons' (model neurons lacking dendrites). C1 Univ Maryland, Dept Zool, College Pk, MD 20742 USA. NIDDK, Math Res Branch, NIH, Bethesda, MD 20892 USA. RP Carr, CE (reprint author), Univ Maryland, Dept Zool, College Pk, MD 20742 USA. EM carr@zool.umd.edu NR 30 TC 202 Z9 205 U1 1 U2 11 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON, ENGLAND N1 9XW SN 0028-0836 J9 NATURE JI Nature PD MAY 21 PY 1998 VL 393 IS 6682 BP 268 EP 272 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZP513 UT WOS:000073761000054 PM 9607764 ER PT J AU Simpson, RM Zhao, TM Hubbard, BS Said, W Kindt, TJ AF Simpson, RM Zhao, TM Hubbard, BS Said, W Kindt, TJ TI Source and route of exposure influence infectivity of a molecular clone of human T cell leukemia virus type I SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID TROPICAL SPASTIC PARAPARESIS; CENTRAL-NERVOUS-SYSTEM; HTLV-I; PROVIRAL DNA; INVIVO; MYELOPATHY; LYMPHOMA; MYELONEUROPATHY; LYMPHOCYTES; DISEASE AB Infection with human T cell leukemia virus type I (HTLV-I) is typically asymptomatic, but does result in diverse diseases ranging from adult T cell leukemia to spastic neuromyelopathy. To date, differences in HTLVI provirus structure have not been correlated with pathogenic or asymptomatic outcome of infection, Molecular clones of HTLV-I are now available and represent a powerful tool to link virus structure to pathogenesis, Present studies to explore in vivo infectivity and pathogenicity of an HTLV-I molecular clone, K30p, have utilized the rabbit as a model system. This clone was administered to neonatal or adult rabbits by several different routes and infectivity and pathogenicity were examined, Detection of antiviral humoral immune responses, presence of provirus in tissue samples, and isolation of virus in cultures of blood lymphocytes were used to establish systemic HTLV-I infection. Intramuscular, but not nervous system, exposure to K30p HTLVI naked DNA resulted in infection, Conversely, neural exposure to T cells that had been transfected with the K30p HTLV-I DNA consistently resulted in systemic infection. Despite detection of HTLV-I provirus in brain and spinal cord of some infected rabbits, no clinical or neuropathological changes occurred. Source and route of virus exposure played a role in infectivity, but did not influence the pathogenic outcome of HTLV-I infection. C1 NIAID, Immunogenet Lab, NIH, Twinbrook Facil, Rockville, MD 20852 USA. RP Simpson, RM (reprint author), NIAID, Immunogenet Lab, NIH, Twinbrook Facil, 12441 Parklawn Dr, Rockville, MD 20852 USA. NR 22 TC 5 Z9 5 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD MAY 20 PY 1998 VL 14 IS 8 BP 711 EP 715 DI 10.1089/aid.1998.14.711 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA ZP671 UT WOS:000073776800010 PM 9618084 ER PT J AU Wu, T Bloom, ML Yu, JM Tisdale, JF Dunbar, CE AF Wu, T Bloom, ML Yu, JM Tisdale, JF Dunbar, CE TI Murine bone marrow expressing the neomycin resistance gene has no competitive disadvantage assessed in vivo SO HUMAN GENE THERAPY LA English DT Article ID HEMATOPOIETIC STEM-CELLS; RETROVIRAL TRANSDUCTION; PERIPHERAL-BLOOD; W/WV MICE; REPOPULATION; ENGRAFTMENT; POPULATIONS; RECIPIENTS; SYSTEM; ASSAY AB The neomycin phosphotransferase (neo) gene is one of the most common marker genes used in gene transfer experimentation, but potential effects of neo gene expression in vivo have not been systematically investigated. Several early clinical retroviral gene transfer studies have suggested that neo gene expression could have deleterious effects on hematopoiesis, owing to a discrepancy between the level of neo-marked transduced marrow progenitor cells compared with mature circulating progeny cells posttransplantation (Brenner et al., 1993; Kohn et al., 1995; Brenner, 1996b), We examined the long-term in vivo repopulating ability of bone marrow from transgenic mice expressing neo from a strong constitutive promoter using a competitive repopulation assay, Different ratios of neo transgenic and wild-type congenic marrow cells were cotransplanted into W/W-v recipient mice. The percentages of blood cells containing the neo transgene in each group of recipient mice monitored for 4 months posttransplantation closely matched the input ratios of neo transgenic to congenic control marrow cells. Similar concordances of engraftment with input ratios of neo transgenic cells were also found in spleen, thymus, and whole marrow of recipient mice at 4 months posttransplantation, Analysis of the beta-hemoglobin phenotype (beta(single) for the neo transgenic and C57 control cells and beta(diffuse) for th, congenic competitor HW80 cells) in recipients confirmed erythroid repopulation from neo transgenic marrow cells at levels matching the input ratios, We conclude that hematopoietic cells expressing neo had no engraftment or maturation defects detectable in vivo. These results suggest that the low-level contribution of vector-marked cells to circulating populations in clinical trials is not due to direct deleterious effects of neo gene expression on hematopoiesis. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 28 TC 14 Z9 15 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD MAY 20 PY 1998 VL 9 IS 8 BP 1157 EP 1164 DI 10.1089/hum.1998.9.8-1157 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA ZP912 UT WOS:000073794800005 PM 9625254 ER PT J AU Davis, BR Saitta, FP Bauer, G Bunnell, BA Morgan, RA Schwartz, DH AF Davis, BR Saitta, FP Bauer, G Bunnell, BA Morgan, RA Schwartz, DH TI Targeted transduction of CD34(+) cells by transdominant negative rev-expressing retrovirus yields partial anti-HIV protection of progeny macrophages SO HUMAN GENE THERAPY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN T-CELLS; MEDIATED GENE-TRANSFER; CORD-BLOOD-CELLS; PERIPHERAL-BLOOD; CANCER-PATIENTS; BONE-MARROW; REPLICATION; INFECTION; LYMPHOCYTES AB Congenitally acquired HIV infection may be uniquely suited to treatment via genetic engineering of CD34(+) hematopoietic stem/progenitor cells, However, current technologies yield only a small percentage of mature cells that carry the inserted genes, and expression is frequently suppressed. Since clinical trials employing these methodologies have been proposed for anti-HIV gene therapy of HIV-infected children, we wished to assess, by in vitro modeling, the expected limits of transduction efficiency, expression, and antiviral activity using currently available methods. We measured retrovirus-mediated transduction in cord blood progenitors and their in vitro-derived progeny macrophages by Mo-MuLV vectors expressing a transdominant negative Rev (Rev(TD)), CFU-GM transduction efficiency ranged from 7 to 85%, with an average of 28%, Semiquantitative DNA PCR demonstrated less than or equal to 100 vector sequence copies per 1000 cells in monocyte/macrophage cultures, which mere grown without selection to better model in vivo conditions, When challenged with the macrophage-tropic HIV-1(BaL) isolate, cultured macrophages from mock-transduced CFU-GM colonies supported infection in eight of eight experimental cultures, control LXSN-transduced progenitors supported infection in six of eight cultures, while macrophages derived from Rev(TD)-transduced CFU-GM colonies supported infection in four of eight cultures, Although these results support the ability of neo(r) retroviral vectors containing Rev(TD) to inhibit HIV replication, they indicate that further optimization of transduction efficiency and sustained expression will be required for effective anti-HIV protection in vivo. C1 Univ Texas, Med Branch, Sealy Ctr Oncol & Hematol, Dept Microbiol & Immunol,Dept Internal Med, Galveston, TX 77555 USA. Johns Hopkins Univ, Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. NIH, Natl Ctr Human Genome Res, Clin Gene therapy Branch, Baltimore, MD 21205 USA. RP Davis, BR (reprint author), Univ Texas, Med Branch, Sealy Ctr Oncol & Hematol, Dept Microbiol & Immunol,Dept Internal Med, Med Res Bldg 9-104,301 Univ Blvd, Galveston, TX 77555 USA. NR 32 TC 11 Z9 11 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD MAY 20 PY 1998 VL 9 IS 8 BP 1197 EP 1207 DI 10.1089/hum.1998.9.8-1197 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA ZP912 UT WOS:000073794800010 PM 9625259 ER PT J AU Strickler, HD Rosenberg, PS Devesa, SS Fraumeni, JF Goedert, JJ AF Strickler, HD Rosenberg, PS Devesa, SS Fraumeni, JF Goedert, JJ TI SV40-contaminated poliovirus vaccine and childhood cancer risk - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID TUMORS C1 NCI, NIH, Bethesda, MD 20892 USA. RP Strickler, HD (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 20 PY 1998 VL 279 IS 19 BP 1528 EP 1528 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA ZN087 UT WOS:000073608100027 ER PT J AU Clore, GM Gronenborn, AM Szabo, A Tjandra, N AF Clore, GM Gronenborn, AM Szabo, A Tjandra, N TI Determining the magnitude of the fully asymmetric diffusion tensor from heteronuclear relaxation data in the absence of structural information SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID N-15 NMR RELAXATION; ROTATIONAL DIFFUSION; HIV PROTEASE C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem 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; Szabo, Attila/H-3867-2012 OI Clore, G. Marius/0000-0003-3809-1027; NR 14 TC 51 Z9 51 U1 0 U2 1 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 MAY 20 PY 1998 VL 120 IS 19 BP 4889 EP 4890 DI 10.1021/ja980192m PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA ZP974 UT WOS:000073807700051 ER PT J AU Bennett, AE Weliky, DP Tycko, R AF Bennett, AE Weliky, DP Tycko, R TI Quantitative conformational measurements in solid state NMR by constant-time homonuclear dipolar recoupling SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ANGLE-SPINNING NMR; MAGIC-ANGLE; ROTATING SOLIDS; EXCHANGE SPECTROSCOPY; MOLECULAR-STRUCTURE; RESONANCE NMR; COUPLINGS; SEQUENCES; MELITTIN C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. NR 30 TC 64 Z9 66 U1 2 U2 11 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 MAY 20 PY 1998 VL 120 IS 19 BP 4897 EP 4898 DI 10.1021/ja980191u PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA ZP974 UT WOS:000073807700055 ER PT J AU Pack, SD Boni, R Vortmeyer, AO Pak, E Zhuang, ZP AF Pack, SD Boni, R Vortmeyer, AO Pak, E Zhuang, ZP TI Detection of gene deletion in single metastatic tumor cells in the excision margin of a primary cutaneous melanoma SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. RP Zhuang, ZP (reprint author), NCI, Pathol Lab, NIH, 9000 Rockville Pike,Bldg 10 Room 2A33, Bethesda, MD 20892 USA. RI Pack, Svetlana/C-2020-2014 NR 5 TC 0 Z9 0 U1 0 U2 0 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 20 PY 1998 VL 90 IS 10 BP 782 EP 783 DI 10.1093/jnci/90.10.782 PG 2 WC Oncology SC Oncology GA ZN919 UT WOS:000073696700015 PM 9605650 ER PT J AU Rajapandi, T Wu, CB Eisenberg, E Greene, L AF Rajapandi, T Wu, CB Eisenberg, E Greene, L TI Characterization of D10S and K71E mutants of human cytosolic Hsp70 SO BIOCHEMISTRY LA English DT Article ID SHOCK COGNATE PROTEIN; ATP HYDROLYTIC ACTIVITY; UNCOATING ATPASE; MOLECULAR CHAPERONE; SUBSTRATE-BINDING; CLATHRIN BASKETS; STRUCTURAL BASIS; COATED VESICLES; DISSOCIATION; NUCLEOTIDE AB To determine the effect of mutations at the nucleotide-binding site of recombinant Hsp70 on its interaction with protein and peptide substrates, point mutations were made at D10 and K71, two residues at the active site. The D10S mutation weakened both ATP and ADP binding, while the K71E mutation weakened only ATP binding. In binding experiments using Hsp70 with no bound nucleotide, the mutated Hsp70s interacted with clathrin and peptide just like the wild-type Hsp70. However, the D10 mutation completely abolished the effects of both ATP and ADP on peptide and clathrin binding. The K71 mutation also abolished the effect of ATP on substrate binding, but ADP, which still bound tightly, had its normal effect on substrate binding. In addition, the D10S and K71E mutants had greatly reduced ability to uncoat clathrin-coated vesicles at pH 7.0, bind to clathrin baskets at pH 6.0, and undergo polymerization induced by YDJ1 in the presence of ATP. We conclude, first, that nucleotides must bind strongly to Hsp70 to affect substrate binding and, second, that interaction of Hsp70 with DnaJ homologues may also require a strongly bound ATP. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Greene, L (reprint author), NHLBI, Cell Biol Lab, NIH, 9000 Rockville Pike,Bldg 3,Room B1-10,3,Ctr Dr,MS, Bethesda, MD 20892 USA. NR 31 TC 21 Z9 23 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 19 PY 1998 VL 37 IS 20 BP 7244 EP 7250 DI 10.1021/bi972252r PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZP586 UT WOS:000073768300024 PM 9585537 ER PT J AU Chourpa, I Riou, JF Millot, JM Pommier, Y Manfait, M AF Chourpa, I Riou, JF Millot, JM Pommier, Y Manfait, M TI Modulation in kinetics of lactone ring hydrolysis of camptothecins upon interaction with topoisomerase I cleavage sites on DNA SO BIOCHEMISTRY LA English DT Article ID MOLECULAR-INTERACTIONS; ANTITUMOR-ACTIVITY; CYTO-TOXICITY; DERIVATIVES; CELLS; INHIBITORS; ANALOGS; BINDING; CPT-11; MICROSPECTROFLUOROMETRY AB The kinetics of hydrolysis of the alpha-hydroxylactone ring of anticancer agents belonging to the camptothecin (CPT) series has been followed using their fluorescence emission. Data obtained for CPT, CPT-11, and SN-38, either in their free form or in the presence of DNA and/or topoisomerase I (top1), have been compared. DNA was modeled using three types of double-strand oligonucleotides corresponding to top1 cleavage site enhanced in the presence of the drug (olg1), top1 site independent of CPT (olg2), and nonspecific synthetic oligonucleotide containing only AT and no GC base pairs (olg3). Cleavage assays indicated the absence of top1-mediated cleavage on olg3, both in the presence and in the absence of CPT. The kinetics data also showed ratio-dependent stabilization of the lactone forms of CPTs when in the presence of an excess of olg1 or olg2, but not of olg3. These observations correlate with the previously reported preferential binding of CPTs to guanines. Although lactone hydrolysis was not perturbed by top1 alone, this enzyme hindered lactone stabilization by specific oligonucleotides. After addition of top1 to CPT-olg1 or CPT-olg2 complexes, the lactone ring of the drug was destabilized. No lactone stabilization was observed when olg1 was added to CPT-top1 complexes or when olg1-top1 complexes were added to CPT. C1 Univ Reims, UFR Pharm, Lab Spect Biomol, F-51096 Reims, France. Rhone Poulenc Rorer SA, Dept Biol, F-94403 Vitry, France. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Manfait, M (reprint author), Univ Reims, UFR Pharm, Lab Spect Biomol, 51 Rue Cognacq Jay, F-51096 Reims, France. OI Chourpa, Igor/0000-0003-2116-0735 NR 31 TC 23 Z9 23 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 19 PY 1998 VL 37 IS 20 BP 7284 EP 7291 DI 10.1021/bi972902r PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZP586 UT WOS:000073768300029 PM 9585542 ER PT J AU Shiota, T Jones, M Chikada, M Fleishman, CE Castellucci, JB Cotter, B DeMaria, AN von Ramm, OT Kisslo, J Ryan, T Sahn, DJ AF Shiota, T Jones, M Chikada, M Fleishman, CE Castellucci, JB Cotter, B DeMaria, AN von Ramm, OT Kisslo, J Ryan, T Sahn, DJ TI Real-time three-dimensional echocardiography for determining right ventricular stroke volume in an animal model of chronic right ventricular volume overload SO CIRCULATION LA English DT Article DE imaging; echocardiography; ventricles ID 3-DIMENSIONAL ECHOCARDIOGRAPHY; VALIDATION AB Background-The lack of a suitable noninvasive method for assessing right ventricular (RV) volume and function has been a major deficiency of two-dimensional (2D) echocardiography. The aim of our animal study was to test a new real-time three-dimensional (3D) echo imaging system for evaluating RV stroke volumes. Methods and Results-Three to 6 months before hemodynamic and 3D ultrasonic study, the pulmonary valve was excised from 6 sheep (31 to 59 kg) to induce RV volume overload. At the subsequent session, a total of 14 different steady-state hemodynamic conditions were studied, Electromagnetic (EM) flow probes were used for obtaining aortic and pulmonic flows. A unique phased-array volumetric 3D imaging system developed at the Duke University Center for Emerging Cardiovascular Technology was used for ultrasonic imaging. Real-time volumetric images of the RV were digitally stored, and RV stroke volumes were determined by use of parallel slices of the 3D RV data set and subtraction of end-systolic cavity volumes from end-diastolic cavity volumes. Multiple regression analyses showed a good correlation and agreement between the EM-obtained RV stroke volumes (range, 16 to 42 mL/beat) and those obtained by the new real-time 3D method (r=0.80; mean difference, -2.7+/-6.4 mL/beat). Conclusions-The real-time 3D system provided good estimation of strictly quantified reference RV stroke volumes, suggesting an important application of this new 3D method. C1 Oregon Hlth Sci Univ, Clin Care Ctr Congenital Heart Dis, Portland, OR 97201 USA. Duke Univ, Med Ctr, Lab Anim Med & Surg, NHLBI, Durham, NC USA. Duke Univ, Med Ctr, Ctr Emerging Cardiovasc Technol, Durham, NC USA. Univ Calif San Diego, Med Ctr, La Jolla, CA 92093 USA. RP Sahn, DJ (reprint author), Oregon Hlth Sci Univ, Clin Care Ctr Congenital Heart Dis, 3181 SW Sam Jackson Pk Rd,UHN 60, Portland, OR 97201 USA. EM sahnd@ohsu.edu FU NHLBI NIH HHS [HL-58104] NR 20 TC 124 Z9 132 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 19 PY 1998 VL 97 IS 19 BP 1897 EP 1900 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA ZN450 UT WOS:000073647100005 PM 9609081 ER PT J AU Mannes, AJ Caudle, RM O'Connell, BC Iadarola, MJ AF Mannes, AJ Caudle, RM O'Connell, BC Iadarola, MJ TI Adenoviral gene transfer to spinal cord neurons: intrathecal vs. intraparenchymal administration SO BRAIN RESEARCH LA English DT Article DE adenovirus; gene therapy; beta-galactosidase; spinal cord; motor neurons; subarachnoid; MUG; central nervous system ID CENTRAL-NERVOUS-SYSTEM; RECOMBINANT ADENOVIRUS; BETA-GALACTOSIDASE; VIRAL VECTORS; BRAIN; EXPRESSION; CELLS; INFLAMMATION; DELIVERY; LIVER AB The spinal cord is the site of many chronic, debilitating, neurological disorders that may be amenable to gene therapy. The present study, using quantitative and anatomical methods, examines the ability of replication deficient adenovirus to transfer a transcription cassette composed of the cytomegalovirus promoter driving the expression of the LacZ reporter gene (AdCMV beta gal) to spinal-cord neurons. Rats were microinjected with AdCMV beta gal into the spinal-cord parenchyma or subarachnoid space and sacrificed between 1 and 60 days post-infusion. The spinal cord was assayed for P-galactosidase (P-gal) activity fluorometrically (MUG). Intraparenchymal injection resulted in significant beta-gal activity at day 1, which peaked at day 7, and decreased at day 14 (21-, 57- and 9.8-fold of control respectively). The spatial distribution of beta-gal activity on day 7 was confined to the l-cm section containing the injection site but was detected 2 cm caudal to this section by day 14. Histochemical staining and immunocytochemistry revealed a prominent reaction product in neurons, particularly motor neurons, and glia within the ventral grey matter bilaterally. Intrathecal viral injections showed comparatively modest, yet significant increases in beta-gal activity throughout the spinal cord with the greatest activity (170% control) closest to the catheter tip. This study demonstrates that AdCMV beta gal injected into the ventral spinal cord results in extensive in vivo neuronal gene transfer with beta-gal activity reaching a peak by day 7 and remaining detectable at 60 days. Intrathecal viral injections result in greater spatial distribution but a comparatively lower level of expression. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIDR, PNMB, NIH, Bethesda, MD 20892 USA. NIDR, GTTB, NIH, Bethesda, MD 20892 USA. RP Iadarola, MJ (reprint author), NIDR, PNMB, NIH, Bld 49,Rm 1A11,49 Convent Dr,MSC 4410, Bethesda, MD 20892 USA. EM iadarola@yoda.nidr.nih.gov OI O'Connell, Brian/0000-0003-4529-7664 FU NIGMS NIH HHS [T32 GM07612] NR 29 TC 55 Z9 57 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 18 PY 1998 VL 793 IS 1-2 BP 1 EP 6 DI 10.1016/S0006-8993(97)01422-4 PG 6 WC Neurosciences SC Neurosciences & Neurology GA ZX807 UT WOS:000074557400001 PM 9630472 ER PT J AU Van Horn, JD Gold, JM Esposito, G Ostrem, JL Mattay, V Weinberger, DR Berman, KF AF Van Horn, JD Gold, JM Esposito, G Ostrem, JL Mattay, V Weinberger, DR Berman, KF TI Changing patterns of brain activation during maze learning SO BRAIN RESEARCH LA English DT Article DE frontal lobe; maze learning; episodic memory; procedural memory; visuospatial memory; positron emission tomography; regional cerebral blood flow ID POSITRON EMISSION TOMOGRAPHY; SPATIAL WORKING-MEMORY; EPISODIC MEMORY; ATTENTION; PET; PERFORMANCE; MECHANISMS; RETRIEVAL; DISEASE; LESIONS AB Recent research has found that patterns of brain activation involving the frontal cortex during novel task performance change dramatically following practice and repeat performance. Evidence for differential left vs, right frontal lobe activation, respectively, during episodic memory encoding and retrieval has also been reported. To examine these potentially related issues regional cerebral blood flow (rCBF) was measured in 15 normal volunteers using positron emission tomography (PET) during the naive and practiced performance of a maze task paradigm. SPM analysis indicated a largely right-sided, frontal lobe activation during naive performance. Following training and practice, performance of the same maze task elicited a more posterior pattern of rCBF activation involving posterior cingulate and precuneus. The change in the pattern of rCBF activation between novel and practiced task conditions agrees with results found in previous studies using repeat task methodology, and indicates that the neural circuitry required for encoding novel task information differs from that required when the same task has become familiar and information is being recalled. The right-sided preponderance of activation during naive performance may relate to task novelty and the spatially-based nature of the stimuli, whereas posterior areas activated during repeat performance are those previously found to be associated with visuospatial memory recall. Activation of these areas, however, does not agree with previously reported findings of left-sided activation during verbal episodic memory encoding and right-sided activation during retrieval, suggesting different neural substrates for verbal and visuospatial processing within memory. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIMH, Clin Brain Disorders Branch, Ctr Neurosci, St Elizabeths Hosp, Washington, DC 20032 USA. RP Van Horn, JD (reprint author), NIMH, Unit PET, CBDB, NIH, 9000 Rockville Pike,Bldg 10,Room 4C-108, Bethesda, MD 20892 USA. EM vanhorn@alw.nih.gov NR 45 TC 28 Z9 28 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 18 PY 1998 VL 793 IS 1-2 BP 29 EP 38 DI 10.1016/S0006-8993(98)00051-1 PG 10 WC Neurosciences SC Neurosciences & Neurology GA ZX807 UT WOS:000074557400005 PM 9630492 ER PT J AU Kustova, Y Ha, JH Espey, MG Sei, Y Morse, D Basile, AS AF Kustova, Y Ha, JH Espey, MG Sei, Y Morse, D Basile, AS TI The pattern of neurotransmitter alterations in LP-BM5 infected mice is consistent with glutamatergic hyperactivation SO BRAIN RESEARCH LA English DT Article DE mouse; met-enkephalin; gamma-amino butyric acid; acetylcholine; substance-P; striatum; immunodeficiency ID RETROVIRUS-INDUCED IMMUNODEFICIENCY; PLATELET-ACTIVATING-FACTOR; GAMMA-AMINOBUTYRIC-ACID; CENTRAL-NERVOUS-SYSTEM; QUINOLINIC ACID; AMINO-ACIDS; EXTRACELLULAR LEVELS; ARACHIDONIC-ACID; OPIOID-PEPTIDES; BRAIN-REGIONS AB To gain insight into the neurochemical pathologies contributing to AIDS dementia complex, neurotransmitter levels were measured in the brains of mice infected with the LP-BM5 leukemia retrovirus. These mice develop immunologic and cognitive deficits analogous to human HTV-1 infection. Met-enkephalin and substance-P levels declined approximately 50% in the striatum and hypothalamus beginning as early as 4 weeks after infection. Hippocampal met-enkephalin levels were reduced to 50% only at 12 weeks after inoculation. Significant decreases (60-70%) in acetylcholine concentrations were observed in the striatum, cerebral cortex and hippocampus by 12 weeks after virus inoculation, while striatal GABA concentrations decreased to 50-60% at 8-12 weeks after infection. Striatal somatostatin levels were unchanged. Administration of the NMDA receptor antagonists MK-801 or LY 274614 ameliorated the decline in striatal met-enkephalin levels observed in mice after 8 weeks of infection. This pattern of neurotransmitter depletion and the ability of NMDA receptor antagonists to attenuate the loss of striatal met-enkephalin are consistent with an excitotoxic lesion. Thus, the elevation of glutamate levels secondary to glial activation may contribute to the contemporaneous development of cognitive deficits observed in mice infected with the LP-BM5 virus. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIDDK, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. RP Basile, AS (reprint author), NIDDK, Lab Bioorgan Chem, NIH, Bldg 8,Room 1A15, Bethesda, MD 20892 USA. NR 47 TC 14 Z9 14 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 18 PY 1998 VL 793 IS 1-2 BP 119 EP 126 DI 10.1016/S0006-8993(98)00167-X PG 8 WC Neurosciences SC Neurosciences & Neurology GA ZX807 UT WOS:000074557400015 PM 9630562 ER PT J AU Johren, O Hauser, W Saavedra, JM AF Johren, O Hauser, W Saavedra, JM TI Chemical lesion of the inferior olive reduces [I-125]sarcosine(1)-angiotensin II binding to AT(2) receptors in the cerebellar cortex of young rats SO BRAIN RESEARCH LA English DT Article DE ang II receptor subtype; AT(1A); AT(1B); 3-acetylpyridine; climbing fiber; Purkinje cell ID ANGIOTENSIN CONVERTING ENZYME; CLIMBING FIBERS; GENE-EXPRESSION; HYBRIDIZATION HISTOCHEMISTRY; MULTIPLE INNERVATION; TYPE-2 RECEPTOR; PURKINJE-CELLS; MESSENGER-RNA; MOUSE-BRAIN; LOCALIZATION AB In young rats, AT(2) receptors and AT(2) receptor mRNA are discretely localized in neurons of the inferior olive, with highest expression in the medial nucleus. We previously detected AT(2) receptor binding, but not AT(2) receptor mRNA, in the molecular layer of the cerebellar cortex. To determine whether AT, receptors are expressed in climbing fiber terminals which arise to the molecular layer from the inferior olive and innervate Purkinje cells, we chemically destroyed olivary neurons of 2-week-old rats by intraperitoneal (i.p.) injection of the neurotoxin 3-acetylpyridine. Lesions of the inferior olive reduced [I-125]Sar(1)-Ang II binding to AT(2) receptors and AT(2) receptor mRNA levels in this area by 50%, and produced a similar decrease in AT(2) receptor binding in the molecular layer of the cerebellar cortex. The extent of binding reduction was similar 3 days and 7 days after the lesion. 3-Acetylpyridine lesions did not change [I-125]Sar(1)-Ang II binding to AT(1) receptors in the molecular layer of the cerebellar cortex or AT(1) receptor mRNA levels in Purkinje cells. AT(2) receptor binding and AT(2) receptor mRNA levels in the deep cerebellar nuclei were also not affected by 3-acetylpyridine. Our results support the hypothesis that AT(2) receptors are produced by inferior olivary neurons and transported through climbing fibers to the molecular layer of the cerebellar cortex. The high expression of AT(2) receptors in the inferior olivary-cerebellar pathway during a crucial time in postnatal development of climbing fiber-Purkinie cell connectivity suggest a role of AT(2) receptors in the development of this pathway. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIMH, Pharmacol Sect, Bethesda, MD 20892 USA. RP Johren, O (reprint author), NIMH, Pharmacol Sect, 10 Ctr Dr,MSC 1514,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. RI Johren, Olaf/G-6967-2011 NR 39 TC 13 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 18 PY 1998 VL 793 IS 1-2 BP 176 EP 186 DI 10.1016/S0006-8993(98)00170-X PG 11 WC Neurosciences SC Neurosciences & Neurology GA ZX807 UT WOS:000074557400020 PM 9630617 ER PT J AU Orlandi, PA Fishman, PH AF Orlandi, PA Fishman, PH TI Filipin-dependent inhibition of cholera toxin: Evidence for toxin internalization and activation through caveolae-like domains SO JOURNAL OF CELL BIOLOGY LA English DT Article ID GPI-ANCHORED PROTEINS; COATED PIT FORMATION; CULTURED-CELLS; ADENYLATE-CYCLASE; EPITHELIAL-CELLS; INTRACELLULAR TRAFFICKING; ENDOPLASMIC-RETICULUM; MEDIATED TRANSPORT; DIPHTHERIA-TOXIN; GOLGI-APPARATUS AB The mechanism by which cholera toxin (CT) is internalized from the plasma membrane before its intracellular reduction and subsequent activation of adenylyl cyclase is not well understood. Ganglioside G(M1), the receptor for CT, is predominantly clustered in detergent-insoluble glycolipid rafts and in caveolae, noncoated, cholesterol-rich invaginations on the plasma membrane. In this study, we used filipin, a sterol-binding agent that disrupts caveolae and caveolae-like structures, to explore their role in the internalization and activation of CT in CaCo-2 human intestinal epithelial cells. When toxin internalization was quantified, only 33% of surface-bound toxin was internalized by filipin-treated cells within 1 h compared with 79% in untreated cells. However, CT activation as determined by its reduction to form the Al peptide and CT activity as measured by cyclic AMP accumulation were inhibited in filipin-treated cells. Another sterol-binding agent, 2-hydroxy-beta-cyclodextrin, gave comparable results. The cationic amphiphilic drug chlorpromazine, an inhibitor of clathrin-dependent, receptor-mediated endocytosis, however, affected neither CT internalization, activation, nor activity in contrast to its inhibitory effects on diphtheria toxin cytotoxicity. As filipin did not inhibit the latter, the two drugs appeared to distinguish between caveolae- and coated pit-mediated processes. In addition to its effects in CaCo-2 cells that express low levels of caveolin, filipin also inhibited CT activity in human epidermoid carcinoma A431 and Jurkat T lymphoma cells that are, respectively, rich in or lack caveolin. Thus, filipin inhibition correlated more closely with alterations in the biochemical characteristics of CT-bound membranes due to the interactions of filipin with cholesterol rather than with the expressed levels of caveolin and caveolar structure. Our results indicated that the internalization and activation of CT was dependent on and mediated through cholesterol-and glycolipid-rich microdomains at the plasma membrane rather than through a specific morphological structure and that these glycolipid microdomains have the necessary components required to mediate endocytosis. C1 NINDS, Membrane Biochem Sect, Cellular & Mol Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Orlandi, PA (reprint author), US FDA, Ctr Food Safety & Appl Nutr, OPDFB, DVA,VMB, HFS-327,200 C St, Washington, DC 20204 USA. NR 47 TC 537 Z9 547 U1 5 U2 31 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 MAY 18 PY 1998 VL 141 IS 4 BP 905 EP 915 DI 10.1083/jcb.141.4.905 PG 11 WC Cell Biology SC Cell Biology GA ZP540 UT WOS:000073763700006 PM 9585410 ER PT J AU Templeton, TJ Keister, DB Muratova, O Procter, JL Kaslow, DC AF Templeton, TJ Keister, DB Muratova, O Procter, JL Kaslow, DC TI Adherence of erythrocytes during exflagellation of Plasmodium falciparum microgametes is dependent on erythrocyte surface sialic acid and glycophorins SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE malaria; Plasmodium falciparum; exflagellation; microgamete; rosetting ID HUMAN MALARIA PARASITE; BLOOD-GROUP ANTIGENS; INFECTED ERYTHROCYTES; TRANS-SIALIDASE; INVASION; RECEPTOR; GALLINACEUM; MEMBRANE; PROTEINS; INVITRO AB Malaria male gametocytes within a newly ingested infected blood meal in the mosquito midgut emerge from erythrocytes and extrude approximately eight flagellar microgametes in a process termed exflagellation. In culture, and in blood removed from infected patients, emerging mi crogametes avidly adhere to neighboring uninfected and infected erythrocytes, as well as to emerged female macrogametes, creating "exflagellation centers". The mechanism of erythrocyte adherence is not known nor has it been determined for what purpose microgametes may bind to erythrocytes. The proposition of a function underlying erythrocyte adherence is supported by the observation of species-specificity in adhesion: microgametes of the human malaria Plasmodium falciparum can bind human erythrocytes but not chicken erythrocytes, whereas avian host Plasmodium gallinaceum microgametes bind chicken but not human erythrocytes. In this study we developed a binding assay in which normal, enzyme-treated, variant or null erythrocytes are identified by a cell surface fluorescent label and assayed for adherence to exflagellating microgametes. Neuraminidase, trypsin or ficin treatment of human erythrocytes eliminated their ability to adhere to Plasmodium falciparum microgametes, suggesting a role of sialic acid and one or more glycophorins in the binding to a putative gamete receptor. Using nulls lacking glycophorin A [En(a-)], glycophorin B (S-s-U-) or a combination of glycophorin A and B (M-k/M-k) we showed that erythrocytes lacking glycophorin B retain the ability to bind but a lack of glycophorin A reduced adherence by exflagellating microgametes. We propose that either the sialic acid moiety of glycophorins, predominantly glycophorin A, or a more complex interaction involving the glycophorin peptide backbone, is the erythrocyte receptor for adhesion to microgametes. C1 NIAID, Parasit Dis Lab, Malaria Vaccines Sect, Bethesda, MD 20892 USA. Warren Grant Magnuson Clin Ctr, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. RP Templeton, TJ (reprint author), NIAID, Parasit Dis Lab, Malaria Vaccines Sect, Bldg 4,Rm B1-31, Bethesda, MD 20892 USA. EM ttempleton@atlas.niaid.nih.gov NR 62 TC 27 Z9 27 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAY 18 PY 1998 VL 187 IS 10 BP 1599 EP 1609 DI 10.1084/jem.187.10.1599 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA ZP559 UT WOS:000073765600006 PM 9584138 ER PT J AU Moriuchi, H Moriuchi, M Fauci, AS AF Moriuchi, H Moriuchi, M Fauci, AS TI Factors secreted by human T lymphotropic virus type I (HTLV-I)-infected cells can enhance or inhibit replication of HIV-1 in HTLV-I-uninfected cells: Implications for in vivo coinfection with HTLV-I and HIV-1 SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE HIV; HTLV-I; Tax; chemokines; chemokine receptors ID HUMAN-IMMUNODEFICIENCY-VIRUS; INFECTIOUS MOLECULAR CLONE; TRANS-ACTIVATOR PROTEIN; LONG TERMINAL REPEAT; LEUKEMIA-VIRUS; DISEASE PROGRESSION; CHEMOKINE; TAX; LYMPHOCYTES; EXPRESSION AB It remains controversial whether human T lymphotropic virus type I (HTLV-I) coinfection leads to more rapid progression of human immunodeficiency virus (HIV) disease in dually infected individuals. To investigate whether HTLV-I infection of certain cells can modulate HIV-1 infection of surrounding cells, primary CD4(+) T cells were treated with cell-free supernatants from HTLV-I-infected MT-2 cell cultures. The primary CD4(+) T cells became resistant to macrophage (M)-tropic HIV-1 but highly susceptible to T cell (T)-tropic HIV-1. The CC chemokines RANTES (regulated on activation, normal T cell expressed and secreted), macrophage inflammatory protein (MIP)-1 alpha, and MIP-1 beta in the MT-2 cell supernatants were identified as the major suppressive factors for M-tropic HIV-1 as well as the enhancers of T-tropic HIV-1 infection, whereas soluble Tax protein increased susceptibility to both M-and T-tropic HIV-1. The effect of Tax or CC chemokines on T-tropic HIV-1 was mediated, at least in part, by increasing HIV Env-mediated fusogenicity. Our data suggest that the net effect of HTLV-I coinfection in HIV-infected individuals favors the transition from M-to T-tropic HIV phenotype, which is generally indicative of progressive HIV disease. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Moriuchi, H (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Rm 6A11, Bethesda, MD 20892 USA. EM hmoriuchi@atlas.niaid.nih.gov NR 57 TC 58 Z9 59 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 MAY 18 PY 1998 VL 187 IS 10 BP 1689 EP 1697 DI 10.1084/jem.187.10.1689 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA ZP559 UT WOS:000073765600015 PM 9584147 ER PT J AU Lloyd-Jones, D Camargo, CA Lapuerta, P Giugliano, RP O'Donnell, CJ AF Lloyd-Jones, D Camargo, CA Lapuerta, P Giugliano, RP O'Donnell, CJ TI Electrocardiographic and clinical predictors of acute myocardial infarction in patients with unstable angina pectoris SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY DISEASE; RISK STRATIFICATION; DEPRESSION; MECHANISMS; PROGNOSIS AB Among patients with unstable angina pectoris (UAP), those who have non-ST-elevatian acute myocardial infarction (AMI) are at higher risk for subsequent adverse events. To determine predictors of AMI in patients with UAP, we studied consecutive nonreferral patients with UAP or AMI admitted from the emergency department to the intensive care or telemetry units of an urban teaching hospital over 1 year. There were 280 study patients (mean age 66 years, 1/3 women); 24% had AMI at presentation, whereas 76% had UAP without evidence of AMI. Thresholds of greater than or equal to 3 involved leads (odds ratio [OR] 3.3; 95% confidence intervals [CI] 1.6 to 6.9) and greater than or equal to 0.2 mV (OR 5.1; 95% CI 2.2 to 11.6) of ST depression on the presenting electrocardiogram were strongly associated with AMI. The multivariate predictors of AMI were reported duration of symptoms > 4 hours (OR 3.8; 95% CI 1.9 to 7.3), absence of prior revascularization (OR 3.5; 95% CI 1.6 to 7.5), absence of beta-blocker use before presentation (OR 2.8; 95% CI 1.3 to 5.8), and presence of new ST depression (OR 2.8; 95% CI 1.4 to 5.7). Using the 4 multivariate predictors, a prediction rule was developed. The percentages of patients with AMI when 0, 1, 2, 3, or 4 characteristics were present, respectively, were 7%, 6%, 24%, 46%, and 83% (p < 0.001). A similar prediction rule developed from the Thrombolysis in Myocardial Ischemia ill trial was validated in our cohort. Among patients with UAP, electrocardiographic and clinical variables can help immediately identify those at high risk for AMI at presentation. (C) 1998 by Excerpta Medica, Inc. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Massachusetts Gen Hosp, Cardiac Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Channing Lab, Boston, MA 02115 USA. Univ So Calif, Sch Med, Div Gen Internal Med, Los Angeles, CA USA. RP Lloyd-Jones, D (reprint author), NHLBI, Framingham Heart Study, 5 Thurber St, Framingham, MA 01702 USA. RI Lloyd-Jones, Donald/C-5899-2009 FU NHLBI NIH HHS [HL-03533, HL-07575] NR 21 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 MAY 15 PY 1998 VL 81 IS 10 BP 1182 EP 1186 DI 10.1016/S0002-9149(98)00155-6 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ZN230 UT WOS:000073622900003 PM 9604942 ER PT J AU Jones, E Feverstein, IM Tucker, E Summers, RM Spray, TI Hoeg, JM AF Jones, E Feverstein, IM Tucker, E Summers, RM Spray, TI Hoeg, JM TI Aortic hypoplasia in homozygous familial hypercholesterolemia SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article AB Diagnosis of hypoplastic aortic root with ultrafast computed tomography provides important clinical information in homozygous familial hypercholesterolemic patients with supravalvular aortic stenosis. C1 NHLBI, Dept Radiol, Cardiol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Hoeg, JM (reprint author), Bldg 10,Room 7N115,10 Ctr Dr MSC 1666, Bethesda, MD 20892 USA. NR 7 TC 4 Z9 5 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 MAY 15 PY 1998 VL 81 IS 10 BP 1242 EP + DI 10.1016/S0002-9149(98)00114-3 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ZN230 UT WOS:000073622900021 PM 9604960 ER PT J AU Gillum, RF Mussolino, ME Sempos, CT AF Gillum, RF Mussolino, ME Sempos, CT TI Baseline serum total cholesterol and coronary heart disease incidence in African-American women (The NHANES I epidemiologic follow-up study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID RISK-FACTORS; BLACK POPULATIONS; BLOOD-PRESSURE; ARTERY DISEASE; WHITE MEN; MORTALITY AB Proportional-hazards analyses for African-American women aged 25 to 74 revealed a variable association of coronary heart disease risk with baseline serum total cholesterol (after adjusting for age fifth vs first quintile: RR = 1.62, 95% confidence interval [CI] 0.89 to 2.98, p = 0.12; after adjusting for age, systolic blood pressure, body mass index, smoking, history of diabetes, low education, and low family income: RR = 1.88, 95% CI 1.02 to 3.45, p = 0.04). Perhaps due to the relatively small number of events, the association of serum total cholesterol with coronary heart disease incidence in African-American women was not consistently significant. C1 Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Off anal Epidemiol & Hlth Promot, Hyattsville, MD 20782 USA. NHLBI, Bethesda, MD 20892 USA. RP Gillum, RF (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Off anal Epidemiol & Hlth Promot, 6525 Belcrest Rd, Hyattsville, MD 20782 USA. NR 20 TC 6 Z9 6 U1 1 U2 1 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAY 15 PY 1998 VL 81 IS 10 BP 1246 EP + DI 10.1016/S0002-9149(98)00122-2 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ZN230 UT WOS:000073622900023 PM 9604962 ER PT J AU Durham, LK Longini, IM Halloran, ME Clemens, JD Nizam, A Rao, M AF Durham, LK Longini, IM Halloran, ME Clemens, JD Nizam, A Rao, M TI Estimation of vaccine efficacy in the presence of waning: Application to cholera vaccines SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cholera; communicable diseases; epidemiologic methods; statistics; survival analysis; vaccines ID FIELD TRIAL; FOLLOW-UP; MODELS; BANGLADESH; REGRESSION; RESIDUALS AB The authors present a nonparametric method for estimating vaccine efficacy as a smooth function of time from vaccine trials. Use of the method requires a minimum of assumptions. Estimation is based on the smoothed case hazard rate ratio comparing the vaccinated with the unvaccinated, The estimation procedure allows investigators to assess time-varying changes in vaccine-induced protection, such as those produced by waning and boosting, The authors use the method to reanalyze data from a vaccine trial of two cholera vaccines in rural Bangladesh. This analysis reveals the differential protection and waning effects for the vaccines as a function of biotype and age. C1 Emory Univ, Rollins Sch Publ Hlth, Dept Biostat, Atlanta, GA 30322 USA. NICHHD, Div Epidemiol Stat & Prevent, NIH, Bethesda, MD USA. RP Longini, IM (reprint author), Emory Univ, Rollins Sch Publ Hlth, Dept Biostat, Atlanta, GA 30322 USA. FU NIAID NIH HHS [R01-AI32042, T32-AI07442] NR 18 TC 30 Z9 30 U1 0 U2 4 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAY 15 PY 1998 VL 147 IS 10 BP 948 EP 959 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZM905 UT WOS:000073588100007 PM 9596473 ER PT J AU Schuck, P Millar, DB AF Schuck, P Millar, DB TI Rapid determination of molar mass in modified Archibald experiments using direct fitting of the Lamm equation SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE analytical ultracentrifugation; sedimentation velocity; sedimentation equilibrium ID SEDIMENTATION AB A new method is described that allows measurement of the molar mass of the solute within 15 to 30 min after start of a conventional long-column sedimentation equilibrium experiment. A series of scans of the concentration distribution in close vicinity of the meniscus, taken in rapid succession after the start of the centrifuge run, is analyzed by direct fitting using the Lamm equation and the Svedberg equation. In case of a single solute, this analysis of the initial depletion at the meniscus reveals its buoyant molar mass and sedimentation coefficient with an accuracy of approximately 10% and provides gross information about sample heterogeneity. This method can be used to study macromolecules that do not possess the prolonged stability needed in conventional sedimentation equilibrium experiments and it can increase the efficiency of sedimentation equilibrium experiments of previously uncharacterized samples. C1 NIH, OD, BEPS, Bethesda, MD 20892 USA. NIDDK, Sect Phys Biochem, Biochem Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Schuck, P (reprint author), NIH, OD, BEPS, Bldg 13,Rm 3N17,13 South Dr, Bethesda, MD 20892 USA. OI Schuck, Peter/0000-0002-8859-6966 NR 16 TC 20 Z9 20 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAY 15 PY 1998 VL 259 IS 1 BP 48 EP 53 DI 10.1006/abio.1998.2638 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA ZR521 UT WOS:000073985900007 PM 9606142 ER PT J AU Zhang, XL Herring, CJ Romano, PR Szczepanowska, J Brzeska, H Hinnebusch, AG Qin, J AF Zhang, XL Herring, CJ Romano, PR Szczepanowska, J Brzeska, H Hinnebusch, AG Qin, J TI Identification of phosphorylation sites in proteins separated by polyacrylamide gel electrophoresis SO ANALYTICAL CHEMISTRY LA English DT Article ID IONIZATION MASS-SPECTROMETRY; PHOSPHOAMINO ACID ANALYSIS; LAYER CELLULOSE PLATES; DOUBLE-STRANDED-RNA; TYROSINE PHOSPHORYLATION; DESORPTION IONIZATION; SELECTIVE DETECTION; SIGNAL INTEGRATION; COMPLEX-MIXTURES; KINASE DAI AB We report a fast, sensitive, and robust procedure for the identification of precise phosphorylation sites in proteins separated by polyacrylamide gel electrophoresis by a combination of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI/TOF) and online capillary liquid chromatography electrospray tandem ion trap mass spectrometry (LC/ESI/MS/MS). With this procedure, a single phosphorylation site was identified on as little as 20 ng (500 fmol) of the baculovirus-expressed catalytic domaine of myosin I heavy-chain kinase separated by gel electrophoresis. The phosphoprotein is digested in the gel with trypsin, and the resulting peptides are extracted with greater-than 60% yield and analyzed by MALDI/TOF before and after digestion with a phosphatase to identify the phosphopeptides. The phosphopeptides are then separated and fragmented in an online LC/ESI ion trap mass spectrometer to identify the precise phosphophorylation sites. This procedure eliminates any off-line HPLC separation and minimizes sample handling. The use of MALDI/TOF and LCQ, two types of mass spectrometers that are widely available to the biological community, will make this procedure readily accessible to biologists. We applied this technique to identify two autophosphorylation sites and to assign at least another 12 phosphorylation sites to two tryptic peptides in a series of experiments using a gel slice containing only 200 ng (3 pmol) of human double-stranded RNA-activated protein kinase expressed in a mutant strain of the yeast Saccharomyces cerevisiae. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NICHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Qin, J (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 10,9000 Rockville Pike,Room 7N307, Bethesda, MD 20892 USA. NR 41 TC 171 Z9 175 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD MAY 15 PY 1998 VL 70 IS 10 BP 2050 EP 2059 DI 10.1021/ac971207m PG 10 WC Chemistry, Analytical SC Chemistry GA ZN641 UT WOS:000073666700006 PM 9608844 ER PT J AU Xiang, BS Ferretti, J Fales, HM AF Xiang, BS Ferretti, J Fales, HM TI Use of mass spectrometry to ensure purity of recombinant proteins: A cautionary note SO ANALYTICAL CHEMISTRY LA English DT Article AB Electrospray mass spectrometry was used to confirm the identity and purity of the unlabeled and isotopically labeled vnd/NK2-A35T homeodomain protein prepared for NMR experiments. A series of events involving adduction by urea, carbamoylation of amino acid groups, and the presence of nickel ion resulted in protein masses shifted from their expected values, thus emphasizing that observed discrepancies in mass may have sources other than an error in amino acid sequence. Procedures used to detect and remedy these problems are described. C1 NHLBI, Biophys Chem Lab, Bethesda, MD 20892 USA. RP Fales, HM (reprint author), NHLBI, Biophys Chem Lab, Bethesda, MD 20892 USA. NR 5 TC 4 Z9 4 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD MAY 15 PY 1998 VL 70 IS 10 BP 2188 EP 2190 DI 10.1021/ac971258j PG 3 WC Chemistry, Analytical SC Chemistry GA ZN641 UT WOS:000073666700027 ER PT J AU Strober, W Ludviksson, BR Fuss, IJ AF Strober, W Ludviksson, BR Fuss, IJ TI The pathogenesis of mucosal inflammation in murine models of inflammatory bowel disease and Crohn disease SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID TUMOR-NECROSIS-FACTOR; GROWTH-FACTOR-BETA; CD4(+) T-CELLS; ESTABLISHED EXPERIMENTAL COLITIS; MYELIN BASIC-PROTEIN; HAPTEN-INDUCED MODEL; ULCERATIVE-COLITIS; ORAL TOLERANCE; IMMUNE-RESPONSES; MICE AB In recent years, it has become apparent that overproduction of the Th1 cytokines interleukin-12 and interferon-gamma is the probable driving force behind murine models of intestinal inflammation resembling Crohn disease and intestinal inflammation in humans with Crohn disease. In addition, studies of murine models strongly suggest that this overproduction is associated with inadequate secretion of the counter-regulatory and anti-inflammatory cytokine transforming growth factor-beta. Thus, mucosal inflammation in models (and possibly in humans) may result from an imbalance between normally occurring positive (immunogenic or inflammatory) responses and negative (tolerogenic or anti-inflammatory) mucosal immune responses. These new findings and the hypotheses that arise from them are being used to construct new approaches to the treatment of Crohn disease that are based on the administration of anti-inflammatory cytokines and anticytokine antibodies. C1 NIAID, Mucosal Immun Sect, NIH, Bethesda, MD 20892 USA. RP Strober, W (reprint author), NIAID, Mucosal Immun Sect, NIH, Bldg 10,Room 11N-238, Bethesda, MD 20892 USA. OI Ludviksson, Bjorn/0000-0002-6445-148X NR 62 TC 122 Z9 123 U1 2 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD MAY 15 PY 1998 VL 128 IS 10 BP 848 EP 856 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA ZM889 UT WOS:000073586500009 PM 9599198 ER PT J AU Schlezinger, JJ Parker, C Zeldin, DC Stegeman, JJ AF Schlezinger, JJ Parker, C Zeldin, DC Stegeman, JJ TI Arachidonic acid metabolism in the marine fish Stenotomus chrysops (Scup) and the effects of cytochrome P450 1A inducers SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE arachidonic acid; cytochrome P450 1A; Stenotomus chrysops ID EPOXYEICOSATRIENOIC ACIDS; MICROSOMAL CYTOCHROME-P-450; BIOCHEMICAL-CHARACTERIZATION; ENANTIOFACIAL SELECTIVITY; CROSS-REACTIVITY; GROWTH-HORMONE; MESSENGER-RNA; GUINEA-PIG; LIVER; EPOXYGENASE AB Cytochrome P450-mediated arachidonic acid (AA) metabolism was investigated in the marine fish scup, Stenotomus chrysops. Liver microsomes incubated with AA and NADPH produced epoxyeicosatrienoic acids (EETs) and their hydration products (dihydroxyeicosatrienoic acids, DHETs), midchain conjugated dienols (midchain HETEs), and C-16-through C-20-alcohols of AA (omega-terminal HETEs), all identified by HPLC and GC/MS. Gravid females had 4-fold lower AA metabolism rates than males but identical metabolite profiles. The 5,6-EET (inferred from stable metabolites) was most abundant (47% of total EETs) followed by 14,15-, 11,12-, and 8,9-EET (27, 13, and 13%, respectively). The 12-HETE represented 25% of total HETEs followed in abundance by 16-, 15-, 11-, 19-, 20-, 8-, and 9-HETE. Antibodies against scup CYP1A and a scup CYP2B-like protein inhibited liver microsomal AA metabolism by 30 and 46%, respectively. GC/MS analysis revealed EETs and DHETs as endogenous constituents in scup liver; the predominant EETs were 8,9- and 14,15-EET, followed by a lesser amount of 11,12-EET. Chiral analysis showed a preference for the S,R-enantiomers of endogenous 8,9-, 11,12-, and 14,15-EET (optical purities 80, 64, and 64%, respectively). Treatment of scup with the CYP1A inducer benzo(alpha)pyrene (BP) increased liver microsomal formation of EETs and HETEs by 2.7-fold in spring and 1.7-fold in summer. BP treatment did not affect microsomal EET regioselectivity, but shifted hydroxylation in favor of 19-HETE and induced 17-HETE formation. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) treatment in summer did not induce liver microsomal AA metabolism rates, yet BP and TCDD both increased endogenous EET content of liver (5-and 3-fold, respectively), with a shift to 14,15-EET. BP treatment increased the selectivity for the S,R-enantiomers of endogenous 8,9-, 11,12-, and 14,15-EET (optical purities 91, 84, and 83%, respectively). Kidney, gill, and heart microsomes all metabolized AA, at rates 10- to 30-fold less than liver microsomes. Similar amounts of endogenous 8,9- and 14,15-EET and less 11,12-EET were detected in heart and kidney, and there was a strong enantioselectivity for 8(R),9(S)-EET in heart (optical purity 78%) but not in kidney. BP treatment did not alter the total EET content in these organs but did shift the regiochemical profile in heart to favor 14,15-EET. Thus, scup liver and extrahepatic organs metabolize AA via multiple cytochrome P450 (CYP) forms to eicosanoids in vitro and in vivo. BP or TCDD induced endogenous AA metabolism in liver, altering EET regioselectivity and, with BP, stereoselectivity. While AhR agonists alter metabolism of AA in early diverging vertebrates expressing both CYP1A and AhR, the magnitude of effects may depend upon the type of inducer. (C) 1998 Academic Press. C1 Woods Hole Oceanog Inst, Dept Biol, Woods Hole, MA 02543 USA. NIEHS, Pulm Pathobiol Lab, Res Triangle Pk, NC 27709 USA. RP Woods Hole Oceanog Inst, Dept Biol, Woods Hole, MA 02543 USA. EM jstegeman@whoi.edu FU NIEHS NIH HHS [P42-ES07381] NR 67 TC 23 Z9 24 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 EI 1096-0384 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD MAY 15 PY 1998 VL 353 IS 2 BP 265 EP 275 DI 10.1006/abbi.1998.0651 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZQ203 UT WOS:000073833100010 PM 9606961 ER PT J AU Johns, DG Gao, WY AF Johns, DG Gao, WY TI Selective depletion of DNA precursors - An evolving strategy for potentiation of dideoxynucleoside activity against human immunodeficiency virus SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE anti-HIV drugs; combination therapy; drug resistance; dideoxynucleosides; HIV-1 mutants; HIV-1 replication ID HIV-1 REVERSE-TRANSCRIPTASE; RIBONUCLEOTIDE REDUCTASE; DEOXYCYTIDINE KINASE; TYPE-1 REPLICATION; TRIPHOSPHATE POOLS; T-CELLS; HYDROXYUREA; RESISTANCE; ZIDOVUDINE; DIDANOSINE AB Human immunodeficiency virus type 1 (HIV-1) is wholly dependent on its host cell for a variety of essential metabolites. Among the latter are the deoxynucleoside-5'-triphosphates (dNTPs) required for reverse transcription of the single-stranded RNA viral genome into double-stranded viral DNA. Since viral DNA synthesis has an absolute requirement for all four dNTPs, restriction of a single one of these is sufficient to inhibit HIV-1 replication. To date, this therapeutic strategy has been most successful when depletion of the individual dNTP is coupled with exposure to its corresponding chain-terminating dideoxynucleoside (ddN). While several examples of such combined therapy have been defined and studied in vitro, that which has been investigated most extensively at both the laboratory and the clinical level is ddATP exposure combined with dATP depletion [with dATP restriction being induced by the ribonucleotide reductase inhibitor hydroxyurea (HU) and ddATP generated from its prodrug 2',3'-dideoxyinosine (ddl)]. Several long-term clinical trials of the hydroxyurea/2',3'-dideoxyinosine combination have been completed, with plasma viral RNA being reduced to undetectable levels in a substantial fraction (one-third to one-half) of the patients treated. The major advantages of this and analogous combinations discussed in this review are their low cost relative to other current multiple drug protocols and their potential for retention of activity against drug-resistant HIV mutants. (C) 1998 Elsevier Science Inc. C1 NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Expt Retrovirol Sect, Med Branch, Div Clin Sci,NIH, Bethesda, MD 20892 USA. RP Johns, DG (reprint author), NCI, Med Chem Lab, Div Basic Sci, NIH, Bldg 37,Rm 5B22, Bethesda, MD 20892 USA. NR 55 TC 30 Z9 33 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD MAY 15 PY 1998 VL 55 IS 10 BP 1551 EP 1556 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ZL938 UT WOS:000073488600002 PM 9633990 ER PT J AU Xu, ASL Chu, CK London, RE AF Xu, ASL Chu, CK London, RE TI F-19 NMR study of the uptake of 2 '-fluoro-5-methyl-beta-L-arabinofuranosyluracil in erythrocytes - Evidence of transport by facilitated and nonfacilitated pathways SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE 2 '-fluoro-5-methyl-beta-L-arabinofuranosyluracil; nucleoside analogs; membrane transport; erythrocytes; F-19 NMR ID HEPATITIS-B VIRUS; EPSTEIN-BARR-VIRUS; NUCLEOSIDE TRANSPORT; PYRIMIDINE NUCLEOSIDES; NUCLEOBASE TRANSPORT; MEMBRANE-TRANSPORT; ANIMAL-CELLS; INHIBITION; PERMEATION; DIFFUSION AB The F-19 NMR resonances of intra- and extracellular 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU) in suspensions of human erythrocytes are well resolved. This phenomenon allows its transport behavior to be monitored in a F-19 NMR time-course experiment. The rate of L-FMAU uptake at 25 degrees in a suspension containing L-FMAU at an initial extracellular concentration of 4 mM was 7.6 +/- 1.0 X 10(-7) pmol cell(-1) sec(-1) (N = 5). Concentration-dependent uptake studies of L-FMAU indicate the existence of both saturable and nonsaturable transport mechanisms, with a K-m for the saturable uptake of approximately 1 mM. Although the transport of L-FMAU at 25 degrees was inhibited significantly (54-65%) by nitrobenzylthioinosine (NBTI) and dipyridamole, consistent with the participation of the nucleoside transporter, these inhibitors did not achieve complete blockage of L-FMAU uptake. The participation of the nucleobase transporter in L-FMAU uptake was ruled out by the absence of competition with uracil uptake, and by the lack of inhibition by papaverine. In addition, the NBTI-insensitive uptake of L-FMAU was not affected by pretreatment of the cells with the sulfhydryl reagent, p-chloromercuriphenylsulfonic acid (pCMBS). However, the NBTI- and dipyridamole-insensitive transport of L-FMAU was found to increase upon treatment of the erythrocytes with butanol, an agent that affects membrane fluidity. The partition coefficient of L-FMAU in octanol/phosphate-buffered saline determined by absorption spectrophotometry was 0.31. These data indicate that under the conditions of the studies, L-FMAU uptake by erythrocytes proceeds by both the nucleoside transporter and nonfacilitated membrane diffusion. (C) 1998 Elsevier Science Inc. C1 NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Univ Georgia, Coll Pharm, Dept Med Chem, Athens, GA 30602 USA. RP London, RE (reprint author), NIEHS, Struct Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM LONDON@NIEHS.NIH.GOV FU NIAID NIH HHS [AI-33655] NR 44 TC 5 Z9 5 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD MAY 15 PY 1998 VL 55 IS 10 BP 1611 EP 1619 DI 10.1016/S0006-2952(98)00017-3 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ZL938 UT WOS:000073488600009 PM 9633997 ER PT J AU Yang, TJ Krausz, KW Shou, MG Yang, SK Buters, JTM Gonzalez, FJ Gelboin, HV AF Yang, TJ Krausz, KW Shou, MG Yang, SK Buters, JTM Gonzalez, FJ Gelboin, HV TI Inhibitory monoclonal antibody to human cytochrome P450 2B6 SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE monoclonal antibody; human cytochrome P450 2B6; baculovirus; vaccinia virus; cDNA expression; phenanthrene; diazepam; testosterone; 7-ethoxycoumarin ID CDNA-EXPRESSED HUMAN; HUMAN-LIVER; MESSENGER-RNAS; METABOLISM; PURIFICATION; BENZOPYRENE; RODENT; FORMS; 2E1; RAT AB The human cytochrome P450 2B6 metabolizes, among numerous other substrates, diazepam, 7-ethoxycoumarin, testosterone, and phenanthrene. A recombinant baculovirus containing the human 2B6 cDNA was constructed and used to express 2B6 in Sf9 insect cells. The 2B6 was present at 1.8 +/- 0.4% of the total cellular protein and was purified to a specific content of 13.3 nmol/mg protein. Mice were immunized with the purified 2B6, and a total of 811 hybridomas were obtained from the fusion of NS-1 myeloma cells and spleen cells of the immunized mice. Monoclonal antibodies (MAbs) from 24 of the hybrids exhibited immunobinding to 2B6 as determined by ELISA. One of the MAbs, 49-10-20, showed a strong immunoblotting activity and was highly inhibitory to 2B6 enzyme activity. MAb 49-10-20 inhibited cDNA-expressed 2B6-catalyzed metabolism of diazepam, phenanthrene, 7-ethoxycoumarin, and testosterone by 90-91%. MAb 49-10-20 showed extremely high specificity for 2B6 and did not bind to 17 other human and rodent P450s or inhibit the metabolism of phenanthrene catalyzed by human 1A2, 2A6, 2C8, 2C9, 2D6, 2E1, 3A4, and 3A5. MAb 49-10-20 was used to determine the contribution of 2B6 to the metabolism of phenanthrene and diazepam in human liver. In ten liver samples, MAb 49-10-20 inhibited phenanthrene metabolism variably by a wide range of 8-42% and diazepam demethylation by 1-23%. The degree of inhibition by the 2B6 specific MAb 49-10-20 defines the contribution of 2B6 to phenanthrene anti diazepam metabolism in each human liver. This technique using inhibitory MAb 49-10-20 determines the contribution of 2B6 to the metabolism of its substrates in a human tissue containing multiple P450s. This study is a prototype for the use of specific and highly inhibitory MAbs to determine individual P450 function. (C) 1998 Elsevier Science Inc. C1 NCI, Mol Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. RP Gelboin, HV (reprint author), NCI, Mol Carcinogenesis Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. RI Buters, Jeroen/G-5070-2011 NR 27 TC 46 Z9 46 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD MAY 15 PY 1998 VL 55 IS 10 BP 1633 EP 1640 DI 10.1016/S0006-2952(98)00018-5 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ZL938 UT WOS:000073488600011 PM 9633999 ER PT J AU Sharif, KA Moscow, JA Goldman, ID AF Sharif, KA Moscow, JA Goldman, ID TI Concentrating capacity of the human reduced folate carrier (hRFC1) in human ZR-75 breast cancer cell lines SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE transport; methotrexate; reduced folate carrier; folate ID L1210 LEUKEMIA-CELLS; METHOTREXATE TRANSPORT-SYSTEM; PLASMA-MEMBRANE VESICLES; INCREASED EXPRESSION; MEDIATED TRANSPORT; BINDING PROTEINS; RECEPTOR; ANION; SENSITIVITY; CDNA AB Human RFC1 (hRFC1) transfected in transport-deficient methotrexate MTX(R)ZR-75-1 human breast carcinoma cells (MTX(R)ZR-75/RFC) were used to investigate the impact of hRFC1 overexpression on influx and concenerative transport of methotrexate (MTX). Eight-fold overexpression of hRFC1, as determined by northern analysis, resulted in a di-fold increase in MTX influx accompanied by a 2.4-fold increase in the steady-state level of free drug as compared with wild-type 2R-75-1 cells when the extracellular MTX level was 0.5 mu M. When extracellular MTX was increased to 10 mu M, the increase in influx equaled the increase in the transmembrane chemical gradient for MTX in the transfectant relative to wild-type cells. By 50 min, similar to 16-20 anal 25% of the intracellular H-3 represented MTX polyglutamates by HPLC analysis at [MTX](e) = 0.5 and 10 mu M in wild-type and transfected cells, respectively. Overexpression of hRFC1 enhanced sensitivity to MTX in MTX(R)ZR-75-1 cells by more than 250-fold. The data indicate that overexpression of hRFC1 in human cells results in comparable increases in influx and transmembrane gradients. This is different from what was reported when mouse RFC1 was transfected into murine leukemia cells, resulting in large, more symmetrical increases in the MTX bidirectional transport kinetics with a much smaller change in steady-state levels. The changes in the human cells transfected with hRFC1 however, were similar to what has been observed by other investigators when RFC1 expression is increased by low folate selective pressure. (C) 1998 Elsevier Science Inc. C1 Albert Einstein Coll Med, Albert Einstein Comprehens Canc Ctr, Bronx, NY 10461 USA. Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA. NCI, Pediat Branch, Bethesda, MD 20892 USA. NCI, Med Branch, Bethesda, MD 20892 USA. RP Goldman, ID (reprint author), Albert Einstein Coll Med, Albert Einstein Comprehens Canc Ctr, Chanin 2,1300 Morris Pk Ave, Bronx, NY 10461 USA. FU NCI NIH HHS [CA-39807] NR 39 TC 9 Z9 10 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD MAY 15 PY 1998 VL 55 IS 10 BP 1683 EP 1689 DI 10.1016/S0006-2952(98)00039-2 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ZL938 UT WOS:000073488600017 PM 9634005 ER PT J AU Dolan, ME Roy, SK Garbiras, BJ Helft, P Paras, P Chae, MY Moschel, RC Pegg, AE AF Dolan, ME Roy, SK Garbiras, BJ Helft, P Paras, P Chae, MY Moschel, RC Pegg, AE TI O-6-alkylguanine-DNA alkyltransferase inactivation by ester prodrugs of O-6-benzylguanine derivatives and their rate of hydrolysis by cellular esterases SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE O-6-benzylguanine; alkyltransferase; ester prodrug; esterase; tumor ID TUMOR XENOGRAFTS; 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA BCNU; ALKYLATING-AGENTS; SENSITIVITY; CELLS; O6-BENZYLGUANINE; ENHANCEMENT; DEPLETION; RESISTANT; PROTEIN AB To modulate the bioavailability and perhaps improve the tumor cell selectivity of O-6-alkylguanine -DNA alkyltransferase (AGT) inactivators, pivaloyloxymethyl ester derivatives of O-6-benzylguanine (BG) were synthesized and tested as AGT inactivators and as substrates for cellular esterases. The potential prodrugs examined were the 7- and 9-pivaloyloxymethyl derivatives of O-6-benzylguanine (7- and 9-esterBG), and of 8-aza-O-6-benzylguanine (8-aza-7-esterBG and 8-aza-9-esterBG) and the 9-pivaloyloxymethyl derivative of 8-bromo-O-6-benzylguanine (8-bromo-9-esterBG). The benzylated purines were all potent inactivators of the pure ACT and of the AGT activity in HT29 cells and cell extracts. Each ester was at least 75 times less potent than the corresponding benzylated purine against the pure human AGT. In contrast, the activities of esters and their respective benzylated purine were similar in crude cell extracts and in intact cells. The increase in potency of esters in cellular extracts could be explained by a conversion of the respective prodrug to the more potent benzylated purine in the presence of cellular esterases. The apparent catalytic activity (V-max/K-m) of liver microsomal esterase for 8-azaBG ester prodrugs was 70-130 times greater than for BG prodrugs and 10-20 times greater than fur 8-bromo-9-esterBG. Tumor cell hydrolysis of the esters varied considerably as a function of cell type and prodrug structure. These data suggest that these or related prodrugs may be advantageous for selective AGT inactivation in certain tumor types. (C) 1998 Elsevier Science Inc. C1 Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. NCI, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Pharmacol, Hershey, PA 17033 USA. RP Dolan, ME (reprint author), Univ Chicago, Hematol Oncol Sect, 5841 S Maryland Ave,Box MC2115, Chicago, IL 60637 USA. FU NCI NIH HHS [CA71976, CA71627, CA57725] NR 31 TC 11 Z9 11 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD MAY 15 PY 1998 VL 55 IS 10 BP 1701 EP 1709 DI 10.1016/S0006-2952(98)00047-1 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ZL938 UT WOS:000073488600019 PM 9634007 ER PT J AU Moretti, S Alesse, E Di Marzio, L Zazzeroni, F Ruggeri, B Marcellini, S Famularo, G Steinberg, SM Boschini, A Cifone, MG De Simone, C AF Moretti, S Alesse, E Di Marzio, L Zazzeroni, F Ruggeri, B Marcellini, S Famularo, G Steinberg, SM Boschini, A Cifone, MG De Simone, C TI Effect of L-carnitine on human immunodeficiency virus-1 infection-associated apoptosis: A pilot study SO BLOOD LA English DT Article ID PROGRAMMED CELL-DEATH; T-CELLS; INDUCED DESTRUCTION; FLOW-CYTOMETRY; HUMAN MYOTUBES; HIV-1 TAT; CERAMIDE; ACTIVATION; LYMPHOCYTES; AIDS AB The Fas/Fas ligand system is involved in uncontrolled apoptosis, which ultimately leads to the loss of T lymphocytes in human immunodeficiency virus (HIV)-infected individuals. The signal transduced by Fas receptor involves the activation of an acidic sphingomyelinase, sphingomyelin breakdown, and ceramide production. Our recent reports have shown that L-carnitine inhibits Fas-induced apoptosis and ceramide production both in vitro and in vivo. The aim of this study was to study, in a preliminary fashion, the impact of long-term L-carnitine administration on CD4 and CD8 absolute counts, rate, and apoptosis in HIV-1-infected subjects. The generation of cell-associated ceramide and HIV-1 viremia was also investigated. Eleven, asymptomatic, HIV-1-infected subjects, who refused any antiretroviral treatment despite experiencing a progressive decline of CD4 counts, were treated with daily infusions of L-carnitine (6 g) for 4 months. Immunologic and virologic measures and safety were monitored at the start of the treatment and then on days 15, 30, 90, and 150. L-carnitine therapy resulted in an increase of absolute CD4 counts, which was statistically significant on day 90 and 150 (P = .010 and P = .019 respectively). A positive, not significant trend was also observed even in the change in absolute counts of CD8 lymphocytes. L-carnitine therapy also led to a drop in the frequency of apoptotic CD4 and CD8 lymphocytes. This reduction occurred gradually, but changes in actual values between each time point and baseline were strongly significant (P = .001 at the end of the study compared with the baseline). A strong reduction (P = .001) in cell-associated ceramide levels was found at the end of the study. In general, HIV-1 viremia increased slightly. No toxicity related to L-carnitine therapy was observed and dose reductions were not necessary. In HIV-1-infected subjects, long-term infusions of L-carnitine produced substantial increases in the rate and absolute counts of CD4 and, to a lesser degree, of CD8 lymphocytes. This was paralleled by a reduced frequency of apoptotic cells of both subgroups and a decline in the levels of ceramide. No clinically relevant change of HIV-1 viremia was observed. (C) 1998 by The American Society of Hematology. C1 Univ Aquila, Dept Expt Med, I-67100 Laquila, Italy. Univ La Sapienza, Dept Infect Dis, Rome, Italy. Ctr Med di San Patrignano, Rimini, Italy. NCI, NIH, Bethesda, MD 20892 USA. RP De Simone, C (reprint author), Univ Aquila, Dept Expt Med, Via Vetoio 10,Coppito 2, I-67100 Laquila, Italy. RI Di Marzio, Luisa/H-9969-2012; OI Zazzeroni, Francesca/0000-0002-4474-3274; CIFONE, Maria Grazia/0000-0002-9923-5445 NR 40 TC 52 Z9 53 U1 0 U2 5 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 15 PY 1998 VL 91 IS 10 BP 3817 EP 3824 PG 8 WC Hematology SC Hematology GA ZM210 UT WOS:000073515700032 PM 9573019 ER PT J AU Murata, T Taguchi, J Puri, RK AF Murata, T Taguchi, J Puri, RK TI Interleukin-13 receptor alpha ' but not a chain: A functional component of interleukin-4 receptors SO BLOOD LA English DT Article ID COMMON GAMMA-CHAIN; CARCINOMA-CELLS; SIGNAL-TRANSDUCTION; STAT PROTEINS; EXPRESSION; IL-4; CLONING; MITOGENESIS; INHIBITION; SUBUNIT AB In hematopoietic cells, interleukin-2 receptor (IL-2R) gamma chain (termed gamma(c)) is shown to be a component of the IL-4R system, whereas in nonhematopoietic cells, gamma(c) is absent and it is not a component of the IL-4R system. Here, we show that the IL-13R alpha' chain (termed IL-13R alpha') but not the IL-13R alpha chain (termed IL-13R alpha) can substitute for gamma(c) and, thus, IL-13R alpha' forms a novel component of the IL-4R system, This conclusion was drawn on the basis of chemical cross-linking, immunoprecipitation, the ability of IL-10R alpha' but not IL-13R alpha to augment IL-4 binding affinity, and the requirement of IL-13R alpha' for IL-4-induced STAT6 activation in Chinese hamster ovary (CHO) cells transfected with various receptor subunits. Cotransfection of IL-4 receptor p140 (termed IL-4R beta) with gamma(c) or IL-13R alpha' increased IL-4 binding affinity and allowed for STAT6 activation in response to IL-4, However, cotransfection of all three chains did not further increase IL-4 binding or alter the extent of STAT6 activation suggesting that all three chains together do not seem to participate in IL-4 function. Instead, IL-4R beta heterodimerizes with gamma(c) or IL-13R alpha' and mediates STAT6 activation. Cotransfection of IL-4R beta with IL-13R alpha neither increased IL-4 binding affinity nor allowed for STAT6 activation in response to IL-4 indicating that IL-13R alpha does not convert binding affinity nor transmit signals for IL-4, Because IL-4 phosphorylates JAK1 and JAK2 tyrosine kinases in nonhematopoietic cells, we investigated whether JAK1 and JAK2 are required for IL-4-induced STAT6 activation in various transfectants. Cotransfection experiments with different chains of IL-4R and kinase-deficient JAK1 and JAK2 mutants in CHO cells showed that JAK1 and JAK2 are required for optimal activation of STAT6 in the alpha'beta transfectant but only partially in the beta gamma(c) transfectant, Taken together, our results show that IL-13R alpha' is a novel functional component of the IL-4R system and that JAK1 and JAK2 mediate IL-4-induced optimal activation of STAT6 in nonhematopoietic cells. C1 US FDA, Ctr Biol Evaluat & Res, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), US FDA, Ctr Biol Evaluat & Res, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, NIH Bldg 29B,Room 2NN10,29 Lincoln Dr,MSC 4555, Bethesda, MD 20892 USA. NR 30 TC 103 Z9 103 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 15 PY 1998 VL 91 IS 10 BP 3884 EP 3891 PG 8 WC Hematology SC Hematology GA ZM210 UT WOS:000073515700039 PM 9573026 ER PT J AU Hytiroglou, P Kotoula, V Thung, SN Tsokos, M Fiel, MI Papadimitriou, CS AF Hytiroglou, P Kotoula, V Thung, SN Tsokos, M Fiel, MI Papadimitriou, CS TI Telomerase activity in precancerous hepatic nodules SO CANCER LA English DT Article DE cancer; cirrhosis; dysplastic nodule; hepatocellular carcinoma; liver; precancerous lesion; regenerative nodule; telomerase activity ID CHRONIC LIVER-DISEASE; HEPATOCELLULAR CARCINOMAS; MACROREGENERATIVE NODULES; ADENOMATOUS HYPERPLASIA; DYSPLASTIC NODULES; IMMORTAL CELLS; CIRRHOSIS; EXPLANTS; CANCER; LESION AB BACKGROUND. Recent studies have demonstrated that telomerase, a reverse transcriptase linked to cellular "immortalization," is activated in a variety of malignant human tumors. This study was conducted to determine whether telomerase activity represents a marker of malignant transformation in precancerous (dysplastic) nodules arising in patients with cirrhosis. METHODS. Telomerase activity was evaluated in frozen tissue samples of 14 cirrhotic liver specimens and 30 large nodular lesions contained therein, including 13 large regenerative nodules/low grade dysplastic nodules, 10 high grade dysplastic nodules, and 7 hepatocellular carcinomas (HCCs). A modified telomeric repeat amplification protocol was used. RESULTS. There was a clear-cut difference in telomerase activity levels between HCC (positive or strongly positive) and cirrhotic liver samples (weakly positive or negative). The majority of large noncancerous nodules (86%) exhibited telomerase activity levels similar to HCCs. However, such activity was not limited to dysplastic lesions but also was detected in some large regenerative nodules. CONCLUSIONS. These findings suggest that telomerase activation is an early event in large nodule formation in cirrhosis, which may facilitate the action of other factors in the process of carcinogenesis. Telomerase activity in large hepatic nodules is not always indicative of malignant transformation. (C) 1998 American Cancer Society. C1 Aristotelian Univ Salonika, Sch Med, Dept Pathol, GR-54006 Thessalonica, Greece. Mt Sinai Sch Med, Lillian & Henry M Stratton Hans Popper Dept Patho, New York, NY USA. NCI, Pathol Lab, Sect Pediat Pathol & Electron Microscopy, NIH, Bethesda, MD 20892 USA. RP Hytiroglou, P (reprint author), Aristotelian Univ Salonika, Sch Med, Dept Pathol, GR-54006 Thessalonica, Greece. NR 31 TC 46 Z9 48 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 MAY 15 PY 1998 VL 82 IS 10 BP 1831 EP 1838 DI 10.1002/(SICI)1097-0142(19980515)82:10<1831::AID-CNCR4>3.0.CO;2-Q PG 8 WC Oncology SC Oncology GA ZL108 UT WOS:000073399600004 PM 9587114 ER PT J AU Palka, JA Phang, JM AF Palka, JA Phang, JM TI Prolidase in human breast cancer MCF-7 cells SO CANCER LETTERS LA English DT Article DE fibroblasts; collagen; integrins; extracellular matrix; breast cancer cells ID GENE-EXPRESSION; DEFICIENCY; COLLAGEN; PROTEINS; PROLINE; IMINODIPEPTIDURIA; INTEGRINS; CLEAVAGE; PH AB Prolidase (EC 3.4.13.9) is an ubiquitously distributed imidodipeptidase that catalyzes the hydrolysis of dipeptides containing C-terminal proline or hydroxyproline. The enzyme plays an important role in the recycling of proline for collagen synthesis and cell growth. We have shown previously that prolidase activity in normal human skin fibroblasts is regulated by the interaction of type I collagen with beta(1) integrin receptor. In the present study, we investigate prolidase activity in MCF-7 cells and find it is only one-third of that in normal human skin fibroblasts. The relative difference in prolidase activity is corroborated by enzyme protein with Western immunoblot analysis. We propose that the decrease in prolidase activity is due to derangement of regulation by the collagen-beta(1) integrin receptor axis. Supporting evidence comes from the following observations: (1) relative collagen content elaborated by MCF-7 cells as compared to fibroblasts is lower by 30% in sparse cells and by 80% at confluence; (2) collagenase treatment of both cell types results in decreased enzyme activity; (3) in contrast to fibroblasts, prolidase activity in MCF-7 cells is not stimulated by the addition of type I collagen or beta(1) integrin antibodies (agonist for beta(1) integrin receptor); and (4) in contrast to fibroblasts, MCF-7 cells express only trace amounts of beta(1) integrin receptor as shown by Western immunoblot analysis. Thus, we conclude that depressed prolidase activity in MCF-7 cells may be a result of disturbances in signaling mediated by beta(1) integrin-collagen interaction. (C) 1998 Elsevier Science Ireland Ltd. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Nutr & Mol Regulat, Div Basic Sci, Frederick, MD 21702 USA. RP Phang, JM (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Nutr & Mol Regulat, Div Basic Sci, Bldg 560,Room 12-91, Frederick, MD 21702 USA. NR 24 TC 23 Z9 23 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD MAY 15 PY 1998 VL 127 IS 1-2 BP 63 EP 70 DI 10.1016/S0304-3835(98)00011-1 PG 8 WC Oncology SC Oncology GA ZM994 UT WOS:000073597200009 PM 9619859 ER PT J AU Thompson, PA Shields, PG Freudenheim, JL Stone, A Vena, JE Marshall, JR Graham, S Laughlin, R Nemoto, T Kadlubar, FF Ambrosone, CB AF Thompson, PA Shields, PG Freudenheim, JL Stone, A Vena, JE Marshall, JR Graham, S Laughlin, R Nemoto, T Kadlubar, FF Ambrosone, CB TI Genetic polymorphisms in catechol-O-methyltransferase, menopausal status, and breast cancer risk SO CANCER RESEARCH LA English DT Article ID ESTROGEN METABOLISM AB Polymorphic catechol-O-methyltransferase (COMT) catalyzes the O-methylation of estrogen catechols, In a case-control study, we evaluated the association of the low-activity allele (COMTMet) viith breast cancer risk. Compared to women with COMTVal/Val, COMTMet/Met was associated with an increased risk among premenopausal women [odds ratio (OR), 2.1; confidence interval (CI), 1.4-4.3] but was inversely associated with postmenopausal risk (OR, 0.4; CI, 0.2-0.7). The association of risk with at least one low-activity COMTMet allele was strongest among the heaviest premenopausal a omen (OR, 5.7; CI, 1.1-30.1) and among the leanest postmenopausal women (OR, 0.3; CI, 0.1-0.7), suggesting that COMT, mediated by body mass index, may be playing differential roles in human breast carcinogenesis, dependent upon menopausal status. C1 Natl Ctr Toxicol Res, Div Mol Epidemiol, Jefferson, AR 72079 USA. NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14214 USA. Arizona Canc Ctr, Tucson, AZ 85724 USA. RP Ambrosone, CB (reprint author), Natl Ctr Toxicol Res, Div Mol Epidemiol, 3900 NCTR Rd, Jefferson, AR 72079 USA. RI Shields, Peter/I-1644-2012 FU NCI NIH HHS [CA/ES62995, CA01633, CA11535] NR 32 TC 166 Z9 169 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 1998 VL 58 IS 10 BP 2107 EP 2110 PG 4 WC Oncology SC Oncology GA ZP382 UT WOS:000073746700015 PM 9605753 ER PT J AU Smith, MT Zhang, LP Wang, YX Hayes, RB Li, GL Wiemels, J Dosemeci, M Titenko-Holland, N Xi, LQ Kolachana, P Yin, SN Rothman, N AF Smith, MT Zhang, LP Wang, YX Hayes, RB Li, GL Wiemels, J Dosemeci, M Titenko-Holland, N Xi, LQ Kolachana, P Yin, SN Rothman, N TI Increased translocations and aneusomy in chromosomes 8 and 21 among workers exposed to benzene SO CANCER RESEARCH LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; MOLECULAR DELINEATION; FUSION TRANSCRIPT; CHAIN-REACTION; ABERRATIONS; LYMPHOCYTES; HUMANS; RISK; GENE AB Chromosome aberrations in peripheral blood lymphocytes have been used for many Sears to monitor human populations exposed to potential carcinogens. Recent reports have confirmed the validity of this approach by demonstrating that elevated levels of chromosome aberrations in lymphocytes are associated with subsequent increased cancer risk, especially for increased mortality from hematological malignancies including acute myeloid leukemia (AML), We postulated that this approach could be improved in two ways: (a) by detecting oncogenic disease-specific aberrations; and (b) by using chromosome painting so that many more metaphases could be analyzed. Numerical and structural aberrations in chromosomes 8 and 21 are commonly observed in AML, In the present study, we painted chromosomes 8 and 21 in lymphocyte metaphases from 43 healthy workers exposed to benzene, an established cause of AML, and from 44 matched controls. To examine dose-response relationships the workers sere divided into two groups at the median exposure level, a lower-exposed group (less than or equal to 31 ppm; n = 21), and a higher-exposed group (>31 ppm; n = 22), Benzene exposure was associated with significant increases in hyperdiploidy of chromosomes 8 (1.2, 1.5, and 2.4 per 100 metaphases; P < 0.0001) and 21 (0.9, 1.1, and 1.9 per 100 metaphases; P < 0.0001). Translocations between chromosomes 8 and 21 were increased up to Ii-fold in highly exposed workers (0.01, 0.04, and 0.16 per 100 metaphases; P < 0.0001), In one highly exposed individual, these translocations were reciprocal and were detectable by reverse transcriptase-PCR, These data indicate a potential role for t(8;21) in benzene-induced leukemogenesis and are consistent with the hypothesis that detection of specific chromosome aberrations may be a powerful approach to identify populations at increased risk of leukemia. C1 Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Chinese Acad Prevent Med, Inst Occupat Med, Beijing 100050, Peoples R China. RP Smith, MT (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. FU NIEHS NIH HHS [P42 ES04705, P30 ES01896, R01 ES06721] NR 41 TC 90 Z9 96 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 1998 VL 58 IS 10 BP 2176 EP 2181 PG 6 WC Oncology SC Oncology GA ZP382 UT WOS:000073746700025 PM 9605763 ER PT J AU Yuan, BZ Miller, MJ Keck, CL Zimonjic, DB Thorgeirsson, SS Popescu, NC AF Yuan, BZ Miller, MJ Keck, CL Zimonjic, DB Thorgeirsson, SS Popescu, NC TI Cloning, characterization, and chromosomal localization of a gene frequently deleted in human liver cancer (DLC-1) homologous to rat RhoGAP SO CANCER RESEARCH LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; HEPATOCELLULAR-CARCINOMA; PROSTATE-CANCER; 8P21.3-P22; TUMORS AB The isolation of genes involved in cancer development is critical for uncovering the molecular basis of cancer. We report here the isolation of the full-length cDNA and chromosomal localization of a new gene frequently deleted in liver cancer (DLC-1) that was identified by representational difference analysis, Loss of heterozygosity was detected for DLC-1 in 7 of 16 primary hepatocellular carcinomas (HCCs) and in 10 of 11 HCC cell lines. Although mRNA for DLC-1 was expressed in all normal human tissues, it was not expressed in 4 of 14 HCC cell lines. Full-length cDNA for DLC-1 of 3800 bp encodes a protein of 1091 amino acids, has 86% homology with rat p122 RhoGAP gene, and was localized by fluorescence in situ hybridization on chromosome 8 at bands p21.3-22. Deletions on the short arm of chromosome 8 are recurrent in liver, breast, lung, and prostate cancers, suggesting the presence of tumor suppressor genes. DLC-1 may be a tumor suppressor gene in liver cancer as well as in other cancers. C1 NCI, Div Basic Sci, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Popescu, NC (reprint author), NCI, Div Basic Sci, Expt Carcinogenesis Lab, NIH, Bldg 37,Room 3C28,37 Convent Dr MSC4255, Bethesda, MD 20892 USA. NR 27 TC 266 Z9 300 U1 3 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 1998 VL 58 IS 10 BP 2196 EP 2199 PG 4 WC Oncology SC Oncology GA ZP382 UT WOS:000073746700028 PM 9605766 ER PT J AU Vannucci, SJ Reinhart, R Maher, F Bondy, CA Lee, WH Vannucci, RC Simpson, IA AF Vannucci, SJ Reinhart, R Maher, F Bondy, CA Lee, WH Vannucci, RC Simpson, IA TI Alterations in GLUT1 and GLUT3 glucose transporter gene expression following unilateral hypoxia-ischemia in the immature rat brain SO DEVELOPMENTAL BRAIN RESEARCH LA English DT Article DE blood-brain barrier; neuron; neonatal brain damage ID CEREBRAL GLUCOSE; MESSENGER-RNA; ENERGY-METABOLISM; BLOOD-FLOW; C-FOS; EVOLUTION; PROTEINS; DAMAGE; CELLS; HYBRIDIZATION AB The brain damage produced by unilateral cerebral hypoxia-ischemia in the immature rat results from major alterations in cerebral energy metabolism and glucose utilization which begin during the course of the insult and proceed into the recovery period. Consistent with a lack of pathology, the alterations in the hemisphere contralateral to the carotid artery ligation are transient and return to normal within 24 h of recovery, whereas the hemisphere ipsilateral to the Ligation exhibits both early and late responses, and infarction. The facilitative glucose transporter proteins mediate glucose transport across the blood-brain barrier (55 kDa GLUT1), and into neurons and glia (GLUT3 and 45 kDa GLUT1), and demonstrate both early and late responses to perinatal hypoxia-ischemia. This study employed in situ hybridization histochemistry to investigate the temporal and regional patterns of GLUT1 and GLUTS gene expression following a severe (2.5 h) hypoxic-ischemic insult in the 7-day old rat brain. Enhanced GLUT1 mRNA expression was apparent in cerebral microvessels of both hemispheres and remained elevated in the ipsilateral hemisphere through 24 h of recovery, consistent with our previous observation of increased microvascular 55 kDa GLUT1 protein. The expression of the neuronal isoform, GLUTS, was enhanced in penumbral regions, such as piriform cortex and amygdala, but was rapidly reduced in the affected areas of cortex, hippocampus and thalamus, reflecting necrosis. The late response, observed at 72 h of recovery, was characterized by extensive necrosis in the ipsilateral hemisphere, loss of GLUTS expression, and a gliotic reaction including increased GLUT1 in GFAP-positive astrocytes. This study demonstrates that cerebral hypoxia-ischemia in the immature rat produces both immediate-early and long-term effects on the glucose transporter proteins at the level of gene expression. (C) 1998 Elsevier Science B.V. C1 Penn State Univ, Milton S Hershey Med Ctr, Dept Pediat, Hershey, PA 17033 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Dept Anat, Indianapolis, IN 46202 USA. RP Vannucci, SJ (reprint author), Penn State Univ, Milton S Hershey Med Ctr, Dept Pediat, Hershey, PA 17033 USA. NR 44 TC 55 Z9 57 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-3806 J9 DEV BRAIN RES JI Dev. Brain Res. PD MAY 15 PY 1998 VL 107 IS 2 BP 255 EP 264 DI 10.1016/S0165-3806(98)00021-2 PG 10 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA ZR746 UT WOS:000074009600010 ER PT J AU Blagosklonny, MV An, WG Romanova, LY Trepel, J Fojo, T Neckers, L AF Blagosklonny, MV An, WG Romanova, LY Trepel, J Fojo, T Neckers, L TI p53 inhibits hypoxia-inducible factor-stimulated transcription SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IN-VITRO; ACTIVATION; ARREST; CELLS; CHECKPOINT; APOPTOSIS; PROTEIN; BINDING; MUTANT; P21 AB p53 is required for hypoxia-induced apoptosis in vivo, although the mechanism by which this occurs is not known. Conversely, induction of the hypoxia-inducible factor-1 (HIF-1) transactivator stimulates transcription of a number of genes crucial to survival of the hypoxic state. Here we demonstrate that p53 represses HIF-1-stimulated transcription. Although higher levels of p53 are required to inhibit HIF than are necessary to transcriptionally activate p53 target genes, these levels of p53 are similar to those that stimulate cleavage of poly(ADP-ribose) polymerase, an early event in apoptosis, Transfection of full-length p300 stimulates both p53-dependent and HIF-dependent transcription but does not relieve p53-mediated inhibition of HIF. In contrast, a p300 fragment, which binds to p53 but not to HIF-1, prevents p53-dependent repression of HIF activity. Transcriptionally inactive p53, mutated in its DNA binding domain, retains the ability to block HIF transactivating activity, whereas a transcriptionally inactive double point mutant defective for p300 binding does not inhibit HIF. Finally, depletion of doxorubicin-induced endogenous p53 by E6 protein attenuates doxorubicin-stimulated inhibition of HIF, suggesting that a p53 level sufficient for HIF inhibition can be achieved in vivo. These data support a model in which stoichiometric binding of p53 to a HIF/p300 transcriptional complex mediates inhibition of HIF activity. C1 NCI, Med Branch, Dept Expt Therapeut, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, Dept Cell & Canc Biol, NIH, Bethesda, MD 20892 USA. NCI, Genet Lab, NIH, Bethesda, MD 20892 USA. RP Blagosklonny, MV (reprint author), NCI, Med Branch, Dept Expt Therapeut, NIH, Bldg 10,Rm 12N226, Bethesda, MD 20892 USA. NR 22 TC 222 Z9 239 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 MAY 15 PY 1998 VL 273 IS 20 BP 11995 EP 11998 DI 10.1074/jbc.273.20.11995 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZN277 UT WOS:000073629800003 PM 9575138 ER PT J AU Nemansky, M Thotakura, NR Lyons, CD Ye, S Reinhold, BB Reinhold, VN Blithe, DL AF Nemansky, M Thotakura, NR Lyons, CD Ye, S Reinhold, BB Reinhold, VN Blithe, DL TI Developmental changes in the glycosylation of glycoprotein hormone free alpha subunit during pregnancy SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN CHORIONIC-GONADOTROPIN; ASPARAGINE-LINKED OLIGOSACCHARIDES; ANION-EXCHANGE CHROMATOGRAPHY; PULSED AMPEROMETRIC DETECTION; BETA-SUBUNIT; SUGAR CHAINS; TROPHOBLASTIC DISEASES; LUTEINIZING-HORMONE; CARBOHYDRATE CHAINS; MASS-SPECTROMETRY AB Glycoprotein hormone alpha subunit, in its free form (free alpha), is a major placental product. Its glycosylation was found to change dramatically during the advancement of pregnancy. In this study, we have analyzed these glycosylation changes in five normal pregnancies, Binding to Lens culinaris lectin increased dramatically in all subjects between weeks 14 and 17 from the last menstrual period, indicating more core fucosylation as well as possible changes in branching of glycans, Studies using Datura stramonium agglutinin confirmed that the type of triantennary branching changed in this period of pregnancy. The precise structural nature of Obese changes was determined by high-pH anion-exchange chromatography and electrospray ionization mass spectrometry. Amounts of core fucosylation and of triantennary glycans increased substantially from early to late second trimester, and a shift was observed from 1-->4/1-->3- toward predominantly 1-->6/1-->6-branched triantennary structures. The glycosylation changes occurred in all five individuals at the same time period in gestation, suggesting developmental regulation of N-acetylglucosaminyltransferases IV and V and alpha 6-fucosyltransferase during normal pregnancy. These enzymatic activities also appear to be affected in malignant transformation of the trophoblast. Our findings have important implications for the proposed use of specific forms of glycosylation as markers for cancer, as the relative amounts of these glycans in normal pregnancy will be determined by gestational age. C1 NICHD, Unit Glycobiol, Dev Endocrinol Branch, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Dept Microbiol & Immunol, Boston, MA 02118 USA. RP Blithe, DL (reprint author), NICHD, Contracept & Reprod Hlth Branch, NIH, Bldg 61E,Rm 8B13, Bethesda, MD 20892 USA. FU NCRR NIH HHS [5P41RR10888]; NIGMS NIH HHS [R01 GM54045] NR 51 TC 19 Z9 20 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 15 PY 1998 VL 273 IS 20 BP 12068 EP 12076 DI 10.1074/jbc.273.20.12068 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZN277 UT WOS:000073629800014 PM 9575149 ER PT J AU Lefebvre, P Mouchon, A Lefebvre, B Formstecher, P AF Lefebvre, P Mouchon, A Lefebvre, B Formstecher, P TI Binding of retinoic acid receptor heterodimers to DNA - A role for histones NH2 termini SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GLUCOCORTICOID RESPONSE ELEMENT; TRANSCRIPTION FACTOR-BINDING; NUCLEOSOMAL DNA; FACILITATED BINDING; TRANSLATIONAL POSITION; PROTEIN; ACETYLATION; ACTIVATION; CBP; COACTIVATOR AB The retinoic acid signaling pathway is controlled essentially through two types of nuclear receptors, RARs and RXRs. Ligand dependent activation or repression of retinoid-regulated genes is dependent on the binding of retinoic acid receptor (RAR)/9-cis-retinoic acid receptor (RXR) heterodimers to retinoic acid response element (RARE). Although unliganded RXR/RAR heterodimers bind constitutively to DNA in vitro, a clear in vivo ligand-dependent occupancy of the RARE present in the RAR beta 2 gene promoter has been reported (Dey, A., Minucci, S., and Ozato, K. (1994) Mol. Cell. Biol. 14, 8191-8201). Nucleosomes are viewed as general repressors of the transcriptional machinery, in part by preventing the access of transcription factors to DNA. The ability of hRXR alpha/hRAR alpha heterodimers to bind to a nucleosomal template in vitro has therefore been examined. The assembly of a fragment from the RAR beta 2 gene promoter, which contains a canonical DR5 RARE, into a nucleosome core prevented hRXR alpha/hRAR alpha binding to this DNA, in conditions where a strong interaction is observed with a linear DNA template. However, histone tails removal by limited proteolysis and histone hyperacetylation yielded nucleosomal RAREs able to bind to hRXR alpha/hRAR alpha heterodimers. These data establish therefore the role of histones NH2 termini as a major impediment to retinoid receptors access to DNA, and identify histone hyperacetylation as a potential physiological regulator of retinoid-induced transcription. C1 Fac Med Henri Warembourg, Lab Biochim Struct, INSERM, U459, F-59045 Lille, France. RP Lefebvre, P (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bldg 6,Rm 2A11, Bethesda, MD 20892 USA. RI Lefebvre, Philippe/F-2685-2010 OI Lefebvre, Philippe/0000-0002-9366-5129 NR 63 TC 22 Z9 22 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 MAY 15 PY 1998 VL 273 IS 20 BP 12288 EP 12295 DI 10.1074/jbc.273.20.12288 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZN277 UT WOS:000073629800045 PM 9575180 ER PT J AU Newitt, JA Bernstein, HD AF Newitt, JA Bernstein, HD TI A mutation in the Escherichia coli secY gene that produces distinct effects on inner membrane protein insertion and protein export SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ENDOPLASMIC-RETICULUM MEMBRANE; SIGNAL RECOGNITION PARTICLE; CYTOPLASMIC MEMBRANE; SECRETORY PROTEINS; CONDUCTING CHANNEL; 4.5S RNA; TRANSLOCATION; MUTANTS; OCCURS; RIBONUCLEOPROTEIN AB E. coli strains that contain the secY40 mutation are cold-sensitive, but protein export defects have not been observed even at the nonpermissive temperature. Here we describe experiments designed to explain the conditional phenotype associated with this allele, We found that combining the secY40 mutation with defects in the signal recognition particle targeting pathway led to synthetic lethality. Since the signal recognition particle is required for the insertion of inner membrane proteins (IMPs) into the cytoplasmic membrane but not for protein export, this observation prompted us to examine the effect of the secY40 mutation on IMP biogenesis. The membrane insertion of all IMPs that we tested was impaired at both permissive and nonpermissive temperatures in secY40 cells grown in either rich or minimal medium. The magnitude of the insertion defects was greatest in cells grown at low temperature in rich medium, conditions in which the growth defect was most pronounced. Consistent with previous reports, we could not detect protein export defects in secY40 cells grown in minimal medium. Upon growth in rich medium, only slight protein export defects were observed. Taken together, these results suggest that the impairment of IMP insertion causes the cold sensitivity of secY40 strains. Furthermore, these results provide the first evidence that the protein export and membrane protein insertion functions of the translocon are genetically separable. C1 NIDDK, GBB, NIH, Bethesda, MD 20892 USA. RP Bernstein, HD (reprint author), NIDDK, GBB, NIH, 10 Ctr Dr,MSC 1810, Bethesda, MD 20892 USA. NR 44 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 MAY 15 PY 1998 VL 273 IS 20 BP 12451 EP 12456 DI 10.1074/jbc.273.20.12451 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZN277 UT WOS:000073629800067 PM 9575202 ER PT J AU Grimaud, R Kessel, M Beuron, F Steven, AC Maurizi, MR AF Grimaud, R Kessel, M Beuron, F Steven, AC Maurizi, MR TI Enzymatic and structural similarities between the Escherichia coli ATP-dependent proteases, ClpXP and ClpAP SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SPECIFICITY COMPONENT; MOLECULAR CHAPERONE; PROTEIN; SEQUENCE; PURIFICATION; PROTEOLYSIS; DEGRADATION; ACTIVATOR; HSLV AB Escherichia coli ClpX, a member of the Clp family of ATPases, has ATP-dependent chaperone activity and is required for specific ATP-dependent proteolytic activities expressed by ClpP, Gel filtration and electron microscopy showed that ClpX subunits (M-r 46,000) associate to form a six-membered ring (M-r similar to 280,000) that is stabilized by binding of ATP or nonhydrolyzable analogs of ATP, ClpP, which is composed of two seven-membered rings stacked face-to-face, interacts with the nucleotide-stabilized hexamer of ClpX to form a complex that could be isolated by gel filtration. Electron micrographs of negatively stained ClpXP preparations showed side views of 1:1 and 2:1 ClpXP complexes in which ClpP was flanked on either one or both sides by a ring of ClpX, Thus, as was seen for ClpAP, a symmetry mismatch exists in the bonding interactions between the seven-membered rings of ClpP and the six-membered rings of ClpX, Competition studies showed that ClpA may have a slightly higher affinity (similar to 2-fold) for binding to ClpP, Mixed complexes of ClpA, ClpX, and ClpP with the two ATPases bound simultaneously to opposite faces of a single ClpP molecule were seen by electron microscopy, In the presence of ATP or nonhydrolyzable analogs of ATP, ClpXP had nearly the same activity as ClpAP against oligopeptide substrates (>10,000 min(-1)/tetradecamer of ClpP), Thus, ClpX and ClpA interactions with ClpP result in structurally analogous complexes and induce similar conformational changes that affect the accessibility and the catalytic efficiency of ClpP active sites. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NIAMS, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. RP Maurizi, MR (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Rm 1B07,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. NR 37 TC 192 Z9 194 U1 1 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 15 PY 1998 VL 273 IS 20 BP 12476 EP 12481 DI 10.1074/jbc.273.20.12476 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZN277 UT WOS:000073629800070 PM 9575205 ER PT J AU Olivera, A Kohama, T Tu, ZX Milstien, S Spiegel, S AF Olivera, A Kohama, T Tu, ZX Milstien, S Spiegel, S TI Purification and characterization of rat kidney sphingosine kinase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INOSITOL 1,4,5-TRISPHOSPHATE 3-KINASE; CELLULAR PROLIFERATION; ACID SPHINGOMYELINASE; SIGNAL-TRANSDUCTION; LIPID 2ND-MESSENGERS; CALCIUM MOBILIZATION; INDUCED APOPTOSIS; PHOSPHOLIPASE-D; 2ND MESSENGER; SMOOTH-MUSCLE AB Sphingosine kinase catalyzes the formation of the bioactive sphingolipid metabolite sphingosine l-phosphate, which plays important roles in numerous physiological processes, including growth, survival, and motility. We have purified rat kidney sphingosine kinase 6 x 10(5)-fold to apparent homogeneity. The purification procedure involved ammonium sulfate precipitation followed by chromatography on an anion exchange column. Partially purified sphingosine kinase was found to be stabilized by the presence of high salt, and thus, a scheme was developed to purify sphingosine kinase using sequential dye-ligand chromatography steps (since the enzyme bound to these matrices even in the presence of salt) followed by EAH-Sepharose chromatography. This 385-fold purified sphingosine kinase bound tightly to cahmodulin-Sepharose and could be eluted in high yield with EGTA in the presence of 1 M Nacl. After concentration, the calmodulin eluate was further purified by successive high pressure Liquid chromatography separations on hydroxylapatite, Mono Q, and Superdex 75 gel filtration columns. Purified sphingosine kinase has an apparent molecular mass of similar to 49 kDa under denaturing conditions on SDS-polyacrylamide gel, which is similar to the molecular mass determined by gel filtration, suggesting that the active form is a monomer. Sphingosine kinase shows substrate specificity for D-erythro-sphingosine and does not catalyze the phosphorylation of phosphatidylinositol, diacylglycerol, ceramide, DL-threo-dihydrosphingosine, or N,N-dimethylsphingosine. However, the latter two sphingolipids were potent competitive inhibitors. With sphingosine as substrate, the enzyme had a broad pH optimum of 6.6-7.5 and showed Michaelis-Menten kinetics, with K-m values of 5 and 93 mu M for sphingosine and ATP, respectively. This study provides the basis for molecular characterization of a key enzyme in sphingolipid signaling. C1 Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, 353 Basic Sci Bldg,3900 Reservoir Rd NW, Washington, DC 20007 USA. EM spiegel@biochem1.basic-sci.georgetown.edu FU NIGMS NIH HHS [GM43880] NR 51 TC 172 Z9 179 U1 1 U2 15 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 MAY 15 PY 1998 VL 273 IS 20 BP 12576 EP 12583 DI 10.1074/jbc.273.20.12576 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZN277 UT WOS:000073629800083 PM 9575218 ER PT J AU Janne, PA Suchy, SF Bernard, D MacDonald, M Crawley, J Grinberg, A Wynshaw-Boris, A Westphal, H Nussbaum, RL AF Janne, PA Suchy, SF Bernard, D MacDonald, M Crawley, J Grinberg, A Wynshaw-Boris, A Westphal, H Nussbaum, RL TI Functional overlap between murine Inpp5b and Ocrl1 may explain why deficiency of the murine ortholog for OCRL1 does not cause Lowe syndrome in mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE mouse; mutant strain; phosphoinositides; Fanconi syndrome; cataract ID 75-KDA INOSITOL POLYPHOSPHATE-5-PHOSPHATASE; EMBRYONIC STEM-CELLS; OCULOCEREBRORENAL SYNDROME; HUMAN-PLATELETS; GENE; 5-PHOSPHATASE; IDENTIFICATION; PHENOTYPE; DISEASES; MODELS AB The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked human genetic disorder characterized by mental retardation, congenital cataracts, and renal tubular dysfunction. The Lowe syndrome gene, OCRL1, encodes a phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi complex. The pathogenesis of Lowe syndrome due to deficiency of a phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi complex is unknown. We have used targeted disruption in embryonic stem cells to make mice deficient in Ocrl1, the mouse homologue for OCRL1, as an animal model for the disease. Surprisingly, mice deficient in Ocrl1 do not develop the congenital cataracts, renal Fanconi syndrome, or neurological abnormalities seen in the human disorder. We hypothesized that Ocrl1 deficiency is complemented in mice by inositol polyphosphate 5-phosphatase (Inpp5b), an autosomal gene that encodes a phosphatidylinositol bisphosphate 5-phosphatase highly homologous to Ocrl1. We created mice deficient in Inpp5b; the mice were viable and fertile without phenotype except for testicular degeneration Ln males beginning after sexual maturation. We crossed mice deficient in Ocrl1 to mice deficient in Inpp5b. No liveborn mice or embryos lacking both enzymes were found, demonstrating that Ocrl1 and Inpp5b have overlapping functions in mice and suggesting that the lack of phenotype in Ocrl1-deficient mice may be due to compensating Inpp5b function. C1 Natl Human Genome Res Inst, Lab Genet Dis Res, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19102 USA. NIMH, Expt Therapeut Branch, Bethesda, MD 20892 USA. NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. RP Nussbaum, RL (reprint author), Natl Human Genome Res Inst, Lab Genet Dis Res, Bldg 49,Room 4A72 NIH,49 Convent Dr, Bethesda, MD 20892 USA. EM rlnuss@nhgri.nih.gov FU NICHD NIH HHS [R01-HD-23245]; NIGMS NIH HHS [T32-GM-07170] NR 36 TC 104 Z9 106 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAY 15 PY 1998 VL 101 IS 10 BP 2042 EP 2053 DI 10.1172/JCI2414 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA ZP981 UT WOS:000073808800003 PM 9593760 ER PT J AU Mott, DM Pratley, RE Bogardus, C AF Mott, DM Pratley, RE Bogardus, C TI Postabsorptive respiratory quotient and insulin-stimulated glucose storage rate in nondiabetic Pima Indians are related to glycogen synthase fractional activity in cultured myoblasts SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE glycogen synthase; skeletal muscle; cell culture; insulin action; obesity ID HUMAN SKELETAL-MUSCLE; PHOSPHORYLATION STATE; ENERGY-EXPENDITURE; CELL-CULTURES; WEIGHT-GAIN; MALONYL-COA; METABOLISM; RESISTANCE; SENSITIVITY; DIACYLGLYCEROL AB A decreased ratio of fat to carbohydrate oxidation rate (an elevated respiratory quotient) predicts the development of obesity. Skeletal muscle accounts for a major fraction of total body lipid oxidation and is the principle site for reduced glucose storage in insulin-resistant subjects. The potentially important role that muscle has in promoting obesity or insulin resistance may be based on metabolic control intrinsic to skeletal muscle. Cultured skeletal muscle provides a system to examine the importance of inherent metabolic traits in muscle biopsies from obese and insulin-resistant subjects. Glycogen synthase fractional activity (GSFA) was measured in cultured myoblasts from 21 Pima Indians characterized in vivo using indirect calorimetry and a euglycemic hyperinsulinemic clamp. Basal GSFA in cultured muscle cells is inversely correlated with postabsorptive respiratory quotient of the muscle donors (r = -0.66, P = 0.001) and with in vivo high dose insulin-stimulated glucose storage rates (r = 0.47, P = 0.04). These results indicate that the postabsorptive respiratory quotients and insulin-mediated glucose storage rates in vivo share a common regulatory mechanism with GSFA in cultured myoblasts, Abnormal regulation of glycogen synthase phosphorylation state may be aln intrinsic defect in skeletal muscle associated with obesity and insulin resistance. C1 NIH, Clin Diabet & Nutr Sect, Phoenix, AZ 85016 USA. RP Mott, DM (reprint author), NIH, Clin Diabet & Nutr Sect, 4212 N 16th St,Room 541, Phoenix, AZ 85016 USA. NR 35 TC 12 Z9 12 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAY 15 PY 1998 VL 101 IS 10 BP 2251 EP 2256 DI 10.1172/JCI1778 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA ZP981 UT WOS:000073808800024 PM 9593781 ER PT J AU Gadina, M Stancato, LM Bacon, CM Larner, AC O'Shea, JJ AF Gadina, M Stancato, LM Bacon, CM Larner, AC O'Shea, JJ TI Cutting edge: Involvement of SHP-2 in multiple aspects of IL-2 signaling: Evidence for a positive regulatory role SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECEPTOR-BETA-CHAIN; PROTEIN-TYROSINE-PHOSPHATASE; JANUS KINASES; ACTIVATION; PHOSPHORYLATION; INTERLEUKIN-2; TRANSDUCTION; RECRUITMENT; ASSOCIATION; INHIBITION AB Binding of IL-2 to its receptor activates several biochemical pathways, but precisely how these pathways are linked is incompletely understood. Here, we report that SHP-2, an SH2-domain containing tyrosine phosphatase, associates with different molecules of the IL-2 signaling cascade, Upon IL-2 stimulation, SHP-2 was coimmunoprecipitated with Grb2 and the p85 subunit of phosphatidylinositol 3-kinase. In contrast, SHP-2 was constitutively associated with JAK1 and JAK3, Finally, SHP-2 expression amplified STAT-dependent transcriptional activation whereas a dominant negative allele inhibited transactivation and the IL-2-induced activation of MAPK (mitogen-activated protein kinase), These results demonstrate the involvement of SHP-2 in multiple pathways of the IL-2 signaling cascade and provide evidence for its positive regulatory role. C1 NIAMSD, Lymphocyte Cell Biol Sect, Arthritis & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Cytokine Biol, Bethesda, MD 20814 USA. RP Gadina, M (reprint author), Bldg 10,Room 9N228,10 Ctr Dr MSC 1820, Bethesda, MD 20892 USA. NR 32 TC 56 Z9 57 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 1998 VL 160 IS 10 BP 4657 EP 4661 PG 5 WC Immunology SC Immunology GA ZM053 UT WOS:000073500000001 PM 9590209 ER PT J AU Anderson, HA Roche, PA AF Anderson, HA Roche, PA TI Phosphorylation regulates the delivery of MHC class II invariant chain complexes to antigen processing compartments SO JOURNAL OF IMMUNOLOGY LA English DT Article ID DI-LEUCINE MOTIF; CYTOPLASMIC TAIL; ENDOCYTIC PATHWAY; RAPID INTERNALIZATION; ENDOPLASMIC-RETICULUM; ASSEMBLY PROTEINS; SORTING SIGNALS; DOWN-REGULATION; CELL-SURFACE; IN-VIVO AB Transport of newly synthesized MHC class II glycoproteins to endosomal Ag processing compartments is mediated by their association with the invariant chain Oil, Targeting to these compartments is dependent upon recognition of leucine-based endosomal/lysosomal targeting motifs in the Ii cytosolic domain. Ii, like many molecules that contain leucine-based endosomal targeting motifs, is phosphorylated in vivo. In this report we demonstrate that the cytosolic domain of the p35 Ii isoform is phosphorylated in class II Ii complexes isolated from human B lymphoblastoid cell lines or freshly obtained PBMC, Mutation of serine residue 6 or 8 prevents phosphorylation of Ii-p35 expressed in HeLa cells, Treatment of B lymphoblastoid cell lines with the serine/threonine kinase inhibitor staurosporine prevented Ii phosphorylation and significantly delayed trafficking of newly synthesized class II Ii complexes to endosomal Ag processing compartments. By contrast, staurosporine had no effect on the rate of transport of class I or class II glycoproteins through the Golgi apparatus and did not inhibit the delivery of the chimeric molecule Tac-DM beta to endocytic compartments, suggesting that staurosporine does not nonspecifically inhibit protein transport to the endocytic pathway. These results demonstrate that phosphorylation regulates the efficient targeting of MHC class II Ii complexes to Ag processing compartments and strongly suggest that this effect is mediated by phosphorylation of the MHC class II-associated Ii chain. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Roche, PA (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B17,9800 Rockville Pike, Bethesda, MD 20892 USA. NR 47 TC 47 Z9 48 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 MAY 15 PY 1998 VL 160 IS 10 BP 4850 EP 4858 PG 9 WC Immunology SC Immunology GA ZM053 UT WOS:000073500000024 PM 9590232 ER PT J AU Anton, LC Snyder, HL Bennink, JR Vinitsky, A Orlowski, M Porgador, A Yewdell, JW AF Anton, LC Snyder, HL Bennink, JR Vinitsky, A Orlowski, M Porgador, A Yewdell, JW TI Dissociation of proteasomal degradation of biosynthesized viral proteins from generation of MHC class I-associated antigenic peptides SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHYMOTRYPSIN-LIKE ACTIVITY; RESTRICTED LYMPHOCYTES-T; HEAT-SHOCK PROTEINS; ENDOPLASMIC-RETICULUM; INTERFERON-GAMMA; PROTEOLYTIC ACTIVITY; 20S PROTEASOME; INFECTED-CELLS; COMPLEX; EXPRESSION AB To study the role of proteasomes in Ag presentation, we analyzed the effects of proteasome inhibitors Cbz-Leu-Leu-Leucinal and lactacystin on the ability of mouse fibroblast cells to present recombinant vaccinia virus gene products to MRC class I-restricted T cells. The effects of the inhibitors depended on the determinant analyzed, For influenza virus nucleoprotein (NP), presentation of the immunodominant K-k-restricted determinant (NP50-57) was marginally inhibited, whereas presentation of the immunodominant K-d-restricted determinant (NP147-155) was enhanced, particularly by lactacystin, Biochemical purification of peptides confirmed that lactacystin enhanced the generation of K-d-NP147-155 complexes fourfold. Lactacystin also enhanced the recovery of one K-d-restricted vaccinia virus determinant from HPLC fractions, while inhibiting recovery of another. The inhibitors were used at sufficient concentrations to block presentation of biosynthesized full-length OVA and to completely stabilize a rapidly degraded chimeric ubiquitin-NP fusion protein. Strikingly, presentation of antigenic peptides from this protein was unaffected by proteasome inhibitors. We also observed that proteasome inhibitors induced expression of cytosolic and endoplasmic reticulum stress-responsive proteins. These data demonstrate first that the processes of protein degradation and generation of antigenic peptides from cytosolic proteins can be dissociated, and second that effects of proteasome inhibitors on Ag presentation may reflect secondary effects on cellular metabolism. C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. NIAID, Immunol Lab, Bethesda, MD 20892 USA. CUNY Mt Sinai Sch Med, New York, NY 10029 USA. RP Bennink, JR (reprint author), NIH, Room 213,Bldg 4, Bethesda, MD 20892 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012; Anton, Luis/C-4740-2013 OI Anton, Luis/0000-0001-9665-011X FU NIDDK NIH HHS [DK25377] NR 75 TC 53 Z9 54 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 MAY 15 PY 1998 VL 160 IS 10 BP 4859 EP 4868 PG 10 WC Immunology SC Immunology GA ZM053 UT WOS:000073500000025 PM 9590233 ER PT J AU Senyshyn, J Baumgartner, RA Beaven, MA AF Senyshyn, J Baumgartner, RA Beaven, MA TI Quercetin sensitizes RBL-2H3 cells to polybasic mast cell secretagogues through increased expression of Gi GTP-binding proteins linked to a phospholipase C signaling pathway SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BASOPHILIC LEUKEMIA-CELLS; KINASE-C; HISTAMINE-SECRETION; TYROSINE PHOSPHORYLATION; COMPOUND 48/80; ADENOSINE RECEPTORS; SIMILAR MECHANISMS; ARACHIDONIC-ACID; CROSS-LINKING; SUBSTANCE-P AB Polybasic secretagogues such as mastoparan, compound 48/80, substance P, and somatostatin stimulate secretion in rat peritoneal mast cells through direct activation of the heterotrimeric G protein, G(i-3). Cultured RBL-2H3 mast cells do not normally respond to these secretagogues, but, as reported here, they do so after prolonged exposure to the kinase inhibitor, quercetin, This inhibitor, which causes phenotypic changes in RBL-2H3 cells, induces a substantial increase (more than sevenfold) in the expression of ct subunits of the pertussis toxin-sensitive G proteins, G(i-2) and G(i-3). Compound 48/80-induced secretion is associated with transient hydrolysis of phosphoinositides and a transient increase in cytosolic calcium ions. These responses are inhibited by pertussis toxin, and in addition, secretion is blocked by calcium chelation and the protein kinase C inhibitor, Ro31-7549, These results delineate a pathway for compound 48/80-induced secretion in mast cells via G(i) protein(s), phospholipase C, calcium, and protein kinase C, The results also imply that phospholipase C, most likely phospholipase C beta 3, can be transiently activated in RBL-2H3 cells by subunits of G(i) proteins to induce cellular responses. C1 Natl Inst Heart Lung & Blood Dis, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Beaven, MA (reprint author), Natl Inst Heart Lung & Blood Dis, Lab Mol Immunol, NIH, Bldg 10,Room 8N109, Bethesda, MD 20892 USA. OI Senyshyn, Anatoliy/0000-0002-1473-8992 NR 66 TC 58 Z9 60 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 MAY 15 PY 1998 VL 160 IS 10 BP 5136 EP 5144 PG 9 WC Immunology SC Immunology GA ZM053 UT WOS:000073500000058 PM 9590266 ER PT J AU Calabresi, PA Fields, NS Farnon, EC Frank, JA Bash, CN Kawanashi, T Maloni, H Jacobson, S McFarland, HF AF Calabresi, PA Fields, NS Farnon, EC Frank, JA Bash, CN Kawanashi, T Maloni, H Jacobson, S McFarland, HF TI ELI-spot of Th-1 cytokine secreting PBMC's in multiple sclerosis: correlation with MRI lesions SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE multiple sclerosis; MRI; cytokines; ELISA; blood brain barrier ID TUMOR-NECROSIS-FACTOR; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; RESONANCE-IMAGING LESIONS; MYELIN BASIC-PROTEIN; INCREASED FREQUENCY; PERIPHERAL-BLOOD; DISEASE-ACTIVITY; FACTOR-ALPHA; CELLS; EXPRESSION AB The Th1-like cytokines, interleukin 2 (IL-2), interferon gamma (IFN-gamma), and lymphotoxin alpha (LT-alpha) have been implicated in the immunopathogenesis of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), an animal model of immune mediated demyelination. These cytokines have been associated with opening of the blood brain barrier (BBB) in EAE and in vitro, but not in MS. We used an enzyme-linked immunospot (ELI-spot) assay to measure relative numbers of cytokine-secreting peripheral blood mononuclear cells (PBMC) from eight MS patients who were followed with serial monthly contrast-enhanced head magnetic resonance imagings (MRI) and phlebotomy. We found a significant positive correlation between changes in IL-2 secreting cells and MRI lesions over a 6-month time period. There was a weaker association between contrast-enhancing MRT lesions and IFN-gamma or LT-alpha secreting cells. These data are the first to show a significant positive correlation between any cytokine and serial gadolinium (Gd-) MRI disease activity in MS patients. The association between IFN-gamma and LT-alpha secretion and MRI lesions is less clear. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NIH, Lab Diagnost Radiol Res, Off Director, Bethesda, MD 20892 USA. RP Calabresi, PA (reprint author), NINDS, Neuroimmunol Branch, NIH, Bldg 10,Room 5B-16,10 Ctr Dr,MSC-1400, Bethesda, MD 20892 USA. EM pcalabresi@lifespan.org NR 26 TC 22 Z9 23 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 MAY 15 PY 1998 VL 85 IS 2 BP 212 EP 219 DI 10.1016/S0165-5728(98)00008-3 PG 8 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA ZT006 UT WOS:000074038100013 PM 9630170 ER PT J AU Rajan, P McKay, RDG AF Rajan, P McKay, RDG TI Multiple routes to astrocytic differentiation in the CNS SO JOURNAL OF NEUROSCIENCE LA English DT Article DE astrocytic differentiation; CNS stem cells; mammalian CNS development; intracellular signaling; CNTF; BMP4; EGF ID CILIARY NEUROTROPHIC FACTOR; STAT PROTEINS; FACTOR-RECEPTOR; NERVOUS-SYSTEM; IN-VIVO; ACTIVATION; GENE; TRANSCRIPTION; CELLS; ASSOCIATION AB Ciliary neurotrophic factor (CNTF) acts instructively to switch multipotent stem cells ct the CNS to an astrocytic fate, Here we show that CNTF causes activation of janus kinase-signal transducers and activators of transcription and mitogen-activated protein kinase (MAPK) pathways with differential kinetics in these cells. Inhibition studies indicate that activation of the MAPK pathway is required early in the differentiation process, whereas activation of signal transducer and activator of transcription (STAT) proteins is required for commitment to an astrocytic fate. Bone morphogenetic proteins have also been shown to cause astrocytic differentiation but do not cause STAT activation or astrocytic differentiation in fibroblast growth factor 2-expanded fetal stem cells used here. These results show that there are two distinct routes to initiate astrocytic commitment in multipotent CNS precursors. C1 NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP McKay, RDG (reprint author), NINDS, Mol Biol Lab, NIH, Bldg 36,Room 5A29, Bethesda, MD 20892 USA. NR 35 TC 289 Z9 300 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 MAY 15 PY 1998 VL 18 IS 10 BP 3620 EP 3629 PG 10 WC Neurosciences SC Neurosciences & Neurology GA ZL895 UT WOS:000073484300014 PM 9570793 ER PT J AU Dijkstra, I Tilders, FJH Aguilera, G Kiss, A Rabadan-Diehl, C Barden, N Karanth, S Holsboer, F Reul, JMHM AF Dijkstra, I Tilders, FJH Aguilera, G Kiss, A Rabadan-Diehl, C Barden, N Karanth, S Holsboer, F Reul, JMHM TI Reduced activity of hypothalamic corticotropin-releasing hormone neurons in transgenic mice with impaired glucocorticoid receptor function SO JOURNAL OF NEUROSCIENCE LA English DT Article DE corticotropin-releasing hormone (CRH); glucocorticoid receptor (GR); transgenic (TG) mice; IL-1 beta; paraventricular nucleus; HPA axis; CRH receptor ID MESSENGER-RIBONUCLEIC-ACID; PITUITARY-ADRENOCORTICAL SYSTEM; SPLANCHNIC NERVE-STIMULATION; II CORTICOSTEROID RECEPTORS; RAT ANTERIOR-PITUITARY; FACTOR CRF; BEHAVIORAL-RESPONSES; PARAVENTRICULAR NUCLEUS; FACTOR IMMUNOREACTIVITY; ADRENALECTOMIZED RATS AB Loss of central glucocorticoid receptor (GR) function is thought to be involved in the development of neuroendocrine and psychiatric disorders associated with corticotropin-releasing hormone (CRH) hyperactivity. The possible causal relationship between defective GR function and altered activity of CRH neurons was studied in transgenic mice (TG) expressing antisense RNA against GR. Immunocytochemical studies showed significant reductions in CRH immunoreactive neurons in the paraventricular nucleus (PVN) and in CRH and vasopressin (AVP) stores in the external zone of the median eminence. Concomitantly, stimulus-evoked CRH secretion from mediobasal hypothalami of TG mice in vitro was reduced significantly. However, CRH mRNA levels in the PVN of TG mice were marginally lower than those in wild-type (WT) mice. I-125-CRH binding autoradiography revealed no differences between WT and TG animals in any of the brain regions that were studied. Basal plasma corticosterone (cort) levels and I-125-CRH binding, CRH-R-1 mRNA, POMC mRNA, and POMC hnRNA levels in the anterior pituitary gland were similar in WT and TG mice. Intraperitoneal injection of interleukin-1 beta (IL-1 beta) increased plasma cort levels, CRH mRNA in the PVN, and anterior pituitary POMC hnRNA similarly in WT and TG mice. The injection of saline significantly reduced anterior pituitary CRH-R, mRNA levels in WT mice, but not in TG mice, whereas IL-1 beta produced a decrease in these mRNA levels in both strains. The data show that long-term GR dysfunction can be associated with reduced activity of CRH neurons in the PVN and decreased sensitivity of pituitary CRH-R-1 mRNA to stimulus-induced downregulation. Moreover, the hypothalamic changes observed in this model suggest that impaired GR function, at least if present since early embryonic life, does not necessarily result in CRH hyperexpression as major depression. C1 Vrije Univ Amsterdam, Neurosci Res Inst, Fac Med, Dept Pharmacol,Grad Sch Neurosci Amsterdam, NL-1081 BT Amsterdam, Netherlands. NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. CHU Laval, Res Ctr, MRC, Quebec City, PQ G1V 4G2, Canada. Univ Laval, Dept Physiol, Quebec City, PQ G1V 4G2, Canada. Max Planck Inst Psychiat, Dept Neuroendocrinol, Sect Neuroimmunoendocrinol, D-80804 Munich, Germany. RP Tilders, FJH (reprint author), Vrije Univ Amsterdam, Neurosci Res Inst, Fac Med, Dept Pharmacol,Grad Sch Neurosci Amsterdam, Van Der Boechorststr 7, NL-1081 BT Amsterdam, Netherlands. NR 83 TC 59 Z9 60 U1 2 U2 7 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 MAY 15 PY 1998 VL 18 IS 10 BP 3909 EP 3918 PG 10 WC Neurosciences SC Neurosciences & Neurology GA ZL895 UT WOS:000073484300039 PM 9570818 ER PT J AU Simpson, PB Holtzclaw, LA Langley, DB Russell, JT AF Simpson, PB Holtzclaw, LA Langley, DB Russell, JT TI Characterization of ryanodine receptors in oligodendrocytes, type 2 astrocytes, and O-2A progenitors SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE ryanodine receptors; oligodendrocytes; astrocytes; Ca2+ release; waves; caffeine ID CALCIUM WAVES; GLIAL-CELLS; INTRACELLULAR CALCIUM; CULTURED ASTROCYTES; ENDOPLASMIC-RETICULUM; ADENOSINE RECEPTORS; GLUTAMATE-RECEPTOR; RELEASE CHANNEL; ACID RECEPTORS; AMPA RECEPTORS AB In this study we have investigated the expression of ryanodine receptors (RyRs), and the ability of caffeine to evoke RyR-mediated elevation of intracellular Ca2+ levels ([Ca2+](i)) in glial cells of the oligodendrocyte/ type 2 astrocyte lineage. Immunocytochemistry with specific antibodies identified ryanodine receptors in cultured oligodendrocytes, type 2 astrocytes, and O-2A progenitor cells, at high levels in the perinuclear region and in a variegated pattern along processes, Glia acutely isolated from rat brain and in aldehyde-fixed sections of cortex were similarly found to express RyRs. Caffeine (5-50 mM) caused an increase in [Ca2+](i) in most cultured type 2 astrocytes and in 50% of oligodendrocytes. Responses elicited by caffeine were inhibited by pretreatment with ryanodine (10 mu M) or thapsigargin (1 mu M), and the peak response was unaffected by removal of [Ca2+](O). O-2A progenitor cells, in contrast, were largely unresponsive to caffeine treatment. Pretreatment with kainate (200 mu M) to activate Ca2+ entry increased the magnitude of caffeine-evoked [Ca2+](i) elevations in type 2 astrocytes and oligodendrocytes, and caused caffeine to activate responses in a significant proportion of previously non-responding O-2A progenitors. In both type 2 astrocytes and oligodendrocytes, caffeine evoked Ca2+ changes which propagated as wavefronts from several initiation sites, These wave amplification sites were characterized by significantly higher local Ca2+ release kinetics. Our results indicate that several gLial cell types express RyRs, and that their functionality differs within different cell types of the oligodendrocyte Lineage. In addition, ionotropic glutamate receptor activation fills the caffeine-sensitive Ca2+ stores in these cells. (C) 1998 Wiley-Liss, Inc. C1 NICHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Russell, JT (reprint author), NICHD, Lab Cellular & Mol Neurophysiol, NIH, Bldg 49,Room 5A-78, Bethesda, MD 20892 USA. EM james@helix.nih.gov NR 66 TC 26 Z9 27 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 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD MAY 15 PY 1998 VL 52 IS 4 BP 468 EP 482 DI 10.1002/(SICI)1097-4547(19980515)52:4<468::AID-JNR11>3.0.CO;2-# PG 15 WC Neurosciences SC Neurosciences & Neurology GA ZL618 UT WOS:000073452800011 PM 9589392 ER PT J AU Ghedin, E Charest, H Matlashewski, G AF Ghedin, E Charest, H Matlashewski, G TI A2rel: a constitutively expressed Leishmania gene linked to an amastigote-stage-specific gene SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article ID DONOVANI; IDENTIFICATION; CLEAVAGE; PROTEINS; INVITRO; CLONING AB The A2-A2rel gene copies are arranged in tandem arrays on a 850 kb chromosome in Leishmania donovani. Contrary to A2 mRNA which displays amastigote-stage-specific expression, A2rel gene expression is constitutive throughout the L. donovani life cycle. The A2rel sequence was found to be conserved in all Leishmania species tested, while the A2 sequence is specific to L. donovani and L. mexicana. The A2rel full length cDNA is of 2.3 kb and it contains one open reading frame coding for a putative protein of 436 amino acids. (C) 1998 Elsevier Science B.V. All rights reserved. C1 McGill Univ, Inst Parasitol, St Anne De Bellevue, PQ H9X 3V9, Canada. NIAID, Parasit Dis Lab, Immunobiol Sect, NIH, Bethesda, MD 20892 USA. RP Matlashewski, G (reprint author), McGill Univ, Inst Parasitol, Macdonald Campus,21 111 Lakeshore Rd, St Anne De Bellevue, PQ H9X 3V9, Canada. NR 13 TC 12 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD MAY 15 PY 1998 VL 93 IS 1 BP 23 EP 29 DI 10.1016/S0166-6851(98)00027-9 PG 7 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA ZT679 UT WOS:000074113700003 PM 9662025 ER PT J AU Rein, T DePamphilis, ML Zorbas, H AF Rein, T DePamphilis, ML Zorbas, H TI Identifying 5-methylcytosine and related modifications in DNA genomes SO NUCLEIC ACIDS RESEARCH LA English DT Review ID LIGATION-MEDIATED PCR; POLYMERASE CHAIN-REACTION; PERFORMANCE LIQUID-CHROMATOGRAPHY; RESTRICTION-MODIFICATION ENZYMES; DROSOPHILA-MELANOGASTER DNA; SINGLE-COPY GENE; METHYLATION ANALYSIS; SEQUENCE SPECIFICITY; IN-VIVO; CYTOSINE METHYLATION AB Intense interest in the biological roles of DNA methylation, particularly in eukaryotes, has produced at least eight different methods for identifying 5-methylcytosine and related modifications in DNA genomes, However, the utility of each method depends not only on its simplicity but on its specificity, resolution, sensitivity and potential artifacts. Since these parameters affect the interpretation of data, they should be considered in any application. Therefore, we have outlined the principles and applications of each method, quantitatively evaluated their specificity, resolution and sensitivity, identified potential artifacts and suggested solutions, and discussed a paradox in the distribution of m(5)C in mammalian genomes that illustrates how methodological limitations can affect interpretation of data, Hopefully, the information and analysis provided here will guide new investigators entering this exciting field. C1 Univ Munich, Inst Biochem, D-81377 Munich, Germany. NICHHD, NIH, Bethesda, MD 20892 USA. RP Zorbas, H (reprint author), Univ Munich, Inst Biochem, Feodor Lynen Str 25, D-81377 Munich, Germany. NR 101 TC 78 Z9 88 U1 3 U2 7 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 MAY 15 PY 1998 VL 26 IS 10 BP 2255 EP 2264 DI 10.1093/nar/26.10.2255 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZP804 UT WOS:000073790100001 PM 9580672 ER PT J AU Berger, I Tereshko, V Ikeda, H Marquez, VE Egli, M AF Berger, I Tereshko, V Ikeda, H Marquez, VE Egli, M TI Crystal structures of B-DNA with incorporated 2 '-deoxy-2 '-fluoro-arabino-furanosyl thymines: implications of conformational preorganization for duplex stability SO NUCLEIC ACIDS RESEARCH LA English DT Article ID NUCLEIC-ACIDS; ANTISENSE OLIGONUCLEOTIDES; MOLECULAR-STRUCTURE; DOUBLE HELIX; TATA-BOX; A-DNA; HYDRATION; OLIGODEOXYNUCLEOTIDES; ENVIRONMENT; NUCLEOSIDES AB The fundamental conformational states of right-handed double helical DNA, the A-and B-forms, are associated with distinct puckers of the sugar moieties, The furanose conformation itself is affected by the steric and electronic nature of the ring substituents, For example, a strongly electronegative substituent at the C2' position, such as in the 2'-deoxy-2'-fluororibofuranosyl analogue, will drive the conformational equilibrium towards the C3'-endo type (north), Conversely, the 2'-deoxy-2'-fluoroarabinofuranosyl modification with opposite stereochemistry at C2' appears to have a preference for a C2'-endo type pucker (south), Incorporation of 2'-fluoroarabinofuranosyl thymines was previously shown to enhance the thermodynamic stability of B-DNA duplexes, We have determined the crystal structures of the B-DNA dodecamer duplexes [d(CGCGAASSCGCG)](2) and [d(CGCGAASTCGCG)](2) with incorporated 2'-deoxy-2'-fluoroarabinofuranosyl thymines S (south) at 1.55 Angstrom resolution. In the crystal structures, all S residues adopt an O4'-endo conformation least), well compatible with an overall B-form duplex geometry, In addition to the increased rigidity of S nucleosides, a clathrate-like ordered water structure around the 2'-fluorines may account for the observed larger thermodynamic stability of DNA duplexes containing 2'-deoxy-2'-fluoroarabino thymidines. C1 ETH Honggerberg, Inst Mol Biol & Biophys, CH-8093 Zurich, Switzerland. Northwestern Univ, Sch Med, Dept Mol Pharmacol & Biol Chem, Chicago, IL 60611 USA. NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Egli, M (reprint author), ETH Honggerberg, Inst Mol Biol & Biophys, CH-8093 Zurich, Switzerland. EM m-egli@nwu.edu FU NIGMS NIH HHS [R01 GM-55237] NR 51 TC 85 Z9 85 U1 1 U2 7 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 MAY 15 PY 1998 VL 26 IS 10 BP 2473 EP 2480 DI 10.1093/nar/26.10.2473 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZP804 UT WOS:000073790100031 PM 9580702 ER PT J AU Di Cunto, F Topley, G Calautti, E Hsiao, J Ong, L Seth, PK Dotto, GP AF Di Cunto, F Topley, G Calautti, E Hsiao, J Ong, L Seth, PK Dotto, GP TI Inhibitory function of p21(Cip1/WAF1) in differentiation of primary mouse keratinocytes independent of cell cycle control SO SCIENCE LA English DT Article ID P21(WAF1/CIP1) EXPRESSION; TERMINAL DIFFERENTIATION; GROWTH; P21; PROTEIN; PROGRESSION; WAF1/CIP1; CALCIUM; PCNA AB The cyclin-dependent kinase inhibitor p21(Cip1/WAF1) has been implicated as an inducer of differentiation. However, although expression of p21 is increased in postmitotic cells immediately adjacent to the proliferative compartment, its expression is decreased in cells further along the differentiation program. Expression of the p21 protein was decreased in terminally differentiated primary keratinocytes of mice, and this occurred by a proteasome-dependent pathway. Forced expression of p21 in these cells inhibited the expression of markers of terminal differentiation at both the protein and messenger RNA levels. These inhibitory effects on differentiation were not observed with a carboxyl-terminal truncation mutant or with the unrelated cyclin-dependent kinase inhibitor p16(INK4a), although all these molecules exerted similar inhibition of cell growth. These findings reveal an inhibitory role of p21 in the late stages of differentiation that does not result from the effects of p21 on the cell cycle. C1 Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Univ Turin, Dept Genet Biol & Med Chem, Torino, Italy. NCI, Med Branch, Breast Canc Sect, Bethesda, MD 20892 USA. RP Dotto, GP (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, 13th St, Charlestown, MA 02129 USA. EM Paolo_Dotto@cbrc.mgh.harvard.edu OI CALAUTTI, Vincenzo/0000-0002-4439-9709; di cunto, ferdinando/0000-0001-9367-6357 FU NCI NIH HHS [CA16038]; NIAMS NIH HHS [AR39190] NR 24 TC 222 Z9 224 U1 0 U2 2 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 MAY 15 PY 1998 VL 280 IS 5366 BP 1069 EP 1072 DI 10.1126/science.280.5366.1069 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZN615 UT WOS:000073663600045 PM 9582119 ER PT J AU Troendle, JF AF Troendle, JF TI Testing for treatment differences with dropouts present in clinical trials - A composite approach by Weichung J. Shih and Hui Quan, Statistics in Medicine, 16, 1225-1239 (1997) SO STATISTICS IN MEDICINE LA English DT Letter C1 NICHHD, Biometry & Math Stat Branch, NIH, Bethesda, MD 20892 USA. RP Troendle, JF (reprint author), NICHHD, Biometry & Math Stat Branch, NIH, Bld 6100,Rm 7B13, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD MAY 15 PY 1998 VL 17 IS 9 BP 1062 EP 1063 DI 10.1002/(SICI)1097-0258(19980515)17:9<1062::AID-SIM836>3.0.CO;2-V PG 2 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 ZL763 UT WOS:000073469000009 PM 9612891 ER PT J AU van Toor, AJ AF van Toor, AJ TI In fact, just a fairy tale SO TIJDSCHRIFT VOOR DIERGENEESKUNDE LA Dutch DT Letter C1 NCI, Bethesda, MD 20892 USA. RP van Toor, AJ (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ROYAL NETHERLANDS VETERINARY ASSOC PI UTRECHT PA PO BOX 14031, 3508 UTRECHT, NETHERLANDS SN 0040-7453 J9 TIJDSCHR DIERGENEESK JI Tijdschr. Diergeneeskd. PD MAY 15 PY 1998 VL 123 IS 10 BP 330 EP 330 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA ZQ652 UT WOS:000073889500009 ER PT J AU Seeley, MR Faustman, EM AF Seeley, MR Faustman, EM TI Evaluation of P19 cells for studying mechanisms of developmental toxicity: application to four direct-acting alkylating agents SO TOXICOLOGY LA English DT Article DE developmental toxicity; embryonic carcinoma cells; P19 cells ID EMBRYONAL CARCINOMA-CELLS; INDUCED NEURAL DIFFERENTIATION; GAMMA-AMINOBUTYRIC ACID; HIGH-AFFINITY UPTAKE; RETINOIC ACID; NEURONAL DIFFERENTIATION; C-SRC; EXPRESSION; CULTURE; INDUCTION AB P19 cells are pluripotent murine embryonic carcinoma (EC) cells that can be induced by all-trans-retinoic acid (RA) to differentiate into cells that are biochemically and morphologically similar to cells of the central nervous system. We have established these cells as a reproducible cell system to evaluate potential effects of agents disrupting neuronal differentiation. The viability of P19 cells was assessed using a neutral red assay. Uptake of [H-3]-gamma-amino butyric acid ([H-3]GABA) was assessed as a marker of neuronal differentiation. We observed significant increases in [H-3]GABA over time, corresponding with the appearance of cells with neuronal morphologies. 2,4-Diaminobutyric acid, a specific inhibitor of high affinity neuronal GABA uptake, reduced [H-3]GABA uptake by approximately 75%. Additionally, [H-3]GABA uptake in cells treated with dimethylsulfoxide (DMSO), which differentiate into mesodermal derivatives, was approximately 25% of uptake observed in RA-exposed, neuronally differentiated P19 cells. The morphology of P19 cell cultures correlated with [H-3]GABA uptake: high [H-3]GABA uptake was only observed in cultures with distinct neuronal morphologies. These results suggest that [H-3]GABA uptake is a good indicator of neuronal differentiation in P19 cells. The responsiveness of P19 cells to developmental toxicants was assessed by comparing effects in P19 cells with effects observed previously in primary cultures of differentiating rat embryo midbrain (CNS) cells. Alkylating agents chosen for this investigation include methylnitrosourea (MNU), ethylnitrosourea (ENU), methyl methanesulfonate (MMS), and ethyl methanesulfonate (EMS). The rank order of potency of these alkylating agents in the CNS cells was MMS,MNU > ENU > EMS. With the exception of ENU, concentrations that caused effects on growth and differentiation in the P19 cells were very comparable to those causing similar effects in CNS cell cultures. Our results with P19 cells suggest that this EC cell line may also be a useful in vitro cell system for studying mechanisms of developmental toxicity, with the advantages of being an established cell line. (C) 1998 Published by Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Washington, Dept Environm Hlth, Seattle, WA 98105 USA. Ctr Human Dev & Disabil, Seattle, WA 98195 USA. NIEHS, Ctr Ecogenet & Environm Hlth, Seattle, WA 98195 USA. Inst Risk Assessment & Risk Commun, Seattle, WA 98195 USA. RP Faustman, EM (reprint author), Univ Washington, Dept Environm Hlth, XD-41,Room 208,4225 Roosevelt Way NE, Seattle, WA 98105 USA. FU NIEHS NIH HHS [ES-07032, ES-03157] NR 35 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD MAY 15 PY 1998 VL 127 IS 1-3 BP 49 EP 58 DI 10.1016/S0300-483X(98)00036-5 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 104FD UT WOS:000075003300006 PM 9699793 ER PT J AU Contreras, JL Wang, PX Eckhoff, DE Lobashevsky, AL Asiedu, C Frenette, L Robbin, ML Hubbard, WJ Cartner, S Nadler, S Cook, WJ Sharff, J Shiloach, J Thomas, FT Neville, DM Thomas, JM AF Contreras, JL Wang, PX Eckhoff, DE Lobashevsky, AL Asiedu, C Frenette, L Robbin, ML Hubbard, WJ Cartner, S Nadler, S Cook, WJ Sharff, J Shiloach, J Thomas, FT Neville, DM Thomas, JM TI Peritransplant tolerance induction with anti-CD3-immunotoxin - A matter of proinflammatory cytokine control (Retracted article. See vol 85, pg. 920, 2008) SO TRANSPLANTATION LA English DT Article; Retracted Publication ID DONOR BONE-MARROW; TOTAL LYMPHOID IRRADIATION; NF-KAPPA-B; POSTTRANSPLANT ANTITHYMOCYTE GLOBULIN; INCOMPATIBLE ALLOGRAFT ACCEPTANCE; MIXED ALLOGENEIC CHIMERISM; RHESUS-MONKEYS; DENDRITIC CELLS; IFN-GAMMA; IN-VIVO AB Background. Tolerance is gaining momentum as an approach to reduce lifelong immunosuppressive therapy while improving transplant longevity. Anti-CD3 immunotoxin (IT), FN18-CRM9, has potential to induce tolerance owing to its exceptional ability to deplete sessile lymph node T cells. However, if initiated at the time of transplantation, alpha-CD3-IT alone elicits a proinflammatory cytokine response, precluding establishment of tolerance. Methods. Four groups of rhesus monkeys received kidney allografts and immunosuppression, Three groups received alpha-CD3-IT alone or alpha-CD3-IT supplemented with 15-deoxyspergualin (DSG) and/or methylprednisolone (MP). One group received alpha-CD3-monoclonal antibody with DSG and MP. Cytokines were measured by enzyme-linked immunosorbent assay. Results. Supplementing peritransplant alpha-CD3-IT treatment with a brief course of DSG and IMP promoted rejection-free kidney allograft acceptance in 75% of macaques followed for up to 550 days. Among those given alpha-CD3-IT alone or with MP, none were long-term survivors, Tolerance developed after alpha-CD3-IT, DSG, and MP treatment, but not when the unconjugated alpha-CD3 monoclonal antibody was substituted for IT. Systemic production of proinflammatory cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha induced after peritransplant alpha-CD3-IT was prevented only in animals given DSG. Despite high levels of interleukin (IL)-12 in the first month after transplant, tolerant recipients exhibited IL-12 resistance, rut evidenced by baseline plasma levels of IFN-gamma but elevated IL-4. DSG was shown to inhibit IL-la-driven IFN-gamma production by a mechanism associated with inhibition of nuclear factor kappa-B. Conclusions, In this model, peritransplant induction of tolerance is promoted by efficient elimination of sessile lymph node T cells and control of the proinflammatory IFN-gamma response by a mechanism that appears to involve resistance to IL-12. C1 Univ Alabama Birmingham, UAB Transplant Ctr, Birmingham, AL 35294 USA. Univ Alabama Birmingham, Dept Surg, Div Transplantat Immunol, Birmingham, AL 35294 USA. Univ Alabama Birmingham, Dept Anesthesia, Birmingham, AL 35294 USA. Univ Alabama Birmingham, Dept Radiol, Birmingham, AL 35294 USA. Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. Bristol Myers Squibb Co, Pharmaceut Res Inst, Seattle, WA 98121 USA. NIMH, Mol Biol Lab, NIH, Bethesda, MD USA. NIDDK, Cellular & Dev Biol Lab, Biotechnol Unit, NIH, Bethesda, MD USA. RP Thomas, JM (reprint author), Univ Alabama Birmingham, UAB Transplant Ctr, Boshell Diabet Bldg 802,1808 7th St S, Birmingham, AL 35294 USA. EM jthomas@uab.edu FU NIAID NIH HHS [R0I AII22293, R0I AI39793] NR 66 TC 70 Z9 71 U1 6 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD MAY 15 PY 1998 VL 65 IS 9 BP 1159 EP 1169 DI 10.1097/00007890-199805150-00003 PG 11 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA ZN734 UT WOS:000073676600003 PM 9603161 ER PT J AU Kirken, RA Evans, GA Duhe, RJ DaSilva, L Malabarba, MG Erwin, RA Farrar, WL AF Kirken, RA Evans, GA Duhe, RJ DaSilva, L Malabarba, MG Erwin, RA Farrar, WL TI Mechanisms of cytokine signal transduction: IL-2, IL-4 and prolactin as hematopoietin receptor models SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article; Proceedings Paper CT 1st International Symposium on Cytokines and the Type I Type II Paradigm CY OCT 25-30, 1996 CL CAIRNS, AUSTRALIA DE cytokine signal transduction; IL-2; IL-4; prolactin ID PROTEIN-TYROSINE KINASE; JANUS KINASE; ACTIVATION; JAK2; PHOSPHORYLATION; ASSOCIATION; PATHWAY; CELLS; PROLIFERATION; ALPHA AB Cytokines, hormones and hematopoietic growth factors transduce biological signals across the cell membrane via a highly conserved family of single membrane-spanning receptors. The intracellular signal transducing machinery responsible for mediating these responses has remained largely unknown. However, recent identification of a homologous class of tyrosine kinases, Janus Kinases (JAKs), and a related family of transcription factors, signal transducers and activators of transcription (STATs), has shed new light on the molecular mechanisms responsible for mediating hematopoietin signaling and immune response. Current research efforts within the field of cytokine signaling have now shifted to understanding how these molecules are activated by hematopoietic receptors, positively and negatively regulated by kinases and phosphatases, and how they impact on gene transcription to ultimately coordinate cell homeostasis, proliferation and differentiation. This article will review some of our results identifying the involvement of JAKs, STATs, and secondary effector molecules activated following engagement of hematopoietic receptors for IL-2, IL-4, and prolactin. Here, we provide evidence for the ingenious ability of cytokine receptors to selectively recruit and activate these proteins among a repertoire of possible alternative biochemical messengers as a means to affect unique and general cell responses. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Div Basic Sci, Frederick, MD 21702 USA. RP Kirken, RA (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, POB B,Bldg 560,Rm 31-76, Frederick, MD 21702 USA. RI Malabarba, Maria Grazia/L-4805-2015 OI Malabarba, Maria Grazia/0000-0002-9457-2047 NR 27 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD MAY 15 PY 1998 VL 63 IS 1-2 BP 27 EP 36 DI 10.1016/S0165-2427(98)00079-8 PG 10 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA ZW928 UT WOS:000074462400005 PM 9656438 ER PT J AU Saunders, RC Kolachana, BS Bachevalier, J Weinberger, DR AF Saunders, RC Kolachana, BS Bachevalier, J Weinberger, DR TI Neonatal lesions of the medial temporal lobe disrupt prefrontal cortical regulation of striatal dopamine SO NATURE LA English DT Article ID VENTRAL TEGMENTAL AREA; CAUDATE-NUCLEUS; SUBCORTICAL DOPAMINE; RHESUS-MONKEY; RELEASE; CORTEX; RATS; SCHIZOPHRENIA; PROJECTIONS; DAMAGE AB The effects of early brain damage are often, but not always, milder than the effects of comparable damage in adults, depending on the age at which injury occurred, the region of the brain damaged, and the brain functions involved(1-7). Studies of the impact of early brain damage have generally focused on functions primarily associated with the neural structures injured, even though the development and function of distant but interconnected neural systems might also show effects. Here we examine the regulation of striatal dopamine by the dorsolateral prefrontal cortex, in adult monkeys that had had either neonatal or adult lesions of the medial-temporal lobe and in normal animals. We use microdialysis to measure the dopamine response in the caudate nucleus after the infusion of amphetamine into the dorsolateral prefrontal cortex. Normal animals and those with adult lesions showed a reduction in dopamine overflow; in contrast, monkeys with neonatal lesions showed increased dopamine release. Thus, early injury to the primate medial-temporal lobe disrupts the normal regulation of striatal dopamine activity by the dorsolateral prefrontal cortex during adulthood. Early focal lesions may have substantial and long-lasting impacts on the function of a distant neural system. C1 Univ Texas, Dept Neurobiol & Anat, Houston, TX 77030 USA. St Elizabeths Hosp, NIMH, Ctr Neurosci, Clin Brain Disorders Branch, Washington, DC 20032 USA. RP Saunders, RC (reprint author), NIMH, Clin Brain Disorders Branch, Bldg 49,Room 1B80,49 Convent Dr, Bethesda, MD 20892 USA. EM rcs@ln.nimh.nih.gov NR 29 TC 112 Z9 112 U1 0 U2 1 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON, ENGLAND N1 9XW SN 0028-0836 J9 NATURE JI Nature PD MAY 14 PY 1998 VL 393 IS 6681 BP 169 EP 171 DI 10.1038/30245 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZN200 UT WOS:000073619900048 PM 9603519 ER PT J AU Belshe, RB Mendelman, PM Treanor, J King, J Gruber, WC Piedra, P Bernstein, DI Hayden, FG Kotloff, K Zangwill, K Iacuzio, D Wolff, M AF Belshe, RB Mendelman, PM Treanor, J King, J Gruber, WC Piedra, P Bernstein, DI Hayden, FG Kotloff, K Zangwill, K Iacuzio, D Wolff, M TI The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE OTITIS-MEDIA; SYSTEMIC ANTIBODY-RESPONSES; MIDDLE-EAR FLUIDS; A VIRUS-VACCINES; INACTIVATED VACCINE; RESPIRATORY VIRUSES; YOUNG-CHILDREN; RECOMBINANT; VIRULENCE; INFECTION AB Background. Influenzavirus vaccine is used infrequently in healthy children, even though the rates of influenza in the group are high. We conducted a multicenter, double-blind, placebo-controlled trial of a live attenuated, cold-adapted, trivalent influenzavirus vaccine in children 15 to 71 months old. Methods. Two hundred eighty-eight children were assigned to receive one dose of vaccine or placebo given by intranasal spray, and 1314 were assigned to receive two doses approximately 60 days apart. The strains included in the vaccine were antigenically equivalent to those in the inactivated influenzavirus vaccine in use at the time. The subjects were monitored with viral cultures for influenza during the subsequent influenza season. A case of influenza was defined as an illness associated with the isolation of wild-type influenzavirus from respiratory secretions. Results. The intranasal vaccine was accepted and well tolerated. Among children who were initially seronegative, antibody titers increased by a factor of four in 61 and 96 percent, depending on the influenza strain. Culture-positive influenza was significantly less common in the vaccine group (14 cases among 1070 subjects) than the placebo group (95 cases among 532 subjects). The vaccine efficacy was 93 percent (95 percent confidence interval, 88 to 96 percent) against culture-confirmed influenza. Both the one-dose regimen (89 percent efficacy) and the two-dose regimen (94 percent efficacy) were efficacious, and the vaccine was efficacious against both strains of influenza circulating in 1996-1997, A(H3N2) and B. The vaccinated children had significantly fewer febrile illnesses, including 30 percent fewer episodes of febrile otitis media (95 percent confidence interval, 18 to 45 percent; P < 0.001). Conclusions. A live attenuated, cold-adapted influenzavirus vaccine was safe, immunogenic, and effective against influenza A(H3N2) and B in healthy children. (C) 1998, Massachusetts Medical Society. C1 St Louis Univ, Hlth Sci Ctr, Div Infect Dis, Dept Med, St Louis, MO 63110 USA. Aviron, Mt View, CA USA. Univ Rochester, Dept Med, Rochester, NY USA. Univ Maryland, Dept Pediat, Baltimore, MD 21201 USA. Vanderbilt Univ, Dept Pediat, Nashville, TN USA. Baylor Coll Med, Dept Microbiol & Immunol, Houston, TX 77030 USA. Childrens Hosp, Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA. Univ Virginia, Dept Internal Med, Charlottesville, VA USA. Univ Virginia, Dept Pathol, Charlottesville, VA 22903 USA. Harbor UCLA Med Ctr, Dept Pediat, Los Angeles, CA USA. Kaiser UCLA Vaccine Program, Los Angeles, CA USA. NIAID, Div Microbial & Infect Dis, NIH, Bethesda, MD 20892 USA. Emmes Corp, Potomac, MD USA. RP Belshe, RB (reprint author), St Louis Univ, Hlth Sci Ctr, Div Infect Dis, Dept Med, 3635 Vista Ave,FDT-8N, St Louis, MO 63110 USA. RI kotloff, karen/E-7768-2012 OI kotloff, karen/0000-0003-1808-6431 FU NIAID NIH HHS [N01-AI-45248, N01-AI-45250, N01-AI-45251] NR 31 TC 618 Z9 640 U1 1 U2 25 PU MASS MEDICAL SOC PI BOSTON PA 10 SHATTUCK, BOSTON, MA 02115 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 14 PY 1998 VL 338 IS 20 BP 1405 EP 1412 DI 10.1056/NEJM199805143382002 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA ZM667 UT WOS:000073563700002 PM 9580647 ER PT J AU Chiariello, M Visconti, R Carlomagno, F Melillo, RM Bucci, C de Franciscis, V Fox, GM Jing, SQ Coso, OA Gutkind, JS Fusco, A Santoro, M AF Chiariello, M Visconti, R Carlomagno, F Melillo, RM Bucci, C de Franciscis, V Fox, GM Jing, SQ Coso, OA Gutkind, JS Fusco, A Santoro, M TI Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret SO ONCOGENE LA English DT Article DE tyrosine kinase; transformation; jun; MEN2; thyroid ID GTP-BINDING PROTEINS; THYROID PAPILLARY CARCINOMAS; SIGNALING PATHWAY; GROWTH-FACTOR; HIRSCHSPRUNGS-DISEASE; ACTIVATION DOMAIN; RET/PTC1 ONCOGENE; ADAPTER PROTEINS; RESPONSE GENES; AP-1 ACTIVITY AB The RET proto-oncogene encodes a functional receptor tyrosine kinase (Ret) for the Glial cell line Derived Neurotrophic Factor (GDNF). RET is involved in several neoplastic and non-neoplastic human diseases. Oncogenic activation of RET is detected in human papillary thyroid tumours and in multiple endocrine neoplasia type 2 syndromes. Inactivating mutations of RET have been associated to the congenital megacolon, i.e. Hirschprung's disease. In order to identify pathways that are relevant for Ret signalling to the nucleus, we have investigated its ability to induce the c-Jun NH2-terminal protein kinases (JNK). Here we show that triggering the endogenous Pet, expressed in PC12 cells, induces JNK activity; moreover, Ret is able to activate JNK either when transiently transfected in COS-1 cells or when stably expressed in NIH3T3 fibroblasts or in PC Cl 3 epithelial thyroid cells. JNK activation is dependent on the Pet kinase function, as a kinase-deficient RET mutant, associated with Hirschsprung's disease, fails to activate JNK. The pathway leading to the activation of JNK by RET is clearly divergent from that leading to the activation of ERK: substitution of the tyrosine 1062 of Pet, the Shc binding site, for phenylalanine abrogates ERK but not JNK activation. Experiments conducted with dominant negative mutants or with negative regulators demonstrate that JNK activation by Pet is mediated by Rho/Rac related small GTPases and, particularly, by Cdc42. C1 Univ Naples Federico II, Fac Med & Chirurg, Dipartimento Biol & Patol Cellulare & Mol, CNR,Ctr Endocrinol & Oncol Sperimentale, I-80131 Naples, Italy. Amgen, Thousand Oaks, CA 91320 USA. NIDR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Univ Reggio Calabria, Fac Med & Chirurg Catanzaro, Dipartimento Med Sperimentale & Clin, I-88100 Catanzaro, Italy. RP Santoro, M (reprint author), Univ Naples Federico II, Fac Med & Chirurg, Dipartimento Biol & Patol Cellulare & Mol, CNR,Ctr Endocrinol & Oncol Sperimentale, Via S Pansini 5, I-80131 Naples, Italy. RI Gutkind, J. Silvio/A-1053-2009; Visconti, Roberta/C-5299-2009; Bucci, Cecilia/F-6699-2012; Chiariello, Mario/O-3642-2014; OI Chiariello, Mario/0000-0001-8434-5177; Fusco, Alfredo/0000-0003-3332-5197; MELILLO, Rosa Marina/0000-0002-9233-5275 NR 71 TC 97 Z9 101 U1 0 U2 3 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 14 PY 1998 VL 16 IS 19 BP 2435 EP 2445 DI 10.1038/sj.onc.1201778 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ZN694 UT WOS:000073672300002 PM 9627110 ER PT J AU Rubino, D Driggers, P Arbit, D Kemp, L Miller, B Coso, O Pagliai, K Gray, K Gutkind, S Segars, J AF Rubino, D Driggers, P Arbit, D Kemp, L Miller, B Coso, O Pagliai, K Gray, K Gutkind, S Segars, J TI Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action SO ONCOGENE LA English DT Article DE estrogen receptor; signal transduction; Rho GTPase; Cdc42Hs; Dbl; Rho GEF; Lbc ID GUANINE-NUCLEOTIDE EXCHANGE; GTP-BINDING PROTEINS; LIGAND-INDEPENDENT ACTIVATION; STEROID-HORMONE RECEPTORS; HUMAN BREAST-CANCER; TRANSCRIPTIONAL ACTIVATION; MEDIATED TRANSCRIPTION; SIGNALING PATHWAYS; STRUCTURAL SIMILARITIES; SEQUENCE SIMILARITY AB Regulation of gene activation by the estrogen receptor (ER) is complex and involves co-regulatory proteins, oncoproteins (such as Fos and Jun), and phosphorylation signaling pathways. Here we report the cloning and initial characterization of a novel protein, Err, that contains a region of identity to the oncogenic Rho-guanine nucleotide exchange (Rho-GEF) protein Lbc, and a unique region capable of binding to nuclear hormone receptors, including the ER, Western and immunohistochemistry studies showed Brx to be expressed in estrogen-responsive reproductive tissues, including breast ductal epithelium, Err bound specifically to the ER via an interaction that required distinct regions of ER and Brx. Furthermore, overexpression of Brx in transfection experiments using an estrogen-responsive reporter revealed that Err augmented gene activation by the ER in an element-specific and ligand-dependent manner, Moreover, activation of ER by Brx could be specifically inhibited by a dominant-negative mutant of Cdc42Hs, but not by dominant negative mutants of RhoA or Rac1. Taken together, these data suggest that Err represents a novel modular protein that may integrate cytoplasmic signaling pathways involving Rho family GTPases and nuclear hormone receptors. C1 NICHHD, Off Sci Director, NIH, Bethesda, MD 20892 USA. NICHD, DEB, NIH, Bethesda, MD 20892 USA. NIDR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. RP Segars, J (reprint author), NICHHD, Off Sci Director, NIH, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009 NR 76 TC 60 Z9 64 U1 1 U2 4 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 14 PY 1998 VL 16 IS 19 BP 2513 EP 2526 DI 10.1038/sj.onc.1201783 PG 14 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ZN694 UT WOS:000073672300009 PM 9627117 ER PT J AU Rifkind, BM Rossouw, JE AF Rifkind, BM Rossouw, JE TI Of designer drugs, magic bullets, and gold standards SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID POSTMENOPAUSAL WOMEN; THERAPY C1 NHLBI, Bethesda, MD 20892 USA. RP Rifkind, BM (reprint author), 2 Rockledge Ctr,8701 Rockledge Dr,Suite 10193, Bethesda, MD 20892 USA. NR 19 TC 6 Z9 7 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 13 PY 1998 VL 279 IS 18 BP 1483 EP 1485 DI 10.1001/jama.279.18.1483 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA ZL718 UT WOS:000073463500040 PM 9600485 ER PT J AU Lin, B Islam, N Friedman, S Yagi, H Jerina, DM Whalen, DL AF Lin, B Islam, N Friedman, S Yagi, H Jerina, DM Whalen, DL TI Change of rate limiting step in general acid-catalyzed benzo[a]pyrene diol epoxide hydrolysis SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MUTAGENIC 7,8-DIOL 9,10-EPOXIDES; ANION COMBINATION REACTIONS; CARCINOGEN BENZOPYRENE; PRODUCT DISTRIBUTIONS; BASE CATALYSIS; ADDUCTS; STEREOCHEMISTRY; CARBOCATIONS; NUCLEOPHILES; HYDROCARBONS AB he rates of reaction of (+/-)-7 beta,8 alpha-Dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (1) in 1:9 dioxane-water buffer solutions containing primary amines whose pK(a) values span the range of 5.4-10.7 have been determined. For those amines with pK(a) values < ca. 8, only the acid form (RNH3+) gives rise to a kinetic term for reaction with 1. The rate-limiting step of this reaction is general acid-catalyzed epoxide ring opening to yield a discrete alpha-hydroxycarbocation, followed by a fast reaction of this intermediate with solvent. The intermediate alpha-hydroxycarbocation is sufficiently stable so that its reactions with external nucleophiles and bases compete with its reaction with solvent. For those amines with pK(a) > ca. 8, both acid and base forms of the buffer react with 1. The magnitude of the kinetic term in the base form of the amine (RNH2) increases with amine pK(a) and is attributed to nucleophilic addition of the amine to the epoxide group. Curvatures in plots of the kinetic term due to buffer (k(buff)) as a function of the mole fraction of buffer acid for substituted ammonium ions with pK(a) > 8 are interpreted in terms of a change in rate-limiting step of the general acid-catalyzed pathway from epoxide ring opening at low amine base:concentrations to reaction of amine base acting as either a general base or nucleophile with an alpha-hydroxycarbocation at higher amine base concentrations, Thus, epoxide ring opening of 1 in buffer solutions of the more baste amines is a reversible reaction. Rate and product studies of the reaction of 1 in acid solutions (pH 5.5) and in Tris buffer solutions containing sodium azide show that azide ion is effective in trapping the alpha-hydroxycarbocation intermediate; subsequent to its rate-limiting formation by reaction of 1 with either H+ or Tris-H+. These results demonstrate that the intermediate formed from epoxide ring opening of 1 with acids has a sufficient lifetime so that its reaction with azide ion competes with its reaction with solvent. C1 Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Whalen, DL (reprint author), Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. OI Lin, Binshan/0000-0002-8481-302X NR 28 TC 16 Z9 16 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAY 13 PY 1998 VL 120 IS 18 BP 4327 EP 4333 DI 10.1021/ja972982m PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA ZN435 UT WOS:000073645600010 ER PT J AU Nosworthy, NJ Peterkofsky, A Konig, S Seok, YJ Szczepanowski, RH Ginsburg, A AF Nosworthy, NJ Peterkofsky, A Konig, S Seok, YJ Szczepanowski, RH Ginsburg, A TI Phosphorylation destabilizes the amino-terminal domain of enzyme I of the Escherichia coli phosphoenolpyruvate : sugar phosphotransferase system SO BIOCHEMISTRY LA English DT Article ID SALMONELLA-TYPHIMURIUM; SCANNING CALORIMETRY; GLUTAMINE-SYNTHETASE; PROTEIN; TRANSPORT; STABILITY; HPR; REFINEMENT; MODEL; NMR AB Thermal stabilities of enzyme I (63 562 M-r subunit), in the Escherichia coli phosphoenolpyruvate (PEP),sugar phosphotransferase system (PTS), and a cloned amino-terminal domain of enzyme I (EIN; 28 34-6 M,) were investigated by differential scanning calorimetry (DSC) and far-UV circular dichroism (CD) at PH 7.5. EIN expressed in a Delta pts E. coli strain showed a single, reversible, two-state transition with T-m = 57 degrees C and an unfolding enthalpy of similar to 140 kcal/mol, In contrast, monomeric EIN expressed in a wild-type strain (pts(+)) had two endotherms with T-m congruent to 50 and 57 degrees C and overall Delta H = 140 kcal/mol and was converted completely to the more stable form after five DSC scans from 10 to 75 DC (without changes in CD: similar to 58% alpha-helices). Thermal conversion to a more stable form was correlated with dephosphorylation of EIN by mass spectral analysis. Dephospho-enzyme I (monomer reversible arrow dimer) exhibited endotherms for C-and N-terminal domain unfolding with T-m = 41 and 54 degrees C, respectively. Thermal unfolding of the C-terminal domain occurred over a broad temperature range (similar to 30-50 degrees C), was scan rate-and concentration-dependent, coincident with a Light scattering decrease and Trp residue exposure, and independent of phosphorylation. Reversible thermal unfolding of the nonphosphorylated N-terminal domain was more cooperative, occurring from 50 to 60 degrees C. DSC of partially phosphorylated enzyme I indicated that the amino-terminal domain was destabilized by phosphorylation (from T-m = 54 to similar to 48 degrees C). A decrease in conformational stability of the amino-terminal domain of enzyme I produced by phosphorylation of the active-site His 189 has the physiological consequence of promoting phosphotransfer to the phosphocarrier protein, HPr. C1 NHLBI, Sect Prot Chem, Biochem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Macromol Sect, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Ginsburg, A (reprint author), NHLBI, Sect Prot Chem, Biochem Lab, NIH, Bldg 3,Room 208, Bethesda, MD 20892 USA. RI Konig, Simone/B-6504-2008 OI Konig, Simone/0000-0003-0672-7246 NR 41 TC 40 Z9 40 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 MAY 12 PY 1998 VL 37 IS 19 BP 6718 EP 6726 DI 10.1021/bi980126x PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZP874 UT WOS:000073797300011 PM 9578555 ER PT J AU Greenland, P Grundy, S Pasternak, RC Lenfant, C AF Greenland, P Grundy, S Pasternak, RC Lenfant, C TI Problems on the pathway from risk assessment to risk reduction SO CIRCULATION LA English DT Editorial Material DE editorials; risk factors; coronary disease ID AWARENESS C1 Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. Univ Texas, SW Med Ctr, Ctr Human Nutr, Dallas, TX 75235 USA. Massachusetts Gen Hosp, Cardiac Unit, Dept Med, Div Cardiovasc, Boston, MA 02114 USA. NHLBI, Dept Med, Bethesda, MD 20892 USA. RP Greenland, P (reprint author), Northwestern Univ, Sch Med, Dept Prevent Med, 680 N Lake Shore Dr,Suite 1102, Chicago, IL 60611 USA. EM p-greenland@nwu.edu NR 13 TC 23 Z9 23 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 12 PY 1998 VL 97 IS 18 BP 1761 EP 1762 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA ZM245 UT WOS:000073519200002 PM 9603527 ER PT J AU O'Donnell, CJ Lindpaintner, K Larson, MG Rao, VS Ordovas, JM Schaefer, EJ Myers, RH Levy, D AF O'Donnell, CJ Lindpaintner, K Larson, MG Rao, VS Ordovas, JM Schaefer, EJ Myers, RH Levy, D TI Evidence for association and genetic linkage of the angiotensin-converting enzyme locus with hypertension and blood pressure in men but not women in the Framingham Heart Study SO CIRCULATION LA English DT Article DE angiotensin; trials; genetics; genes; hormones; hypertension; blood pressure ID CORONARY-ARTERY DISEASE; DELETION POLYMORPHISM; MYOCARDIAL-INFARCTION; INCREASED RISK; POPULATION; FAMILIES; DNA; SEGREGATION; FERTILITY; JAPANESE AB Background-There is controversy regarding the association of the angiotensin-converting enzyme deletion-insertion (ACE D/I) polymorphism with systemic hypertension and with blood pressure. We investigated these relations in a large population-based sample of men and women by using association and linkage analyses. Methods and Results-The study sample consisted of 3095 participants in the Framingham Heart Study. Blood pressure measurements were obtained at regular examinations. The ACE D/I polymorphism was identified by using a polymerase chain reaction assay. In logistic regression analysis, the adjusted odds ratios for hypertension among men for the DD and DI genotypes were 1.59 (95% confidence interval [CI], 1.13 to 2.23) and 1.18 (95% CI, 0.87 to 1.62), respectively, versus II (Chi(2) P=.02). In women, adjusted odds ratios for the DD and DI genotypes were 1.00 (95% CI, 0.70 to 1.44) and 0.78 (95% CI, 0.56 to 1.09), respectively (P=.14). In linear regression analysis, there was an association of the ACE DD genotype with increased diastolic blood pressure in men (age-adjusted P=.03, multivariate-adjusted P=.14) but not women. Quantitative trait linkage analyses in 1044 pairs of siblings, by using both ACE D/I and a nearby microsatellite polymorphism of the human growth hormone gene, supported a role of the ACE locus in influencing blood pressure in men but not in women. Conclusions-In our large, population-based sample, then is evidence for association and genetic linkage of the ACE locus with hypertension and with diastolic blood pressure in men but not women, Our data support the hypothesis that ACE, or a nearby gene, is a sex-specific candidate gene for hypertension. Confirmatory studies in other large population-based samples are warranted. C1 NHLBI, Framingham Heart Study, Framingham, MA 01701 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Unit,Dept Med, Boston, MA USA. Harvard Univ, Beth Israel Hosp, Sch Med, Div Cardiol, Boston, MA USA. Harvard Univ, Beth Israel Hosp, Sch Med, Div Clin Epidemiol, Boston, MA USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Cardiol, Boston, MA USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Cardiovasc Div, Boston, MA USA. Tufts Univ, Mol Biol Sect, Lipid Metab Lab, Jean Mayer US Dept Agr,Human Nutr Res Ctr Aging, Boston, MA 02111 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Epidemiol & Prevent Med, Boston, MA 02118 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP O'Donnell, CJ (reprint author), NHLBI, Framingham Heart Study, 5 Thurber St, Framingham, MA 01701 USA. EM chris@fram.nhlbi.nih.gov FU NHLBI NIH HHS [HL-54776, K04-HL-03138-01, N01-HC-38038] NR 45 TC 380 Z9 398 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 12 PY 1998 VL 97 IS 18 BP 1766 EP 1772 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA ZM245 UT WOS:000073519200004 PM 9603529 ER PT J AU Wilson, PWF D'Agostino, RB Levy, D Belanger, AM Silbershatz, H Kannel, WB AF Wilson, PWF D'Agostino, RB Levy, D Belanger, AM Silbershatz, H Kannel, WB TI Prediction of coronary heart disease using risk factor categories SO CIRCULATION LA English DT Article DE coronary disease; prediction; hypertension; cholesterol ID DENSITY-LIPOPROTEIN CHOLESTEROL; PHYSICAL-ACTIVITY; CARDIOVASCULAR-DISEASE; ESTROGEN USE; FOLLOW-UP; FRAMINGHAM; PREVENTION; FIBRINOGEN; MORTALITY; THERAPY AB Background-The objective of this study was to examine the association of Joint National Committee (JNC-V) blood pressure and National Cholesterol Education Program (NCEP) cholesterol categories with coronary heart disease (CHD) risk, to incorporate them into coronary prediction algorithms, and to compare the discrimination properties of this approach with other noncategorical prediction functions. Methods and Results-This work was designed as a prospective, single-center study in the setting of a community-based cohort. The patients were 2489 men and 2856 women 30 to 74 years old at baseline with 12 years of follow-up. During the 12 years of follow-up, a total of 383 men and 227 women developed CHD, which was significantly associated with categories of blood pressure, total cholesterol, LDL cholesterol, and HDL cholesterol tall P<.001). Sex-specific prediction equations were formulated to predict CHD risk according to age, diabetes, smoking, JNC-V blood pressure categories, and NCEP total cholesterol and LDL cholesterol categories. The accuracy of this categorical approach was found to be comparable to CHD prediction when the continuous variables themselves were used. After adjustment for other factors, approximate to 28% of CHD events in men and 29% in women were attributable to blood pressure levels that exceeded high normal (greater than or equal to 130/85). The corresponding multivariable-adjusted attributable risk percent associated with elevated total cholesterol (greater than or equal to 200 mg/dL) was 27% in men and 34% in women. Conclusions-Recommended guidelines of blood pressure, total cholesterol, and LDL cholesterol effectively predict CHD risk in a middle-aged white population sample. A simple coronary disease prediction algorithm was developed using categorical variables, which allows physicians to predict multivariate CHD risk in patients without overt CHD. C1 NHLBI, Framingham Heart Study, Framingham, MA 01701 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Boston Univ, Sch Med, Framingham Heart Study, Framingham, MA USA. RP Wilson, PWF (reprint author), NHLBI, Framingham Heart Study, 5 Thurber St, Framingham, MA 01701 USA. EM peter@fram.nhlbi.nih.gov FU NHLBI NIH HHS [N01-HC-38038] NR 65 TC 4751 Z9 4944 U1 82 U2 578 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 12 PY 1998 VL 97 IS 18 BP 1837 EP 1847 PG 11 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA ZM245 UT WOS:000073519200014 PM 9603539 ER PT J AU Kloner, RA Bolli, R Marban, E Reinlib, L Braunwald, E Reinlib, LJ Bonow, RO Borgers, M Downey, J Feigenbaum, H Ganote, C Gross, G Jennings, R Levitsky, S McCully, JD Mentzer, R Miller, WP Przyklenk, K Rahimtoola, S Vatner, S Yellon, D AF Kloner, RA Bolli, R Marban, E Reinlib, L Braunwald, E Reinlib, LJ Bonow, RO Borgers, M Downey, J Feigenbaum, H Ganote, C Gross, G Jennings, R Levitsky, S McCully, JD Mentzer, R Miller, WP Przyklenk, K Rahimtoola, S Vatner, S Yellon, D TI Medical and cellular implications of stunning, hibernation, and preconditioning - An NHLBI Workshop SO CIRCULATION LA English DT Review DE stunning, myocardial; hibernation; preconditioning; ischemia; infarction ID CORONARY-ARTERY DISEASE; LEFT-VENTRICULAR FUNCTION; PROTEIN-KINASE-C; ACUTE MYOCARDIAL-INFARCTION; FREE-RADICAL SCAVENGERS; DISMUTASE PLUS CATALASE; OXYGEN-FREE-RADICALS; ISOLATED RAT-HEART; TWO-DIMENSIONAL ECHOCARDIOGRAPHY; CARDIAC SARCOPLASMIC-RETICULUM C1 Hosp Good Samaritan, Inst Heart, Res Lab, Los Angeles, CA 90017 USA. Univ So Calif, Los Angeles, CA USA. Univ Louisville, Louisville, KY 40292 USA. Johns Hopkins Univ, Baltimore, MD USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. NHLBI, Bethesda, MD 20892 USA. Northwestern Univ, Sch Med, Chicago, IL USA. Janssen Res Fdn, B-2340 Beerse, Belgium. Univ S Alabama, Mobile, AL 36688 USA. Indiana Univ, Indianapolis, IN 46204 USA. Quillen Coll Med, Johnson City, TN USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. Duke Univ, Med Ctr, Durham, NC USA. Univ Kentucky, Med Ctr, Lexington, KY USA. Univ Wisconsin, Madison, WI USA. Allegheny Univ Hlth Sci, Pittsburgh, PA USA. UCL Hosp & Med Sch, Hatter Inst, London, England. RP Kloner, RA (reprint author), Hosp Good Samaritan, Inst Heart, Res Lab, 1225 Wilshire Blvd, Los Angeles, CA 90017 USA. RI Kloner, Robert/B-2971-2012 NR 247 TC 310 Z9 337 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 12 PY 1998 VL 97 IS 18 BP 1848 EP 1867 PG 20 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA ZM245 UT WOS:000073519200015 PM 9603540 ER PT J AU Trieschmann, L Martin, B Bustin, M AF Trieschmann, L Martin, B Bustin, M TI The chromatin unfolding domain of chromosomal protein HMG-14 targets the N-terminal tail of histone H3 in nucleosomes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID POLYACRYLAMIDE-GEL ELECTROPHORESIS; MOBILITY GROUP PROTEIN-17; CORE PARTICLE; TRANSCRIPTION; BINDING; DNA; ORGANIZATION; MODULATION; HMG14 AB Nonhistone chromosomal protein HMG-14 is a nucleosomal binding protein that unfolds the higher-order chromatin structure and enhances the transcriptional potential of chromatin, but not that of DNA, Both the transcriptional enhancement and the chromatin unfolding activities of HMG-14 are mediated through the C-terminal region of the protein. Here we study the molecular interactions of both this region and the N-terminal region of HMG-14 with nucleosome cores, By protein photocrosslinking we demonstrate that the N-terminal domain of HMG-14 targets a restricted region in histone II2B, whereas the C-terminal chromatin unfolding domain of HMG-14 targets a restricted region in the N terminus of histone H3. The N-terminal regions of the core histones are involved in the folding of oligonucleosomes and are the target of various activities associated with chromatin unfolding and transcriptional activation, We suggest that specific interactions between the C-terminal domain of HMG-14 and the N-terminal tail of histone H3 reduce the compaction of chromatin, These findings provide insights into the molecular mechanism whereby HMG-14/-17 proteins reduce the repressive effect of chromatin, and they also broaden the scope of the molecular interactions involving the N termini of the core histones in nucleosomes. C1 NCI, DBS, LMC, Prot Sect, Bethesda, MD 20892 USA. NIMH, Clin Neurosci Branch, Unit Mol Struct, NIH, Bethesda, MD 20892 USA. RP Bustin, M (reprint author), NCI, DBS, LMC, Prot Sect, Bldg 37,Room 3D-12, Bethesda, MD 20892 USA. EM bustin@helix.nih.gov RI Bustin, Michael/G-6155-2015 NR 47 TC 51 Z9 51 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 12 PY 1998 VL 95 IS 10 BP 5468 EP 5473 DI 10.1073/pnas.95.10.5468 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZM977 UT WOS:000073595500011 PM 9576905 ER PT J AU Favit, A Grimaldi, M Nelson, TJ Alkon, DL AF Favit, A Grimaldi, M Nelson, TJ Alkon, DL TI Alzheimer's-specific effects of soluble beta-amyloid on protein kinase C-alpha and -gamma degradation in human fibroblasts SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PRECURSOR PROTEIN; DISEASE FIBROBLASTS; SKIN FIBROBLASTS; CORTICAL-NEURONS; BRAIN; ACTIVATION; CALCIUM; PHOSPHORYLATION; SECRETION; RELEASE AB Alzheimer's disease (AD) is a multifactorial disease in which beta-amyloid peptide (beta AP) plays a critical role. We report here that the soluble fraction 1-40 of beta AP differentially degrades protein kinase C-alpha and -gamma (PKC alpha and PKC gamma) isoenzymes in normal (age-matched controls, AC) and AD fibroblasts most likely through proteolytic cascades. Treatment with nanomolar concentrations of beta AP(1-40) induced a 75% decrease in PKC alpha, but not PKC gamma, immunoreactivity in AC fibroblasts, In the AD fibroblasts, a 70% reduction of the PKC gamma, but not PKC alpha, immunoreactivity was observed after beta AP treatment. Preincubation of AC or AD fibroblasts with 50 mu M lactacystine, a selective proteasome inhibitor, prevented beta-AP(1-40)-mediated degradation of PKC alpha in the AC cells, and PKC gamma in the AD fibroblasts. The effects of beta AP(1-40) on PKC alpha in AC fibroblasts were prevented by inhibition of protein synthesis and reversed by PKC activation. A 3-hr treatment with 100 nM phorbol 12-myristate 13-acetate restored the PKC alpha signal in treated AC cells but it did not reverse the effects of beta AP(1-40) on PKC gamma in the AD fibroblasts. Pretreatment with the protein synthesis inhibitor, cycloheximide (CHX. 100 mu M), inhibited the effects of beta AP(1-40) on PKC alpha and blocked the rescue effect of phorbol 12-myristate 13-acetate in AC fibroblasts but did not modify PKC gamma immunoreactivity in AD cells, These results suggest that beta AP(1-40) differentially affects PKC regulation in AC and AD cells via proteolytic degradation and that PKC activation exerts a protective role via de novo protein synthesis in normal but not AD cells. C1 NINDS, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. RP Alkon, DL (reprint author), NINDS, Lab Adapt Syst, NIH, Bldg 36,Room 4A-21, Bethesda, MD 20892 USA. EM dalkon@codon.nih.gov OI Grimaldi, Maurizio/0000-0002-7331-7055 NR 54 TC 69 Z9 69 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 12 PY 1998 VL 95 IS 10 BP 5562 EP 5567 DI 10.1073/pnas.95.10.5562 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZM977 UT WOS:000073595500028 PM 9576922 ER PT J AU Henning, KA Moskowitz, N Ashlock, MA Liu, PP AF Henning, KA Moskowitz, N Ashlock, MA Liu, PP TI Humanizing the yeast telomerase template SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RNA COMPONENT; PROTEIN; RAP1; SEQUENCE; DNA; END AB Saccharomyces cerevisiae contains an irregular telomere sequence (TG(1-3))(n), which differs from the regular repeat (TTAGGG)(n) found at the telomeres of higher organisms including humans. We have modified the entire Ig-nt template region of the S. cerevisiae telomerase RNA gene (TLC1) to produce (TTAGGG)(n) repeats, the human telomere sequence. Haploid yeast strains with the tlc1-human allele are viable with no growth retardation and express the humanized gene at a level comparable to wild type. Southern hybridization demonstrates that (TTAGGG)(n) repeats are added onto the yeast chromosome ends in haploid strains with the tlc1-human allele, and sequencing of rescued yeast artificial chromosome ends has verified the addition of human telomeric repeats at the molecular level. These data suggest that the irregularity of the yeast telomere sequence is because of the template sequence of the yeast telomerase RNA. Haploid strains with the tlc1-human allele will provide an important tool for studying the function of telomerase and its regulation by telomere-binding proteins, and these strains will serve as good hosts for human artificial chromosome assembly and propagation. C1 Nat Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Liu, PP (reprint author), Nat Human Genome Res Inst, Genet & Mol Biol Branch, NIH, 49 Convent Dr,Room 3A18, Bethesda, MD 20892 USA. RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X NR 29 TC 36 Z9 36 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 12 PY 1998 VL 95 IS 10 BP 5667 EP 5671 DI 10.1073/pnas.95.10.5667 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZM977 UT WOS:000073595500047 PM 9576941 ER PT J AU Luckhart, S Vodovotz, Y Cui, LW Rosenberg, R AF Luckhart, S Vodovotz, Y Cui, LW Rosenberg, R TI The mosquito Anopheles stephensi limits malaria parasite development with inducible synthesis of nitric oxide SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID AEDES-AEGYPTI; PLASMODIUM-FALCIPARUM; MESSENGER-RNA; SYNTHASE; GAMBIAE; GAMMA; CELLS; INACTIVATION; MACROPHAGE; INHIBITION AB We have discovered that the mosquito Anopheles stephensi, a natural vector of human malaria, limits parasite development with inducible synthesis of nitric oxide (NO), Elevated expression of A. stephensi NO synthase (NOS), which is highly homologous to characterized NOS genes, was detected in the midgut and carcass soon after invasion of the midgut by Plasmodium, Early induction is likely primed by bacterial growth in the blood meal. Later increases in A. stephensi NOS expression and enzyme activity occurred at the beginning of sporozoite release. Circulating levels of nitrite/nitrate, end-products of NO synthesis, were significantly higher in Plasmodium-infected mosquitoes. Dietary provision of the NOS substrate L-arginine reduced Plasmodium infections in A. stephensi. In contrast, dietary provision of a NOS inhibitor significantly increased parasite numbers in infected mosquitoes, confirming that A. stephensi limits Plasmodium development with NO. C1 Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Dept Entomol, Washington, DC 20307 USA. NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Luckhart, S (reprint author), Virginia Tech, Dept Biochem, 111 Engel Hall, Blacksburg, VA 24061 USA. NR 41 TC 270 Z9 284 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 12 PY 1998 VL 95 IS 10 BP 5700 EP 5705 DI 10.1073/pnas.95.10.5700 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZM977 UT WOS:000073595500053 PM 9576947 ER PT J AU Evans, GL Morgan, RA AF Evans, GL Morgan, RA TI Genetic induction of immune tolerance to human clotting factor VIII in a mouse model for hemophilia A SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE factor VIII-deficient mice; immune tolerance; gene therapy; transplantation ID HEMATOPOIETIC STEM-CELLS; COLONY-STIMULATING FACTOR; VON-WILLEBRAND-FACTOR; MESSENGER-RNA; BONE-MARROW; INHIBITORS; THERAPY; MICE; ANTIGEN; SURVIVAL AB Patients with severe coagulation factor VIII deficiency require frequent infusions of human factor VIII (hFVIII) concentrates to treat life-threatening hemorrhages. Because these patients are immunologically hFVIII-naive, a significant treatment complication is the development of inhibitors or circulating alloantibodies against hFVIII, which bind the replaced glycoprotein, increase its plasma clearance, and inhibit its activity, preventing subsequent treatments from having a therapeutic effect. A genetic approach toward the induction of immunologic unresponsiveness to hFVIII has the conceptual advantage of a long-term, stable elimination of undesired immune responses against hFVIII. Here, we report that in a factor VIII (FVIII)-deficient mouse model for severe hemophilia Al genetic modification of donor bone marrow cells with a retroviral vector encoding hFVIII, and transplant to hemophiliac mouse recipients, results in the induction of immune tolerance to FVIII in 50% of treated animals after immunization with hFVIII, despite the fact that hFVIII protein or activity is undetectable. In tolerized animals, the titers of anti-hFVIII binding antibodies and of hFVIII inhibitor antibodies were significantly reduced, and there was evidence for hFVIII unresponsiveness in CD4(+) T cells. Importantly, the plasma clearance of hFVIII was significantly decreased in tolerized animals and was not significantly different from that seen in a FVIII-naive hemophiliac mouse. This model system will prove useful for the evaluation of genetic therapies for hFVIII immunomodulation and bring genetic therapies for hFVIII tolerance closer to clinical application for patients with hemophilia A. C1 NIH, Natl Human Genome Res Inst, Clin Gene Therapy Branch, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NIH, Natl Human Genome Res Inst, Clin Gene Therapy Branch, Bldg 10,10 Ctr Dr,MSC 1851,Room 10C103, Bethesda, MD 20892 USA. EM rmorgan@nhgri.nih.gov NR 38 TC 77 Z9 77 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 12 PY 1998 VL 95 IS 10 BP 5734 EP 5739 DI 10.1073/pnas.95.10.5734 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZM977 UT WOS:000073595500059 PM 9576953 ER PT J AU Baloh, RH Gorodinsky, A Golden, JP Tansey, MG Keck, CL Popescu, NC Johnson, EM Milbrandt, J AF Baloh, RH Gorodinsky, A Golden, JP Tansey, MG Keck, CL Popescu, NC Johnson, EM Milbrandt, J TI GFR alpha 3 is an orphan member of the GDNF/neurturin/persephin receptor family SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NEURONS IN-VIVO; NEUROTROPHIC FACTOR; TYROSINE KINASE; SURVIVAL FACTOR; GDNF; PROMOTES; RET; MOTONEURONS; CELLS AB GDNF, neurturin, and persephin are transforming growth factor beta-related neurotrophic factors known collectively as the GDNF family (GF). GDNF and neurturin signal through a multicomponent receptor complex containing a signaling component (the Ret receptor tyrosine kinase) and either of two glycosyl-phosphatidylinositol-linked binding components (GDNF family receptor alpha components 1 and 2, GFR alpha 1 or GFR alpha 2), whereas the receptor for persephin is unknown. Herein we describe a third member of the GF coreceptor family called GFR alpha 3 that is encoded by a gene located on human chromosome 5q31.2-32, GFR alpha 3 is not expressed in the central nervous system of the developing or adult animal but is highly expressed in several developing and adult sensory and sympathetic ganglia of the peripheral nervous system. GFR alpha 3 is also expressed at high levels in developing, but not adult, peripheral nerve. GFR alpha 3 is a glycoprotein that is glycosyl-phosphatidylinositol-linked to the cell surface like GFR alpha 1 and GFR alpha 2. Fibroblasts expressing Ret and GFR alpha 3 do not respond to any of the known members of the GDNF family, suggesting that GFR alpha 3 interacts with an unknown ligand or requires a different or additional signaling protein to function. C1 Washington Univ, Sch Med, Dept Pathol & Internal Med, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Biol Mol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Pharmacol, St Louis, MO 63110 USA. NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Milbrandt, J (reprint author), Washington Univ, Sch Med, Dept Pathol & Internal Med, 660 S Euclid Ave,Box 8118, St Louis, MO 63110 USA. FU NIA NIH HHS [R01 AG013729, R01 AG13729, R01 AG13730, R01 AG013730] NR 31 TC 96 Z9 101 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 12 PY 1998 VL 95 IS 10 BP 5801 EP 5806 DI 10.1073/pnas.95.10.5801 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZM977 UT WOS:000073595500071 PM 9576965 ER PT J AU Whitley, RJ Jacobson, MA Friedberg, DN Holland, GN Jabs, DA Dieterich, DT Hardy, WD Polis, MA Deutsch, TA Feinberg, J Spector, SA Walmsley, S Drew, WL Powderly, WG Griffiths, PD Benson, CA Kessler, HA AF Whitley, RJ Jacobson, MA Friedberg, DN Holland, GN Jabs, DA Dieterich, DT Hardy, WD Polis, MA Deutsch, TA Feinberg, J Spector, SA Walmsley, S Drew, WL Powderly, WG Griffiths, PD Benson, CA Kessler, HA CA Int AIDS Society TI Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy - Recommendations of an international panel SO ARCHIVES OF INTERNAL MEDICINE LA English DT Review ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; IMMUNE-DEFICIENCY-SYNDROME; CENTRAL-NERVOUS-SYSTEM; PATIENTS RECEIVING GANCICLOVIR; BRONCHOALVEOLAR LAVAGE FLUID; POLYMERASE CHAIN-REACTION; HIV-INFECTED PATIENTS; CEREBROSPINAL-FLUID; INTRAVITREAL GANCICLOVIR; VIRUS INFECTION AB Objective: To provide recommendations for the treatment of acquired immunodeficiency syndrome-related cytomegalovirus (CMV) end-organ diseases, including retinitis, colitis, pneumonitis, and neurologic diseases. Participants: A 17-member panel of physicians with expertise in clinical and virological research and inpatient care in the field of CMV diseases. Evidence: Available clinical and virological study results. Recommendations are rated according to the quality and strength of available evidence. Recommendations were limited to the treatment of CMV diseases; prophylaxis recommendations are not included. Process: The panel was convened in February 1997 and met regularly through November 1997. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. Conclusions: Although the epidemiological features of CMV diseases are changing in the setting of potent, combination antiretroviral therapy, continued attention must be paid to CMV diseases in patients infected with the human immunodeficiency virus to prevent irreversible endorgan dysfunction. The initial and maintenance treatment of CMV retinitis must be individualized based on the characteristics of the lesions, including location and extent, specific patient factors,and characteristics of available therapies among others. Management of relapse or refractory retinitis must be likewise individualized. Ophthalmologic screening for patients at high risk for retinitis or who have a prior diagnosis of extraretinal disease is recommended. Recommendations for gastrointestinal, pulmonary, and neurologic manifestations are included. C1 Univ Alabama, Sch Med, Birmingham, AL 35233 USA. Univ Calif San Francisco, Sch Med, San Francisco, CA USA. NYU, Sch Med, New York, NY USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NIAID, Bethesda, MD 20892 USA. Rush Med Coll, Chicago, IL 60612 USA. Univ Cincinnati, Coll Med, Cincinnati, OH USA. Univ Toronto, Dept Med, Toronto, ON, Canada. Washington Univ, Sch Med, St Louis, MO USA. Royal Free Hosp, Sch Med, London, England. RP Whitley, RJ (reprint author), Univ Alabama, Sch Med, 1600 7th Ave S,Suite 616, Birmingham, AL 35233 USA. EM Rwhitley@peds.uab.edu OI Polis, Michael/0000-0002-9151-2268 NR 112 TC 106 Z9 108 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 MAY 11 PY 1998 VL 158 IS 9 BP 957 EP 969 DI 10.1001/archinte.158.9.957 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA ZL888 UT WOS:000073483600004 PM 9588429 ER PT J AU Langlois, JA Visser, M Davidovic, LS Maggi, S Li, GH Harris, TB AF Langlois, JA Visser, M Davidovic, LS Maggi, S Li, GH Harris, TB TI Hip fracture risk in older white men is associated with change in body weight from age 50 years to old age SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID BONE-MINERAL DENSITY; ELDERLY MEN; POSTMENOPAUSAL WOMEN; PHYSICAL-ACTIVITY; MUSCLE STRENGTH; ADIPOSE-TISSUE; GROWTH-HORMONE; OBESE MALES; MASS INDEX; US ADULTS AB Background: Change in body weight is a potentially modifiable risk factor for hip fracture in older women but, to our knowledge, its relationship to risk in older men has not been reported previously. Objective: To investigate the effects of weight loss and weight gain from age SO years to old age on the risk of hip fracture among elderly men. Methods: The association between weight change and risk of hip fracture was studied in a cohort of 2413 community-dwelling white men aged 67 years or older from 3 sites of the Established Populations for Epidemiologic Study of the Elderly. Results: The older men in this study, observed for a total of 13 620 person-years during the 8 years of followup, experienced 72 hip fractures, yielding an overall incidence rate of 5.3 per 1000 person-years. Extreme weight loss (greater than or equal to 10%) beginning at age 50 years was associated in a proportional hazards model with increased risk of hip fracture (relative risk, 1.8; 95% confidence interval, 1.04 3.3). Weight loss of 10% or more was associated with several indicators of poor health, including physical disability, low mental status score, and low physical activity (P<.05). Weight gain of 10% or more beginning at age 50 years provided borderline protection against the risk of hip fracture (relative risk, 0.4; 95% confidence interval, 0.1-1.00). Conclusions: Despite differences between older men and women in the incidence of and risk factors for hip fracture, weight history is also an important determinant of the risk of hip fracture among older men. Weight loss of 10% or more beginning at age 50 years increases the risk of hip fracture in older white men; weight gain of 10% or more decreases the risk of hip fracture. The relationship between extreme weight loss and poor health suggests that weight loss is a marker of frailty that may increase the risk of hip fracture in older men. Physicians should include weight history in their assessment of the risk of hip fracture among older men. C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Univ Vermont, Sch Med, Burlington, VT 05405 USA. Univ Padua, Ist Med Interna, I-35100 Padua, Italy. Johns Hopkins Univ, Sch Med, Dept Emergency Med, Baltimore, MD USA. RP Langlois, JA (reprint author), Ctr Dis Control & Prevent, Natl Ctr Injury Prevent & Control, Div Acute Care Rehabil Res & Disabil Prevent, 4770 Buford Hwy NE MS-F-41, Atlanta, GA 30341 USA. NR 66 TC 56 Z9 58 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 MAY 11 PY 1998 VL 158 IS 9 BP 990 EP 996 DI 10.1001/archinte.158.9.990 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA ZL888 UT WOS:000073483600007 PM 9588432 ER PT J AU Patel, Y Gough, G Coffin, RS Thomas, S Cohen, JI Latchman, DS AF Patel, Y Gough, G Coffin, RS Thomas, S Cohen, JI Latchman, DS TI Cell type specific repression of the varicella zoster virus immediate early gene 62 promoter by the cellular Oct-2 transcription factor SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE Oct-2; transactivation; (varicella zoster virus); (herpes simplex virus) ID HERPES-SIMPLEX VIRUS; SENSORY NEURONS; B-CELLS; PROTEIN; TRANSACTIVATION; EXPRESSION; ELEMENTS; BINDING; DOMAIN; SEQUENCE AB The cellular transcription factor Oct-2.1 has previously been shown to repress the transactivation of the varicella tester virus (VZV) immediate early gene promoter by viral transactivators but not to inhibit its basal activity, In the case of the related virus herpes simplex virus (HSV), the effect of Oct-2 on the IE promoters has been shown to be cell type specific and to differ between the different alternatively spliced forms of Oct-2. Here we show that as well as Oct-2.1, the Oct-2.4 and 2.5 isoforms which are expressed in neuronal cells can inhibit transactivation of the VZV immediate early promoter regardless of the cell type used. In contrast, all the isoforms of Oct-2 can inhibit basal activity of the VZV promoter in neuronal cells but not in other cell types indicating that this effect is cell type specific. These effects are discussed in terms of the differential regulation of latent infections with HSV or VZV in dorsal root ganglia. (C) 1998 Elsevier Science B.V. C1 UCL, Sch Med, Windeyer Inst Med Sci, Dept Mol Pathol, London W1P 6DB, England. Glaxo Wellcome Med Res Ctr, Stevenage, Herts, England. NIAID, Clin Invest Lab, Med Virol Sect, Bethesda, MD 20892 USA. RP Latchman, DS (reprint author), UCL, Sch Med, Windeyer Inst Med Sci, Dept Mol Pathol, Windeyer Bldg,46 Cleveland St, London W1P 6DB, England. NR 29 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD MAY 11 PY 1998 VL 1397 IS 3 BP 268 EP 274 DI 10.1016/S0167-4781(97)00216-9 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZQ803 UT WOS:000073904600006 PM 9582435 ER PT J AU Zhan, SL Zhan, SX Zhang, LJ Van, M Young, C Helman, LJ AF Zhan, SL Zhan, SX Zhang, LJ Van, M Young, C Helman, LJ TI Biallelic expression of all four IGF-II promoters and its association with increased methylation of H19 gene in human brain SO BRAIN RESEARCH LA English DT Article DE IGF-II; H19; imprinting; CNS; methylation ID GROWTH-FACTOR-II; UNIPARENTAL PATERNAL DISOMY; WILMS-TUMOR; IMPRINTING STATUS; MUSCLE TUMORS; RELAXATION; CANCER; RNA; RHABDOMYOSARCOMA; HEPATOBLASTOMA AB The human IGF-II gene is maternally imprinted in all tissues except adult liver and the choroid plexus/leptomeninges of the central nervous system where IGF-II is biallelically expressed. In human liver, it has recently been reported that this biallelic expression only involves the promoter P1 while the promoters P2-P4 direct IGF-II transcription monoallelically. To explore whether or not biallelic expression of the IGF-II promoters in human CNS displays the same pattern as in liver, we examined the allelic expression status of the four IGF-II promoters in human brain. We found that all four IGF-II promoters in human fetal and adult brain were expressed from both parental alleles. Furthermore, the levels of methylation of the 3' region of H19 gene in fetal brain were higher than those in other tissues with monoallelic expression of IGF-II. Since similar findings have been reported in Wilms' tumor, these data suggest a similar mechanism may be responsible for loss of imprinting of IGF-II in normal brain and Wilms' tumor. (C) 1998 Elsevier Science B.V. C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Helman, LJ (reprint author), NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NR 44 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 11 PY 1998 VL 792 IS 2 BP 283 EP 290 DI 10.1016/S0006-8993(98)00157-7 PG 8 WC Neurosciences SC Neurosciences & Neurology GA ZU326 UT WOS:000074185500012 PM 9593943 ER PT J AU Corness, J Stevens, B Fields, RD Hokfelt, T AF Corness, J Stevens, B Fields, RD Hokfelt, T TI NGF and LIF both regulate galanin gene expression in primary DRG cultures SO NEUROREPORT LA English DT Article DE cytokine; dorsal root ganglia (DRG); leukemia inhibitory factor (LIF); nerve growth factor (NGF); sensory neurons ID LEUKEMIA INHIBITORY FACTOR; NERVE GROWTH-FACTOR; VASOACTIVE INTESTINAL POLYPEPTIDE; PRIMARY SENSORY NEURONS; ROOT GANGLION NEURONS; DIFFERENTIATION FACTOR; NEUROPEPTIDE EXPRESSION; SYMPATHETIC NEURONS; SCIATIC-NERVE; PERIPHERAL AXOTOMY AB BOTH target-derived and injury-induced factors could be involved in the axotomy-induced increases in galanin expression in dorsal root ganglion (DRG) neurons. Galanin mRNA levels were studied in primary cultures of E13.5 embryos, grown for 14 days in culture, in response to two candidate molecules, nerve growth factor (NGF) and leukemia inhibitory factor (LIF). In these cultures, NGF withdrawal alone resulted in a significant increase in galanin mRNA. Addition of LIF onto NGF-containing cultures did not produce a significant increase, while addition of LIF to NGF-deprived cultures caused an upregulation of galanin mRNA which was significantly stronger than that of NGF withdrawal alone. Thus, NGF withdrawal and LIF increase act together to up-regulate galanin gene transcription in DRG neurons. (C) 1998 Rapid Science Ltd. C1 Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. NICHHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Corness, J (reprint author), Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. NR 29 TC 28 Z9 28 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD MAY 11 PY 1998 VL 9 IS 7 BP 1533 EP 1536 DI 10.1097/00001756-199805110-00053 PG 4 WC Neurosciences SC Neurosciences & Neurology GA ZR650 UT WOS:000074000000055 PM 9631462 ER PT J AU Bavelier, D Corina, D Jezzard, P Clark, V Karni, A Lalwani, A Rauschecker, JP Braun, A Turner, R Neville, HJ AF Bavelier, D Corina, D Jezzard, P Clark, V Karni, A Lalwani, A Rauschecker, JP Braun, A Turner, R Neville, HJ TI Hemispheric specialization for English and ASL: left invariance right variability SO NEUROREPORT LA English DT Article DE fMRI; hemispheric specialization; neurobiology of language; plasticity; sentence processing; sign language ID LANGUAGE; CORTEX AB FUNCTIONAL magnetic resonance imaging (fMRI) was used to compare the cerebral organization during sentence processing in English and in American sign language (ASL). Classical language areas within the left hemisphere were recruited by both English in native speakers and ASL in native signers. This suggests a bias of the left hemisphere to process natural languages independently of the modality through which language is perceived. Furthermore, in contrast to English, ASL strongly recruited right hemisphere structures. This was true irrespective of whether the native signers were deaf or hearing. Thus, the specific processing requirements of the language also in part determine the organization of the language systems of the brain. (C) 1998 Rapid Science Ltd. C1 Georgetown Inst Cognit & Computat Sci, Washington, DC 20007 USA. Univ Washington, Dept Psychol, Seattle, WA 98195 USA. Univ Oxford, MFRIB, Oxford OX3 9DU, England. NIH, Bethesda, MD 20892 USA. Weizmann Inst Sci, IL-76100 Rehovot, Israel. Univ Calif San Francisco, San Francisco, CA 94143 USA. Inst Neurol, London WC1N 3BG, England. Univ Oregon, Dept Psychol, Eugene, OR 97403 USA. RP Bavelier, D (reprint author), Georgetown Inst Cognit & Computat Sci, 4000 Reservoir Rd, Washington, DC 20007 USA. RI Turner, Robert/C-1820-2008; Rauschecker, Josef/A-4120-2013; Clark, Vincent/B-3343-2010; OI Clark, Vincent/0000-0002-9151-2102; Jezzard, Peter/0000-0001-7912-2251 NR 22 TC 53 Z9 53 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD MAY 11 PY 1998 VL 9 IS 7 BP 1537 EP 1542 DI 10.1097/00001756-199805110-00054 PG 6 WC Neurosciences SC Neurosciences & Neurology GA ZR650 UT WOS:000074000000056 PM 9631463 ER PT J AU Long, JC Knowler, WC Hanson, RL Robin, RW Urbanek, M Moore, E Bennett, PH Goldman, D AF Long, JC Knowler, WC Hanson, RL Robin, RW Urbanek, M Moore, E Bennett, PH Goldman, D TI Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an American Indian population SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article ID CROSS-FOSTERING ANALYSIS; NOVELTY SEEKING; SEGREGATION ANALYSIS; REPEAT POLYMORPHISM; MULTIPLE THRESHOLDS; COMPLEX TRAITS; RECEPTOR GENE; HETEROGENEITY; ASSOCIATION; INHERITANCE AB To identify specific genes affecting vulnerability or resistance, me performed a whole-autosomal genome scan for genetic linkage to alcohol dependence in a Southwestern American Indian tribe. Genotypes at 517 autosomal microsatellite loci and clinical evaluations mere available for 152 subjects belonging to extended pedigrees and forming 172 sib-pairs, Highly suggestive evidence for linkage emerged for two genomic regions using two-and multipoint sib-pair regression methods; both regions harbored neurogenetic candidate genes. The best evidence is seen with D11S1984 (nominal P = 0.00007, lod congruent to 3.1) on chromosome 11p, in close proximity to the DRD4 dopamine receptor and tyrosine hydroxylase (TH) genes. Good evidence is seen with D4S3242 (nominal P = 0.0002, lod congruent to 2.8) on chromosome 4p, near the pi GABA receptor gene. Interestingly, three loci in the alcohol dehydrogenase gene cluster on chromosome 4q showed evidence for linkage with two-point analyses, but not multipoint analysis. (C) 1998 Wiley-Liss, Inc. C1 NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. RP Long, JC (reprint author), NIAAA, Neurogenet Lab, NIH, Pk 5 Bldg,Rm 451,MSC 8110,12420 Parklawn Dr, Bethesda, MD 20892 USA. RI Hanson, Robert/O-3238-2015; Goldman, David/F-9772-2010 OI Hanson, Robert/0000-0002-4252-7068; Goldman, David/0000-0002-1724-5405 FU NCRR NIH HHS [1 P41 RR03655] NR 38 TC 290 Z9 296 U1 5 U2 11 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 MAY 8 PY 1998 VL 81 IS 3 BP 216 EP 221 DI 10.1002/(SICI)1096-8628(19980508)81:3<216::AID-AJMG2>3.0.CO;2-U PG 6 WC Genetics & Heredity SC Genetics & Heredity GA ZL222 UT WOS:000073411000002 PM 9603607 ER PT J AU Gomez, DE Tejera, AM Olivero, OA AF Gomez, DE Tejera, AM Olivero, OA TI Irreversible telomere shortening by 3 '-azido-2 ',3 '-dideoxythymidine (AZT) treatment SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID REVERSE-TRANSCRIPTASE INHIBITORS; HUMAN FIBROBLASTS; SENESCENCE; LENGTH; CELLS AB Telomeres shorten by 30 to 50 bp with each cell division. Germ line, tumor and stem cells overcome progressive shortening by elongating their telomeres with telomerase. Previously we demonstrated that 3'-azido-2',3'-dideoxythymidine (AZT), incorporates into telomeric DNA. To determine if telomeric AZT incorporation was a telomerase mediated phenomenon, we subjected tumor cells to long-term AZT exposure. Here we report the shortening of the telomeric sequences of Hf,La cells cultured with 800 mu M AZT for 15 passages. Southern blots of HeLa DNA cultured with AZT and digested with SAU 3AI, Alu I, and Rsa I revealed a progressive shortening of the telomeric repeats when probed with a human biotinylated telomeric probe. The shortened telomeric repeats did not elongate after culturing without AZT for an additional 25 passages. No evidence of senescence could be detected. (C) 1998 Academic Press. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. Natl Univ Quilmes, Mol Oncol Lab, RA-1876 Bernal, Argentina. RP Olivero, OA (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bldg 37 Rm 3B15,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. RI Tejera, Agueda/L-1946-2015; OI Gomez, Daniel E/0000-0002-8629-0787 NR 14 TC 82 Z9 88 U1 1 U2 6 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 8 PY 1998 VL 246 IS 1 BP 107 EP 110 DI 10.1006/bbrc.1998.8555 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZP868 UT WOS:000073796700020 PM 9600076 ER PT J AU Goransson, O Wijkander, J Manganiello, V Degerman, E AF Goransson, O Wijkander, J Manganiello, V Degerman, E TI Insulin-induced translocation of protein kinase B to the plasma membrane in rat adipocytes SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE insulin; adipocyte; protein kinase B; plasma membrane; phosphatidylinositol 3-kinase ID PLECKSTRIN HOMOLOGY DOMAIN; MOLECULAR-CLONING; AKT AB Protein kinase B (PKB) has previously been shown to be activated in response to insulin and growth factor stimulation. The activation mechanism has been suggested to involve translocation of PKB to membranes, where it is phosphorylated and activated. Insulin-induced translocation of PKB has not been demonstrated in a physiological target cell. Therefore we have used the primary rat adipocyte to investigate insulin-induced translocation of PKB. In the presence of 1 nM insulin translocation of PKB was detected within 30 seconds and was blocked by wortmannin, a selective phosphatidylinositol 3-kinase inhibitor. This translocation was potentiated by the tyrosine phosphatase inhibitor vanadate. Subcellular localization studies revealed that PKB translocated to the plasma membrane. (C) 1998 Academic Press. C1 Univ Lund, Dept Cell & Mol Biol, Sect Mol Signalling, S-22100 Lund, Sweden. NHLBI, Pulm Crit Care Med Branch, Bethesda, MD 20892 USA. RP Goransson, O (reprint author), Univ Lund, Dept Cell & Mol Biol, Sect Mol Signalling, POB 94, S-22100 Lund, Sweden. NR 33 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 8 PY 1998 VL 246 IS 1 BP 249 EP 254 DI 10.1006/bbrc.1998.8602 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZP868 UT WOS:000073796700045 PM 9600101 ER PT J AU Jhee, KH Yang, LH Ahmed, SA McPhie, P Rowlett, R Miles, EW AF Jhee, KH Yang, LH Ahmed, SA McPhie, P Rowlett, R Miles, EW TI Mutation of an active site residue of tryptophan synthase (beta-serine 377) alters cofactor chemistry SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MITOCHONDRIAL ASPARTATE-AMINOTRANSFERASE; ESCHERICHIA-COLI; SALMONELLA-TYPHIMURIUM; ABSORPTION-SPECTRA; SEMIEMPIRICAL CALCULATIONS; 3-DIMENSIONAL STRUCTURE; PYRIDOXAL-PHOSPHATE; SPATIAL STRUCTURE; ALPHA-SUBUNIT; MUTAGENESIS AB To better understand how an enzyme controls cofactor chemistry, we have changed a tryptophan synthase residue that interacts with the pyridine nitrogen of the pyridoxal phosphate cofactor from a neutral Ser (beta-Ser(377)) to a negatively charged Asp or Glu, The spectroscopic properties of the mutant enzymes are altered and become similar to those of tryptophanase and aspartate aminotransferase, enzymes in which an Asp residue interacts with the pyridine nitrogen of pyridoxal phosphate. The absorption spectrum of each mutant enzyme undergoes a pH-dependent change (pK(a) similar to 7.7) from a form with a protonated internal aldimine nitrogen (lambda(max), = 416 nm) to a deprotonated form (lambda(max), = 336 nm), whereas the absorption spectra of the wild type tryptophan synthase beta(2), subunit and alpha(2) beta(2), complex are pH-independent. The reaction of the S377D alpha(2) beta(2) complex with L-serine, L-tryptophan, and other substrates results in the accumulation of pronounced absorption bands (lambda(max), = 498-510 nm) ascribed to quinonoid intermediates. We propose that the engineered Asp or Glu residue changes the cofactor chemistry by stabilizing the protonated pyridine nitrogen of pyridoxal phosphate, reducing the pK(a) of the internal aldimine nitrogen and promoting formation of quinonoid intermediates. C1 NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Miles, EW (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bldg 8,Rm 225,8 Ctr Dr MSC 0830, Bethesda, MD 20892 USA. EM EdithM@intra.niddk.nih.gov NR 46 TC 25 Z9 25 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 8 PY 1998 VL 273 IS 19 BP 11417 EP 11422 DI 10.1074/jbc.273.19.11417 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZM408 UT WOS:000073536700005 PM 9565551 ER PT J AU Steinert, PM Kartasova, T Marekov, LN AF Steinert, PM Kartasova, T Marekov, LN TI Biochemical evidence that small proline-rich proteins and trichohyalin function in epithelia by modulation of the biomechanical properties of their cornified cell envelopes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN EPIDERMAL-KERATINOCYTES; CROSS-LINKED ENVELOPE; HUMAN LORICRIN; INTERMEDIATE FILAMENTS; PRECURSOR PROTEINS; RETINOIC ACID; EXPRESSION; CALCIUM; FAMILY; GENE AB The cornified cell envelope (CE) is a specialized structure involved in barrier function in stratified squamous epithelia, and is assembled by transglutaminase cross-linking of several proteins. Murine forestomach epithelium undergoes particularly rigorous mechanical trauma, and these CEs contain the highest known content of small proline-rich proteins (SPRs). Sequencing analyses of these CEs revealed that SPRs function as cross-bridgers by joining other proteins by use of multiple adjacent glutamines and lysines on only the amino and carboxyl termini and in functionally non-polar ways. Forestomach CEs also use trichohyalin as a novel cross-bridging protein. We performed mathematical modeling of amino acid compositions of the CEs of mouse and human epidermis of different body sites. Although the sum of loricrin + SPRs was conserved, the amount of SPRs varied in relation to the presumed physical requirements of the tissues. Our data suggest that SPRs could serve as modifiers of a composite CE material composed of mostly loricrin; we propose that increasing amounts of cross-bridging SPRs modify the structure of the CE, just as cross-linking proteins strengthen other types of tissues. In this way, different epithelia may use varying amounts of the cross-bridging SPRs to alter the biomechanical properties of the tissue in accordance with specific physical requirements and functions. C1 NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. RP Steinert, PM (reprint author), NIAMS, Skin Biol Lab, NIH, Bldg 6,Rm 425,9000 Rockville Pike, Bethesda, MD 20892 USA. EM pemast@helix.nih.gov NR 60 TC 85 Z9 85 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 8 PY 1998 VL 273 IS 19 BP 11758 EP 11769 DI 10.1074/jbc.273.19.11758 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZM408 UT WOS:000073536700053 PM 9565599 ER PT J AU Asano, K Mizobuchi, K AF Asano, K Mizobuchi, K TI An RNA pseudoknot as the molecular switch for translation of the repZ gene encoding the replication initiator of IncI alpha plasmid ColIb-P9 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ESCHERICHIA-COLI; MESSENGER-RNA; DNA; EXPRESSION; PROTEIN; CLONING; FRAGMENTS; TARGETS; SIGNALS; REGION AB Translation initiation of the repZ gene encoding the replication initiator of plasmid ColIb-P9 is not only negatively regulated by the action of the antisense Inc RNA encoded in the leader region, but is also coupled to the translation and termination of a transcribed leader sequence, repY, a positive regulatory element for repZ gene expression. This translational coupling depends on base pairing between two complementary sequences, 5'-rGGCG-3' and 5'-rCGCC-3', which are located upstream of and in the middle of repY, respectively, and have the potential to form a pseudoknot with the stem-loop structure I, Another stem-loop called structure III near the 3'-end of repY sequesters both the 5'-rCGCC-3' sequence and the repZ ribosome-binding site. Here we show that the RepZ mRNA leader sequence synthesized in vitro indeed contains several stem-loop structures including structures I and III, but not the pseudoknot, However, disruption of structure III, without changing the repZ ribosome-binding site, by means of base substitution and deletion induces base pairing between the two short complementary sequences distantly separated, resulting in the formation of a pseudoknot, When the pseudoknot is allowed to form in vivo due to the same mutations, a maximum level of repZ expression is obtained comparable to one observed in the absence of Inc RNA. These results strengthen our previously proposed model that the pseudoknot induced by the translation and termination of the repY reading frame functions as the molecular switch for translational initiation of the repZ gene. C1 Univ Tokyo, Grad Sch Sci, Dept Biochem & Biophys, Tokyo 113, Japan. Univ Electrocommun, Dept Appl Phys & Chem, Chofu, Tokyo 182, Japan. RP Asano, K (reprint author), NICHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. NR 30 TC 23 Z9 23 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 MAY 8 PY 1998 VL 273 IS 19 BP 11815 EP 11825 DI 10.1074/jbc.273.19.11815 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZM408 UT WOS:000073536700060 PM 9565606 ER PT J AU Asano, K Niimi, T Yokoyama, S Mizobuchi, K AF Asano, K Niimi, T Yokoyama, S Mizobuchi, K TI Structural basis for binding of the plasmid ColIb-P9 antisense Inc RNA to its target RNA with the 5 '-rUUGGCG-3 ' motif in the loop sequence SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID REPZ GENE-EXPRESSION; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; MESSENGER-RNA; DNA; REPLICATION; CLONING; SYSTEM; VITRO AB The sequence 5'-rUUGGCG-3' is conserved within the loop regions of antisense RNAs or their targets involved in replication of various prokaryotic plasmids, In IncI alpha plasmid ColIb-P9, the partially base paired al-nucleotide loop of a stem-loop called structure I within RepZ mRNA contains this hexanucleotide sequence, and comprises the target site for the antisense Inc RNA. In this report, we find that the base pairing interaction at the 5'-rGGC-3' sequence in the hexanucleotide motif is important for interaction between Inc RNA and structure I. In addition, the 21-base loop domain of structure I is folded tighter than predicted, with the hexanucleotide sequence at the top. The second U residue in the sequence is favored for Inc RNA binding in a base-specific manner. On the other hand, the upper domain of the Inc RNA stem-loop is loosely structured, and maintaining the loop sequence single-stranded is important for the intermolecular interaction. Based on these results, we propose that a structural feature in the loop I domain, conferred probably by the conserved 5'-rUUGGCG-3' sequence, favors binding to a complementary, single-stranded RNA. This model also explains how the RepZ mRNA pseudoknot, described in the accompanying paper (Asano, I,, and Mizobuchi, K. (1998) J. Biol. Chem. 273, 11815-11825) is formed specifically with structure I. A possible conformation adopted by the 5'-rUUGGCG-3' loop sequence is discussed. C1 Univ Tokyo, Grad Sch Sci, Dept Biochem & Biophys, Tokyo 113, Japan. Univ Electrocommun, Dept Appl Phys & Chem, Chofu, Tokyo 182, Japan. RP Asano, K (reprint author), NICHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. RI Yokoyama, Shigeyuki/N-6911-2015 OI Yokoyama, Shigeyuki/0000-0003-3133-7338 NR 33 TC 36 Z9 36 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 8 PY 1998 VL 273 IS 19 BP 11826 EP 11838 DI 10.1074/jbc.273.19.11826 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZM408 UT WOS:000073536700061 PM 9565607 ER PT J AU Kim, S Nelson, PG AF Kim, S Nelson, PG TI Transcriptional regulation of the prothrombin gene in muscle SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ENHANCER-BINDING-FACTOR; THROMBIN RECEPTOR; NEURITE RETRACTION; MESSENGER-RNA; ACTIN GENE; EXPRESSION; CELLS; ACTIVATION; DIFFERENTIATION; LOCALIZATION AB Thrombin has been shown to mediate neurite retraction in neurons and synapse elimination at the neuromuscular junction. The presence of prothrombin mRNA has been demonstrated in brain and in muscle, but extra-hepatic regulation of the prothrombin gene has not been investigated. To identify cis-acting DNA elements involved in the expression of the prothrombin gene in muscle, we have isolated and analyzed a 1.3-kilobase pair promoter region of the mouse prothrombin gene. Using a series of transiently transfected plasmid constructs in which gene segments of the prothrombin promoter were linked to the luciferase gene, we have identified a sequence, -302 to -210, essential for prothrombin promoter activity in Ca-myotubes. Fine analysis revealed that deletion of nucleotides between -248 and -235 eliminated prothrombin promoter activity in C2-myotubes, Furthermore, electrophoretic mobility shift assays demonstrated that a nuclear factor present in C2-myotubes, but not in Ca-myoblasts or HepG2 hepatocytes, specifically binds to the sequence -241 to -225, Substitutional mutation of nucleotides -237 to -231 abolished myotube-specific promoter activity and inhibited the nuclear factor binding. Quantitative reverse transcription polymerase chain reaction demonstrated the expression of prothrombin mRNA in myotubes, but not in myoblasts, of primary, C2, and G8 muscle cells. This result correlates with the lack of prothrombin promoter activity in C2-myoblasts, The data thus suggest that a myotube-specific nuclear factor binds to a cis-acting sequence encompassing the core nucleotides -237 to -231 and plays a critical role in muscle-specific, differentiation-dependent expression of the mouse prothrombin gene. C1 NICHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Kim, S (reprint author), NICHD, Dev Neurobiol Lab, NIH, Bldg 49,Rm 5A38,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 34 TC 17 Z9 17 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 8 PY 1998 VL 273 IS 19 BP 11923 EP 11929 DI 10.1074/jbc.273.19.11923 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZM408 UT WOS:000073536700074 PM 9565620 ER PT J AU Richards, RG Walker, MP Sebastian, J DiAugustine, RP AF Richards, RG Walker, MP Sebastian, J DiAugustine, RP TI Insulin-like growth factor-1 (IGF-1) receptor-insulin receptor substrate complexes in the uterus - Altered signaling response to estradiol in the IGF-1(m/m) mouse SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FACTOR-I RECEPTOR; YEAST 2-HYBRID SYSTEM; PHOSPHATIDYLINOSITOL 3-KINASE; TYROSINE PHOSPHORYLATION; GENE-EXPRESSION; PHOSPHOINOSITIDE 3-KINASE; REGULATORY SUBUNIT; EGF-RECEPTOR; SH3 DOMAINS; P85 SUBUNIT AB Some of the actions of estradiol occur through stimulation of growth factor pathways in target organs. Tyrosine-phosphorylated (Tyr(P)) insulin-like growth factor-1 receptor (IGF-1R) and the insulin receptor substrate (IRS)-1 are found in the uterus of mice treated with estradiol, Immunoprecipitates of uterine Tyr(P) IRS-1 contained both p85, the regulatory subunit of phosphatidylinositol (PI) 3-kinase, and PI 3-kinase catalytic activity. Estradiol also stimulated binding of IRS-1 and PI 3-kinase to the IGF-1R, Depletion of IRS-1 from uterine extracts reduced PI 3-kinase associated with the receptor, which suggests that binding of the enzyme to IGF-1R occurs primarily in a complex that also contains IRS-1, Following treatment with estradiol, formation of Tyr(P) IGF-1R, Tyr(P) IRS-1, and the p85 IRS-I complex was very weak in the uterus of IGF-1(m/m) mice, which are severely deficient in IGF-1, This indicated that most, if not all, of the estradiol-stimulated Tyr phosphorylation of uterine IRS-1 originates from ligand activation of IGF-1R kinase. IRS-2 was also Tyr-phosphorylated in the normal uterus and bound more IGF-1R and p85 in response to estradiol; however, a marked decrease in levels of uterine IRS-2 occurred 12-24 h after treatment with estradiol, Since IRS-2 was present in IGF-1R precipitates and a recombinant form of IGF-1 (long R-3 IGF-1) stimulated formation of Tyr(P) IRS-2, hormonal activation of this docking protein probably occurs through the IGF-1R In summary, our findings show that estrogen activation of uterine IGF-1R kinase results in enhanced binding of p85 (PI 3-kinase) to IRS-1 and IRS-S, The formation of one or both of these complexes may be important for the potent mitogenic action of this steroid. That estradiol stimulated a decrease of IRS-2, but not of IRS-1, suggests that these docking proteins have different roles in hormone-induced signaling in the uterus. C1 NIEHS, Hormones & Canc Grp, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP DiAugustine, RP (reprint author), NIEHS, Hormones & Canc Grp, Mol Carcinogenesis Lab, NIH, 111 TW Alexander Dr,MD D4-04, Res Triangle Pk, NC 27709 USA. EM diaugus2@niehs.nih.gov NR 64 TC 38 Z9 39 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 MAY 8 PY 1998 VL 273 IS 19 BP 11962 EP 11969 DI 10.1074/jbc.273.19.11962 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZM408 UT WOS:000073536700079 PM 9565625 ER PT J AU Priola, SA Chesebro, B AF Priola, SA Chesebro, B TI Abnormal properties of prion protein with insertional mutations in different cell types SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; SCRAPIE PRION; CULTURED-CELLS; BIOCHEMICAL-PROPERTIES; COPPER-BINDING; GENE; MUTANT; PRP; INFECTION; FORM AB Inherited forms of the human transmissible spongiform encephalopathy Creutzfeldt-Jakob disease (CJD) have been associated with mutations in the normal soluble, protease-sensitive form of the host prion protein (PrP-sen). Normal PrP protein contains five copies of a repeating eight-amino acid region, and PrP molecules with six or more copies of this region are associated with disease in familial CJD. It has been hypothesized that these mutations might facilitate spontaneous formation of the abnormal, aggregated protease-resistant PrP isoform, PrP-res, associated with clinical CJD and other transmissible spongiform encephalopathies (TSE). In the present experiments, hamster PrP molecules with 5 (wild-type), 7, 9, or 11 copies of this repeat region were generated and expressed in mouse fibroblast cells or mouse neuroblastoma cells. In mouse fibroblast cells, mutant hamster PrP molecules expressing 7, 9, and 11 copies of the octapeptide repeat sequence showed altered cell surface expression, but both mutant and wild-type hamster PrP-sen molecules demonstrated abnormal properties of aggregation and increased protease resistance. By contrast in mouse neuroblastoma cells, hamster PrP-sen with 5, 9, and 11 octapeptide repeats were expressed normally on the cell surface, but only PrP-sen molecules with 9 or 11 copies of the repeat motif had abnormal properties of aggregation and increased protease resistance. Overall, regardless of cell type, hamster PrP molecules with greater than 7 octapeptide repeats were more aggregated and more protease-resistant than molecules with 7 repeats or less. However, these abnormal molecules were at least 1000-fold less protease-resistant than bona fide PrP-res derived from TSE-infected brain tissue, and they showed no increased ability to form PrP-res in a cell-free system. C1 NIAID, Persistent Viral Dis Lab, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Priola, SA (reprint author), NIAID, Persistent Viral Dis Lab, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. EM spriola@nih.gov NR 40 TC 69 Z9 71 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 MAY 8 PY 1998 VL 273 IS 19 BP 11980 EP 11985 DI 10.1074/jbc.273.19.11980 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZM408 UT WOS:000073536700081 PM 9565627 ER PT J AU Dubois, M Zemb, T Fuller, N Rand, RP Parsegian, VA AF Dubois, M Zemb, T Fuller, N Rand, RP Parsegian, VA TI Equation of state of a charged bilayer system: Measure of the entropy of the lamellar-lamellar transition in DDABr SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID OSMOTIC-STRESS MEASUREMENTS; DNA DOUBLE HELICES; PHOSPHATIDYLCHOLINE BILAYERS; PHOSPHOLIPID-BILAYERS; UNCHARGED MOLECULES; AQUEOUS-SOLUTIONS; HYDRATION FORCES; PHASE-EQUILIBRIA; WATER-SYSTEMS; TEMPERATURE AB The synthetic cationic double-chain surfactant didodecyldimethylammonium bromide shows two distinct thermodynamically stable lamellar phases; a dilute L-alpha, phase stabilized predominantly by electrostatic forces, and a condensed L-alpha' phase stabilized by "hydration" forces. Using six different experimental methods, applying osmotic stress from 10(2) to 10(9) Pa and varying temperature from 20 degrees C to 70 degrees C, we have measured the osmotic pressure vs interbilayer distance and thus mapped the phase diagram with an equation of state. In this binary system, the area per headgroup as well as bilayer thickness vary with concentration and temperature. Hence, lateral compressibility has to be taken into account in the free energy balance. The osmotic stress needed to effect the swollen-to-collapsed lamellar phase transition is determined as a function of temperature. From these data the entropy of the L-alpha-L-alpha' transition is found to be a strong function of temperature. Below 40 degrees C, condensation from the dilute L-alpha, phase, the change of entropy is negative as might be expected. Above 40 degrees C the entropy of condensation is positive, demonstrating that there is a release of degrees of freedom associated with the bilayer condensation. These data allow us to think far more critically about the forces that stabilize bilayer systems. (C) 1998 American Institute of Physics. C1 CEA Saclay, Serv Chim Mol, F-91191 Gif Sur Yvette, France. Brock Univ, Dept Biol Sci, St Catharines, ON L2S 3A1, Canada. NIH, Bethesda, MD 20892 USA. RP Dubois, M (reprint author), CEA Saclay, Serv Chim Mol, F-91191 Gif Sur Yvette, France. RI ZEMB, Thomas/E-5958-2010 NR 68 TC 85 Z9 85 U1 2 U2 8 PU AMER INST PHYSICS PI WOODBURY PA CIRCULATION FULFILLMENT DIV, 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2999 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD MAY 8 PY 1998 VL 108 IS 18 BP 7855 EP 7869 DI 10.1063/1.476505 PG 15 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA ZL319 UT WOS:000073420800042 ER PT J AU Chen, X Tordova, M Gilliland, GL Wang, LC Li, Y Yan, HG Ji, XH AF Chen, X Tordova, M Gilliland, GL Wang, LC Li, Y Yan, HG Ji, XH TI Crystal structure of apo-cellular retinoic acid-binding protein type II (R111M) suggests a mechanism of ligand entry SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE cellular retinoic acid-binding protein type II; retinoic acid; crystal structure; ligand entry; intracellular lipid-binding proteins ID FATTY-ACID; ESCHERICHIA-COLI; SECONDARY STRUCTURE; REFINEMENT; RAT; APOPROTEIN; RECEPTOR; CRYSTALLOGRAPHY; PURIFICATION; EXPRESSION AB The crystal structure of unliganded mutant R111M of human cellular retinoic acid-binding protein type II (apo-CRABPII (R111M)) has been determined at 2.3 Angstrom and refined fro a crystallographic R-factor of 0.18. Although the mutant protein has lower affinity for all-trans-retinoic acid (RA) than the wild-type, it is properly folded, and its conformation is very similar to the wild-type. apo-CRABPII (R111M) crystallizes in space group P1 with two molecules in the unit cell. The two molecules have high structural similarity except that their alpha 2 helices differ strikingly. Analyses of the molecular conformation and crystal packing environment suggest that one of the two molecules assumes a conformation compatible with RA entry. Three structural elements encompassing the opening of the binding pocket exhibit large conformational changes, when compared with holo-CRABPII, which include the alpha 2 helix and the beta C-beta D and beta E-beta F hairpin loops. The alpha 2 helix is unwound at its N terminus, which appears to be essential for the opening of the RA-binding pocket. Three arginine side-chains (29, 59, and 132) are found with their guanidino groups pointing into the RA-binding pocket. A three-step mechanism of TCA entry has been proposed, addressing the opening of the RA entrance, the electrostatic potential that directs entry of RA into the binding pocket, and the intramolecular interactions that stabilize the RA.CRABPII complex via locking the three flexible structural elements when RA is bound. (C) 1998 Academic Press Limited. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. Univ Maryland, Ctr Adv Res Biotechnol, Inst Biotechnol, Rockville, MD 20850 USA. NIST, Rockville, MD 20850 USA. Michigan State Univ, Dept Biochem, E Lansing, MI 48824 USA. RP Ji, XH (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, POB B, Frederick, MD 21702 USA. RI Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 NR 58 TC 26 Z9 27 U1 0 U2 2 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 8 PY 1998 VL 278 IS 3 BP 641 EP 653 DI 10.1006/jmbi.1998.1734 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZP641 UT WOS:000073773800013 PM 9600845 ER PT J AU Ptitsyn, OB AF Ptitsyn, OB TI Protein folding and protein evolution: Common folding nucleus in different subfamilies of c-type cytochromes? SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE protein folding; folding nucleation; transition state structure; cytochromes c ID MOLTEN GLOBULE STATE; TRANSITION-STATE; CHYMOTRYPSIN INHIBITOR-2; CRYSTAL-STRUCTURE; 2.5-A RESOLUTION; X-RAY; MECHANISM; MODEL; INTERMEDIATE; DIVERGENCE AB Amino acid sequences of seven subfamilies of cytochromes c (mitochondrial cytochromes c, c(1); chloroplast cytochromes c(6), c(f); bacterial cytochromes c(2),c(550),c(551); in total 164 sequences) have been compared. Despite extensive homology within eukaryotic subfamilies, homology between different subfamilies is very weak. Other than the three heme-binding residues (Cys13, Cys14, His18, in numeration of horse cytochrome c) there are only four positions which are conserved in all subfamilies: Gly/Ala6, Phe/Tyr10, Leu/Val/Phe94 and Tyr/Trp/Phe97. In all 17 cytochromes c with known D-structures, these residues form a network Of conserved contacts (6-94, 6-97, 10-94, 10-97 and 94-97). Especially strong is the contact between aromatic groups in positions 10 and 97, which corresponds to 13 interatomic contacts. As residues 6, 10 and residues 94, 97 are in (i, i + 4) and (i, i + 3) positions in the N and C-terminal helices, respectively, the above mentioned system of con served contacts consists mainly of contacts between one turn of N-terminal helix and one turn of C-terminal helix. The importance of the contacts between interfaces of these helices has been confirmed by the existence of these contacts in both equilibrium and kinetic molten globule-like folding intermediates,as well as by mutational evidence that these contacts are involved in tight packing between the N and C-helices. Since these four residues are not involved in heme binding and have no other apparent functional role, their conservation in highly diverged cytochromes c suggests that they are of a critical importance for protein folding. The author assumes that they are involved in a common folding nucleus of all subfamilies of c-type cytochromes. (C) 1998 Academic Press Limited. C1 NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. Russian Acad Sci, Inst Prot Res, Pushchino 142292, Moscow Region, Russia. RP Ptitsyn, OB (reprint author), NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. NR 59 TC 105 Z9 108 U1 0 U2 8 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 MAY 8 PY 1998 VL 278 IS 3 BP 655 EP 666 DI 10.1006/jmbi.1997.1620 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZP641 UT WOS:000073773800014 PM 9600846 ER PT J AU Jacobsen, LK Mittleman, BB Kumra, S Lenane, MC Barracchini, KC Adams, S Simonis, T Paul, PR Long, RT Sharp, W Sidransky, E Ginns, EI Rapoport, JL AF Jacobsen, LK Mittleman, BB Kumra, S Lenane, MC Barracchini, KC Adams, S Simonis, T Paul, PR Long, RT Sharp, W Sidransky, E Ginns, EI Rapoport, JL TI HLA antigens in childhood onset schizophrenia SO PSYCHIATRY RESEARCH LA English DT Article DE schizophrenia; children; HLA; genetics; autoimmune ID SEQUENCE-SPECIFIC PRIMERS; MAJOR HISTOCOMPATIBILITY COMPLEX; CHRONIC ACTIVE HEPATITIS; RHEUMATOID-ARTHRITIS; PCR-SSP; JAPANESE SCHIZOPHRENICS; GENETIC-HETEROGENEITY; DIAGNOSTIC-INTERVIEW; ENDOGENOUS PSYCHOSES; INFLUENZA EPIDEMICS AB Evidence of immune system abnormalities in adult schizophrenia has prompted examination of the human leukocyte antigen (HLA) system. Childhood onset schizophrenia offers a unique opportunity to test neurodevelopmental hypotheses of schizophrenia, including those which implicate components of the immune system. In the present study, class I and II HLA antigens were typed using sequence-specific primers and the polymerase chain reaction in 28 childhood onset schizophrenics and 51 ethnically matched healthy subjects. Groups were compared for frequencies of HLA antigens reported to be associated with schizophrenia and/or autoimmune disorders. We hypothesized that antigen frequencies would differ between schizophrenic and healthy children, suggesting that some dimension of the neurodevelopmental disturbance experienced by these children may be mediated by subtle abnormalities of immune function. There were no significant differences between schizophrenic and healthy subjects in the frequency of any antigen tested. These findings do not support HLA-associated pathology in childhood onset schizophrenia. (C) 1998 Elsevier Science Ireland Ltd. C1 Yale Univ, Sch Med, Dept Psychiat 116A, Vet Affairs Connecticut Healthcare Syst, W Haven, CT 06516 USA. NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. NIH, Ctr Clin, HLA Lab, Bethesda, MD 20892 USA. NIMH, Clin Neurosci Branch, Bethesda, MD 20892 USA. RP Jacobsen, LK (reprint author), Yale Univ, Sch Med, Dept Psychiat 116A, Vet Affairs Connecticut Healthcare Syst, 950 Campbell Ave, W Haven, CT 06516 USA. NR 98 TC 12 Z9 13 U1 3 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD MAY 8 PY 1998 VL 78 IS 3 BP 123 EP 132 DI 10.1016/S0165-1781(98)00015-8 PG 10 WC Psychiatry SC Psychiatry GA ZU824 UT WOS:000074238900001 PM 9657416 ER PT J AU Agosto, M Allan, J Benson, C Berger, EA Blumenthal, R Burton, D Clements, J Coffin, J Connor, R Cullen, B Desrosiers, R Dimitrov, D Doms, R Emerman, M Feinberg, M Fultz, P Gerard, C Gonsalves, G Haase, A Haigwood, N Hirsch, V Ho, D Hoxie, JA Hu, SL Hunter, E Johnson, P Kawata, PA Korber, B Kuiken, C Learn, GH Leitner, T Lewis, G Link, D Luban, J Luzuriaga, K Malim, M Marx, P McCune, JM Montefiori, D Moore, J Morrow, C Mosier, D Muesing, M Nixon, D Nunberg, J Overbaugh, J Parren, P Planelles, V Pope, M Posnett, DN Siliciano, R Steinman, R Stevenson, M Swanstrom, R Walker, BD Wolinsky, S Zingale, D AF Agosto, M Allan, J Benson, C Berger, EA Blumenthal, R Burton, D Clements, J Coffin, J Connor, R Cullen, B Desrosiers, R Dimitrov, D Doms, R Emerman, M Feinberg, M Fultz, P Gerard, C Gonsalves, G Haase, A Haigwood, N Hirsch, V Ho, D Hoxie, JA Hu, SL Hunter, E Johnson, P Kawata, PA Korber, B Kuiken, C Learn, GH Leitner, T Lewis, G Link, D Luban, J Luzuriaga, K Malim, M Marx, P McCune, JM Montefiori, D Moore, J Morrow, C Mosier, D Muesing, M Nixon, D Nunberg, J Overbaugh, J Parren, P Planelles, V Pope, M Posnett, DN Siliciano, R Steinman, R Stevenson, M Swanstrom, R Walker, BD Wolinsky, S Zingale, D TI AIDS vaccine development SO SCIENCE LA English DT Letter C1 Natl Minor AIDS Council, Washington, DC USA. SW Fdn Med Res, San Antonio, TX USA. Univ Colorado, Denver, CO 80202 USA. NIAID, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. Scripps Res Inst, La Jolla, CA USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. Tufts Univ, Boston, MA 02111 USA. Aaron Diamond AIDS Res Ctr, New York, NY USA. Duke Univ, Durham, NC USA. Harvard Univ, Southborough, MA USA. Univ Penn, Philadelphia, PA 19104 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Emory Univ, Atlanta, GA 30322 USA. Univ Alabama, Birmingham, AL USA. Treatment Act Grp, New York, NY USA. Univ Minnesota, Minneapolis, MN 55455 USA. Univ Washington, Seattle, WA 98195 USA. Ohio State Univ, Columbus, OH 43210 USA. Los Alamos Natl Lab, Los Alamos, NM USA. Univ Maryland, Baltimore, MD 21201 USA. Gay Mens Hlth Crisis Inc, New York, NY USA. Columbia Univ, New York, NY 10027 USA. Univ Massachusetts, Worcester, MA 01605 USA. Univ Calif San Francisco, Gladstone Inst Virol & Immunol, San Francisco, CA 94143 USA. Rockefeller Univ, New York, NY 10021 USA. Cornell Univ, Coll Med, New York, NY USA. Univ N Carolina, Chapel Hill, NC 27515 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Northwestern Univ, Sch Med, Chicago, IL USA. AIDS Act Council, Washington, DC USA. RP Agosto, M (reprint author), Natl Minor AIDS Council, Washington, DC USA. RI Wolinsky, Steven/B-2893-2012; Steinman, Ralph/F-7729-2012 NR 1 TC 2 Z9 2 U1 0 U2 2 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 MAY 8 PY 1998 VL 280 IS 5365 BP 803 EP + PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZM380 UT WOS:000073532900002 PM 9599148 ER PT J AU Koblin, BA Heagerty, P Sheon, A Buchbinder, S Celum, C Douglas, JM Gross, M Marmor, M Mayer, K Metzger, D Seage, G AF Koblin, BA Heagerty, P Sheon, A Buchbinder, S Celum, C Douglas, JM Gross, M Marmor, M Mayer, K Metzger, D Seage, G TI Readiness of high-risk populations in the HIV Network for Prevention Trials to participate in HIV vaccine efficacy trials in the United States SO AIDS LA English DT Article DE vaccine trials; homosexual men; injecting drug users; women; HIV ID INJECTION-DRUG USERS; MEN; FEASIBILITY AB Objective: To determine the willingness of populations at high risk of HIV-1 infection to participate in HIV vaccine efficacy trials, determine factors influencing decisionmaking, and evaluate knowledge levels of vaccine trial concepts. Design: Cross-sectional study. Methods: HIV-1-negative homosexual men, male and female injecting drug users and non-injecting women at heterosexual risk were recruited in eight cities in the United States (n = 4892). Results: A substantial proportion of the study population (77%) would definitely (27%) or probably (50%) be willing to participate in a randomized vaccine efficacy trial. Increased willingness was associated with high-risk behaviors, lower education level, being uninsured or covered by public insurance, and not having been in a previous vaccine preparedness study. Altruism and a desire for protection from the vaccine were major motivators for participation. Major concerns included positive HIV-1 antibody test due to vaccine, safety of the vaccine, and possible problems with insurance or foreign travel. Baseline knowledge of vaccine trial concepts was low. Conclusions: It is likely that high-risk volunteers will be willing to enroll in HIV vaccine efficacy trials. A variety of participant and community educational strategies are needed to address participant concerns, and to ensure understanding of key concepts prior to giving consent for participation. (C) 1998 Lippincott-Raven Publishers. C1 New York Blood Ctr, Lab Epidemiol, New York, NY 10021 USA. Fred Hutchinson Canc Res Ctr, HIVNET Stat Ctr, Seattle, WA 98104 USA. NIAID, NIH, Bethesda, MD 20892 USA. Denver Dept Publ Hlth, Denver, CO USA. Abt Associates, Cambridge, MA USA. NYU, Med Ctr, New York, NY 10016 USA. Boston Univ, Sch Publ Hlth, Boston, MA USA. Univ Penn, Philadelphia, PA 19104 USA. RP Koblin, BA (reprint author), New York Blood Ctr, Lab Epidemiol, 310 E 67th St, New York, NY 10021 USA. RI Metzger, David/D-9499-2012; OI Marmor, Michael/0000-0001-6605-2661 FU NCRR NIH HHS [M01RR00096]; NIAID NIH HHS [N01-AI-45200, N01-AI-35176] NR 17 TC 107 Z9 109 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0269-9370 J9 AIDS JI Aids PD MAY 7 PY 1998 VL 12 IS 7 BP 785 EP 793 DI 10.1097/00002030-199807000-00015 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA ZM516 UT WOS:000073548000016 PM 9619811 ER PT J AU Hesselgesser, J Taub, D Baskar, P Greenberg, M Hoxie, J Kolson, DL Horuk, R AF Hesselgesser, J Taub, D Baskar, P Greenberg, M Hoxie, J Kolson, DL Horuk, R TI Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1 alpha is mediated by the chemokine receptor CXCR4 SO CURRENT BIOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CENTRAL-NERVOUS-SYSTEM; HUMAN CELL-LINE; TRANSGENIC MICE; SURFACE GLYCOPROTEIN; DNA FRAGMENTATION; NTERA-2 CELLS; PROTEIN GP120; COAT PROTEIN; EXPRESSION AB CXCR4, a seven transmembrane domain G-protein-coupled receptor for the Cys-X-Cys class of chemokines, is one of several chemokine receptors that can act as a co-receptor with CD4 for the human immunodeficiency virus (HIV-1) glycoprotein gp120 [1-3]. CXCR4 can mediate the entry of HIV-1 strains that specifically infect T cells, such as the IIIB strain (see [4] for review). Recent reports indicate that gp120 can signal through CXCR4 [5] and it has been suggested that signal transduction, mediated by the viral envelope, might influence viral-associated cytopathicity or apoptosis [6], Neuronal apoptosis is a feature of HIV-1 infection in the brain [7,8], although the exact mechanism is unknown. Here, we address the possible role of CXCR4 in inducing apoptosis using cells of the hNT human neuronal cell line; these cells resemble immature post-mitotic cholinergic neurons and have a number of neuronal characteristics [9-15], We have previously shown that gp120 from the HIV-1 IIIB strain binds with high affinity to CXCR4 expressed on hNT neurons [15], We now find that both IIIB gp120 and the Cys-X-Cys chemokine SDF-1 alpha can directly induce apoptosis in hNT neurons in the absence of CD4 and in a dose-dependent manner. To our knowledge, this is the first report of a chemokine and an HIV-1 envelope glycoprotein eliciting apoptotic responses through a chemokine receptor. (C) Current Biology Ltd ISSN 0960-9822. C1 Berlex Biosci, Dept Immunol, Richmond, CA 94806 USA. NIA, Dept Immunol, Baltimore, MD 21224 USA. Duke Univ, Med Ctr, Dept Surg, Ctr AIDS Res, Durham, NC 27710 USA. Univ Penn, Sch Med, Dept Hematol Oncol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. RP Hesselgesser, J (reprint author), Berlex Biosci, Dept Immunol, Richmond, CA 94806 USA. EM Joe_Hesselgesser@berlex.com NR 32 TC 326 Z9 334 U1 1 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 34-42 CLEVELAND STREET, LONDON W1P 6LB, ENGLAND SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD MAY 7 PY 1998 VL 8 IS 10 BP 595 EP 598 DI 10.1016/S0960-9822(98)70230-1 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZM927 UT WOS:000073590300019 PM 9601645 ER PT J AU Martin, SF Dorsey, GO Gane, T Hillier, MC Kessler, H Baur, M Matha, B Erickson, JW Bhat, TN Munshi, S Gulnik, SV Topol, IA AF Martin, SF Dorsey, GO Gane, T Hillier, MC Kessler, H Baur, M Matha, B Erickson, JW Bhat, TN Munshi, S Gulnik, SV Topol, IA TI Cyclopropane-derived peptidomimetics. Design, synthesis, evaluation, and structure of novel HIV-1 protease inhibitors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Review ID RESTRICTED PEPTIDE ISOSTERES; HETERONUCLEAR COUPLING-CONSTANTS; MOLECULAR-DYNAMICS SIMULATIONS; DIMENSIONAL NMR-SPECTROSCOPY; HUMAN-IMMUNODEFICIENCY-VIRUS; TRANSITION-STATE; ANTIVIRAL ACTIVITY; CRYSTAL-STRUCTURE; INTRAMOLECULAR CYCLOPROPANATION; THEORETICAL DETERMINATION AB Toward establishing the general efficacy of using trisubstituted cyclopropanes as peptide mimics to stabilize extended peptide structures, the cyclopropanes 20a-d were incorporated as replacements into 9-13, which are analogues of the known HIV-1 protease inhibitors 14 and 15. The syntheses of 20a-d commenced with the Rh-2[5(S)-MEPY](4)-catalyzed cyclization of the allylic diazoesters 16a-d to give the cyclopropyl lactones 17a-d in high enantiomeric excess. Opening of the lactone moiety using the Weinreb protocol and straightforward refunctionalization of the intermediate amides 18a-d gave 20a-d. A similar sequence of reactions was used to prepare the N-methyl-2-pyridyl analogue 28. Coupling of 20a-d and 28 with the known diamino diol 22 delivered 9-13. Pseudopeptides 9-12 were found to be competitive inhibitors of wild-type HIV-1 protease in biological assays having K(i)s of 0.31-0.35 nM for 9, 0.16-0.21 nM for 10, 0.47 nM for 11, and 0.17 nM for 12; these inhibitors were thus approximately equipotent to the known inhibitor 14 (IC50 = 0.22 nM) from which they were derived. On the other hand 13 (K-i = 80 nM) was a weaker inhibitor than its analogue 15 (K-i = 0.11 nM). The solution structures of 9 and 10 were analyzed by NMR spectroscopy and simulated annealing procedures that included restraints derived from homo-and heteronuclear coupling constants and NOEs; because of the molecular symmetry of 9 and 10, a special protocol to treat the NOE data was used. The final structure was checked by restrained and free molecular dynamic calculations using an explicit DMSO solvent box. The preferred solution conformations of 9 and 10 are extended structures that closely resemble the three-dimensional structure of 10 bound to HIV-1 protease as determined by X-ray crystallographic analysis of the complex. This work convincingly demonstrates that extended structures of peptides may be stabilized by the presence of substituted cyclopropanes that serve as peptide replacements. Moreover, the linear structure enforced in solution by the two cyclopropane rings in the pseudopeptides 9-12 appears to correspond closely to the biologically active conformation of the more flexible inhibitors 14 and 15. The present work, which is a combination of medicinal, structural, and quantum chemistry, thus clearly establishes that cyclopropanes may be used as structural constraints to reduce the flexibility of linear pseudopeptides and to help enforce the biologically active conformation of such ligands in solution. C1 Univ Texas, Dept Chem & Biochem, Austin, TX 78712 USA. Tech Univ Munchen, Inst Organ Chem & Biochem, D-85747 Garching, Germany. NCI, Frederick Biomed Supercomp Ctr, Struct Biochem Program, FCRDC, Frederick, MD 21702 USA. RP Martin, SF (reprint author), Univ Texas, Dept Chem & Biochem, Austin, TX 78712 USA. RI Kessler, Horst/C-1178-2010 NR 107 TC 49 Z9 49 U1 0 U2 34 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 7 PY 1998 VL 41 IS 10 BP 1581 EP 1597 DI 10.1021/jm980033d PG 17 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA ZM276 UT WOS:000073522300005 PM 9572884 ER PT J AU Muccio, DD Brouillette, WJ Breitman, TR Taimi, M Emanuel, PD Zhang, XK Chen, GQ Sani, BP Venepally, P Reddy, L Alam, M Simpson-Herren, L Hill, DL AF Muccio, DD Brouillette, WJ Breitman, TR Taimi, M Emanuel, PD Zhang, XK Chen, GQ Sani, BP Venepally, P Reddy, L Alam, M Simpson-Herren, L Hill, DL TI Conformationally defined retinoic acid analogues. 4. Potential new agents for acute promyelocytic and juvenile myelomonocytic leukemias SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; X-RECEPTOR; CHEMOPREVENTIVE ACTIVITY; THYROID-HORMONE; DIFFERENTIATION; GROWTH; ALPHA; PROLIFERATION; BINDING; PROTEIN AB We recently synthesized several conformationally constrained retinoic acid (RA) analogues [8-(2'-cyclohexen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acids with different alkyl substituents at 2' (R-1) and 3' (R-2) positions on the cyclohexene ring] (Muccio et al. J. Med. Chem. 1996, 39, 3625) as cancer chemopreventive agents. UAB8 (R-1 = Et; R-2 = Pr-i), which contains sufficient steric bulk at the terminal end of the polyene chain to mimic the trimethylcyclohexenyl ring of RA, displayed biological properties similar to those of RA. To explore the efficacy of this retinoid in acute promyelocytic leukemia (APL) and juvenile myelomonocytic leukemia (JMML), we evaluated UAB8 isomers in in vitro assays which measure the capacity of retinoids to inhibit aberrant myeloid colony growth from blood or bone marrow cells obtained from human JMML patients and in assays measuring the potential of retinoids to differentiate NB4 cells tan APL cell line). Both (all-E)- and (13Z)-UAB8 were 2-fold more active than RA in the NB4 cell differentiation assay; however, only (all-E)-UAB8 had comparable activity to the natural retinoids in the JMML cell assays. These results were compared to the biological effectiveness of a new retinoid, UAB30 [8-(3',4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid], which had different nuclear receptor binding and transactivational properties than UAB8. Relative to (all-E)-RA and (all-E)-UAB8, (all-E)-UAB30 bound well to RAR alpha but did not activate transcription-mediated RAR alpha homodimers, even though it was effective in RAR beta- and RAR gamma-mediated transactivational assays. In APL assays, this retinoid had much reduced activity and was only moderately effective in JMML assays and in cancer chemoprevention assays. C1 Univ Alabama, Dept Chem, Birmingham, AL 35294 USA. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. NCI, Biol Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Burnham Inst, La Jolla Canc Res Ctr, La Jolla, CA 92037 USA. So Res Inst, Dept Biochem, Birmingham, AL 35205 USA. So Res Inst, Dept Toxicol, Birmingham, AL 35205 USA. RP Muccio, DD (reprint author), Univ Alabama, Dept Chem, Birmingham, AL 35294 USA. OI Emanuel, Peter/0000-0002-9764-2434 FU NCI NIH HHS [R01 CA59446, P01 CA34968, UO1 CA60407] NR 37 TC 38 Z9 38 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 7 PY 1998 VL 41 IS 10 BP 1679 EP 1687 DI 10.1021/jm970635h PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA ZM276 UT WOS:000073522300014 PM 9572893 ER PT J AU Hummer, G Pratt, LR Garcia, AE Garde, S Berne, BJ Rick, SW AF Hummer, G Pratt, LR Garcia, AE Garde, S Berne, BJ Rick, SW TI Reply to comment on "Electrostatic potentials and free energies of solvation of polar and charged molecules" SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID WATER; HYDRATION; MODEL C1 Univ Calif Los Alamos Natl Lab, Div Theoret, Los Alamos, NM 87545 USA. Columbia Univ, Dept Chem, New York, NY 10027 USA. Columbia Univ, Ctr Biomol Simulat, New York, NY 10027 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Hummer, G (reprint author), Univ Calif Los Alamos Natl Lab, Div Theoret, MS K710, Los Alamos, NM 87545 USA. RI Garde, Shekhar/C-3060-2008; Pratt, Lawrence/H-7955-2012; Hummer, Gerhard/A-2546-2013 OI Pratt, Lawrence/0000-0003-2351-7451; Hummer, Gerhard/0000-0001-7768-746X NR 14 TC 41 Z9 42 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5647 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 7 PY 1998 VL 102 IS 19 BP 3841 EP 3843 DI 10.1021/jp980145g PG 3 WC Chemistry, Physical SC Chemistry GA ZP697 UT WOS:000073779400027 ER PT J AU Hall, CD Dafni, U Simpson, D Clifford, D Wetherill, PE Cohen, B McArthur, J Hollander, H Yainnoutsos, C Major, E Millar, L Timpone, J AF Hall, CD Dafni, U Simpson, D Clifford, D Wetherill, PE Cohen, B McArthur, J Hollander, H Yainnoutsos, C Major, E Millar, L Timpone, J CA AIDS Clinical Trials Group 243 Team TI Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID POLYMERASE CHAIN-REACTION; STEREOTAXIC BRAIN BIOPSY; AIDS; DIAGNOSIS; 3'-AZIDO-3'-DEOXYTHYMIDINE; INTERFERON; REMISSION AB Background Progressive multifocal leukoencephalopathy affects about 4 percent of patients with the acquired immunodeficiency syndrome (AIDS), and survival after the diagnosis of leukoencephalopathy averages only about three months. There have been anecdotal reports of improvement but no controlled trials of therapy with antiretroviral treatment plus intravenous or intrathecal cytarabine. Methods In this multicenter trial, 57 patients with human immunodeficiency virus (HIV) infection and biopsy-confirmed progressive multifocal leukoencephalopathy were randomly assigned to receive one of three treatments: antiretroviral therapy alone, antiretroviral therapy plus intravenous cytarabine, or antiretroviral therapy plus intrathecal cytarabine. After a lead-in period of 1 to 2 weeks, active treatment was given for 24 weeks. For most patients, antiretroviral therapy consisted of zidovudine plus either didanosine or stavudine. Results At the time of the last analysis, 14 patients in each treatment group had died, and there were no significant differences in survival among the three groups (P=0.85 by the log-rank test). The median survival times (11, 8, and 15 weeks) were similar to those in previous studies. Only seven patients completed the 24 weeks of treatment. Anemia and thrombocytopenia were more frequent in patients who received antiretroviral therapy in combination with intravenous cytarabine than in the other groups. Conclusions Cytarabine administered either intravenously or intrathecally does not improve the prognosis of HIV-infected patients with progressive multifocal leukoencephalopathy who are treated with the antiretroviral agents we used, nor does high-dose antiretroviral therapy alone appear to improve survival over that reported in untreated patients. (C)1998, Massachusetts Medical Society. C1 Univ N Carolina, Sch Med, Dept Neurol, Chapel Hill, NC 27599 USA. Harvard Univ, Sch Med, Boston, MA USA. Mt Sinai Sch Med, New York, NY USA. Washington Univ, Sch Med, St Louis, MO USA. Yale Univ, Sch Med, New Haven, CT USA. Northwestern Univ, Sch Med, Chicago, IL 60611 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Epidemiol, Baltimore, MD 21205 USA. Univ Calif San Francisco, Sch Med, San Francisco, CA USA. NINDS, Bethesda, MD 20892 USA. Frontier Sci & Technol Res Fdn, Amherst, NY USA. Washington Gen Hosp, Washington, DC USA. RP Hall, CD (reprint author), Univ N Carolina, Sch Med, Dept Neurol, CB702, Chapel Hill, NC 27599 USA. FU NCRR NIH HHS [RR00036-37]; NINDS NIH HHS [1 PO1 NS3228]; PHS HHS [A1-25868] NR 37 TC 196 Z9 202 U1 0 U2 0 PU MASS MEDICAL SOC PI BOSTON PA 10 SHATTUCK, BOSTON, MA 02115 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 7 PY 1998 VL 338 IS 19 BP 1345 EP 1351 DI 10.1056/NEJM199805073381903 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA ZL720 UT WOS:000073463700003 PM 9571254 ER PT J AU Lee, YI Lee, S Lee, Y Bong, YS Hyun, SW Do Yoo, Y Kim, SJ Kim, YW Poo, HR AF Lee, YI Lee, S Lee, Y Bong, YS Hyun, SW Do Yoo, Y Kim, SJ Kim, YW Poo, HR TI The human hepatitis B virus transactivator X gene product regulates Sp1 mediated transcription of an insulin-like growth factor II promoter 4 SO ONCOGENE LA English DT Article DE hepatitis B virus; insulin-like growth factor-II; hepatocellular carcinoma; transactivation ID BOX-BINDING-PROTEINS; LONG TERMINAL REPEAT; DNA-BINDING; SP1-MEDIATED TRANSCRIPTION; TRANS-ACTIVATION; MESSENGER-RNA; EXPRESSION; LIVER; CELLS; SEQUENCES AB Human hepatitis B virus (HBV) is one of the causative agents of hepatocellular carcinoma (HCC). The virus encodes a 17 kDa protein, X, which is known to be a causative agent in the formation of HCC. An insulin-like growth factor-II (IGF-II) is expressed during the formation of HCC. Among the four promoters of the IGF-II gene, promoters 2, 3 and 4 become activated during the formation of HCC. The high frequency of detection of hepatitis B virus X (HBV-X) antigen in liver cells from patients with chronic hepatitis, cirrhosis, and liver cancer suggested that the expressions of HBV-X and IGF-II are associated. Studies were carried out to test the relationship between the HBV-X gene product and the activation of IGF-II promoter 4, We demonstrated that the HBV-X protein increases the endogenous IGF-II expression from promoter 3 and 4 of IGF-II gene. Analysis of the fourth promoter of IGF-II gene showed that the HBV-X gene product positively regulates transcription. Two copies of a motif are responsible for conferring HBV-X regulation on the fourth promoter of IGF-II. These motifs have been identified as Sp1 binding sites, Sp1 binding to IGF-II P4 promoter was identified by gel mobility shift assay using purified Sp1. By using a GAL4-Sp1 fusion protein it was demonstrated that HBV-X positively regulates the Sp1 mediated transcriptional activity of IGF-II in vivo. A protein-affinity chromatography experiment showed that HBV-X protein does not bind directly to Sp1, but HBV-X does augment the DNA binding activity of the phosphorylated form of Sp1 in HepG2 cells. Sp1 was phosphorylated by HBV-X and its DNA-binding activity was up-regulated upon HBV-X transfections. Various HBV-X mutant expression vectors were used for the demonstration of specific interactions between Sp1 and HBV-X. These results indicate that HBV-X functions as a positive regulator of transcription, and that Sp1 is a direct target for the transcriptional regulation of IGF-II. Increasing the DNA binding ability of the phosphorylated form of Sp1 by HBV-X might be an important mechanism for regulating the IGF-II gene expression and possibly promoting cell division during hepatic carcinogenesis. Our experimental results suggest that expression of HBV-X might induce the expression of IGF-II and the IGF-II might play a role in hepatitis B virus pathogenesis during the formation of HCC. C1 Korea Adv Inst Sci & Technol, Korea Res Inst Biosci & Biotechnol, Mol Cell Biol Res Div, Liver Cell Signal Transduct Lab, Taejon 305606, South Korea. NCI, Chemoprevent Lab, NIH, Bethesda, MD 20892 USA. RP Lee, YI (reprint author), Korea Adv Inst Sci & Technol, Korea Res Inst Biosci & Biotechnol, Mol Cell Biol Res Div, Liver Cell Signal Transduct Lab, Taejon 305606, South Korea. NR 68 TC 65 Z9 73 U1 0 U2 5 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 7 PY 1998 VL 16 IS 18 BP 2367 EP 2380 DI 10.1038/sj.onc.1201760 PG 14 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ZL389 UT WOS:000073428000009 PM 9620554 ER PT J AU Kubota, H Rice, KC AF Kubota, H Rice, KC TI Palladium-catalyzed cyanation of hindered, electron-rich aryl triflates by zinc cyanide SO TETRAHEDRON LETTERS LA English DT Article ID ACID AB We examined the palladium-catalyzed cyanation of hindered, electron-rich aryl triflates by zinc cyanide using 2-methoxyphenyl trifluoromethanesulfonate (4) as a model compound The reaction with two equivalents of Zn(CN)(2) and catalytic Pd(PPh3)(4) in DMF at 120 degrees C for 2 hr afforded 2-methoxybenzonitrile (5)in 81% yield. The synthesis of 3-cyano-3-desoxynaltrexone(3), which had not previouly been obtained by the reaction with potassium or sodium cyanid: as a cyanide source, was achieved by applying this procedure to its corresponding triflate 2. Published by Elsevier Science Ltd. C1 NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Rice, KC (reprint author), NIDDK, Med Chem Lab, NIH, Bldg 8,Room B1-23, Bethesda, MD 20892 USA. NR 16 TC 51 Z9 51 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD MAY 7 PY 1998 VL 39 IS 19 BP 2907 EP 2910 DI 10.1016/S0040-4039(98)00414-6 PG 4 WC Chemistry, Organic SC Chemistry GA ZJ628 UT WOS:000073235800009 ER PT J AU Goldstein, AM Falk, RT Fraser, MC Dracopoli, NC Sikorski, RS Clark, WH Tucker, MA AF Goldstein, AM Falk, RT Fraser, MC Dracopoli, NC Sikorski, RS Clark, WH Tucker, MA TI Sun-related risk factors in melanoma-prone families with CDKN2A mutations SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CUTANEOUS MALIGNANT-MELANOMA; SPORADIC MELANOMA; DYSPLASTIC NEVI; HUMAN CANCERS; GENE; P16(INK4A); KINDREDS C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD USA. NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD USA. NCI, Varmus Lab, Bethesda, MD USA. Sequana Therapeut Inc, La Jolla, CA USA. Beth Israel Deaconess Med Ctr, Boston, MA USA. RP Goldstein, AM (reprint author), NIH, Execut Plaza N,Rm 439, Bethesda, MD 20892 USA. RI Tucker, Margaret/B-4297-2015 NR 22 TC 30 Z9 30 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 MAY 6 PY 1998 VL 90 IS 9 BP 709 EP 711 DI 10.1093/jnci/90.9.709 PG 3 WC Oncology SC Oncology GA ZM067 UT WOS:000073501400016 PM 9586669 ER PT J AU Quadroni, M L'Hostis, EL Corti, C Myagkikh, I Durussel, I Cox, J James, P Carafoli, E AF Quadroni, M L'Hostis, EL Corti, C Myagkikh, I Durussel, I Cox, J James, P Carafoli, E TI Phosphorylation of calmodulin alters its potency as an activator of target enzymes SO BIOCHEMISTRY LA English DT Article ID NITRIC-OXIDE SYNTHASE; LIGHT-CHAIN KINASE; BINDING DOMAIN; CASEIN KINASE; PROTEIN-PHOSPHORYLATION; ESCHERICHIA-COLI; CENTRAL HELIX; RAT-LIVER; PURIFICATION; PHOSPHATE AB Previous work has shown that calmodulin (CaM) is constitutively phosphorylated in rat liver, probably by casein kinase II [Quadroni, M., James, P., and Carafoli, E. (1994) J. Biol. Chem. 269, 16116-16122]. A procedure is now described for the isolation of the phosphorylated forms of calmodulin (PCaM) free from CaM, since in vitro phosphorylation experiments yield a 50:50 mixture of 3-4 times phosphorylated CaM and native CaM. The activation of six target enzymes by PCaM was tested: myosin light chain kinase, 3',5'-cyclic nucleotide phosphodiesterase, plasma membrane Ca2+-ATPase, Ca2+-CaM-dependent protein phosphatase 2B (calcineurin), neuronal nitric oxide synthase, and CaM-kinase II. In general, the phosphorylation of CaM caused a decrease in enzyme binding affinity, increasing the K-act by 2-4-fold for MLCK, PDE, PM Ca2+-ATPase, and calcineurin. The V-max at saturating concentrations of PCaM was less affected, with the exception of CaM-kinase II, which was only minimally activated by PCaM and NOS whose V-max was increased 2.6 times by PCaM with respect to CaM. Phosphorylation of calmodulin had very little effect on the binding of calcium to the enzyme despite the fact that Ser 101 which is phosphorylated is located in the third calcium binding loop. CD measurements performed on CaM and PCaM indicated that phosphorylation causes a marked decrease in the a-helical content of the protein. Phosphorylated CaM is very prone to dephosphorylation and was thus tested as a substrate for several phosphatases. It was unaffected by calcineurin (PP2B), but was a reasonable substrate for the pleiotropic phosphatases PP1 gamma and PP2A. C1 ETH Zentrum, Inst Biochem, CH-8092 Zurich, Switzerland. Swiss Fed Inst Technol, Prot Chem Lab, Zurich, Switzerland. NCI, NIH, Bethesda, MD 20892 USA. Univ Geneva, Dept Biochem, CH-1211 Geneva, Switzerland. RP James, P (reprint author), ETH Zentrum, Inst Biochem, Univ Str 16, CH-8092 Zurich, Switzerland. RI Carafoli, Ernesto/K-5192-2016 OI Carafoli, Ernesto/0000-0002-7826-0094 NR 42 TC 43 Z9 43 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 5 PY 1998 VL 37 IS 18 BP 6523 EP 6532 DI 10.1021/bi972930+ PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZM880 UT WOS:000073585600036 PM 9572870 ER PT J AU Keizer, J Smith, GD AF Keizer, J Smith, GD TI Spark-to-wave transition: saltatory transmission of calcium waves in cardiac myocytes SO BIOPHYSICAL CHEMISTRY LA English DT Article; Proceedings Paper CT Workshop on Oscillations, Bistability and Waves in Biochemical and Cellular Systems CY JUN 14-20, 1997 CL FONDAT TREILLES, TOURTOUR, FRANCE HO FONDAT TREILLES DE calcium oscillations; diffusion; calcium sparks; kinetic model ID CA2+-INDUCED CA2+ RELEASE; RYANODINE RECEPTOR ADAPTATION; INOSITOL TRISPHOSPHATE; ENDOPLASMIC-RETICULUM; CYTOSOLIC CALCIUM; OSCILLATIONS; MECHANISMS; DIFFUSION; MODEL; HEART AB Using a modular approach, in which kinetic models of various mechanisms of calcium handling in cells are fine-tuned to in vivo and in vitro measurements before combining them into whole-cell models, three distinct modes of transmission of calcium waves in mature and immature frog eggs have been defined. Two modes of transmission are found in immature eggs, where the inositol 1,4,5-trisphosphate receptor (IP3R) controls release of calcium from the endoplasmic reticulum (ER). The first mode corresponds to an excitable physiological state of the cytoplasm and results in solitary waves that can appear as circular or spiral waves in two dimensions with the wave speed proportional to the square root of the diffusion constant of calcium. A second mode occurs when the state of the cytoplasm is oscillatory and because of the small size of the buffered diffusion constant for calcium, the wave speed can appear to be weakly dependent on diffusion. In the mature frog egg, where the sperm-induced Ca2+ fertilization wave is a propagating front, the cytoplasm appears to be bistable and in this mode the wave speed is also proportional to the square root of the diffusion constant. Here we investigate a fourth mode of propagation for cardiac myocytes, in which calcium release from the sarcoplasmic reticulum (SR) is dominated by clusters of ryanodine receptors spaced at regular intervals. In myocytes a stochastically excitable myoplasm leads to the spontaneous production of calcium 'sparks' that under certain conditions can merge into saltatory waves with a speed proportional to the diffusion constant. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Univ Calif Davis, Inst Theoret Dynam, Davis, CA 95616 USA. Univ Calif Davis, Sect Neurobiol Physiol & Behav, Davis, CA 95616 USA. NIDDKD, Math Res Branch, NIH, Bethesda, MD 20814 USA. RP Keizer, J (reprint author), Univ Calif Davis, Inst Theoret Dynam, Davis, CA 95616 USA. FU NCRR NIH HHS [R01 RR10081] NR 37 TC 84 Z9 84 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 J9 BIOPHYS CHEM JI Biophys. Chem. PD MAY 5 PY 1998 VL 72 IS 1-2 BP 87 EP 100 DI 10.1016/S0301-4622(98)00125-2 PG 14 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA ZW122 UT WOS:000074376400009 PM 9652087 ER PT J AU Melbye, M Poulsen, AG Gallo, D Pedersen, JB Biggar, RJ Larsen, O Dias, F Aaby, P AF Melbye, M Poulsen, AG Gallo, D Pedersen, JB Biggar, RJ Larsen, O Dias, F Aaby, P TI HTLV-1 infection in a population-based cohort of older persons in Guinea-Bissau, West Africa: Risk factors and impact on survival SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID VIRUS TYPE-I; SEXUAL TRANSMISSION; DRUG-USERS; JAPAN; HIV-1; PROGRESSION; PROSTITUTES; PREVALENCE; MORTALITY; MIYAZAKI AB In 1989, a population-based cohort of persons aged greater than or equal to 50 years was established in an urban area of Guinea-Bissau, West Africa. Overall, 346 persons were interviewed in detail about risk behaviors and had capillary blood drawn. Among women, 12.4% were HTLV-1 seropositive, compared with 4.6% in men. No HTLV-2 was found. Seropositivity varied considerably according to place of birth and ethnic group. In women, but not in men, HTLV-1 seropositivity was strongly associated with early sexual debut (10-14 yrs, 33.3%; 15-17 yrs, 26.0%; 18-20 yrs, 6.5%; 21+ yrs, 0%; p(trend) = 0.001), lifetime number of male partners (p(trend) = 0.006), and the male partner's number of co-wives (p(trend) = 0.006). There was also a 3.1-fold increased risk of being HTLV-1 seropositive if the woman was also HIV-2 seropositive. In a multivariate-risk-factor analysis, the strongest association with HTLV-1 was a history of having been bitten by a monkey (n = 11; combined ORadjusted = 10.1; 95% CI 2.3-44.4), Ornamental scarification was associated with a 3.3-fold increased risk. Ethnic affiliation also significantly influenced the risk of being HTLV-1 seropositive, Follow-up performed in January 1996 revealed no difference in survival between HTLV-1-seropositive and -seronegative individuals over 6 years (rate ratio = 1.4, 95% CI 0.7-2.8). In conclusion, this population, which has very high HIV-2 seroprevalence, is also highly endemic for HTLV-1. Whereas sexual behaviors are clearly important for HTLV-1 spread in women, non-sexual risk factors were the only ones of potential importance in men. HTLV-1 had no impact on survival in this older population. (C) 1998 Wiley-Liss, Inc. C1 Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen S, Denmark. Projecto Saude Bandim, Bissau, Guinea Bissau. Dept Hlth Serv, Berkeley, CA USA. NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. MINSAP, Lab Nacl Saude Publ, Bissau, Guinea Bissau. RP Melbye, M (reprint author), Statens Serum Inst, Dept Epidemiol Res, 5 Artillerivej, DK-2300 Copenhagen S, Denmark. EM mme@ssi.dk NR 22 TC 24 Z9 24 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAY 4 PY 1998 VL 76 IS 3 BP 293 EP 298 DI 10.1002/(SICI)1097-0215(19980504)76:3<293::AID-IJC1>3.0.CO;2-Q PG 6 WC Oncology SC Oncology GA ZK245 UT WOS:000073299900001 PM 9579561 ER PT J AU Af Geijersstam, V Wang, ZH Lewensohn-Fuchs, I Eklund, C Schiller, JT Forsgren, M Dillner, J AF Af Geijersstam, V Wang, ZH Lewensohn-Fuchs, I Eklund, C Schiller, JT Forsgren, M Dillner, J TI Trends in seroprevalence of human papillomavirus type 16 among pregnant women in Stockholm, Sweden, during 1969-1989 SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID CERVICAL INTRAEPITHELIAL NEOPLASIA; HERPES-SIMPLEX VIRUS; ANAL EPIDERMOID CARCINOMA; SERUM ANTIBODIES; CHLAMYDIA-TRACHOMATIS; SEXUAL-BEHAVIOR; HPV DNA; INFECTION; RISK; PARTICLES AB To assess long-term trends in the prevalence of oncogenic human papillomavirus (HPV) infection, we performed a cross-sectional serosurvey of the seroprevalence of the major oncogenic HPV type, HPV16, among 3,512 pregnant women undergoing population-based serological screening at the first trimester of pregnancy in the same catchment area in Stockholm, Sweden, during 1969, 1983 or 1989. The overall HPV16 seroprevalence rates were 16% in 1969, 22% in 1983 and 21% in 1989. Seroprevalence was significantly increased, comparing both 1969 vs. 1983 (p = 0.0005) and 1969 vs. 1989 (p = 0.008). By comparison, the previously reported herpes simplex 2 (HSV-2) seroprevalence in the same women increased from 17% in 1969 to 32% in 1983 and 33% in 1989, whereas the seroprevalence rates of HSV-1 were the same (69% in 1969, 63% in 1983 and 68% in 1989). Odds ratios for HPV16-positive women to also be HSV-2-positive were 1.8 in 1969 (p < 0.005), 1.1 in 1983 (p = NS) and 1.0 in 1989. Our results suggest that both HSV-2 and HPV16 became more generally spread in the Swedish population between 1969 and 1983 but that the spread has been stable during the 1980s. (C) 1998 Wiley-Liss, Inc. C1 Karolinska Inst, Ctr Microbiol & Tumor Biol, S-17177 Stockholm, Sweden. Huddinge Univ Hosp, Dept Virol, Stockholm, Sweden. NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. Natl Publ Hlth Inst, Dept Infect Dis Epidemiol, Helsinki, Finland. RP Dillner, J (reprint author), Karolinska Inst, Ctr Microbiol & Tumor Biol, Box 280, S-17177 Stockholm, Sweden. EM joakim.dillner@mrc.ki.se NR 36 TC 28 Z9 28 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 MAY 4 PY 1998 VL 76 IS 3 BP 341 EP 344 DI 10.1002/(SICI)1097-0215(19980504)76:3<341::AID-IJC10>3.0.CO;2-E PG 4 WC Oncology SC Oncology GA ZK245 UT WOS:000073299900010 PM 9579570 ER PT J AU Li, M Xu, F Muller, J Hearing, VJ Gorelik, E AF Li, M Xu, F Muller, J Hearing, VJ Gorelik, E TI Ecotropic C-type retrovirus of B16 melanoma and malignant transformation of normal melanocytes SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID MURINE MELANOCYTES; MOUSE; ANTIGEN; CELLS; MICE; EXPRESSION; ONCOGENE; PROTEIN; GENE; DNA AB We reported previously that B16, JB/RH and JB/MS melanomas of C57BL/6 mice express the common melanoma-associated antigen (MAA) recognized by MM2-9B6 monoclonal antibody (MAb). This MAA is encoded by the env gene of an ecotropic MuLV-type retrovirus that somatically emerged in melanomas of C57BL/6 mite. The potential role of this melanoma-associated retrovirus (MelARV) in melanoma formation remains unknown and has not been previously investigated. To test this, normal melanocyte lines (melan-a and C57M) of C57BL/6 mice were infected with the MelARV produced by B16BL6 melanoma. Infection of these melanocytes with the MelARV was associated with the appearance of the MAA recognized by MM2-9B6 MAb. Most of the infected melanocyte sublines were able to grow only in the presence of 12-O-retradecanoylphorbol-13-acetate (TPA). Two infected melanocyte sublines showed morphological changes, were able to grow in the absence of TPA and, after inoculation into C57BL/6 mice, produced rapidly growing, highly pigmented tumors. These new melanomas, derived from the MelARV-infected melan-a and C57M melanocytes, were termed Meli-AI and Meli-BL, respectively. Southern blot analysis of EcoRI- and HindIII-digested DNAs from these melanomas showed several retroviral insertion sites. One copy of MelARV was found to be inserted at the end of the 6th leucine domain of the c-maf proto-oncogene, which encodes a basic region/leucine zipper transcription factor related to the AP-I family that is able to form homodimers or heterodimers with Fos and Jun transcription factors. Our data indicate that c-map is a common insertion sire of MelARV in BL6, Meli-AI and Meli-BL melanomas, whereas pro such insertion site was found in the melanocytes infected with MelARV but not malignantly transformed. Thus, our data imply that the ecotropic MelARV that somatically emerged in B16 and other melanomas of C57BL/6 mice may play a role in malignant transformation. (C) 1998 Wiley-Liss, Inc. C1 Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gorelik, E (reprint author), Univ Pittsburgh, Inst Canc, Biomed Sci Tower,Room W954, Pittsburgh, PA 15213 USA. FU NCI NIH HHS [CA59903] NR 29 TC 15 Z9 15 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 MAY 4 PY 1998 VL 76 IS 3 BP 430 EP 436 PG 7 WC Oncology SC Oncology GA ZK245 UT WOS:000073299900023 PM 9579583 ER PT J AU Heinz, A Knable, MB Coppola, R Gorey, JG Jones, DW Lee, KS Weinberger, DR AF Heinz, A Knable, MB Coppola, R Gorey, JG Jones, DW Lee, KS Weinberger, DR TI Psychomotor slowing, negative symptoms and dopamine receptor availability - an IBZM SPECT study in neuroleptic-treated and drug-free schizophrenic patients SO SCHIZOPHRENIA RESEARCH LA English DT Article DE psychomotor slowing; negative symptoms; [I-123]IBZM SPECT; schizophrenia ID REACTION-TIME; PARKINSONS-DISEASE; IODINE-123-IBZM; PERFORMANCE; ADDICTION; BINDING AB Anhedonia and psychomotor slowing in schizophrenia have been attributed to a dysfunction of dopaminergic neurotransmission. To differentiate between disease and drug-induced negative symptoms, we examined eight drug-free and eight neuroleptic-treated schizophrenic patients. Positive and negative symptoms and extrapyramidal side effects were assessed using standardized rating scales (PSAS, AMDP, SANS). 'Reaction time' and 'motor speed' were measured using a computer-aided system and striatal dopamine D-2/D-3 receptor availability was assessed using [I-123]IBZM SPECT. Psychomotor reaction time, parkinsonism, affective flattening and avolition were increased in treated patients relative to the untreated cohort and were negatively correlated with dopamine D-2/D-3 receptor availability. Significant positive correlations were found between parkinsonism and affective flattening and between psychomotor slowing and avolition. Positive symptoms were not significantly associated with striatal IBZM binding. These findings support the hypothesis that neuroleptic-induced dopamine D-2/D-3 blockade in the striatum can mimic certain negative symptoms, such as affective flattening and avolition, and indicates that psychomotor testing may be helpful in differentiating between disease and drug-induced negative symptoms. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIMH, Neurosci Ctr St Elizabeths, Clin Brain Disorders Branch, Washington, DC 20032 USA. Ruhr Univ Bochum, Dept Neurol, D-4630 Bochum, Germany. RP Knable, MB (reprint author), NIMH, Neurosci Ctr St Elizabeths, Clin Brain Disorders Branch, Washington, DC 20032 USA. NR 31 TC 76 Z9 76 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAY 4 PY 1998 VL 31 IS 1 BP 19 EP 26 DI 10.1016/S0920-9964(98)00003-6 PG 8 WC Psychiatry SC Psychiatry GA ZP789 UT WOS:000073788600003 PM 9633833 ER PT J AU Gallin, JI Varmus, H AF Gallin, JI Varmus, H TI Revitalization of the Warren G. Magnuson Clinical Center at: The National Institutes of Health SO ACADEMIC MEDICINE LA English DT Article AB For nearly 45 years the Warren G. Magnuson Clinical Center has been the site of the intramural clinical research of the National Institutes of Health. It has served as the largest clinical research facility for the nation and the site for training many of the clinical investigators in the nation's academic medical centers. Research at the Clinical Center has focused on study of orphan diseases and phase 1 and 2 clinical trials, and this research emphasis has made it a special national resource. Over the last decade there has been a dramatic decline in the number of patients seen at the Clinical Center, as well as a perceived decrease in the quality of research performed at the center. The decreased activity is related in part to fiscal constraints and the impact of the changing health care delivery system. The trends at the Clinical Center are particularly distributing because they parallel what is happening at academic health centers across the country Because its success is viewed as vital to national clinical research, a major effort has been undertaken to revitalize the center. This paper reports on the plans and activities undertaken to reorganize the center's management, revitalize its infrastructure for conducting clinical research, establish vital clinical research training, and promote partnerships with extramural investigators who will benefit from access to the center. The hope is that the model established at the NIH Clinical Center will assist in the revitalization of clinical research across the nation. C1 NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Gallin, JI (reprint author), NIH, Warren G Magnuson Clin Ctr, 9000 Rockville Pike,Bldg 10,Room 2C146, Bethesda, MD 20892 USA. NR 13 TC 3 Z9 3 U1 0 U2 0 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD MAY PY 1998 VL 73 IS 5 BP 460 EP 466 DI 10.1097/00001888-199805000-00008 PG 7 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA ZP033 UT WOS:000073709700009 PM 9609853 ER PT J AU Choi, HJ Kang, SW Yang, CH Rhee, SG Ryu, SE AF Choi, HJ Kang, SW Yang, CH Rhee, SG Ryu, SE TI Crystallization and preliminary X-ray studies of hORF6, a novel human antioxidant enzyme SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID THIOL-SPECIFIC ANTIOXIDANT; CLONING; DEFENSE; H2O2 AB HORF6 is a member of the novel antioxidant enzyme family found in humans. A recombinant form of hORF6 expressed and purified from E. coli has been crystallized by the hanging-drop method using various PEG's as precipitating agents. HORF6 crystallizes in two different monoclinic space groups, P2(1) and C2. The P2(1) crystals have unit-cell dimensions of a = 47.85, b = 75.17, c = 63.30 Angstrom and beta = 110.21 degrees and contain two monomers per asymmetric unit, while the C2 crystals have unit-cell dimensions of a = 165.27, b = 95.44, c = 166.44 Angstrom and beta = 128.97 degrees and contain more than six monomers per asymmetric unit. The P2(1) crystals with the smaller unit cell diffract X-rays better and behave well for the X-ray analysis. A native data set from a single crystal of the P2(1) space group has been collected to 2.0 Angstrom resolution. C1 KIST, Korea Res Inst Biosci & Biotechnol, Div Prot Engn, Taejon 305600, South Korea. Seoul Natl Univ, Coll Nat Sci, Dept Chem, Seoul 151742, South Korea. NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. RP Choi, HJ (reprint author), KIST, Korea Res Inst Biosci & Biotechnol, Div Prot Engn, POB 115, Taejon 305600, South Korea. NR 16 TC 8 Z9 8 U1 0 U2 4 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD MAY 1 PY 1998 VL 54 BP 436 EP 437 DI 10.1107/S0907444997011153 PN 3 PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA ZQ149 UT WOS:000073827200025 PM 9761920 ER PT J AU Sgrignoli, A Abati, A Pass, H Lebovics, R Hijazi, Y AF Sgrignoli, A Abati, A Pass, H Lebovics, R Hijazi, Y TI Metastatic mesothelioma presenting as a salivary gland neoplasm SO ACTA CYTOLOGICA LA English DT Letter DE mesothelioma; salivary gland neoplasms ID MALIGNANT PLEURAL MESOTHELIOMA; LYMPH-NODE METASTASIS; DIAGNOSIS C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, Cytopathol Sect, NIH, Bethesda, MD 20892 USA. RP Sgrignoli, A (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2A19, Bethesda, MD 20892 USA. NR 10 TC 5 Z9 5 U1 0 U2 0 PU SCI PRINTERS & PUBL INC PI ST LOUIS PA P.O. DRAWER 12425 8342 OLIVE BLVD, ST LOUIS, MO 63132 USA SN 0001-5547 J9 ACTA CYTOL JI Acta Cytol. PD MAY-JUN PY 1998 VL 42 IS 3 BP 818 EP 820 PG 3 WC Pathology SC Pathology GA ZQ955 UT WOS:000073920000044 PM 9622718 ER PT J AU Hemmer, B Martin, R AF Hemmer, B Martin, R TI Neuroimmunology and multiple sclerosis SO AKTUELLE NEUROLOGIE LA German DT Review ID MYELIN-BASIC-PROTEIN; T-CELL RECEPTOR; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; RESONANCE-IMAGING LESIONS; PLACEBO-CONTROLLED TRIAL; FACTOR-ALPHA PRODUCTION; V-BETA USAGE; OLIGODENDROCYTE GLYCOPROTEIN; PROTEOLIPID PROTEIN AB The occurrence of the acquired immunodeficiency syndrome (AIDS) has intensified immunological research resulting in a better understanding of the mechanisms involved in cellular and antibody-mediated immune responses. The advances, particular in the field of cellular immunology, have strongly influenced the focus of neuroimmunological research. Based on recent findings, new models for the pathogenesis of multiple sclerosis have been developed which resulted in new therapeutical strategies. Here, we summarise the latest progress in basic and clinical immunology as well as clinical neurology related to multiple sclerosis. C1 NINDS, Cellular Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Neurol Klin & Poliklin, Zentrum Nervenheilkunde, Marburg, Germany. Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA. RP Martin, R (reprint author), NINDS, Cellular Immunol Sect, Neuroimmunol Branch, NIH, Bldg 10 Room 5B-16,10 Ctr DR MSC 1400, Bethesda, MD 20892 USA. NR 120 TC 2 Z9 2 U1 0 U2 0 PU GEORG THIEME VERLAG PI STUTTGART PA P O BOX 30 11 20, D-70451 STUTTGART, GERMANY SN 0302-4350 J9 AKTUEL NEUROL JI Aktuelle Neurol. PD MAY PY 1998 VL 25 IS 3 BP 83 EP 95 DI 10.1055/s-2007-1017670 PG 15 WC Clinical Neurology SC Neurosciences & Neurology GA ZU704 UT WOS:000074225100001 ER PT J AU Thurman, RG Bradford, BU Iimuro, Y Adachi, Y Wall, C von Frankenberg, M Ikejima, K Kono, H Enomoto, N Arteel, G Zhong, Z Lemasters, JJ Raleigh, J Kadiiska, M Stefanovic, B Tsukamoto, H Lin, M Brenner, D Forman, DT Gallucci, RM Luster, M Mason, R AF Thurman, RG Bradford, BU Iimuro, Y Adachi, Y Wall, C von Frankenberg, M Ikejima, K Kono, H Enomoto, N Arteel, G Zhong, Z Lemasters, JJ Raleigh, J Kadiiska, M Stefanovic, B Tsukamoto, H Lin, M Brenner, D Forman, DT Gallucci, RM Luster, M Mason, R TI Increased liver injury in female rats is due to hypoxia-reoxygenation triggered by endotoxin and Kupffer cells SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article; Proceedings Paper CT Bordeaux Symposium on Alcohol Feeding Model CY SEP 22-25, 1997 CL BORDEAUX, FRANCE ID FREE-RADICAL ADDUCTS; ALCOHOL; EXPOSURE C1 Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. Univ So Calif, Los Angeles, CA USA. NIEHS, Dept Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Thurman, RG (reprint author), Univ N Carolina, Dept Pharmacol, 1124 Mary Ellen Jones Bldg,CB 7365, Chapel Hill, NC 27599 USA. NR 8 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 1998 VL 22 IS 3 BP 766 EP 768 DI 10.1111/j.1530-0277.1998.tb04341.x PG 3 WC Substance Abuse SC Substance Abuse GA ZP311 UT WOS:000073739600050 ER PT J AU Kaler, SG AF Kaler, SG TI Diagnosis and therapy of Menkes syndrome, a genetic form of copper deficiency SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT International Conference on Genetic and Environmental Determinants of Copper Metabolism CY MAR 17-20, 1996 CL NIH, BETHESDA, MARYLAND SP NIH, Univ Chile HO NIH DE Menkes syndrome; copper; dopamine beta-monooxygenase; catecholamines; mutations; splicing; infants ID KINKY-HAIR SYNDROME; PEPTIDE ALPHA-AMIDATION; OCCIPITAL HORN SYNDROME; C-OXIDASE DEFICIENCY; LYSYL OXIDASE; CANDIDATE GENE; TRANSPORTING ATPASE; SKIN FIBROBLASTS; DISEASE; MUTATIONS AB In the 25 y since copper deficiency was first delineated in persons with Menkes syndrome, advances in our understanding of the clinical, biochemical, and molecular aspects of this rare disorder have surpassed progress in the design of effective therapies. In contrast with purely nutritional copper deficiency, in which copper replacement can be curative, the nature of the basic defect in Menkes syndrome suggests that corrective efforts are likely to be more complicated, a point supported by the cumulative literature on this topic as well as by emerging molecular data. In this paper, certain clinical, biochemical, and molecular aspects of copper histidine treatment in 25 Menkes syndrome patients at the National Institutes of Health are reviewed. The delineation of a distinctive neurochemical pattern in plasma and cerebrospinal fluid, reflecting deficiency of the copper enzyme dopamine beta-monooxygenase, is arguably the most important finding in the study of Menkes syndrome. This abnormal pattern has proven extremely reliable as a rapid diagnostic test, enabling early identification of affected infants-a fundamental requirement for improving clinical outcomes. Of 11 patients identified by prenatal or prompt postnatal testing and treated within the first 10 d of age, one walked at 14 mo of age and has normal neurodevelopment at age 3 y and another infant's early progress appears promising. However, five patients died in infancy and neurodevelopmental outcome was suboptimal in four others. Consideration of additional therapeutic strategies seems necessary, therefore, for most patients and families facing this troublesome form of copper deficiency. C1 NINDS, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. Childrens Hosp, Washington, DC 20010 USA. RP Kaler, SG (reprint author), NINDS, Clin Neurosci Branch, NIH, Bldg 10,Room 4D20,10 Ctr Dr MSC 1424, Bethesda, MD 20892 USA. NR 89 TC 61 Z9 61 U1 0 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 MAY PY 1998 VL 67 IS 5 SU S BP 1029S EP 1034S PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA ZL395 UT WOS:000073428600014 PM 9587147 ER PT J AU Vortmeyer, AO Merino, MJ Boni, R Liotta, LA Cavazzana, A Zhuang, ZP AF Vortmeyer, AO Merino, MJ Boni, R Liotta, LA Cavazzana, A Zhuang, ZP TI Genetic changes associated with primary Merkel cell carcinoma SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE loss of heterozygosity; microdissection; Merkel cell carcinoma; chromosome ID CHROMOSOME-ABNORMALITIES; TRABECULAR CARCINOMA; SHORT ARM; DELETION; TUMOR; SKIN; HETEROZYGOSITY; 1P; PHEOCHROMOCYTOMAS; LINE AB Merkel cell carcinoma (MCC) is a malignant tumor of the skin with a well-established neuroendocrine phenotype but an unknown histogenetic origin. Cytogenetic and molecular studies have shown evidence for genetic changes on the distal portion of chromosome 1p in different tumors with well-established neuroendocrine origins, specifically neuroblastomas, malignant melanomas, and pheochromocytomas. involvement of chromosome 1 in MCC recently has been demonstrated by cytogenetic analysis and analysis of loss of heterozygosity (LOH) in metastatic tumor tissue. We performed analysis of LOH of the distal portion of chromosome 1p in paraffin material of 10 primary MCCs after tissue microdissection, using the polymorphic markers D1S160, D1S243, D1S468, D1S1646, and D1S1598. Seven of 10 analyzed MCCs shared a distal deletion involving 1p35-36. None of the cases showed 1p involvement proximal to 1p35. The findings are similar to those described for malignant melanoma, pheochromocytoma, and neuroblastoma, tumors known to originate from neural crest cells. In conjunction with previous cytogenetic data, we conclude that Merkel cell carcinogenesis shares pathogenetic mechanisms with other neoplasms of neural crest derivation. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. Univ Roma, Cattedra Anat Patol, Roma, Italy. RP Zhuang, ZP (reprint author), NCI, Pathol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 40 TC 33 Z9 33 U1 0 U2 0 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 MAY PY 1998 VL 109 IS 5 BP 565 EP 570 PG 6 WC Pathology SC Pathology GA ZK068 UT WOS:000073281700011 PM 9576574 ER PT J AU Rockhill, B Weinberg, CR Newman, B AF Rockhill, B Weinberg, CR Newman, B TI Population attributable fraction estimation for established breast cancer risk factors: Considering the issues of high prevalence and unmodifiability SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article; Proceedings Paper CT 30th Annual Meeting of the Society-of-Epidemiologic-Research CY JUN 12-15, 1997 CL EDMONTON, CANADA SP Soc Epidemiol Res DE breast neoplasms; risk factors ID EPIDEMIOLOGY AB Established breast cancer risk factors, in addition to being relatively unmodifiable, are highly prevalent among US women. Previous reports of population attributable fraction for the established risk factors have used definitions that resulted in 75-100% of women in the source population labeled exposed. The practical value of such estimates has not been discussed; further, the estimates have frequently been misinterpreted. in the context of examining the interpretation and public health value of such estimates, the authors demonstrate the sensitivity of the population attributable fraction to changes in exposure cutpoints. They use data from the Carolina Breast Cancer Study, a case-control study of breast cancer conducted in North Carolina between 1993 and 1996. For the four established risk factors (menarche before age 14 years,first birth at age 20 years or later/nulliparity, family history of breast cancer, and history of benign breast biopsy), the estimated population attributable fraction was 0.25 (95% confidence interval 0.06-0.48). Over 98% of the source population was exposed to at least one of these risk factors. The population attributable fraction estimate was reduced to 0.15 when more restrictive definitions of early menarche (less than age 12 years) and late age at first full-term pregnancy (30 years or more) were used (proportion exposed, 0.62). Population attributable fractions for established breast cancer risk factors probably have little public health value because of both the high proportions exposed and the relative unmodifiability of the risk factor distributions. C1 Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. RP Rockhill, B (reprint author), Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [P50-CA58223] NR 19 TC 71 Z9 73 U1 0 U2 5 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAY 1 PY 1998 VL 147 IS 9 BP 826 EP 833 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZL332 UT WOS:000073422300006 PM 9583712 ER PT J AU Cleghorn, FR Jack, N Murphy, JR Edwards, J Mahabir, B Paul, R O'Brien, T Greenberg, M Weinhold, K Bartholomew, C Brookmeyer, R Blattner, WA AF Cleghorn, FR Jack, N Murphy, JR Edwards, J Mahabir, B Paul, R O'Brien, T Greenberg, M Weinhold, K Bartholomew, C Brookmeyer, R Blattner, WA TI Direct and indirect estimates of HIV-1 incidence in a high-prevalence population SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cohort studies; cross-sectional studies; genital diseases, male; HIV-1; incidence; prevalence; sexually transmitted diseases; vaccines ID EARLY DIAGNOSTIC-TESTS; PROSPECTIVE COHORT; NORTHERN THAILAND; INCIDENCE RATES; SEROPREVALENCE; INFECTIONS; TRINIDAD; EPIDEMIC; TRIALS; DESIGN AB While the worldwide AIDS epidemic continues to expand, directly measured incidence data are difficult to obtain, Methods to reliably estimate human immunodeficiency virus type 1 (HIV-I) incidence from more easily available data are particularly relevant in those parts of the world where prevalence is rising in heterosexually exposed populations. The authors set out to estimate HIV-1 incidence in a population of heterosexual sexually transmitted disease clinic attendees in Trinidad who had a known high prevalence of HIV-1 subtype B. Over the period 1987-1995, HIV-I incidence estimates from serial cross-sectional studies of HIV-I prevalence, passive follow-up of clinic recidivists, modeling of early markers of HIV-1 infection (p24 antigen screening), and a cohort study of seronegative genital ulcer disease cases were compared. Measuring incidence density in the genital ulcer disease cases directly gave the highest estimate, 6.9% per annum. Screening for the detection of early HIV-1 markets yielded an incidence of 5.0% per annum, while estimating incidence from serial cross-sectional prevalence data and clinic recidivists gave estimates of 3.5% and 4.5% per annum, respectively. These results were found to be internally consistent. Indirect estimates of incidence based an prevalence data can give accurate surrogates of true incidence. Within limitations, even crude measures of incidence are robust enough for health planning and evaluation purposes. For planning vaccine efficacy trials, consistent conservative estimates may be used to evaluate populations before targeting them for cohort studies. C1 Univ Maryland, Inst Human Virol, Div Epidemiol & Prevent, Baltimore, MD 21201 USA. NCI, NIH, Viral Epidemiol Branch, Div Canc Etiol, Bethesda, MD USA. Caribbean Epidemiol Ctr, Port Spain, Trinid & Tobago. Res Triangle Inst, Epidemiol & Med Studies Program, Washington, DC USA. Univ W Indies, Dept Med, Port Spain, Trinid & Tobago. Duke Univ, Ctr AIDS Res, Raleigh, NC USA. Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. RP Cleghorn, FR (reprint author), Univ Maryland, Inst Human Virol, Div Epidemiol & Prevent, Suite N445,725 W Lombard St, Baltimore, MD 21201 USA. FU NCI NIH HHS [NCI-CP-61022-21, NCI-CP-40547] NR 21 TC 18 Z9 18 U1 0 U2 1 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAY 1 PY 1998 VL 147 IS 9 BP 834 EP 839 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZL332 UT WOS:000073422300007 PM 9583713 ER PT J AU Horne, MK Hutchison, KJ AF Horne, MK Hutchison, KJ TI Simultaneous binding of heparin and platelet factor-4 to platelets: Further insights into the mechanism of heparin-lnduced thrombocytopenia SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article DE heparin; platelet factor 4; thrombocytopenia ID MOLECULAR-WEIGHT HEPARIN; HUMAN BLOOD-PLATELETS; FACTOR-IV; UNFRACTIONATED HEPARIN; ANTIBODIES; COMPLEXES; MEMBRANE; PF4 AB Heparin-induced thrombocytopenia (HIT) is mediated by antibody against complexes of platelet factor-4 (PF4) and heparin, Although it has been assumed that these complexes bind to platelets and provide a target for the antibody, this has never been demonstrated. Furthermore, there is evidence suggesting that heparin-PF4 complexes do not bind to platelets. We have analyzed the effect of each ligand on the platelet binding of the other. We particularly focused on the result when heparin and PF4 are in equimolar concentration because we had previously shown that this was the condition under which HIT-IgG increased on the platelet surface. We found that when the molar concentration of PF4 approximates or exceeds that of heparin, the ligands bind simultaneously to the cells and HIT-IgG binds also. However, when heparin is in molar excess, both PF4 binding and HIT-IgG binding are diminished. Our data are consistent with the hypothesis that heparin-PP4 complexes bind via their heparin component to heparin binding sites on the platelet membrane rather than by their PF4 component to PF4 sites. The conditions promoting the binding of the complexes also lead to binding of HIT-IgG. (C) 1998 Wiley-Liss, Inc. C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Clin Pathol, Hematol Serv, Bethesda, MD 20892 USA. RP Horne, MK (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Clin Pathol, Hematol Serv, Room 2C390,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 25 TC 31 Z9 31 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 MAY PY 1998 VL 58 IS 1 BP 24 EP 30 DI 10.1002/(SICI)1096-8652(199805)58:1<24::AID-AJH5>3.0.CO;2-2 PG 7 WC Hematology SC Hematology GA ZL517 UT WOS:000073441500005 PM 9590145 ER PT J AU Kittles, RA Perola, M Peltonen, L Bergen, AW Aragon, RA Virkkunen, M Linnoila, M Goldman, D Long, JC AF Kittles, RA Perola, M Peltonen, L Bergen, AW Aragon, RA Virkkunen, M Linnoila, M Goldman, D Long, JC TI Dual origins of Finns revealed by Y chromosome haplotype variation SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ALPHOID SATELLITE DNA; HUMAN-POPULATIONS; MICROSATELLITE LOCI; ALLELE FREQUENCIES; REPEAT LOCI; FINLAND; POLYMORPHISMS; DISTANCES; LAPPS AB The Finnish population has often been viewed as an isolate founded 2,000 years ago via a route across the Gulf of Finland. The founding event has been characterized as involving a limited number of homogeneous founders, isolation, and subsequent rapid population growth. Despite the purported isolation of the population, levels of gene diversity for the Finns at autosomal and mitochondrial DNA loci are indistinguishable from those of other Europeans. Thus, mixed or dual origins for the Finns have been proposed. Here we present genetic evidence for the dual origins of Finns by evaluating the pattern of Y chromosome variation in 280 unrelated males from nine Finnish provinces. Phylogenetic analysis of 77 haplotype configurations revealed two major starshaped clusters of Y haplotypes, indicative of a population expansion from two common Y haplotypes. Dramatic and quite significant differences in Y haplotype variation were observed between eastern and western regions of Finland, revealing contributions from different paternal types. The geographic distribution and time of expansion for the two common Y haplotypes correlate well with archeological evidence for two culturally and geographically distinct groups of settlers. Also, a northeastern to southwestern gradient of Y haplotype frequencies provides convincing evidence for recent male migration from rural areas into urban Finland. C1 NIAAA, Sect Populat Genet & Linkage, NIH, Bethesda, MD USA. NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. NIAAA, Clin Studies Lab, NIH, Bethesda, MD USA. Natl Publ Hlth Inst, Dept Human Mol Genet, Helsinki, Finland. Univ Helsinki, Dept Psychiat, SF-00180 Helsinki, Finland. RP Kittles, RA (reprint author), Howard Univ, Ctr Canc, 2041 Georgia Ave,Room 507 NW, Washington, DC 20060 USA. RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Bergen, Andrew/0000-0002-1237-7644 NR 37 TC 135 Z9 135 U1 0 U2 4 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY PY 1998 VL 62 IS 5 BP 1171 EP 1179 DI 10.1086/301831 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA ZL922 UT WOS:000073487000022 PM 9545401 ER PT J AU Termanini, B Gibril, F Sutliff, VE Yu, F Venzon, DJ Jensen, RT AF Termanini, B Gibril, F Sutliff, VE Yu, F Venzon, DJ Jensen, RT TI Effect of long-term gastric acid suppressive therapy on serum vitamin B-12 levels in patients with Zollinger-Ellison syndrome SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID PROTEIN-BOUND VITAMIN-B12; PEPTIC-ULCER DISEASE; COBALAMIN DEFICIENCY; OMEPRAZOLE THERAPY; PHARMACOKINETIC PROPERTIES; BACTERIAL OVERGROWTH; MEGALOBLASTIC-ANEMIA; REFLUX ESOPHAGITIS; ATROPHIC GASTRITIS; INTRINSIC-FACTOR AB BACKGROUND AND AIMS: Long-term treatment with H+-K+-adenotriphosphatase (ATPase) inhibitors, such as omeprazole or lansoprazole, for severe gastroesophageal reflux disease is now widely used. Whether such treatment will result in vitamin B-12 deficiency is controversial. We studied whether long-term treatment with omeprazole alters serum vitamin B-12 levels in patients with Zollinger-Ellison syndrome. METHODS: In 131 consecutive patients treated with either omeprazole (n = 111) or histamine H-2-receptor antagonists (n = 20), serum vitamin B-12 and folate levels and complete blood counts were determined after acid secretion had been controlled for at least 6 months. These studies were repeated yearly. Serum vitamin B-12 and folate levels were correlated with the type of antisecretory drug and the extent of inhibition of acid secretion. RESULTS: The mean duration of omeprazole treatment was 4.5 years, and for H-2-receptor antagonists 10 years. Vitamin B-12 levels, but not serum folate levels or any hematological parameter, were significantly (P = 0.03) lower in patients treated with omeprazole, especially those with omeprazole-induced sustained hyposecretion (P = 0.0014) or complete achlorhydria (P <0.0001). In 68 patients with two determinations at least 5 years apart, vitamin B-12 levels decreased significantly (30%; P = 0.001) only in patients rendered achlorhydric. The duration of omeprazole treatment was inversely correlated with vitamin B-12 levels (P = 0.013), but not folate levels. Eight patients (6%) developed subnormal B-12 levels during follow-up. CONCLUSIONS: Long-term omeprazole treatment leads to significant decreases in serum vitamin B-12 but not folate levels. These results suggest patients with Zollinger-Ellison syndrome treated with H+-K+-ATPase inhibitors should have serum vitamin B-12 levels monitored. Furthermore, these results raise the possibility that other patients treated chronically with H+-K+-ATPase inhibitors may develop B-12 deficiency. (C) 1998 by Excerpta Medica, Inc. C1 NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIDDK, Digest Dis Branch, NIH, 10 Ctr Dr MSC 1804, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008 NR 68 TC 94 Z9 97 U1 1 U2 2 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD MAY PY 1998 VL 104 IS 5 BP 422 EP 430 DI 10.1016/S0002-9343(98)00087-4 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA ZQ578 UT WOS:000073882100003 PM 9626024 ER PT J AU Klebanoff, MA Mednick, BR Schulsinger, C Secher, NJ Shiono, PH AF Klebanoff, MA Mednick, BR Schulsinger, C Secher, NJ Shiono, PH TI Father's effect on infant birth weight SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE birth weight; genetics; paternal effects AB OBJECTIVE: We sought to determine whether paternal size at birth and during young adulthood influences the birth weight of the offspring. STUDY DESIGN: This historic cohort study followed up girls born in Copenhagen during 1959 to 1961.; Their pregnancies in 1974 to 1989 were traced through the Danish Population Register, and the Personal Identification Numbers of the fathers of the children were obtained. Paternal birth weight was obtained from midwifery records and adult stature from military draft records. RESULTS: Compared with fathers who weighed at least 4 kg at birth, fathers who weighed 3 to 3.99 kg at birth had infants who were 109 gm lighter, and fathers who weighed <3 kg had infants who were 176 gm lighter after adjustment for maternal birth weight and adult stature, smoking, and medical and socioeconomic factors. After adjustment, fathers in the lowest quartile of adult body mass index had infants that were 105 gm lighter than those of fathers in the highest quartile. Both paternal birth weight and adult body mass index exhibited significant trends in association with infant birth weight. CONCLUSION: independently of maternal size, the lather's physical stature, particularly his own size at. birth, influences the birth weight of his children. C1 NICHHD, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Univ So Calif, Dept Educ Psychol, Los Angeles, CA USA. Univ Copenhagen, Inst Sygdomsforebyggelse, Copenhagen, Denmark. Aarhus Univ, Dept Obstet & Gynecol, Perinatal Res Epidemiol Unit, Aarhus, Denmark. David & Lucile Packard Fdn, Ctr Future Children, Los Altos, CA USA. RP Klebanoff, MA (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, NIH, 6100 Bldg 7B03, Bethesda, MD 20892 USA. FU NICHD NIH HHS [N01-HD-7-2902] NR 14 TC 66 Z9 69 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 MAY PY 1998 VL 178 IS 5 BP 1022 EP 1026 DI 10.1016/S0002-9378(98)70542-3 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA ZP972 UT WOS:000073807400026 PM 9609578 ER PT J AU Iams, JD Goldenberg, RL Mercer, BM Moawad, A Thom, E Meis, PJ McNellis, D Caritis, SN Miodovnik, M Menard, MK Thurnau, GR Bottoms, SF Roberts, JM AF Iams, JD Goldenberg, RL Mercer, BM Moawad, A Thom, E Meis, PJ McNellis, D Caritis, SN Miodovnik, M Menard, MK Thurnau, GR Bottoms, SF Roberts, JM CA NICHHD Matern-Fetal Med Units Network TI The Preterm Prediction Study: Recurrence risk of spontaneous preterm birth SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE preterm birth; fetal fibronectin; cervical length ID LENGTH AB OBJECTIVE: We sought to estimate the risk of spontaneous preterm birth in parous women by use of obstetric history, fetal fibronectin, and sonographic cervical length. STUDY DESIGN: The probability of spontaneous preterm birth before 35 weeks' gestation was estimated from a logistic regression model with data from 1282 parous women analyzed according to gestational age at the most recent prior delivery (prior preterm birth at 18 to 26 weeks, 27 to 31 weeks, 32 to 36 weeks, and greater than or equal to 37 weeks' gestation), fetal fibronectin status (positive = greater than or equal to 50 ng/dl), and cervical length by percentile groups (less than or equal to 10th = less than or equal to 25 nm, 10th to 50th = 26 to 35 mm, and >50th = >35 mm) measured at 22 to 24 weeks' gestation. Fibronectin and cervical length results were blinded for clinical care. RESULTS: Among fetal fibronectin positive women with a prior preterm birth, the estimated recurrence risk of preterm birth <35 weeks' gestation was approximately 65% when the cervix was less than or equal to 25 mm, 45% when the cervix was 26 to 35 mm, and 25% when the cervix was >35 mm at 24 weeks' gestation. For fetal fibronectin negative women with a prior preterm birth, the recurrence risk was 25% when the cervix was less than or equal to 25 mm, 14% when the cervix was 26 to 35 mm, and 7% when the cervix was >35 mm. The risk of preterm birth was increased among women with a history of preterm delivery but was not influenced by the gestational age at delivery of the most recent preterm birth. CONCLUSION: The recurrence risk of spontaneous preterm birth varies widely according to fetal fibronectin and cervical length. Cervical length and fetal fibronectin results had distinct and significant effects on the recurrence risk of preterm birth. Predicted recurrence risk is increased by twofold to fourfold in women with a positive compared with a negative fetal fibronectin, and it increases as cervical length shortens in both fetal fibronectin-positive and fetal fibronectin-negative women. These data may be useful to care for women with a history of preterm birth and to design studies to prevent recurrent premature delivery. C1 Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. Univ Tennessee, Dept Obstet & Gynecol, Memphis, TN 38103 USA. Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 USA. George Washington Univ, Ctr Biostat, Dept Obstet & Gynecol, Washington, DC USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Obstet & Gynecol, Winston Salem, NC 27103 USA. Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. Univ Cincinnati, Dept Obstet & Gynecol, Cincinnati, OH USA. Med Univ S Carolina, Dept Obstet & Gynecol, Charleston, SC 29425 USA. Univ Oklahoma, Dept Obstet & Gynecol, Oklahoma City, OK USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. NICHHD, Dept Obstet & Gynecol, Bethesda, MD 20892 USA. RP Iams, JD (reprint author), Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. OI caritis, steve/0000-0002-2169-0712 FU NICHD NIH HHS [HD21410, HD21414, HD21434] NR 11 TC 119 Z9 125 U1 0 U2 5 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 MAY PY 1998 VL 178 IS 5 BP 1035 EP 1040 DI 10.1016/S0002-9378(98)70544-7 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA ZP972 UT WOS:000073807400028 PM 9609580 ER PT J AU Battey, JF AF Battey, JF TI News from the National Institute on Deafness and Other Communication Disorders SO AMERICAN JOURNAL OF OTOLOGY LA English DT Editorial Material C1 Natl Inst Deafness & Commun Disorders, NIH, Bethesda, MD 20892 USA. RP Battey, JF (reprint author), Natl Inst Deafness & Commun Disorders, NIH, Bldg 31,Rm 3C02, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0192-9763 J9 AM J OTOL JI Am. J. Otol. PD MAY PY 1998 VL 19 IS 3 BP 263 EP 265 PG 3 WC Otorhinolaryngology SC Otorhinolaryngology GA 145DR UT WOS:000077356200001 PM 9596171 ER PT J AU Reynolds, TH Brozinick, JT Rogers, MA Cushman, SW AF Reynolds, TH Brozinick, JT Rogers, MA Cushman, SW TI Mechanism of hypoxia-stimulated glucose transport in rat skeletal muscle: potential role of glycogen SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE muscle contraction; GLUT-4 ID GLUT-4 PROTEIN-CONTENT; PLASMA-MEMBRANE; INSULIN SENSITIVITY; EXERCISE; TRANSLOCATION; CONTRACTIONS; INCREASES; RESPONSIVENESS; DEPLETION; CAPACITY AB We have previously reported that exercise training is associated with enhanced insulin-stimulated glucose transport activity and inhibited hypoxia-stimulated glucose transport activity in rat epitrochlearis muscle. Here we examine the potential role of muscle glycogen in the inhibited glucose transport response to hypoxia. Three days of swim training (2 x 3 h/day) produce a 100% increase in glycogen and a 70% increase in GLUT-4 in epitrochlearis muscle. Glucose transport after 1 h of hypoxia in muscles from fed exercise-trained (ET) rats is not significantly elevated above basal and is 40% lower than that in muscles from fed sedentary (SED) rats. Glycogen levels after 1 h of hypoxia are reduced by 27 and 64% in muscles from fed ET and fed SED rats, respectively. After 2 h of hypoxia, glucose transport is significantly increased above basal in muscles from fed ET rats, but this response is still 55% lower than that in muscles from fed SED rats. After 2 h of hypoxia, glycogen is reduced by 50 and 83% in muscles from fed ET and fed SED rats, respectively. After a modified overnight fast (approximate to 4.5 g of chow), the glucose transport and glycogen responses to 1 h of hypoxia are not significantly different between muscles from ET and SED rats. These findings demonstrate a strong inverse relationship between glycogen and hypoxia-stimulated glucose transport activity and that high levels of glycogen contribute to the inhibited glucose transport response to hypoxia. Furthermore, failure of the overexpression of GLUT-4 after exercise training to enhance the glucose transport response to contraction/hypoxia suggests selective targeting of the additional GLUT-4 to the insulin-responsive pool. C1 NIDDKD, Expt Diabet Metab & Nutr Sect, Diabet Branch, Bethesda, MD 20892 USA. Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. RP Reynolds, TH (reprint author), Geriatr Ctr, 5131 CCGC,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. NR 38 TC 13 Z9 14 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD MAY PY 1998 VL 274 IS 5 BP E773 EP E778 PG 6 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA ZM052 UT WOS:000073499900001 PM 9612232 ER PT J AU Smith, CB Eintrei, C Kang, J Sun, Y AF Smith, CB Eintrei, C Kang, J Sun, Y TI Effects of thiopental anesthesia on local rates of cerebral protein synthesis in rats SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE leucine; brain; amino acid recycling; barbiturate ID PRECURSOR POOL; DEGRADATION; PLASMA; INVIVO; BRAIN; MODEL AB We have examined the effects of a surgical level of thiopental anesthesia in adult male rats on local rates of cerebral protein synthesis with the quantitative autoradiographic L-[1-C-14]leucine method. The relative contribution of leucine derived from protein breakdown to the intracellular precursor amino acid pool for protein synthesis was found to be statistically significantly decreased in the anesthetized rats compared with controls. In the brain as a whole and in 30 of the 35 brain regions examined, rates of protein synthesis were decreased (1-11%) in the anesthetized rats. Decreases were statistically significant (P less than or equal to 0.05) in the brain as a whole and in six of the regions, and they approached statistical significance in an additional 13 regions, indicating a tendency for a generalized but small effect. C1 NIMH, Cerebral Metab Lab, US PHS, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Smith, CB (reprint author), NIMH, Cerebral Metab Lab, US PHS, Dept Hlth & Human Serv, Bldg 36,Rm 1A07,36 Convent Dr,MSC 4030, Bethesda, MD 20892 USA. NR 24 TC 8 Z9 8 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD MAY PY 1998 VL 274 IS 5 BP E852 EP E859 PG 8 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA ZM052 UT WOS:000073499900012 PM 9612243 ER PT J AU Mittur, AV Kaplowitz, N Kempner, ES Ookhtens, M AF Mittur, AV Kaplowitz, N Kempner, ES Ookhtens, M TI Novel properties of hepatic canalicular reduced glutathione transport revealed by radiation inactivation SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE biliary transport; target analysis; canalicular multispecific organic anion transporter ID PERFORMANCE LIQUID-CHROMATOGRAPHY; PLASMA-MEMBRANE VESICLES; PROTEIN-KINASE-C; RAT-LIVER; EFFLUX; MECHANISM; TURNOVER; SYSTEMS; CLONING AB Transport of GSH at the canalicular pole of hepatocytes occurs by a facilitative carrier and can account for similar to 50% of total hepatocyte GSH efflux. A low-affinity unit with sigmoidal kinetics accounts for 90% of canalicular transport at physiological GSH concentrations. A low-capacity transporter with high affinity for GSH has also been reported. It is not known whether the same or different proteins mediate low-and high-affinity GSH transport, although they do differ in inhibitor specificity. The bile of rats with a mutation in the canalicular multispecific organic anion transporter (cMOAT or MRP-8, a 170-kDa protein) is deficient in GSH, implying that cMOAT may transport GSH. However, transport of GSH in canalicular membrane vesicles (CMV) from these mutant rats remains intact. We examined the functional size of the two kinetic components of GSH transport by radiation inactivation of GSH uptake in rat hepatic CMV. High-affinity transport of GSH was inactivated as a single exponential function of radiation dose, yielding a functional size of similar to 70 kDa. In contrast, low-affinity canalicular GSH transport exhibited a complex biexponential response to irradiation, characterized by an initial increase followed by a decrease in GSH transport. Inactivation analysis yielded a similar to 76-kDa size for the low-affinity transporter. The complex inactivation indicated that the low-affinity transporter is associated with a larger protein of similar to 141 kDa, which masked similar to 80% of the potential transport activity in CMV. Additional studies, using inactivation of leukotriene C-4 transport, yielded a functional size of similar to 302 kDa for cMOAT, indicating that it functions as a dimer. C1 Univ So Calif, Sch Med, Dept Med, Liver Dis Res Ctr, Los Angeles, CA 90033 USA. Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90033 USA. NIAMSD, Phys Biol Lab, Bethesda, MD 20892 USA. RP Ookhtens, M (reprint author), Univ So Calif, Sch Med, Dept Med, Liver Dis Res Ctr, 1333 San Pablo St,MMR-428, Los Angeles, CA 90033 USA. FU NIDDK NIH HHS [P30-DK-48522, R37-DK-30312]; PHS HHS [R01-A607467] NR 35 TC 11 Z9 11 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 MAY PY 1998 VL 274 IS 5 BP G923 EP G930 PG 8 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA ZM420 UT WOS:000073538300019 PM 9612274 ER PT J AU Yao, XL Ikezono, T Cowan, M Logun, C Angus, CW Shelhamer, JH AF Yao, XL Ikezono, T Cowan, M Logun, C Angus, CW Shelhamer, JH TI Interferon-gamma stimulates human Clara cell secretory protein production by human airway epithelial cells SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE cytokines; airway inflammation; airway secretion ID TISSUE-SPECIFIC EXPRESSION; RABBIT UTEROGLOBIN; GENE-EXPRESSION; GROWTH-FACTOR; KDA PROTEIN; POSTTRANSCRIPTIONAL REGULATION; HORMONAL-REGULATION; PHOSPHOLIPASE A(2); 10-KDA PROTEIN; AMINO-ACID AB Clara cell secretory protein (CCSP) is an inhibitor of secretory phospholipase A(2). It is produced by airway epithelial cells and is present in airway secretions. Because interferon (IFN)-gamma can induce gene expression in airway epithelial cells and may modulate the inflammatory response in the airway, it was of interest to study the effect of this cytokine on epithelial cell CCSP mRNA expression and CCSP protein synthesis. A human bronchial epithelial cell Line (BEAS-2B) was used for this study. CCSP mRNA was detected by ribonuclease protection assay. IFN-gamma was found to increase CCSP mRNA-expression ina time- and dose-dependent manner. The CCSP mRNA level increased after IFN-gamma (300 U/ml) treatment for 8-36 h, with the peak increase at 18 h. Immunobloting of CCSP protein also demonstrated that IFN-gamma induced the synthesis and secretion of CCSP protein in a time-dependent manner. Nuclear run-on, CCSP reporter gene activity assay, and CCSP mRNA half-life assay demonstrated that IFN-gamma-induced increases in CCSP gene expression were mediated, at least in part, at the posttranscriptional level. The present study demonstrates that IFN-gamma can induce increases in steady-state mRNA levels and protein synthesis of human CCSP protein in airway epithelial cells and may modulate airway inflammatory responses ill this manner. C1 NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Shelhamer, JH (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10,Rm 7-D-43, Bethesda, MD 20892 USA. NR 45 TC 30 Z9 33 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD MAY PY 1998 VL 274 IS 5 BP L864 EP L869 PG 6 WC Physiology; Respiratory System SC Physiology; Respiratory System GA ZM341 UT WOS:000073528800024 PM 9612303 ER PT J AU Harlan, WR AF Harlan, WR TI Prevention research at the National Institutes of Health SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article DE prevention research; environmental interventions; molecular medicine; populational research; information dissemination; NIH; research funding AB Prevention of disease and disability and preservation of health are compelling strategies that are endorsed by the public, health care providers, and researchers. Despite this general acceptance of the concept, the "devil is in the details." What can and should be recommended with confidence to the public and health care providers regarding prevention and how can these recommendations be implemented? Prevention programs should be based on durable evidence of efficacy and should assure that the benefits of interventions and changes exceed the risks. The latter is particularly important for population-based primary prevention because many are influenced but fever may benefit. Prevention research must provide the evidence of benefit and risk. The responsibility of the National Institutes of Health (NIH) is to develop the scientific basis for prevention and to train prevention scientists who are responsible for creating this science base. The interpretation and dissemination of information from research studies are important and necessary aspects to assure translation of the science into personal and public health practices. The components of prevention research are investigation of the factors that place individuals and groups at risk of disease and disability; trials of the interventions that can modify this risk; and testing the approaches that can effectively implement beneficial changes. NIH is committed to addressing these endeavors, and its individual Institutes and Centers support a broad portfolio of prevention research, This paper will provide an overview of NIH support, the functional relationships of prevention research within NIH,and background information that can be useful to those interested in research. C1 NIH, Bethesda, MD 20892 USA. RP Harlan, WR (reprint author), NIH, Bldg 1,Room 260,1 Ctr Dr,MSC 0174, Bethesda, MD 20892 USA. NR 4 TC 6 Z9 6 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAY PY 1998 VL 14 IS 4 BP 302 EP 307 DI 10.1016/S0749-3797(98)00005-1 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA ZT446 UT WOS:000074088700008 PM 9635076 ER PT J AU Simons-Morton, DG Cutler, JA AF Simons-Morton, DG Cutler, JA TI Cardiovascular disease prevention research at the National Heart, Lung, and Blood Institute SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article DE National Institutes of Health; cardiovascular diseases; prevention; research; intervention studies; primary prevention; risk factors ID HEALTH-PROGRAM; RISK-FACTORS; TRIAL; EDUCATION; MORTALITY; MORBIDITY C1 NHLBI, Div Epidemiol & Clin Applicat, Prevent Sci Res Grp, Bethesda, MD 20892 USA. RP Simons-Morton, DG (reprint author), NHLBI, Div Epidemiol & Clin Applicat, Prevent Sci Res Grp, 2 Rockledge Ctr,MSC 7936,6701 Rockledge Dr,Room 8, Bethesda, MD 20892 USA. NR 39 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAY PY 1998 VL 14 IS 4 BP 317 EP 330 DI 10.1016/S0749-3797(97)00057-3 PG 14 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA ZT446 UT WOS:000074088700010 PM 9635078 ER PT J AU Quezado, ZMN Karzai, W Danner, RL Freeman, BD Yan, L Eichacker, PQ Banks, SM Cobb, JP Cunnion, RE Quezado, MJN Sevransky, JE Natanson, C AF Quezado, ZMN Karzai, W Danner, RL Freeman, BD Yan, L Eichacker, PQ Banks, SM Cobb, JP Cunnion, RE Quezado, MJN Sevransky, JE Natanson, C TI Effects of L-NMMA and fluid loading on TNF-induced cardiovascular dysfunction in dogs SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID TUMOR-NECROSIS-FACTOR; NITRIC-OXIDE SYNTHASE; METHYL-L-ARGININE; HUMAN SEPTIC SHOCK; CARDIAC MYOCYTES; CONSCIOUS DOGS; FACTOR-ALPHA; FACTOR CHALLENGES; INTERLEUKIN-2; CONTRACTILITY AB We investigated the effects of N-omega-monomethyl-L-arginine (L-NMMA) and fluid loading on tumor necrosis factor (TNF)-induced cardiovascular dysfunction in awake dogs. L-NMMA (40 mg kg(-1) given intravenously over a period of 10 min, and followed by dosing at 40 mg kg(-1) h(-1) for 6 h) and TNF (20 or 45 mu g kg(-1) given intravenously for 20 min), given alone or in combination, significantly decreased stroke volume, cardiac index, oxygen delivery, and left-ventricular (LV) function plots over a period of 6 h. Of note was that the cardiac-depressant effects of TNF and L-NMMA given together were significantly less than additive. Thus, the combination was beneficial (or significantly less harmful to cardiac performance than expected), possibly because L-NMMA augmented cardiac preload as shown by significant increases in both pulmonary capillary wedge pressure (PCWP) and central venous pressure (CVP). Fluid challenges at 6 h (Ringer's solution at 80 mi kg(-1) given over a period of 30 min) also significantly increased PCWP and CVP, and abolished the beneficial preload effect of L-NMMA on cardiac performance. Thus, after fluid loading, the cardiac-depressant effects of TNF and L-NMMA given together became equal to the sum of those produced by TNF and L-NMMA given separately. Although L-NMMA significantly decreased serum nitrite/nitrate levels, TNF did not increase these end products of nitric oxide (NO) production relative to controls. Therefore, after preload abnormalities were eliminated with fluid loading, L-NMMA had no beneficial effect on TNF-induced cardiac depression, and TNF did not increase end products of NO production. These findings are not consistent with NO being the mechanism of TNF-induced acute cardiac depression. C1 NIH, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Natanson, C (reprint author), NIH, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Bldg 10,Room 7D43,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Quezado, Zenaide/O-4860-2016 OI Quezado, Zenaide/0000-0001-9793-4368 NR 35 TC 10 Z9 10 U1 0 U2 2 PU AMER LUNG ASSOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAY PY 1998 VL 157 IS 5 BP 1397 EP 1405 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA ZM736 UT WOS:000073570700006 PM 9603114 ER PT J AU Givelber, RJ Couropmitree, NN Gottlieb, DJ Evans, JC Levy, D Myers, RH O'Connor, GT AF Givelber, RJ Couropmitree, NN Gottlieb, DJ Evans, JC Levy, D Myers, RH O'Connor, GT TI Segregation analysis of pulmonary function among families in the Framingham Study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID OBSTRUCTIVE LUNG-DISEASE; RESPIRATORY-DISEASE; CIGARETTE-SMOKING; REGRESSIVE MODELS; RISK-FACTORS; TRAITS; DEFICIENCY; MECHANISMS; SYMPTOMS AB Familial aggregation of cross-sectional pulmonary function was examined in 5,003 subjects from 1,408 families participating in the Framingham Study. Subjects, who were members of either the Original Cohort (recruited from 1948 to 1952) or the Offspring Cohort (recruited from 1971 to 1974), underwent spirometry at a mean age of 53 yr. The effects of age, height, weight, and smoking status on FEV1 were evaluated through linear-regression analysis, with separate models for men and women in each cohort. The gender- and cohort-specific standardized residual FEV1 from these models was used as the phenotypic variable in familial correlation and segregation analyses to assess inheritance patterns. In models that assumed no major gene determining FEV1, correlation of pulmonary function was greater for mothers and offspring than for fathers and offspring (p[mo] = 0.190, p[fo] = 0.112; p = 0.06), and sibling correlation exceeded parent-offspring correlation (p[sib] = 0.225; p < 0.01). By comparison with a general model, in which transmission probabilities and residual familiar correlations are arbitrary, models that imposed a Mendelian gene were rejected (p < 0.001). A model with no parent-offspring transmission of a major factor, but with residual familial correlation, provided as good a fit as the general model, suggesting that environmental and/or polygenic genetic influences determine FEV1. C1 Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Allegheny Univ Hlth Sci, Allegheny Ctr Lung & Thorac Dis, Pittsburgh, PA USA. National Heart Lung & Blood Institute, Framingham Heart Study, Framingham, MA USA. RP O'Connor, GT (reprint author), Boston Univ, Sch Med, Ctr Pulm, R-304,80 E Concord St, Boston, MA 02118 USA. EM goconnor@bupula.bu.edu OI O'Connor, George/0000-0002-6476-3926 FU NHLBI NIH HHS [HL-09384, HL-49869, N01-HC-38038] NR 30 TC 72 Z9 78 U1 1 U2 3 PU AMER LUNG ASSOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAY PY 1998 VL 157 IS 5 BP 1445 EP 1451 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA ZM736 UT WOS:000073570700014 PM 9603122 ER PT J AU Hill, EM Eling, T Nettesheim, P AF Hill, EM Eling, T Nettesheim, P TI Changes in expression of 15-lipoxygenase and prostaglandin-H synthase during differentiation of human tracheobronchial epithelial cells SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; ARACHIDONIC-ACID; MONOHYDROXYEICOSATETRAENOIC ACID; LIPOXYGENASE; GENERATION; RETICULOCYTES; PURIFICATION; RELEASE AB The purpose of our studies was to examine differentiation-dependent expression of 15-lipoxygenase (15-LO) and prostaglandin H synthase (PGHS) isoforms in cultured normal human tracheobronchial epithelial cells. In the presence of retinoic acid (RA) the cultures differentiated into a mucociliary epithelium. When cultured in RA-depleted media, the cultures differentiated into a squamous epithelium, In the absence of RA the cultures did not express 15-LO or either of the PGHS isoforms. The PGHS-1 isoform was not expressed in RA-sufficient cultures, but both PGHS-2 messenger RNA (mRNA) and protein were strongly expressed, and prostaglandin E-2 (PGE(2)) was produced during the predifferentiation phase. No PGHS-2, expression or PGE(2) could be detected in fully differentiated mucociliary cultures, 15-LO showed the opposite expression pattern: neither mRNA nor protein were detected during the predifferentiation stage, but both were strongly expressed once mucous differentiation had occurred. Cytosolic phospholipase A, protein was expressed throughout all stages of growth and differentiation. The cultures generated no 15-LO metabolites when incubated with 10 mu M to 50 mu M arachidonic acid (AA) and stimulated with ionophore. However, lysates prepared from such cultures generated 15-hydroxyeicosatetraenoic acid (15-HETE) and 12-HETE from AA, indicating that the cells contained active enzyme. When cultures expressing 15-LO protein were incubated with 10 mu M linoleic acid (LA) instead of AA, and were stimulated with ionophore. they generated 13-hydroxy-9,11-octadecadienoic acid. LA rather than AA appeared to be the preferred substrate for the 15-LO enzyme. Our studies indicated that the expression of 15-LO and PGHS-2 is differentiation dependent in airway epithelial cells. C1 NIEHS, Pulm Pathobiol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Nettesheim, P (reprint author), NIEHS, Pulm Pathobiol Lab, MD D2-01,POB 12233, Res Triangle Pk, NC 27709 USA. NR 25 TC 40 Z9 40 U1 0 U2 0 PU AMER LUNG ASSOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD MAY PY 1998 VL 18 IS 5 BP 662 EP 669 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA ZN867 UT WOS:000073691400008 PM 9569236 ER PT J AU Hinnebusch, BJ Gage, KL Schwan, TG AF Hinnebusch, BJ Gage, KL Schwan, TG TI Estimation of vector infectivity rates for plague by means of a standard curve-based competitive polymerase chain reaction method to quantify Yersinia pestis in fleas SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID PCR; QUANTIFICATION; SIPHONAPTERA; TRANSMISSION; DNA; CERATOPHYLLIDAE AB The prevalence of infectivity within a vector population is a critical factor in arthropod-borne disease epidemiology but it is difficult to estimate. In the case of bubonic plague, infective flea vectors contain large numbers of Yersinia pestis within a bacterial mass that blocks the flea's foregut, and only such blocked fleas are important for biologic transmission. A bacterial quantitation method could therefore be used to assess the prevalence of plague-infective (blocked) fleas in a population. We developed a standard, curve-based, competitive polymerase chain reaction (PCR) procedure to quantitate Y. pestis in individual fleas. The quantitative PCR (Q-PCR) method equaled a colony count reference method in accuracy and precision when evaluated using mock samples and laboratory-infected fleas. The Q-PCR was more reliable than colony count, however, for field-collected fleas and for blocked fleas collected after their death. In a sample of fleas collected from a prairie dog colony in the aftermath of a plague epizootic, 48% were infected but less than 2% contained numbers of Y. pestis indicative of blockage. The method provides a means to monitor plague epizootics and associated risks of flea-borne transmission to humans, and is applicable to the study of other vector-borne diseases. C1 NIAID, Rocky Mt Labs, Microbial Struct & Funct Lab, NIH, Hamilton, MT 59840 USA. Ctr Dis Control & Prevent, Natl Ctr Infect Dis, Div Vector Borne Infect Dis, Plague Branch, Ft Collins, CO USA. RP Hinnebusch, BJ (reprint author), NIAID, Rocky Mt Labs, Microbial Struct & Funct Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 35 TC 31 Z9 34 U1 0 U2 3 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 MAY PY 1998 VL 58 IS 5 BP 562 EP 569 PG 8 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA ZN155 UT WOS:000073615400006 PM 9598442 ER PT J AU Tokuyama, T Garraffo, HM Spande, TF Daly, JW AF Tokuyama, T Garraffo, HM Spande, TF Daly, JW TI A revised structure for alkaloid 205B, a novel 8b-azaacenaphthylene from a poison frog SO ANALES DE LA ASOCIACION QUIMICA ARGENTINA LA English DT Article ID COCCINELLID BEETLE; DIETARY ALKALOIDS; SKIN ALKALOIDS; DENDROBATIDAE AB A provisional structure for a trace tricyclic alkaloid 205B from a Panamanian poison frog, Dendrobates pumilio, has been revised based upon new FTIR, NMR, and Cl(NH3)-MS/MS spectral data, molecular modeling and a reexamination of the original H-1-NMR data. The revised structure, a 4,6,8-trimethyl-8b-azaacenaphthyl-Delta(3,4)-ene, has the originally proposed configurations at C-6 and C-8a inverted and is now compatible with all spectral data. C1 Osaka City Univ, Fac Sci, Osaka 558, Japan. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Tokuyama, T (reprint author), 2-8-16 Daido, Osaka 543, Japan. NR 22 TC 16 Z9 16 U1 0 U2 0 PU ASOC QUIMICA ARGENTINA PI BUENOS AIRES PA SANCHEZ DE BUSTAMANTE 1749, 1425 BUENOS AIRES, ARGENTINA SN 0365-0375 J9 AN ASOC QUIM ARGENT JI An. Asoc. Quim. Argent. PD MAY-DEC PY 1998 VL 86 IS 3-6 BP 291 EP 298 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 151DD UT WOS:000077704700034 ER PT J AU Roberts, RL Williams, JR Wang, AK Carter, CS AF Roberts, RL Williams, JR Wang, AK Carter, CS TI Cooperative breeding and monogamy in prairie voles: Influence of the sire and geographical variation SO ANIMAL BEHAVIOUR LA English DT Article ID MICROTUS-OCHROGASTER; SOCIAL-ENVIRONMENT; ACORN WOODPECKER; MEADOW VOLES; FEMALE; BEHAVIOR; PENNSYLVANICUS; PHILOPATRY; MONTANUS; CHOICE AB Mammalian monogamy is characterized by pair bonding and a relative absence of sexual dimorphism in body size. Alloparental behaviour is a characteristic of mammalian cooperative breeding systems. Studies of prairie voles, Microtus ochrogaster, from stock captured in a resource-abundant habitat in Illinois have supported the assumption that this species is a monogamous, cooperative breeder, while other studies of prairie voles from a more arid habitat in Kansas have called this assumption into question. We hypothesized that reported differences between these populations represented true intraspecific variation. Patterns of sexual dimorphism in body size, partner preferences and parental contact behaviour were compared in prairie voles from stocks originating in Illinois or Kansas. Both Illinois and Kansas voles showed a strong preference for a familiar partner, which is suggestive of monogamy. Sexual dimorphism in body size was observed in Kansas, but not Illinois voles. Illinois voles displayed significantly higher levels of parental contact behaviour than did voles from Kansas. When animals from Illinois and Kansas were crossed, the expression of parental contact behaviour of the 'hybrid' offspring followed the pattern seen in the population of origin of the sire. Removal of the sire prior to the birth of the litter increased alloparenting in Kansas voles, but removal of the sire was associated with lower levels of alloparenting in Illinois voles. Thus, some traits associated with the social system may show intraspecific variation and can be influenced by the presence or absence of the sire during rearing. (C) 1998 The Association for the Study of Animal Behaviour. C1 Univ Maryland, Dept Zool, College Pk, MD 20742 USA. RP Roberts, RL (reprint author), NICHHD, Comparat Ethol Lab, Anim Ctr, NIH, POB 529, Poolesville, MD 20837 USA. NR 37 TC 93 Z9 102 U1 2 U2 22 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0003-3472 J9 ANIM BEHAV JI Anim. Behav. PD MAY PY 1998 VL 55 BP 1131 EP 1140 DI 10.1006/anbe.1997.0659 PN 5 PG 10 WC Behavioral Sciences; Zoology SC Behavioral Sciences; Zoology GA ZR156 UT WOS:000073943000005 ER PT J AU Rao, JKS Letada, P Haverstick, DM Herman, MM Savory, J AF Rao, JKS Letada, P Haverstick, DM Herman, MM Savory, J TI Modifications to the in situ TUNEL method for detection of apoptosis in paraffin-embedded tissue sections SO ANNALS OF CLINICAL AND LABORATORY SCIENCE LA English DT Article ID ALZHEIMERS-DISEASE; DNA FRAGMENTATION; NEURONAL DEATH; IN-SITU; INSITU; IDENTIFICATION; BRAIN AB The in situ detection of cells undergoing apoptosis is increasingly important in the analysis of injury and degeneration in the central nervous system. Limited information is presently available on the quantification of apoptosis in paraffin-embedded brain tissue sections, a technique which would be most useful in the evaluation of archival tissue for diagnostic and experimental purposes. In this report, optimized conditions for tissue digestion and permeabilization using Proteinase K and Triton X and a quantification method for apoptosis detection are described using brain sections from aluminum maltolate-treated aged and young rabbits as compared to untreated matched controls. This method provides optimal staining of apoptotic cells without the problem of tissue destruction, and should prove useful in evaluating the process of apoptosis in neurodegenerative disorders. C1 Univ Virginia, Hlth Sci Ctr, Dept Pathol, Charlottesville, VA 22908 USA. Univ Virginia, Hlth Sci Ctr, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. Natl Inst Hlth, IRP, NIMH,Neuropathol Sect, Neurosci Ctr St Elizabeths,Clin Brain Disorders B, Washington, DC USA. RP Savory, J (reprint author), Univ Virginia, Hlth Sci Ctr, Dept Pathol, Box 168, Charlottesville, VA 22908 USA. NR 16 TC 16 Z9 16 U1 0 U2 1 PU INST CLINICAL SCIENCE INC PI PHILADELPHIA PA 1833 DELANCEY PLACE, PHILADELPHIA, PA 19103 USA SN 0091-7370 J9 ANN CLIN LAB SCI JI Ann. Clin. Lab. Sci. PD MAY-JUN PY 1998 VL 28 IS 3 BP 131 EP 137 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZR843 UT WOS:000074020100001 PM 9646852 ER PT J AU Cooper, GS Sandler, DP AF Cooper, GS Sandler, DP TI Age at natural menopause and mortality SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE menopause; premature ovarian failure; mortality; aging; cancer; cardiovascular disease ID HORMONE REPLACEMENT THERAPY; PREMATURE OVARIAN FAILURE; WOMEN AB PURPOSE: The purpose of this study was to examine the association between age at menopause and mortality in a population-based sample of women in the United States. METHODS: This study was based on data from the National Health and Examination Survey (NHANES) Epidemiologic Follow-up Study; 3191 women aged 50-86 years were included. There were 345 deaths over a mean follow-up time of 4.0 years. We used age stratified and Poisson regression procedures to assess mortality risk by age at natural menopause, with adjustment for age, duration of follow-up, race, education, smoking, and use of hormone replacement therapy. We conducted a separate analysis for surgical menopause with bilateral oophorectomy. RESULTS: Compared with women who were menstruating to age 50 or later, the adjusted mortality rate ratios (RR) were 1.50 (95% confidence interval(CI), 0.97-2.34) for women with a natural menopause at age < 40, 1.04 (95% CI, 0.72-1.51) for those with menopause at age 40-44, and 0.96 (95% CI, 0.72-1.26) for those with menopause at age 45-49. Women with a natural menopause at age 40-44 years experienced an increased risk of cancer-related mortality (adjusted RR 2.34, 95% CI, 1.20-4.58). No age-related increased mortality risk was seen among women who had surgical menopause with bilateral oophorectomy. CONCLUSIONS: This study provides some support for the concert that age at natural menopause serves as a biological marker of health and aging, with potential implications extending beyond cardiovascular diseases. Published by Elsevier Science Inc. C1 NIEHS, Epidemiol Branch A305, Res Triangle Pk, NC 27709 USA. RP Cooper, GS (reprint author), NIEHS, Epidemiol Branch A305, POB 12233, Res Triangle Pk, NC 27709 USA. OI Sandler, Dale/0000-0002-6776-0018 NR 21 TC 147 Z9 148 U1 0 U2 8 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 MAY PY 1998 VL 8 IS 4 BP 229 EP 235 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZK363 UT WOS:000073312900004 PM 9590601 ER PT J AU Levine, PH Fears, TR Cummings, P Hoover, RN AF Levine, PH Fears, TR Cummings, P Hoover, RN TI Cancer and a fatiguing illness in northern Nevada - A causal hypothesis SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE chronic fatigue syndrome; epidemic neuromyasthenia; natural killer cells; non-Hodgkin lymphoma ID DEFINITION; CLUSTERS AB PURPOSE: We investigated the possibility that chronic fatigue syndrome (CFS) predisposes to cancer by comparing the cancer pattern in an area in northern Nevada, where an outbreak of a fatiguing illness, which included cases of CFS, was reported, to an area in southern Nevada, where no such illness was reported. METHODS: Data from the computerized Nevada Cancer Registry were utilized to compare incidence rates of four malignancies-brain cancer, non-Hodgkin lymphoma (NHL), lung cancer, and breast cancer-in Washoe and Lyon Counties, where an unexplained fatiguing illness was reported during 1984-86, with comparably sized Clark County, where no such illness was reported. RESULTS: Higher incidences of NHL and primary brain tumors were noted in the two northern Nevada counties (Washoe and Lyon) in 1986 and 1987 respectively, compared to the southern Nevada (Clark) county. Similar patterns were not seen for breast or lung cancer. CONCLUSIONS: This study provides a model for investigating the possible predisposition of CFS patients to develop cancer using other cohorts, but it is currently premature to accept such a link at this time. Published by Elsevier Science Inc. C1 NCI, Div Canc Epidemiol & Genet, Viral Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Nevada Canc Registry, Reno, NV USA. RP Levine, PH (reprint author), NCI, Div Canc Epidemiol & Genet, Viral Epidemiol Branch, NIH, EPN 434, Bethesda, MD 20892 USA. NR 21 TC 7 Z9 7 U1 0 U2 1 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 MAY PY 1998 VL 8 IS 4 BP 245 EP 249 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZK363 UT WOS:000073312900006 PM 9590603 ER PT J AU Hoover, RN AF Hoover, RN TI Cancer prevention: Better late than never? SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID BREAST-CANCER; RISK; ESTROGEN; HABITS C1 NCI, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. RP Hoover, RN (reprint author), NCI, Epidemiol & Biostat Program, Room 433,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 18 TC 3 Z9 3 U1 0 U2 0 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 MAY 1 PY 1998 VL 128 IS 9 BP 771 EP 772 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA ZK790 UT WOS:000073363800011 PM 9556473 ER PT J AU Uhl, GR AF Uhl, GR TI Hypothesis: The role of dopaminergic transporters in selective vulnerability of cells in Parkinson's disease SO ANNALS OF NEUROLOGY LA English DT Editorial Material ID VESICULAR MONOAMINE TRANSPORTERS; COCAINE RECOGNITION SITES; MESSENGER-RNA; SUBSTANTIA-NIGRA; DIFFERENTIAL EXPRESSION; TYROSINE-HYDROXYLASE; AMINE TRANSPORTER; MIDBRAIN NEURONS; BINDING-SITES; HUMAN-BRAIN C1 Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21224 USA. NIDA, Intramural Res Program, Mol Neurobiol Branch, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21224 USA. RP Uhl, GR (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, POB 5180, Baltimore, MD 21224 USA. NR 71 TC 95 Z9 98 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD MAY PY 1998 VL 43 IS 5 BP 555 EP 560 DI 10.1002/ana.410430503 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA ZL147 UT WOS:000073403500002 PM 9585349 ER PT J AU Dean, AC Graham, BA Dalakas, M Sato, S AF Dean, AC Graham, BA Dalakas, M Sato, S TI Sleep apnea in patients with postpolio syndrome SO ANNALS OF NEUROLOGY LA English DT Article ID POLIOMYELITIS; MUSCLE AB We studied sleep architecture and sleep apnea pattern in patients with postpolio syndrome (PPS). Ten patients with clinical signs of PPS underwent polysomnographic recording for two consecutive nights. Although sleep efficiency and proportions of sleep stages were within the normal range, sleep architecture was disrupted owing to sleep apnea. Patients with bulbar involvement had more frequent sleep apnea (mean sleep apnea index, 11.09) than patients without (apnea index, 5.88). The former also had significantly more central apnea, which occurred more commonly during non-rapid-eye-movement (NREM) than rapid-eye-movement (REM) sleep, than those without bulbar signs. This finding suggests reduction in forebrain control of compromised bulbar respiratory centers during NREM sleep in PPS. C1 NINDS, EEG, NIH, Bethesda, MD 20892 USA. NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dean, AC (reprint author), Univ Utah, Hlth Sci Ctr, Dept Neurol, 50 N Med Dr, Salt Lake City, UT 84132 USA. NR 18 TC 23 Z9 25 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD MAY PY 1998 VL 43 IS 5 BP 661 EP 664 DI 10.1002/ana.410430516 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA ZL147 UT WOS:000073403500015 PM 9585362 ER PT J AU Vucenik, I Kalebic, T Tantivejkul, K Shamsuddin, AM AF Vucenik, I Kalebic, T Tantivejkul, K Shamsuddin, AM TI Novel anticancer function of inositol hexaphosphate: Inhibition of human rhabdomyosarcoma in vitro and in vivo SO ANTICANCER RESEARCH LA English DT Article DE RMS; IP6; growth inhibition; differentiation; nude mice ID PHYTIC ACID; CELL-LINE; GROWTH; DIFFERENTIATION; CANCER; RATS AB Inositol hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate that has been shown to suppress the growth of epithelial cancers, including those of breast and colon. The objective of this study was to investigate whether IP6 inhibits growth of rhabdomyosarcoma (RMS), a tumor of mesenchymal origin, which is the most common soft tissue sarcoma in children. We performed both in vitro and in vivo studies to evaluate the effect of IP6 on human RD cells growth. Our results show that IP6 suppresses growth of rhabdomyosarcoma cell line (RD) in vitro in a dose-dependent fashion. A 50% inhibition of cell growth (IC50) was induced by < 1.0 mM IP6. However, the removal of IP6 from the media, after 72 hours of treatment, allowed cells to recover their logarithmic growth. Exposure of RD cells to IP6 led to differentiation; cells became larger with abundant cytoplasm, expressing higher levels of muscle-specific actin. Consistent with in vitro observation, IP6 suppressed RD cell growth in vivo, in a xenografted nude mice model. When compared to controls, IP6-treated mice produced a 25 fold smaller tumors (p=0.008), as observed after a two week treatment, In a second experiment, wherein the treatment period was extended to five weeks, a 49 fold (p=0.001) reduction in tumor size was observed in mice treated with IP6. Histologically no evidence of tumor cell necrosis was observed These data suggest a potential usefulness of this cytostatic, and non-cytotoxic, compound in novel therapeutic strategies for these types of tumor. C1 Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Med & Res Technol, Baltimore, MD 21201 USA. NCI, Mol Oncol Sect, Pediat Branch, Bethesda, MD 20892 USA. RP Shamsuddin, AM (reprint author), Univ Maryland, Sch Med, Dept Pathol, 10 S Pine St, Baltimore, MD 21201 USA. NR 26 TC 38 Z9 41 U1 1 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDNTIOU-KALAMOU RD KAPANDRITI, POB 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD MAY-JUN PY 1998 VL 18 IS 3A BP 1377 EP 1384 PG 8 WC Oncology SC Oncology GA ZZ517 UT WOS:000074737300007 PM 9673344 ER PT J AU Arah, IN Song, KM Seth, P Cowan, KH Sinha, BK AF Arah, IN Song, KM Seth, P Cowan, KH Sinha, BK TI Role of wild-type p53 in the enhancement of camptothecin cytotoxicity against human prostate tumor cells SO ANTICANCER RESEARCH LA English DT Article DE camptothecin; p53; apoptosis prostate tumor; adenovirus ID DNA TOPOISOMERASE-I; POTENT INHIBITOR; LUNG-CANCER; APOPTOSIS; PROLIFERATION; MODULATION; LINES; VIVO AB The role of wild-type human p53 protein in enhancing camptothecin cytotoxicity was examined by infecting human prostate PC3 cells with adenovirus expressing human wild-type p53 gene (Adwtp53). the prostate PC3 cells are null for p53 gene. Infection induced the synthesis of both wtp53, and WAF1 (p21) proteins, resulting in growth arrest of PC3 cells. In the presence of camptothecin, an inhibitor of topoisomerase 1, significant increases in both p53 and p21 proteins were detected in Adwtp53-infected PC3 cells. While Adwtp53 and camptothecin, as single agents, caused apoptosis and cell death, combinations of camptothecin and Adwtp53 were better in inducing apoptosis and cell death in PC3 cells. In contrast, cisplatin neither stabilized p53 and p21 proteins nor enhanced DNA fragmentation when combined with Adwtp53 in PC3 cells, indicating specificity for camptothecin. These observations suggest that introduction of wild-type p53 gene with topoisomerase I inhibitors may offer a clinical advantage for the treatment of prostate tumors containing mut53 or null for p53 gene. C1 NCI, Dept Dev Therapeut, Med Branch, Div Clin Sci,NIH, Bethesda, MD 20982 USA. RP Sinha, BK (reprint author), NCI, Dept Dev Therapeut, Med Branch, Div Clin Sci,NIH, Bldg 10,Room 12N-226, Bethesda, MD 20982 USA. NR 24 TC 23 Z9 24 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 MAY-JUN PY 1998 VL 18 IS 3A BP 1845 EP 1849 PG 5 WC Oncology SC Oncology GA ZZ517 UT WOS:000074737300077 PM 9673414 ER PT J AU Briasoulis, E Tsokos, M Fountzilas, G Bafaloukos, D Kosmidis, P Samantas, E Skarlos, D Nicolaides, C Pavlidis, N AF Briasoulis, E Tsokos, M Fountzilas, G Bafaloukos, D Kosmidis, P Samantas, E Skarlos, D Nicolaides, C Pavlidis, N TI Bcl2 and p53 protein expression in metastatic carcinoma of unknown primary origin: Biological and clinical implications. A Hellenic Co-operative Oncology Group Study SO ANTICANCER RESEARCH LA English DT Article DE p53; bcl-2; metastatic-cancer; apoptosis; unknown-primary; chemotherapy ID WILD-TYPE P53; INDUCED APOPTOSIS; IMMUNOHISTOCHEMICAL EXPRESSION; FAMILY PROTEINS; GENE MUTATION; CANCER; CELLS; OVEREXPRESSION; BREAST; TUMORS AB We have previously shown that metastatic carcinomas of unknown primary site overexpress several tumour markers as well as the products of the oncogenes c-myc, ras and c-erbB2. We analysed the tissue expression of the protein products of the apoptosis modulation genes p53 and bcl-2 in 47 CUP cases. Formalin-fixed, paraffin embedded tumour specimens were stained with commercially available antibodies to p53 (DO7) and bcl-2 after antigen retrieval by the microwave method Staining was evaluated by intensity (1+ to 3+), percentage of positive cells (1-100%), and the 'intensity times percentage' product defined as the immunoreactivity index with values ranging from 0 to 300. Immunoreactivity index values higher than 150 were considered to characterize protein overexpression. Expression of p53 was identified in 70.2 % of armours while 53% of them showed a high immunoreactivity index. Bcl-2 expression was detected in 65% of tumours and overexpressed in 40%. Overexpression of both proteins was detected in 20% of tumours. The detection of either protein was not associated with any of the major clinicopathological variables studied. Nevertheless, a trend towards a mole favourable response to platin based chemotherapy was seen in the cases that showed a strong expression of both proteins, when analysed by immunoreactivity index and percentage of positive cells. We conclude that CUP overexpress at a high percentage the p53 and the bcl-2 proteins. The observed weak association of strong expression of these proteins with response to platin-based chemotherapy deserves further evaluation in the CUP setting. C1 Ioannia Univ Hosp, Ioannina, Greece. NIH, Bethesda, MD 20892 USA. AHEPA Univ Hosp, Thessloniki, Greece. METAXA Anticanc Hosp, Piraeus, Greece. Agii Anargyri Anticanc Hosp, Athens, Greece. RP Pavlidis, N (reprint author), Univ Ioannina, Sch Med, Oncol Sect, Dept Med, GR-45110 Ioannina, Greece. NR 49 TC 33 Z9 34 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 MAY-JUN PY 1998 VL 18 IS 3B BP 1907 EP 1914 PG 8 WC Oncology SC Oncology GA ZZ518 UT WOS:000074737400006 PM 9677443 ER PT J AU Player, MR Maitra, RK Silverman, RH Torrence, PF AF Player, MR Maitra, RK Silverman, RH Torrence, PF TI Targeting RNase L to human immunodeficiency virus RNA with 2-5A-antisense SO ANTIVIRAL CHEMISTRY & CHEMOTHERAPY LA English DT Article DE 2-5A; human immunodeficiency virus; AIDS; RNA degradation; RNase L; oligonucleotides; RNA secondary structure ID ANTISENSE CHIMERAS; TYPE-1 REPLICATION; 2-5A ANTISENSE; INHIBITION; OLIGODEOXYNUCLEOTIDES; HIV-1; DEGRADATION; INFECTIONS; ANALOGS; GAG AB In an attempt to develop a lead for the application of 2-5A-antisense to the targeted destruction of human immunodeficiency virus (HIV) RNA, specific target sequences within the HIV mRNAs were identified by analysis of the theoretical secondary structure. 2-5A-antisense chimeras were chosen against a total of 11 different sequences: three in the gag mRNA, three in the rev mRNA and five in the tat mRNA. 2-5A-antisense chimera synthesis was accomplished using solid-phase phosphoramidite chemistry. These chimeras were evaluated for their activity in a cell-free assay system using purified recombinant human RNase L to effect cleavage of P-32-labelled RNA transcripts of plasmids derived from HIV NL4-3. This screening revealed that of the three 2-5A-antisense chimeras targeted against gag mRNA, only one had significant HIV RNA cleavage activity, approximately 10-fold-reduced compared to the parent 2-5A tetramer and comparable to that reported for the prototypical 2-5A-anti-PKR chimera, targeted against PKR mRNA. The cleavage activity of this chimera was specific, since a scrambled antisense domain chimera and a chimera without the key 5'-monophosphate moiety were both inactive. The 10 other 2-5A-antisense chimeras against tat and rev had significantly less activity. These results imply that HIV gag RNA, like PKR RNA and a model HIV tat-oligoA-vif RNA, can be cleaved using the 2-5A-antisense approach. The results further imply that not all regions of a potential RNA target are accessible to the 2-5A-antisense approach. C1 NIDDKD, Med Chem Lab, Sect Biomed Chem, NIH, Bethesda, MD 20892 USA. Cleveland Clin Fdn, Lerner Res Inst, Virus Core Lab, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Lerner Res Inst, Dept Canc Biol, Cleveland, OH 44195 USA. RP Torrence, PF (reprint author), NIDDKD, Med Chem Lab, Sect Biomed Chem, NIH, Bethesda, MD 20892 USA. FU NCI NIH HHS [1 PO1 CA 62220] NR 37 TC 12 Z9 12 U1 0 U2 0 PU INT MEDICAL PRESS PI LONDON PA 125 HIGH HOLBORN, LONDON WC1V 6QA, ENGLAND SN 0956-3202 J9 ANTIVIR CHEM CHEMOTH JI Antivir. Chem. Chemother. PD MAY PY 1998 VL 9 IS 3 BP 225 EP 231 PG 7 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Virology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Virology GA ZT302 UT WOS:000074070800003 PM 9875401 ER PT J AU Visser, M Kiel, DP Langlois, J Hannan, MT Felson, DT Wilson, PWF Harris, TB AF Visser, M Kiel, DP Langlois, J Hannan, MT Felson, DT Wilson, PWF Harris, TB TI Muscle mass and fat mass in relation to bone mineral density in very old men and women: the Framingham Heart Study SO APPLIED RADIATION AND ISOTOPES LA English DT Article; Proceedings Paper CT International Symposium on In Vivo Body Composition Studies CY SEP 18-20, 1996 CL MALMO, SWEDEN ID BODY-COMPOSITION; POSTMENOPAUSAL WOMEN; ELDERLY MEN; ABSORPTIOMETRY; ASSOCIATIONS; STRENGTH AB Aim of the study was investigate the cross-sectional relationship between body composition and bone mineral density (BMD) in very old men and women. The study sample consisted of 504 women and 285 men, aged 72-93 yr, participating in examination 22 (1992-1993) of the Framingham Heart Study. Total body BMD, regional BMD, and soft-tissue body composition was measured by dual-energy X-ray absorptiometry. Both muscle mass and percentage body fat were positively associated with total body BMD in women. After adjustment for age, physical activity, smoking status, estrogen use, and thiazide use, BMD increased with increasing tertile of muscle mass (p = 0.007) and with increasing tertile of percentage body fat (p = 0.0001) in women. In men muscle mass, not percentage body fat, was positively associated with BMD. After adjustment for potential confounders, BMD remained associated with muscle mass only (p = 0.02). These results were similar for leg BMD and arm BMD. The study suggests that the influence of muscle and fat mass on bone mineral density is different between very old men and women. Published by Elsevier Science Ltd. C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Div Aging, Boston, MA 02115 USA. Hebrew Rehabil Ctr Aged, Res & Training Inst, Boston, MA 02131 USA. Boston Univ, Ctr Arthritis, Boston, MA USA. Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. RP Visser, M (reprint author), NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. OI Kiel, Douglas/0000-0001-8474-0310 NR 11 TC 34 Z9 34 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0969-8043 J9 APPL RADIAT ISOTOPES JI Appl. Radiat. Isot. PD MAY-JUN PY 1998 VL 49 IS 5-6 BP 745 EP 747 DI 10.1016/S0969-8043(97)00101-2 PG 3 WC Chemistry, Inorganic & Nuclear; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Chemistry; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA ZE053 UT WOS:000072752700100 PM 9569599 ER PT J AU Tabacova, S Baird, DD Balabaeva, L AF Tabacova, S Baird, DD Balabaeva, L TI Exposure to oxidized nitrogen: Lipid peroxidation and neonatal health risk SO ARCHIVES OF ENVIRONMENTAL HEALTH LA English DT Article ID DIOXIDE EXPOSURE; OXIDATIVE STRESS; ANTIOXIDANTS; PREECLAMPSIA; GLUTATHIONE; THROMBOXANE; SURFACTANT; INFANTS AB Pregnant women exposed to extensive environmental contamination by oxidized nitrogen compounds were studied at parturition, their neonatal health status was assessed and the involvement of oxidative stress in pathology was evaluated. Methemoglobin in maternal and cord blood was measured as a biomarker of individual exposure. Blood lipid peroxides and glutathione (reduced and total) were determined as oxidative stress biomarkers. Birthweight, Apgar scares, and clinical diagnosis at birth were used as neonatal health endpoints. Elevated exposure to oxidized nitrogen compounds was associated with increased lipid peroxidation in both maternal and cord blood, Poor birth outcome was associated with high blood lipid peroxides. Controlling for maternal age, parity, and smoking did not affect the relationships materially. The results showed that maternal/fetal exposure to oxidized nitrogen compounds is associated with increased risk of adverse birth outcome and suggest a role of oxidative damage in the pathogenic pathway. C1 Natl Ctr Hyg Med Ecol & Nutr, Sofia 1431, Bulgaria. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Tabacova, S (reprint author), Natl Ctr Hyg Med Ecol & Nutr, Sofia 1431, Bulgaria. OI Baird, Donna/0000-0002-5544-2653 NR 35 TC 23 Z9 26 U1 0 U2 3 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 MAY-JUN PY 1998 VL 53 IS 3 BP 214 EP 221 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 109UR UT WOS:000075342700006 PM 9814718 ER PT J AU Hallett, M AF Hallett, M TI The neurophysiology of dystonia SO ARCHIVES OF NEUROLOGY LA English DT Review ID MOTOR; CORTEX AB Any model for the physiology of dystonia must be able to explain how dystonia can be produced in various circumstances. Brain lesions can cause dystonia; responsible sites include the basal ganglia, brainstem, and thalamus, but the most common site is the putamen. Dystonia can be hereditary, and genetic linkage has been found for both generalized and focal dystonia. The only genetic dystonia for which the gene product is known is Segawa disease, a hereditary progressive dystonia with marked diurnal fluctuation. The defect is in guanosine triphosphate cyclohydrolase I, a gene that makes a cofactor for the synthesis of dopamine, which explains why this form of dystonia should be amenable to treatment. with levodopa. Another example of dystonia in which a disorder of dopamine pharmacology appears responsible is the dystonia occurring in Parkinson disease, either spontaneously or as a result of treatment. Curiously, the dystonia occurs at both peak and trough dopamine levels. C1 NINDS, Div Intramural Res, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Div Intramural Res, Off Clin Director, NIH, Bldg 10,Room 5N226,10 Ctr Dr MSC-1428, Bethesda, MD 20892 USA. NR 11 TC 137 Z9 137 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0003-9942 EI 1538-3687 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD MAY PY 1998 VL 55 IS 5 BP 601 EP 603 DI 10.1001/archneur.55.5.601 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA ZN390 UT WOS:000073641100001 PM 9605716 ER PT J AU Litvan, I Saunders, AM AF Litvan, I Saunders, AM TI Apolipoprotein E4 (epsilon) allele does not affect the onset or symptom severity in progressive supranuclear palsy SO ARCHIVES OF NEUROLOGY LA English DT Letter ID RICHARDSON-OLSZEWSKI-SYNDROME; SPORADIC ALZHEIMERS-DISEASE; COGNITIVE DECLINE; ASSOCIATION; DIAGNOSIS; CRITERIA; DEMENTIA; TANGLES; TAU C1 NINDS, Neuropharmacol Unit, Def & Vet Head Injury Program, Henry M Jackson Fdn,NIH, Bethesda, MD 20892 USA. NINDS, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Litvan, I (reprint author), NINDS, Neuropharmacol Unit, Def & Vet Head Injury Program, Henry M Jackson Fdn,NIH, Fed Bldg,Room 714, Bethesda, MD 20892 USA. EM litvan1@helix.nih.gov OI Litvan, Irene/0000-0002-3485-3445 FU NIA NIH HHS [5P50 AG-05128]; NINDS NIH HHS [NS-31153] NR 30 TC 10 Z9 10 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD MAY PY 1998 VL 55 IS 5 BP 752 EP 754 DI 10.1001/archneur.55.5.752 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA ZN390 UT WOS:000073641100024 PM 9605738 ER PT J AU Yamane, A Takahashi, K Mayo, M Vo, H Shum, L Zeichner-David, M Slavkin, HC AF Yamane, A Takahashi, K Mayo, M Vo, H Shum, L Zeichner-David, M Slavkin, HC TI Induced expression of MyoD, myogenin and desmin during myoblast differentiation in embryonic mouse tongue development SO ARCHIVES OF ORAL BIOLOGY LA English DT Article DE MyoD; myogenin; myf5; desmin; myogenesis; mouse tongue; myogenic regulatory factors; competitive RT-PCR; TGF alpha; mandibular organ culture; serumless and chemically-defined medium ID CELL-CYCLE WITHDRAWAL; SKELETAL-MUSCLE; REGULATORY FACTORS; DNA-BINDING; TGF-ALPHA; MANDIBULAR MORPHOGENESIS; GENE-EXPRESSION; GROWTH; MYF-5; MICE AB Significant progress has been made in defining mechanisms governing myogenesis at the transcriptional levels, bur the extracellular signal-transduction pathways involved in myogenesis are not as yet defined. The developing mouse tongue provides a model for the regulation of myogenesis during precise time periods in embryogenesis. The molecular cues that regulate the close-range autocrine and/or paracrine signalling processes required for the fast-twitch complex tongue musculature are not known. This study was designed to test the hypothesis that transforming growth factor-alpha (TGF alpha) controls myogenesis in embryonic mouse tongue through the induction of myogenic regulatory factors such as myoD, myf5, myogenin and MRF4/myf6/herculin. To test this hypothesis, the effects of exogenous TGF alpha on the transcription of myoD, myf5, myogenin, MRF4 and desmin were examined in tongue samples from embryonic day-10.5 mandibular explants cultured in serum-free, chemically defined medium and then processed for competitive, reverse transcription-polymerase chain reaction. TGF alpha induced myoD, myogenin and desmin expression. Treatment with 20 and 40 ng/ml TGF alpha decreased or downregulated myf5 mRNA. MRF4 was not detected in the explants. TGF alpha apparently induces the early developmental stages of myogenesis through sequential upregulation of myoD and myogenin, downregulation of myf5 and corresponding significant increases in muscle-specific gene expression such as desmin transcription. (C) 1998 Elsevier Science Ltd. All rights reserved. C1 NIH, Craniofacial Dev Sect, Bethesda, MD 20892 USA. Tsurumi Univ, Sch Dent Med, Dept Pharmacol, Yokohama, Kanagawa, Japan. Univ So Calif, Ctr Craniofacial Mol Biol, Los Angeles, CA 90033 USA. RP Slavkin, HC (reprint author), NIH, Craniofacial Dev Sect, Bethesda, MD 20892 USA. RI Zeichner-David, Margarita/A-6567-2008 FU NIAMS NIH HHS [Z01-AR 41114-02-BCTB]; NIDCR NIH HHS [DE-02824] NR 58 TC 30 Z9 30 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0003-9969 J9 ARCH ORAL BIOL JI Arch. Oral Biol. PD MAY PY 1998 VL 43 IS 5 BP 407 EP 416 DI 10.1016/S0003-9969(98)00018-1 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA ZY636 UT WOS:000074643500008 PM 9681116 ER PT J AU Cremers, CWRJ Bolder, C Admiraal, RJC Everett, LA Joosten, FBM van Hauwe, P Green, ED Otten, BJ AF Cremers, CWRJ Bolder, C Admiraal, RJC Everett, LA Joosten, FBM van Hauwe, P Green, ED Otten, BJ TI Progressive sensorineural hearing loss and a widened vestibular aqueduct in Pendred syndrome SO ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article ID MIXED DEAFNESS; PERILYMPHATIC GUSHER; STAPES GUSHER; COCHLEA; DEFECT; MAPS AB Pendred syndrome is an autosomal recessive inherited disorder. Obligatory features are profound deafness in childhood and defective organic binding of iodine in the thyroid gland. Therefore, goiter is a common symptom. Hypoplasia of the cochlea is another feature. Recently, the gene for Pendred syndrome was identified. We describe a boy whose sensorineural hearing loss in both ears progressed rapidly from about 50 to SO dB at the age of 3 years and 3 months to more than 100 dB at the age of 4 years and 4 months. This loss was preceded by a medical history of a progressive hearing loss. The progressive nature of the hearing loss motivated a search for the cause. Dysplasia of the cochlea and a widened vestibular aqueduct were found. The results of thyroid function tests were normal, but he had an elevated level of thyroglobulin. The diagnosis of Pendred syndrome was confirmed by the positive results of a potassium perchlorate test, indicating defective organic binding of iodine in the thyroid gland. It is possible that the widened vestibular aqueduct was responsible for the increase in the hearing impairment. Aside from the branchio-otorenal syndrome, Pendred syndrome is the only other known genetic disorder with a widened vestibular aqueduct. If a child has progressive sensorineural deafness and a widened vestibular aqueduct, it is important to consider a diagnosis of Pendred syndrome. A widened vestibular aqueduct may help to elucidate the pathophysiologic characteristics of hearing loss in these genetic types of deafness in childhood. C1 Univ Nijmegen Hosp, Dept Otorhinolaryngol, NL-6500 HB Nijmegen, Netherlands. Univ Nijmegen Hosp, Dept Radiol, NL-6500 HB Nijmegen, Netherlands. Univ Nijmegen Hosp, Dept Pediat, NL-6500 HB Nijmegen, Netherlands. Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. Univ Antwerp, Dept Med Genet, B-2020 Antwerp, Belgium. RP Cremers, CWRJ (reprint author), Univ Nijmegen Hosp, Dept Otorhinolaryngol, POB 9101, NL-6500 HB Nijmegen, Netherlands. RI Admiraal, R.J.C./L-4171-2015; Cremers, C.W.R.J./L-4254-2015; Otten, B.J./L-4562-2015 NR 39 TC 53 Z9 53 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0886-4470 J9 ARCH OTOLARYNGOL JI Arch. Otolaryngol. Head Neck Surg. PD MAY PY 1998 VL 124 IS 5 BP 501 EP 505 PG 5 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA ZN156 UT WOS:000073615500002 ER PT J AU Lawrence, RC Helmick, CG Arnett, FC Deyo, RA Felson, DT Giannini, EH Heyse, SP Hirsch, R Hochberg, MC Hunder, GG Liang, MH Pillemer, SR Steen, VD Wolfe, F AF Lawrence, RC Helmick, CG Arnett, FC Deyo, RA Felson, DT Giannini, EH Heyse, SP Hirsch, R Hochberg, MC Hunder, GG Liang, MH Pillemer, SR Steen, VD Wolfe, F TI Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States SO ARTHRITIS AND RHEUMATISM LA English DT Review ID SYSTEMIC LUPUS-ERYTHEMATOSUS; GIANT-CELL ARTERITIS; LOW-BACK-PAIN; JUVENILE RHEUMATOID-ARTHRITIS; ADULT DANISH POPULATION; KNEE OSTEO-ARTHRITIS; ANKYLOSING-SPONDYLITIS; GENERAL-POPULATION; PRELIMINARY CRITERIA; PRIMARY FIBROMYALGIA AB Objective. To provide a single source for the best available estimates of the national prevalence of arthritis in general and of selected musculoskeletal disorders (osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, the spondylarthropathies, systemic lupus erythematosus, scleroderma, polymyalgia rheumatica/giant cell arteritis, gout, fibromyalgia, and low back pain), Methods. The National Arthritis Data Workgroup reviewed data from available surveys, such as the National Health and Nutrition Examination Survey series, For overall national estimates, we used surveys based on representative samples, Because data based on national population samples are unavailable for most specific musculoskeletal conditions, we derived data from various smaller survey samples from defined populations. Prevalence estimates from these surveys were linked to 1990 US Bureau of the Census population data to calculate national estimates. We also estimated the expected frequency of arthritis in the year 2020, Results, Current national estimates are provided, with important caveats regarding their interpretation, for self-reported arthritis and selected conditions. An estimated 15% (40 million) of Americans had some form of arthritis in 1995, By the year 2020, an estimated 18.2% (59.4 million) will be affected, Conclusion. Given the limitations of the data on which they are based, this report provides the best available prevalence estimates for arthritis and other rheumatic conditions overall, and for selected musculoskeletal disorders, in the US population. C1 NIAMS, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. Univ Texas, Hlth Sci Ctr, Houston, TX USA. Univ Washington, Seattle, WA 98195 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Mayo Clin, Rochester, MN USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Georgetown Univ, Med Ctr, Washington, DC 20007 USA. Arthrit Res Ctr, Wichita, KS USA. RP Lawrence, RC (reprint author), NIAMS, NIH, Bldg 45,Room 5AS-13, Bethesda, MD 20892 USA. NR 149 TC 1560 Z9 1616 U1 14 U2 131 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD MAY PY 1998 VL 41 IS 5 BP 778 EP 799 DI 10.1002/1529-0131(199805)41:5<778::AID-ART4>3.0.CO;2-V PG 22 WC Rheumatology SC Rheumatology GA ZL248 UT WOS:000073413600003 PM 9588729 ER PT J AU Trun, NJ Marko, JF AF Trun, NJ Marko, JF TI Architecture of a bacterial chromosome SO ASM NEWS LA English DT Article ID ESCHERICHIA-COLI; DNA; CONDENSATION AB A built-in loop-domain structure, proteins, and other macromolecules fold and compact this otherwise unwieldy molecule of DNA. C1 NCI, Mol Biol Lab, Bethesda, MD 20892 USA. Univ Illinois, Dept Phys, Chicago, IL 60680 USA. NR 10 TC 50 Z9 53 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0044-7897 J9 ASM NEWS JI ASM News PD MAY PY 1998 VL 64 IS 5 BP 276 EP 283 PG 8 WC Microbiology SC Microbiology GA ZM077 UT WOS:000073502400016 ER PT J AU Shoaib, M Swanner, LS Beyer, CE Goldberg, SR Schindler, CW AF Shoaib, M Swanner, LS Beyer, CE Goldberg, SR Schindler, CW TI The GABA(B) agonist baclofen modifies cocaine self-administration in rats SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE baclofen; cocaine; self-administration; rat ID VENTRAL TEGMENTAL AREA; NUCLEUS-ACCUMBENS; FOOD-INTAKE; DOPAMINE; NEURONS; BEHAVIOR; RELEASE; REINFORCEMENT; SCHEDULE; ALTERS AB The present experiments were conducted to examine further the ability of GABAergic compounds to modify the reinforcing effects of cocaine. In male Sprague-Dawley rats, behaviour was maintained under a fixed-ratio (FR)-5 with a 240 s timeout (TO) multiple schedule of cocaine (0.66 mg/kg/infusion) and food (45 mg) in 180 min sessions. Once rats could reliably nose-poke for comparable number of reinforcers over sessions, and demonstrate extinction selectively for each reinforcer, pretreatments were examined. The GABA(B) agonist baclofen (2.5-10.0 mg/kg i,p,) administered 30 min before the start of the session, dose-dependently attenuated behaviour maintained by cocaine, whereas responding maintained by food was marginally decreased. 4,5,6,7-Tetrahydroisoxazolo [5,4 c] pyridin-3-ol hydrochloride (THIP) (2-8 mg/kg i,p,) a GABA agonist failed to modify cocaine-maintained or food-maintained responding. In another experiment, behaviour maintained by cocaine (0.66 mg/kg/infusion) under an FR-5 TO 20 s schedule of reinforcement was attenuated by intra-nucleus accumbens (100-300 ng) or intra-ventral tegmental area (300 ng) administration of baclofen, Similar doses of baclofen administered into the striatum had no effect. Repeated systemic pretreatment for 3 days,vith baclofen (2.5 mg/kg i,p,) produced gradual decreases in cocaine-maintained responding. A larger dose (5.0 mg/kg i,p,) tested repeatedly for 5 days decreased the number of cocaine injections self-administered. The present findings demonstrate that modulation of GABA systems may have therapeutic potential for the treatment of psychomotor stimulant abuse. Behav Pharmacol 1998; 9:195-206 (C) 1998 Lippincott-Raven Publishers. C1 NIDA, Preclin Pharmacol Lab, Behav Pharmacol & Genet Sect, Div Intramural Res,NIH, Baltimore, MD USA. RP Shoaib, M (reprint author), Inst Psychiat, Sect Behav Pharmacol, De Crespigny Pk, London SE5 8AF, England. NR 36 TC 123 Z9 126 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD MAY PY 1998 VL 9 IS 3 BP 195 EP 206 PG 12 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA ZW366 UT WOS:000074403800002 PM 9832934 ER PT J AU Van Waes, C Hecht, DA Mousa, SA AF Van Waes, C Hecht, DA Mousa, SA TI Tissue remodeling in cancer and anti-cancer therapy SO BIOCHEMICAL ARCHIVES LA English DT Article DE tissue remodeling; neoplasia; cytokines; angiogenesis; integrins; metalloproteinases ID EXTRACELLULAR-MATRIX; DIFFERENTIAL EXPRESSION; INTEGRIN ALPHA-V-BETA-3; NEOPLASTIC PROSTATE; NEGATIVE REGULATION; TUMOR PROGRESSION; BASEMENT-MEMBRANE; MELANOMA-CELLS; METASTASIS; ADHESION C1 Dupont Merck Pharmaceut Co, Expt Stn, Wilmington, DE 19880 USA. Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, Bethesda, MD USA. Georgetown Univ, Dept Otolaryngol Head & Neck Surg, Washington, DC USA. RP Mousa, SA (reprint author), Dupont Merck Pharmaceut Co, Expt Stn, E400-3456, Wilmington, DE 19880 USA. NR 38 TC 0 Z9 0 U1 0 U2 0 PU MBR PRESS INC PI KENYON PA PO BOX P, KENYON, MN 55946-000P USA SN 0749-5331 J9 BIOCHEM ARCH JI Biochem. Arch. PD MAY PY 1998 VL 14 IS 2 BP 71 EP 91 PG 21 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 104YV UT WOS:000075045300001 ER PT J AU Mori, T Itoh, S Kamataki, T AF Mori, T Itoh, S Kamataki, T TI Molecular cloning and regulation of a novel guinea pig cytochrome P450 (CYP3A20) which differs from guinea pig CYP3A14 in only two amino acid residues SO BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL LA English DT Article DE guinea pig; liver; cytochrome P450; CYP3A subfamily; CYP3A20 cDNA; regulation; dexamethasone; developmental changes; ascorbic acid; S1 mapping analysis; mRNA ID MICROSOMAL CYTOCHROME-P-450; CDNA CLONING; SEQUENCES; SUPERFAMILY; PURIFICATION; NOMENCLATURE; SIGNAL; FORMS; RAT AB A full length cDNA clone of cytochrome P450, encoding 503 amino acid residues, was isolated from a male guinea pig liver cDNA library. The sequence was highly homologous to other members in the CYP3A subfamily and was designated CYP3A20. CYP3A20 and CYP3A14, another guinea pig CYP3A, shared 99.4% nucleotide and 99.6% deduced amino acid sequence homology. There were only two amino acid differences between CYP3A20 and CYP3A14. No significant induction of CYP3A20 mRNA in the livers from male guinea pigs treated with dexamethasone was observed by S1 mapping analysis although CYP3A14 mRNA was induced. The expression of CYP3A20 mRNA in the livers did not change between 5 and 10 weeks after birth while that of CYP3A14 mRNA in livers significantly increased at 10 weeks. This is the first report that the two highly resembling forms of cytochrome P450 display differently regulated expression from each other. C1 Hokkaido Univ, Fac Pharmaceut Sci, Div Drug Metab, Sapporo, Hokkaido 060, Japan. RP Mori, T (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Drug Discovery Res & Dev, Dev Therap Progr,Div Canc Treatm Diag & Ctr, Bldg 1052,Room 105, Frederick, MD 21702 USA. NR 24 TC 1 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS AUST PI MARRICKVILLE PA LOCKED BAG 16, MARRICKVILLE, NSW 2204, AUSTRALIA SN 1039-9712 J9 BIOCHEM MOL BIOL INT JI Biochem. Mol. Biol. Int. PD MAY PY 1998 VL 44 IS 6 BP 1245 EP 1253 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZP889 UT WOS:000073798800021 PM 9623780 ER PT J AU Reiss, WG Piscitelli, SC AF Reiss, WG Piscitelli, SC TI Drug-cytokine interactions - Mechanisms and clinical implications SO BIODRUGS LA English DT Review ID INTERFERON-MEDIATED DEPRESSION; HEPATIC CYTOCHROME-P-450; XANTHINE-OXIDASE; RAT HEPATOCYTES; THEOPHYLLINE PHARMACOKINETICS; PRIMARY CULTURES; METABOLISM; INTERLEUKIN-6; INDUCTION; INHIBITION AB The potential for certain cytokines to alter cytochrome P450-mediated drug metabolism was first described over 20 years ago. Since that time, a number of in vitro studies in a variety of models have confirmed those observations and evaluated the possible mechanisms. Although the actual mechanism(s) remains unknown, several potential theories have been proposed, including the inhibition of mRNA transcription, increased haem oxygenase activity, increased xanthine oxidase activity and the induction of killer cells cytotoxic to liver cells containing cytochrome P450. Clinical data regarding drug-cytokine interactions are currently limited to the results of studies with small patient numbers and case reports. In addition, the results of different reports are often conflicting. Some clinical studies have reported associations between exogenous or endogenous cytokines and alterations in concomitantly administered drugs, whereas others have reported a lack of effect, Differences in cytokine dosages, route of administration, time course of therapy, sample collection times and patient variability are all likely to account for the varied results. In this rapidly expanding field, additional research will better define the mechanisms of these interactions and their clinical implications. C1 NIH, Ctr Clin, Dept Pharm, Clin Pharmacokinet Res Lab, Bethesda, MD 20892 USA. Univ Maryland, Sch Pharm, Dept Pharm Practice & Sci, Pharmacokinet Biopharmaceut Lab, Baltimore, MD USA. RP Piscitelli, SC (reprint author), NIH, Ctr Clin, Dept Pharm, Clin Pharmacokinet Res Lab, Bldg 10,Rm 1N257, Bethesda, MD 20892 USA. NR 35 TC 9 Z9 9 U1 0 U2 0 PU ADIS INTERNATIONAL LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 10, NEW ZEALAND SN 1173-8804 J9 BIODRUGS JI Biodrugs PD MAY PY 1998 VL 9 IS 5 BP 389 EP 395 DI 10.2165/00063030-199809050-00004 PG 7 WC Oncology; Immunology; Pharmacology & Pharmacy SC Oncology; Immunology; Pharmacology & Pharmacy GA ZM164 UT WOS:000073511100004 PM 18020573 ER PT J AU Bertolino, A Callicott, JH Elman, I Mattay, VS Tedeschi, G Frank, JA Breier, A Weinberger, DR AF Bertolino, A Callicott, JH Elman, I Mattay, VS Tedeschi, G Frank, JA Breier, A Weinberger, DR TI Regionally specific neuronal pathology in untreated patients with schizophrenia: A proton magnetic resonance spectroscopic imaging study SO BIOLOGICAL PSYCHIATRY LA English DT Article DE schizophrenia; H-1 magnetic resonance spectroscopic imaging; drug treatment; prefrontal cortex; hippocampal area; N-acetyl-aspartate ID TEMPORAL-LOBE EPILEPSY; FRONTAL LOBES; IN-VIVO; BRAIN; CORTEX; ASPARTATE; SYMPTOMS; INJURY AB Background: Proton magnetic resonance spectroscopic imaging (H-1-MRSI) studies have reported reductions of N-acetyl aspartate (NAA), a marker of neuronal integrity, in the hippocampal region (HIPPO) and dorsolateral prefrontal cortex (DLPFC) of pharmacologically treated patients with schizophrenia. The purpose of the present study was twofold: to exclude drug treatment as a source of the previous findings and to examine NAA relative concentrations in a unique sample of chronically untreated patients. Methods: We studied 12 medication-free patients, 5 of whom were "drug naive" and symptomatic for a mean of 12 years, and 12 control subjects. Ratios of areas under the metabolite peaks of the proton spectra were determined [i.e., NAA/creatine (CRE), NAA/choline (CHO), CHO/CRE] for multiple cortical and subcortical regions. Hippocampal formation and frontal lobe volumes were also measured to test for correlations with H-1-MRSI data. Results: Significant reductions of NAA/CRE and NAA/CHO were found bilaterally in HIPPO and DLPFC. There were no significant changes in CHO/CRE or in NAA ratios in any other area sampled. No significant correlation was found between metabolite ratios, length of illness, and volumes of the hippocampal region and frontal lobe. Mean ratios and effect sizes were not different in chronically ill but still medication-naive patients in comparison with subacute patients and previously studied chronic patients receiving medications. Conclusions: Bilateral reductions of NAA ratios in HIPPO and DLPFC are reliable findings. The findings implicate a relatively localized pattern of neurochemical pathology that does not appear to change with prolonged illness whether medicated or unmedicated. Published 1998 Society of Biological Psychiatry. C1 St Elizabeth Hosp, Ctr Neurosci, NIMH,Clin Brain Disorders Branch, Intramural Res Programs,NIH, Washington, DC 20032 USA. NIMH, Expt Therapeut Branch, Washington, DC USA. NINDS, Neuroimaging Branch, Washington, DC USA. NIH, Lab Diagnost Radiol Res, OD, Washington, DC USA. RP Weinberger, DR (reprint author), St Elizabeth Hosp, Ctr Neurosci, NIMH,Clin Brain Disorders Branch, Intramural Res Programs,NIH, 2700 Martin Luther King Jr Ave SE, Washington, DC 20032 USA. RI Callicott, Joseph/C-9102-2009; Bertolino, Alessandro/O-6352-2016 OI Callicott, Joseph/0000-0003-1298-3334; Bertolino, Alessandro/0000-0002-1251-1380 NR 42 TC 151 Z9 154 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 1998 VL 43 IS 9 BP 641 EP 648 DI 10.1016/S0006-3223(97)00555-6 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA ZK845 UT WOS:000073369600002 PM 9582997 ER PT J AU van Kammen, DP Poltorak, M Kelley, ME Yao, JK Gurklis, JA Peters, JL Hemperly, JJ Wright, RD Freed, WJ AF van Kammen, DP Poltorak, M Kelley, ME Yao, JK Gurklis, JA Peters, JL Hemperly, JJ Wright, RD Freed, WJ TI Further studies of elevated cerebrospinal fluid neuronal cell adhesion molecule in schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Article DE neuronal cell adhesion molecule; schizophrenia; cerebrospinal fluid; cerebrospinal fluid ID N-CAM; NEGATIVE SYMPTOMS; NEURAL DEVELOPMENT; PREFRONTAL CORTEX; DENTATE GYRUS; RAT-BRAIN; NCAM; CSF; EXPRESSION; NOREPINEPHRINE AB Background: The purposes of the present study were to attempt to replicate a previous finding of increased cerebrospinal fluid (CSF) neuronal cell adhesion molecule (N-CAM) in schizophrenia, and to assess whether the increases could be related to medication, clinical state effects, or brain structural measures. Methods: CSF N-CAM was measured by the Western blot technique in 45 DSM-III-R diagnosed male schizophrenic patients both on and off haloperidol treatment and in 20 healthy male control subjects. Results: CSF N-CAM was significantly increased in schizophrenic patients, with no overlap in the ranges, when compared to controls. There were no significant effects of medication or exacerbation on CSF N-CAM. No associations with measures of brain structure were found. Conclusions: Because N-CAM levels were not shown to be different on and off treatment or in exacerbated versus nonexacerbated patients, the higher levels seen in schizophrenic patients may be inherent to the disorder and possibly related to neurodevelopment. Published 1998 Society of Biological Psychiatry. C1 Vet Affairs Med Ctr, Highland Dr Div, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Pittsburgh, PA USA. St Elisabeth Hosp, NIMH, Ctr Neurosci, Sect Preclin Neurosci, Washington, DC USA. Becton Dickinson & Co, Res Ctr, Neurobiol Sect, Res Triangle Pk, NC USA. George Washington Univ, Med Ctr, Dept Neurol, Washington, DC 20037 USA. RP van Kammen, DP (reprint author), Vet Adm Med Ctr, 7180 Highland Dr, Pittsburgh, PA 15206 USA. FU NIMH NIH HHS [MH44-841] NR 53 TC 44 Z9 46 U1 2 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 MAY 1 PY 1998 VL 43 IS 9 BP 680 EP 686 DI 10.1016/S0006-3223(97)00324-7 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA ZK845 UT WOS:000073369600007 PM 9583002 ER PT J AU Paolini, M Pozzetti, L Sapone, A Camerino, A Cantelli-Forti, G AF Paolini, M Pozzetti, L Sapone, A Camerino, A Cantelli-Forti, G TI Testosterone hydroxylase as multibiomarker of effect in evaluating vinclozolin cocarcinogenesis SO BIOMARKERS LA English DT Article DE vinclozolin; testosterone hydroxylase; glutathione S-transferase; cocarcinogenesis ID FUNGICIDE VINCLOZOLIN; ASPERGILLUS-NIDULANS; RAT-LIVER; INDUCTION; SUPPRESSION; MECHANISMS; HYDROLYSIS; TOXICITY; GROWTH AB In this work the modulation of the regio- and stereo-selective hydroxylation of testosterone by vinclozolin was studied in evaluating cocarcinogenic properties. Changes of cytochrome P450-(CYP)-catalysed drug metabolism was investigated in liver, kidney and lung microsomes of Swiss Albino CD1 mice of both sexes after single (625 or 1250 mg kg(-1) b.w.) or repeated (daily 750 mg kg(-1) b.w. for 3 days) i.p. administrations. Treatment of mice with a single dose of vinclozolin caused in a dose-dependent fashion from 2.1 to 14.1-fold increase in the 7 alpha-, 6 beta- and 2 beta-hydroxylations of testosterone in liver. Lower increase in extrahepatic tissues ranging from 2.3 to 8.1-fold for testosterone 6 beta-, 16 beta-, 2 alpha- and 2 beta-hydroxylase activity in the kidney or from 2.2 to 5.l-fold for 6 beta-, 16 alpha-, 16 beta- and 2 beta-hydroxylase activity in the lung were observed. Repeated treatment with this fungicide did not substantially modify the extent and pattern of induction, the liver being the only tissue responsive (up to 7.6-fold increase, 7 beta-hydroxylation) in both male and female. In the kidney (7 alpha-, 6 beta-, 16 beta-, 2 alpha-, 7 alpha-hydroxylations) and lung (6 alpha-, 7 alpha-, 6 beta-, 16 alpha-, 16 beta- and 2 alpha-hydroxylations), a typical sex-dependent induction (up to 9.0-fold, 16 alpha-hydroxylation in the lung, female) was achieved. In general, however, vinclozolin has a complex pattern of induction and suppression of CYP-dependent enzymes, as exemplified from the seduced expression of some hydroxylations depending upon dose, sex and organ considered. For example, after a single administration, 16 beta-hydroxylation was suppressed in liver (up to 78% loss in male, higher dose), whereas 16 alpha-hydroxylation was reduced in kidney up to similar to 50% in both sexes (at the higher dose). Glutathione S-transferase activity, measured as index of post-oxidative reactions, was markedly increased by vinclozolin in the liver (up to 5.2-fold, female) and kidney (up to 3.9-fold, female) but not in the lung. Because both phase I and phase II reactions were enhanced by vinclozolin treatment in liver and kidney, the ratio between activation/detoxification mechanisms was slightly affected. Conversely, this ratio was shifted toward activating mechanisms in the lung, sustaining, in part, the expression of certain type of tumours tissue-dependent. Taken together, these findings seem to indicate the cotoxic, cocarcinogenic and promoting potential of this fungicide. C1 Univ Bologna, Dept Pharmacol, Biochem Toxicol Unit, I-40126 Bologna, Italy. NCI, NIH, Lab Metab, Bethesda, MD 20892 USA. Univ Texas, Med Branch, Dept Prevent Med & Community Hlth, Galveston, TX 77550 USA. RP Paolini, M (reprint author), Univ Bologna, Dept Pharmacol, Biochem Toxicol Unit, Via Irnerio 48, I-40126 Bologna, Italy. RI Sapone, Andrea/E-6704-2013; OI Sapone, Andrea/0000-0001-8496-6977; paolini, moreno/0000-0002-2338-8859 NR 40 TC 13 Z9 13 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI LONDON PA ONE GUNPOWDER SQUARE, LONDON EC4A 3DE, ENGLAND SN 1354-750X J9 BIOMARKERS JI Biomarkers PD MAY-JUN PY 1998 VL 3 IS 3 BP 191 EP 203 PG 13 WC Biotechnology & Applied Microbiology; Toxicology SC Biotechnology & Applied Microbiology; Toxicology GA ZX591 UT WOS:000074533600003 ER PT J AU Rostovtseva, TK Bezrukov, SM AF Rostovtseva, TK Bezrukov, SM TI ATP transport through a single mitochondrial channel, VDAC, studied by current fluctuation analysis SO BIOPHYSICAL JOURNAL LA English DT Article ID PROTEIN-CONDUCTING CHANNEL; RESISTIVE PULSE TECHNIQUE; OUTER-MEMBRANE CHANNEL; GRAMICIDIN-A CHANNELS; ENDOPLASMIC-RETICULUM; SYNTHETIC POLYANION; SUBMICRON PARTICLES; NEUROSPORA-CRASSA; IONIC CHANNELS; LIPID BILAYER AB The "molecular Coulter counter" concept has been used to study transport of ATP molecules through the nanometer-scale aqueous pore of the voltage-dependent mitochondrial ion channel, VDAC. We examine the ATP-induced current fluctuations and the change in average current through a single fully open channel reconstituted into a planar lipid bilayer, At high salt concentration (1 M NaCl), the addition of ATP reduces both solution conductivity and channel conductance, but the effect on the channel is several times stronger and shows saturation behavior even at 50 mM ATP concentration. These results and simple steric considerations indicate pronounced attraction of ATP molecules to VDAC's aqueous pore and permit us to evaluate the effect of a single ATP molecule on channel conductance. ATP addition also generates an excess noise in the ionic current through the channel. Analysis of this excess noise shows that its spectrum is flat in the accessible frequency interval up to several kilohertz. ATP exchange between the pore and the bulk is fast enough not to display any dispersion at these frequencies. By relating the low-frequency spectral density of the noise to the equilibrium diffusion of ATP molecules in the aqueous pore, we calculate a diffusion coefficient D = (1.6-3.3)10(-11) m(2)/s. This is one order of magnitude smaller than the ATP diffusion coefficient in the bulk, but it agrees with recent results on ATP flux measurements in multichannel membranes using the luciferin/luciferase method. C1 NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. St Petersburg Nucl Phys Inst, Gatchina 188350, Russia. RP Bezrukov, SM (reprint author), NICHD, Lab Phys & Struct Biol, Bldg 9,Rm 1E-122, Bethesda, MD 20892 USA. NR 50 TC 110 Z9 115 U1 1 U2 6 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAY PY 1998 VL 74 IS 5 BP 2365 EP 2373 PG 9 WC Biophysics SC Biophysics GA ZL406 UT WOS:000073429700024 PM 9591663 ER PT J AU Ratinov, V Plonsky, I Zimmerberg, J AF Ratinov, V Plonsky, I Zimmerberg, J TI Fusion pore conductance: Experimental approaches and theoretical algorithms SO BIOPHYSICAL JOURNAL LA English DT Article ID RESOLVED CAPACITANCE MEASUREMENTS; SINGLE CELLS; MEMBRANE CAPACITANCE; OPTICAL MEASUREMENTS; ACCESS RESISTANCE; PATCH-CLAMP; EXOCYTOSIS; EVENTS AB Time-resolved admittance measurements provide the basis for studies showing that membrane fusion occurs through the formation and widening of an initially small pore, linking two previously separated aqueous compartments. Here we introduce modifications to this method that correct the cell-pipette (source) admittance for attenuation and phase shifts produced by electrophysiological equipment. Two new approaches for setting the right phase angle are discussed. The first uses the displacement of a patch-clamp amplifier C-slow potentiometer for the calculation of phase. This calculation is based on amplitudes of observed and expected (theoretical) changes in the source admittance. The second approach automates the original phase adjustment, the validity of which we prove analytically for certain conditions. The multiple sine wave approach is modified to allow the calculation of target cell membrane parameters and the conductance of the fusion pore. We also show how this technique can be extended for measurements of the resting potential of the first (voltage-clamped) membrane. We introduce an algorithm for calculation of fusion pore conductance despite a concurrent change in the resistance of the clamped membrane. The sensitivity of the capacitance restoration algorithm to phase shift errors is analyzed, and experimental data are used to demonstrate the results of this analysis. Finally, we show how the phase offset can be corrected "off-line" by restoring the shape of the capacitance increment. C1 NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Zimmerberg, J (reprint author), NICHHD, Lab Cellular & Mol Biophys, NIH, Bldg 10,Rm 10D14,10 Ctr Dr,MSC 1855, Bethesda, MD 20892 USA. NR 18 TC 21 Z9 21 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 MAY PY 1998 VL 74 IS 5 BP 2374 EP 2387 PG 14 WC Biophysics SC Biophysics GA ZL406 UT WOS:000073429700025 PM 9591664 ER PT J AU Konig, S Weiler, S Fales, HM AF Konig, S Weiler, S Fales, HM TI On-line microdialysis for mass spectrometry SO BIOTECHNIQUES LA English DT Article C1 NHLBI, LBC, Ctr Clin, NIH, Bethesda, MD 20892 USA. RP Fales, HM (reprint author), NHLBI, LBC, Ctr Clin, NIH, Bldg 10,Rm 7N318,10 Ctr Dr,MSC 1676, Bethesda, MD 20892 USA. RI Konig, Simone/B-6504-2008 OI Konig, Simone/0000-0003-0672-7246 NR 4 TC 4 Z9 5 U1 0 U2 0 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD MAY PY 1998 VL 24 IS 5 BP 712 EP + PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZL759 UT WOS:000073468300002 PM 9591112 ER PT J AU Wu, SC Spouge, JL Nara, PL AF Wu, SC Spouge, JL Nara, PL TI Increase of primary HIV-1 production in human peripheral blood mononuclear cells by intermittent medium replenishment SO BIOTECHNOLOGY PROGRESS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SOLUBLE CD4; NEUTRALIZATION; RECEPTOR AB Mitogen-stimulated human peripheral blood mononuclear cells (H-PBMCs) are conventionally used to culture primary human immunodeficiency virus type-1 (HIV-1) isolates in vitro. In this study, we attempt to increase the quality of primary HIV-1 stocks harvested from H-PBMC culture using medium replenishment procedures. Experimental/analysis results indicate that more frequent medium replenishment may not lead to improved quantity and quality of harvested virus stock titers,as determined by the viral core (p24) antigen content, viral infectivity, and viral particle-to-infectious unit ratio. This finding implies the conditioning factor(s) present in H-PBMC culture may be important for primary HIV-1 production. The optimal rate for intermittent medium replenishment to achieve the lowest viral particle-to-infectious unit ratio is around 0.25 volume/volume/day. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. NCI, Virus Biol Sect, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Wu, SC (reprint author), Natl Tsing Hua Univ, Dept Life Sci, Hsinchu 30043, Taiwan. EM scwu@life.nthu.edu.tw NR 12 TC 3 Z9 3 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 8756-7938 J9 BIOTECHNOL PROGR JI Biotechnol. Prog. PD MAY-JUN PY 1998 VL 14 IS 3 BP 540 EP 542 DI 10.1021/bp980020t PG 3 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA ZT713 UT WOS:000074117200027 PM 9622540 ER PT J AU Yuen, D Mittal, L Deng, CX Choi, KH AF Yuen, D Mittal, L Deng, CX Choi, KH TI Generation of a primitive erythroid cell line and promotion of its growth by basic fibroblast growth factor SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; IN-VITRO DIFFERENTIATION; EARLY MOUSE EMBRYO; YOLK-SAC; ERYTHROPOIETIN RECEPTOR; GLOBIN GENE; PROGENITORS; EXPRESSION; VASCULOGENESIS; PROLIFERATION AB An immortalized cell line representing the primitive erythroid (EryP) lineage was established from in vitro-differentiated progeny (embryoid bodies [EBs]) of embryonic stem (ES) cells using a retroviral insertional mutation, and has been termed EB-PE for embryoid body-derived primitive erythroid. Even though EB-PE cells are immortalized, they show characteristics of normal EryP cells, such as gene expression and growth factor dependency. In addition, EB-PE cells can differentiate further in culture. Investigation of growth factor requirements of EB-PE cells showed that basic fibroblast growth factor (bFGF) and erythropoietin (Epo) play unique roles in EB-PE proliferation and differentiation. While bFGF was a strong mitogen, Epo was required for both proliferation and differentiation. The unique proliferative response to bFGF coincided with upregulation of its receptor, fibroblast growth factor receptor (fgfr-1), and downregulation of erythropoietin receptor (EpoR) gene expression. Studies of primary EryP cells derived from early EBs, when tested in a colony formation assay, also provided evidence for the mitogenic role of bFGF in concert with Epo, (C) 1998 by The American Society of Hematology. C1 Univ Maryland, Dept Pathol, Program Mol & Cell Biol, Baltimore, MD 21201 USA. NIDDKD, Biochem & Metab Lab, NIH, Bethesda, MD 20892 USA. RP Choi, KH (reprint author), Washington Univ, Dept Pathol, 660 S Euclid Ave,Campus Box 8118, St Louis, MO 63110 USA. RI deng, chuxia/N-6713-2016 FU NHLBI NIH HHS [R29HL55337] NR 48 TC 16 Z9 17 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 1 PY 1998 VL 91 IS 9 BP 3202 EP 3209 PG 8 WC Hematology SC Hematology GA ZJ995 UT WOS:000073274500014 PM 9558375 ER PT J AU Orlic, D Girard, LJ Anderson, SM Pyle, LC Yoder, MC Broxmeyer, HE Bodine, DM AF Orlic, D Girard, LJ Anderson, SM Pyle, LC Yoder, MC Broxmeyer, HE Bodine, DM TI Identification of human and mouse hematopoietic stem cell populations expressing high levels of mRNA encoding retrovirus receptors SO BLOOD LA English DT Article ID UMBILICAL-CORD BLOOD; HUMAN ADENOSINE-DEAMINASE; COLONY-STIMULATING FACTOR; APE LEUKEMIA-VIRUS; BONE-MARROW CELLS; LONG-TERM EXPRESSION; MEDIATED GENE TRANSDUCTION; PROGENITOR CELLS; C-KIT; PERIPHERAL-BLOOD AB One obstacle to retrovirus-mediated gene therapy for human hematopoietic disorders is the low efficiency of gene transfer into pluripotent hematopoietic stem cells (HSC). We have previously shown a direct correlation between retrovirus receptor mRNA levels in mouse HSC and the efficiency with which they are transduced, In the present study, we assayed retrovirus receptor mRNA levels in a variety of mouse and human HSC populations to identify HSC which may be more competent for retrovirus transduction, The highest levels of amphotropic retrovirus receptor (amphoR) mRNA were found in cryopreserved human cord blood HSC, The level of amphoR mRNA in Lin(-)CD34(+)CD38(-) cells isolated from frozen cord blood was 12-fold higher than the level in fresh cord blood Lin(-)CD34(+)CD38(-) cells. In mice, the level of amphoR mRNA in HSC from the bone marrow (BM) of mice treated with stem cell factor and granulocyte-colony stimulating factor was 2.8- to 7.8-fold higher than in HSC from the BM of untreated mice, These findings suggest that HSC from frozen cord blood and cytokine-mobilized BM may be superior targets for amphotropic retrovirus transduction compared with HSC from untreated adult BM, (C) 1998 by The American Society of Hematology. C1 Natl Human Genome Res Inst, Hematopoiesis Sect, Lab Gene Transfer, NIH, Bethesda, MD 20892 USA. James Whitcomb Riley Hosp Children, Dept Pediat, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Dept Microbiol Immunol, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Walther Oncol Ctr, Indianapolis, IN 46202 USA. RP Orlic, D (reprint author), Natl Human Genome Res Inst, Hematopoiesis Sect, Lab Gene Transfer, NIH, Bldg 49,Room 3A11,49 Convent Dr, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [R01 HL 46416, P01 HL 53586, R01 HL 54037] NR 60 TC 43 Z9 45 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 1 PY 1998 VL 91 IS 9 BP 3247 EP 3254 PG 8 WC Hematology SC Hematology GA ZJ995 UT WOS:000073274500019 PM 9558380 ER PT J AU van Rhee, F Savage, D Blackwell, J Orchard, K Dazzi, F Lin, F Chase, A Bungey, J Cross, NCP Apperley, J Szydlo, R Goldman, JM AF van Rhee, F Savage, D Blackwell, J Orchard, K Dazzi, F Lin, F Chase, A Bungey, J Cross, NCP Apperley, J Szydlo, R Goldman, JM TI Adoptive immunotherapy for relapse of chronic myeloid leukemia after allogeneic bone marrow transplant: equal efficacy of lymphocytes from sibling and matched unrelated donors SO BONE MARROW TRANSPLANTATION LA English DT Article DE CML; BMT; adoptive immunotherapy; DLT; unrelated donor ID CHRONIC MYELOGENOUS LEUKEMIA; VERSUS-HOST DISEASE; POLYMERASE CHAIN-REACTION; MINIMAL RESIDUAL DISEASE; 1ST CHRONIC PHASE; T-CELL DEPLETION; LEUKOCYTE TRANSFUSIONS; CHRONIC GRAFT; INFUSIONS; PROPHYLAXIS AB Lymphocyte transfusion from the marrow donor (DLT) is well established as an effective therapy for relapse of CML post allogeneic BMT, Reports thus far have been mostly limited to patients who received DLT from a matched sibling donor. We compared the efficacy and toxicity of DLT in 30 patients who were treated with cells from their HLA-identical sibling (n = 18) or from their phenotypically HLA-matched unrelated marrow donor (n = 12), The overall probability of obtaining a cytogenetic remission was 69% (95%CI: 51-83%) and was not significantly different between the two groups. The disease stage at the time of DLT was the only factor associated with cytogenetic remission by multivariate analysis; patients treated in cytogenetic or molecular relapse (n = 11) were seven times more likely (RR = 7.4 95%CI: 2.4-22.4, P = 0.0005) to respond compared to patients treated for hematologic relapse (n = 19), There was a trend towards more acute GVHD II-IV in the unrelated donor group (58 vs 39%, P = 0.09), but the probability of developing extensive chronic GVHD was not significantly different (56 vs 39%, P = 0.4), We conclude that transfusion of donor cells from HLA-matched volunteer donors does not appreciably increase the risk of GVHD compared with transfusion of cells from HLA-identical siblings in patients with CML who relapse following allogeneic BMT, Conversely, there is no evidence for an increased graft-versus-leukemia effect after DLT from volunteer donors. C1 Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, LRF Adult Leukaemia Unit, London, England. RP van Rhee, F (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. RI apperley, jane/B-4367-2009; Szydlo, Richard/C-6678-2012; Cross, Nicholas/B-4817-2009 OI Szydlo, Richard/0000-0003-1102-8298; Cross, Nicholas/0000-0001-5481-2555 NR 40 TC 50 Z9 51 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAY PY 1998 VL 21 IS 10 BP 1055 EP 1061 DI 10.1038/sj.bmt.1701224 PG 7 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA ZN297 UT WOS:000073631800014 PM 9632281 ER PT J AU Iadarola, MJ Berman, KF Zeffiro, TA Byas-Smith, MG Gracely, RH Max, MB Bennett, GJ AF Iadarola, MJ Berman, KF Zeffiro, TA Byas-Smith, MG Gracely, RH Max, MB Bennett, GJ TI Neural activation during acute capsaicin-evoked pain and allodynia assessed with PET SO BRAIN LA English DT Article DE nociception; neuropathic pain; capsaicin; regional cerebral blood flow; neuroimaging ID POSITRON EMISSION TOMOGRAPHY; ANTERIOR CINGULATE CORTEX; HUMAN CEREBRAL-CORTEX; NEUROGENIC HYPERALGESIA; RECEPTIVE-FIELDS; NEUROPATHIC PAIN; CLIMBING FIBERS; RHESUS-MONKEY; HUMAN BRAIN; NEURONS AB The PET (H2O)-O-15-bolus method was used to image regional brain activity in normal human subjects during intense pain induced by intradermal injection of capsaicin and during post-capsaicin mechanical allodynia (the perception of pain from a normally non-painful stimulus), Images of regional cerebral blood flow were acquired during six conditions: (i) rest; (ii) light brushing of the forearm; (iii) forearm intradermal injection of capsaicin, (iv) and (v) the waning phases of capsaicin pain; and (vi) allodynia, Allodynia was produced by light brushing adjacent to the capsaicin injection site after ongoing pain from the capsaicin injection had completely subsided. Capsaicin treatment produced activation in many discrete brain regions which we classified as subserving four main functions: sensation-perception (primary somatosensory cortex, thalamus and insula); attention (anterior cingulate cortex); descending pain control (periaqueductal grey); and an extensive network related to sensory-motor integration (supplementary motor cortex, bilateral putamen and insula, anterior lobe and vermis of the cerebellum and superior colliculus), Comparison of the noxious and non-noxious stimuli yielded several new insights into neural organization of pain and tactile sensations. Capsaicin pain, which had no concomitant tactile component, produced little or no activation in secondary somatosensory cortex (SII), whereas light brushing produced a prominent activation of SII, suggesting a differential sensitivity of Sn: to tactile versus painful stimuli. The cerebellar vermis was strongly activated by capsaicin, whereas light brush and experimental allodynia produced little or no activation, suggesting a selective association with C-fibre stimulation and nociceptive second-order spinal neurons. The experimental allodynia activated a network that partially overlapped those activated by both pain and light brush alone. Unlike capsaicin-induced pain, allodynia was characterized by bilateral activation of inferior prefrontal cortex, suggesting that prefrontal responses to pain are context dependent. C1 NIDR, PNMB, NIH, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NIH, Off Director, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. RP Iadarola, MJ (reprint author), NIDR, PNMB, NIH, Bldg 49,Room 1A11,49 Convent Dr,MSC 4410, Bethesda, MD 20892 USA. NR 75 TC 251 Z9 253 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAY PY 1998 VL 121 BP 931 EP 947 DI 10.1093/brain/121.5.931 PN 5 PG 17 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA ZQ712 UT WOS:000073895500012 PM 9619195 ER PT J AU Olson, L Cheng, H Zetterstrom, RH Solomin, L Jansson, L Gimenez-Llort, L Hoffer, BJ Perlmann, T AF Olson, L Cheng, H Zetterstrom, RH Solomin, L Jansson, L Gimenez-Llort, L Hoffer, BJ Perlmann, T TI On CNS repair and protection strategies: novel approaches with implications for spinal cord injury and Parkinson's disease SO BRAIN RESEARCH REVIEWS LA English DT Article; Proceedings Paper CT Nobel Symposium on Towards an Understanding of Integrative Brain Functions - Analysis at Multiple Levels CY JUN 04-07, 1997 CL KAAROLINSKA INST, STOCKHOLM, SWEDEN HO KAAROLINSKA INST ID RETINOID-X-RECEPTOR; MICE LACKING GDNF; GROWTH-INHIBITORY PROTEINS; CENTRAL-NERVOUS-SYSTEM; HIGH-AFFINITY LIGAND; NEURITE GROWTH; NGFI-B; DEVELOPMENTAL EXPRESSION; MYELIN; NURR1 AB In the adult mammalian central nervous system lost nerve cells are not replaced and there is no regeneration of injured axons in white matter. Together, these two facts mean that there are no spontaneous reparative mechanisms in operation. Instead, the adult central nervous system copes with the risks of injuries and diseases by protective encapsulation in bone, by a multitude of neuroprotective mechanisms, and finally by the fact that many important functions are represented by a much larger number of neurons-than minimally needed. The long life expectancy of a human being nevertheless means that the risk that the central nervous system is affected by disease, injury or other forms of insults for which it cannot fully compensate is relatively high. Experimentally, two strategies are being pursued in order to develop ways of minimizing various forms of CNS damage, namely neuroprotective and reparative strategies. Here we present a possible reparative intervention applicable to spinal cord injury based on multiple white-to-gray matter peripheral nerve bridge grafts and work based on the specific role of Nurrl for dopamine neuron development, suggesting that development of ligands to transcription factor might be a new inroad to neuroprotective treatments in Parkinson's disease. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. Vet Gen Hosp, Dept Neurosurg, Neurol Inst, Taipei, Taiwan. Ludwig Inst Canc Res, Stockholm Branch, S-17177 Stockholm, Sweden. NIDA, Div Intramural Res, NIH, Baltimore, MD 21224 USA. RP Olson, L (reprint author), Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. NR 39 TC 8 Z9 9 U1 0 U2 1 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 MAY PY 1998 VL 26 IS 2-3 BP 302 EP 305 DI 10.1016/S0165-0173(97)00051-9 PG 4 WC Neurosciences SC Neurosciences & Neurology GA ZZ932 UT WOS:000074783900021 PM 9651546 ER PT J AU Srivastava, RK Srivastava, AR Park, YG Agrawal, S Cho-Chung, YS AF Srivastava, RK Srivastava, AR Park, YG Agrawal, S Cho-Chung, YS TI Antisense depletion of RI alpha subunit of protein kinase A induces apoptosis and growth arrest in human breast cancer cells SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE antisense; protein kinase A; apoptosis ID I REGULATORY SUBUNIT; GENE-EXPRESSION; DIFFERENTIATION; OLIGODEOXYNUCLEOTIDE; OLIGONUCLEOTIDES; INHIBITION; THERAPY; DEATH AB In recent years, several laboratories have explored the possibility of using antisense oligodeoxynucleotides for specific manipulation of gene expression leading to cancer treatment. The enhanced expression of the RI alpha subunit of cyclic AMP-dependent protein kinase type I (PKA-I) has been correlated with cancer cell growth. In the present study, the effects of an antisense oligodeoxynucleotide targeted against RI alpha subunit of PKA-I on growth inhibition and apoptosis in MDA-MB-231 human breast cancer cells were investigated. The growth inhibitory effects of RI alpha antisense oligodeoxynucleotide correlated with a decrease in the RI alpha mRNA and protein levels. The growth inhibition was accompanied by changes in the cell cycle phase distribution, cell morpbology, cleavage of poly (ADP-ribose) polymerase (PARP), and appearance of apoptotic nuclei. By comparison, mismatched control oligodeoxynucleotide had no effect. On the basis of these results, it can be suggested that the RI alpha antisense oligodeoxynucleotide, which efficiently depletes the growth stimulatory RI alpha and induces apoptosis/differentiation, could be used as a therapeutic agent for breast cancer treatment. C1 NCI, Cellular Biochem Sect, Lab Tumor & Biol, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Cho-Chung, YS (reprint author), NCI, Cellular Biochem Sect, Lab Tumor & Biol, NIH, Bldg 10,Room 5B05, Bethesda, MD 20892 USA. NR 26 TC 26 Z9 27 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 MAY PY 1998 VL 49 IS 2 BP 97 EP 107 DI 10.1023/A:1005905723550 PG 11 WC Oncology SC Oncology GA ZY073 UT WOS:000074583900002 PM 9696392 ER PT J AU Boyer, JL Mohanram, A Camaioni, E Jacobson, KA Harden, TK AF Boyer, JL Mohanram, A Camaioni, E Jacobson, KA Harden, TK TI Competitive and selective antagonism of P2Y(1) receptors by N-6-methyl 2 '-deoxyadenosine 3 ',5 '-bisphosphate SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE P2Y(1) antagonist; P2Y(1) receptor; inositol lipid signalling; turkey erythrocytes; phospholipase C ID P-2-PURINOCEPTOR ANTAGONISTS; PPADS; P-2Y-PURINOCEPTORS; RESPONSES AB The antagonist activity of N-6-methyl 2'-deoxyadenosine 3',5'-bisphosphate (N6MABP) has been examined at the phospholipase C-coupled P2Y(1) receptor of turkey erythrocyte membranes. N6MABP antagonized 2MeSATP-stimulated inositol phosphate hydrolysis with a potency approximately 20 fold greater than the previously studied parent molecule, adenosine 3',5'-bisphosphate. The P2Y(1) receptor antagonism observed with N6MABP was competitive as revealed by Schild analysis (pK(B) = 6.99 +/- 0.13). Whereas N6MABP was an antagonist at the human P2Y(1) receptor, no antagonist effect of N6MABP was observed at the human P2Y(2), human P2Y(4) or rat P2Y(6) receptors. C1 Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. NIDDK, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. RP Boyer, JL (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol, CB 7365,Mary Ellen Jones Bldg, Chapel Hill, NC 27599 USA. RI Jacobson, Kenneth/A-1530-2009; OI Jacobson, Kenneth/0000-0001-8104-1493; Camaioni, Emidio/0000-0002-8529-0849 FU Intramural NIH HHS [Z01 DK031116-20] NR 11 TC 176 Z9 177 U1 0 U2 3 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD MAY PY 1998 VL 124 IS 1 BP 1 EP 3 DI 10.1038/sj.bjp.0701837 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ZM365 UT WOS:000073531200001 PM 9630335 ER PT J AU Peoples, RW Li, CY AF Peoples, RW Li, CY TI Inhibition of NMDA-gated ion channels by the P2 purinoceptor antagonists suramin and reactive blue 2 in mouse hippocampal neurones SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE NMDA; suramin; reactive blue 2; purinoceptor; glycine; hippocampus ID D-ASPARTATE RECEPTORS; MAMMALIAN NEURONS; SYNAPTIC TRANSMISSION; CULTURED NEURONS; RAT HIPPOCAMPUS; ATP RECEPTOR; CURRENTS; BLOCK; ZN2+; PHARMACOLOGY AB 1 The action of suramin and reactive blue 2 on N-methyl-D-aspartate (NMDA)-activated ion current was studied in mouse hippocampal neurones in culture by use of whole-cell patch-clamp recording. 2 Suramin and reactive blue 2 inhibited steady-state current activated by 25 mu M NMDA with IC50 values of 68 and 11 mu M, respectively. 3 Reactive blue 2 produced a gradual decline of NMDA-activated current to a steady-state, but this slow onset was not an indication of use-dependence, as it could be eliminated by exposure to reactive blue 2 before NMDA application In addition, NMDA-activated current recovered completely from inhibition by reactive blue 2 in the absence of agonist. 4 The slow onset of inhibition by reactive blue 2 was not apparently due to an action at an intracellular site, as inclusion of 250 mu M reactive blue 2 in the recording pipette did not alter inhibition by 25 mu M reactive blue 2 applied externally. 5 Reactive blue 2 and suramin inhibited NMDA-gated channels in a voltage-independent manner. 6 Reactive blue 2, 25 mu M, decreased the maximal response to NMDA from 1441 to 598 pA without changing its EC50. In contrast, 75 mu M suramin increased the EC50 for NMDA from 13 to 35 mu M, and decreased the maximal response to NMDA from 1822 to 1498 pA. Schild analysis of suramin inhibition of NMDA-activated current yielded a nonlinear plot. 7 Both agents decreased the maximal response to glycine without altering its EC50. 8 Suramin and reactive blue 2 appear to inhibit NMDA receptor-channels in a manner that is noncompetitive with respect to both NMDA and glycine. However, inhibition by suramin differed from that by reactive blue 2, in that suramin significantly increased the EC50 of NMDA. C1 NIAAA, Mol & Cellular Neurobiol Lab, NIH, Rockville, MD 20852 USA. RP Peoples, RW (reprint author), NIAAA, Mol & Cellular Neurobiol Lab, NIH, 12501 Washington Ave, Rockville, MD 20852 USA. NR 40 TC 30 Z9 30 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD MAY PY 1998 VL 124 IS 2 BP 400 EP 408 DI 10.1038/sj.bjp.0701842 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ZQ109 UT WOS:000073822600019 PM 9641559 ER EF