FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Saxena, SK Sirdeshmukh, R Ardelt, W Mikulski, SM Shogen, K Youle, RJ AF Saxena, SK Sirdeshmukh, R Ardelt, W Mikulski, SM Shogen, K Youle, RJ TI Entry into cells and selective degradation of tRNAs by a cytotoxic member of the RNase A family SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID P-30 PROTEIN; AMPHIBIAN RIBONUCLEASE; INHIBITION; SEQUENCE; EMBRYOS AB Onconase (P-30 protein), an enzyme in the ribonuclease A superfamily, exerts cytostatic, cytotoxic, and antiviral activity when added to the medium of growing mammalian cells. We find that onconase enters living mammalian cells and selectively cleaves tRNA with no detectable degradation of rRNA. The RNA specificity of onconase in vitro using reticulocyte lysate and purified RNA substrates indicates that proteins associated with rRNA protect the rRNA from the onconase ribonucleolytic action contributing to the cellular tRNA selectivity of onconase. The onconase-mediated tRNA degradation in cells appears to be accompanied by increased levels of tRNA turnover and induction of tRNA synthesis perhaps in response to the selective toxin-induced loss of tRNA. Degradation products of tRNA(3)(Lys) which acts as a primer for HIV-1 replication, were clearly detected in cells infected with HIV-1 and treated with sublethal concentrations of onconase. However, a new synthesis of tRNA(3)(Lys) also seemed to occur in these cells resulting in plateauing of the steady-state levels of this tRNA, We conclude that the degradation of tRNAs may be a primary factor in the cytotoxic activity of onconase. C1 NINCDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Alfacell Corp, Mol Biol Lab, Bloomfield, NJ 07003 USA. Ctr Cellular & Mol Biol, Hyderabad 500007, Andhra Pradesh, India. RP Youle, RJ (reprint author), NINCDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. OI Saxena, Shailendra K/0000-0003-2856-4185 NR 18 TC 86 Z9 90 U1 0 U2 3 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 APR 26 PY 2002 VL 277 IS 17 BP 15142 EP 15146 DI 10.1074/jbc.M108115200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 545EH UT WOS:000175203000100 PM 11839736 ER PT J AU Wilson, MA Ricci, AR Deroo, BJ Archer, TK AF Wilson, MA Ricci, AR Deroo, BJ Archer, TK TI The histone deacetylase inhibitor trichostatin A blocks progesterone receptor-mediated transactivation of the mouse mammary tumor virus promoter in vivo SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BREAST-CANCER CELLS; IN-VIVO; TRANSCRIPTION FACTORS; SODIUM-BUTYRATE; GENE-EXPRESSION; NUCLEOSOME STRUCTURE; H4 ACETYLATION; MMTV PROMOTER; CHROMATIN; COMPLEX AB Post-translational modifications of histones play an important role in modulating gene transcription within chromatin. We used the mouse mammary tumor virus (MMTV) promoter, which adopts an ordered nucleosomal structure, to investigate the impact of a specific inhibitor of histone deacetylase, trichostatin A (TSA), on progesterone receptor-activated transcription. TSA induced global histone hyperacetylation, and this effect occurred independently of the presence of hormone. Interestingly, chromatin immunoprecipitation analysis revealed no significant change in the level of acetylated histones associated with the MMTV promoter following high TSA treatment. In human breast cancer cells, in which the MMTV promoter adopts a constitutively "open" chromatin structure, treatment with TSA converted the MMTV promoter into a closed structure. Addition of hormone did not overcome this TSA-induced closure of the promoter chromatin. Furthermore, TSA treatment resulted in the eviction of the transcription factor nuclear factor-1 from the promoter and reduced progesterone receptor-induced transcription. Kinetic experiments revealed that a loss of chromatin-remodeling proteins was coincident with the decrease in MMTV transcriptional activity and the imposition of repressed chromatin architecture at the promoter. These results demonstrate that deacetylase inhibitor treatment at levels that induce global histone acetylation may leave specific regulatory regions relatively unaffected and that this treatment may lead to transcriptional inhibition by mechanisms that modify chromatin-remodeling proteins rather than by influencing histone acetylation of the local promoter chromatin structure. C1 NIEHS, Chromatin & Gene Express Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Western Ontario, Dept Obstet & Gynaecol, London, ON N6A 4L6, Canada. Univ Western Ontario, Dept Biochem, London, ON N6A 4L6, Canada. RP Archer, TK (reprint author), NIEHS, Chromatin & Gene Express Sect, Reprod & Dev Toxicol Lab, NIH, 111 Alexander Dr,MD E4-06,POB 12233, Res Triangle Pk, NC 27709 USA. OI Wilson, Melissa/0000-0002-5391-7838 NR 44 TC 41 Z9 43 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 26 PY 2002 VL 277 IS 17 BP 15171 EP 15181 DI 10.1074/jbc.M200349200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 545EH UT WOS:000175203000103 PM 11821430 ER PT J AU Dohke, Y Turner, RJ AF Dohke, Y Turner, RJ TI Evidence that the transmembrane biogenesis of aquaporin 1 is cotranslational in intact mammalian cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IN-VITRO TRANSLATION; ENDOPLASMIC-RETICULUM MEMBRANE; WATER CHANNELS; TOPOLOGY; PROTEIN; TRANSLOCATION; INSERTION; CHIP28; DETERMINANTS; INTEGRATION AB Most polytopic membrane proteins are believed to integrate into the membrane of the endoplasmic reticulum (ER) cotranslationally. However, recent studies with Xenopus oocytes and dog pancreatic microsomes have suggested that this is not the case for human aquaporin 1 (AQP1). These experiments indicate that membrane-spanning segments (MSSs) 2 and 4 of AQP1 do not integrate into the membrane cotranslationally so that this protein initially adopts a four MSS topology. A later maturation event involving a 180-degree rotation of MSS 3 from an N-lum/C-cyt to an N-cyt/C-lum orientation and the concomitant integration of MSSs 2 and 4 into the membrane results in the final six MSS topology. Here we examine the biogenesis of AQP1 in the human embryonic kidney cell line HEK-293T. To do this, we constructed an expression vector for a fusion protein consisting of the enhanced green fluorescent protein followed by an insertion site for AQP1 sequences and a C-terminal glycosylation tag. We then transiently transfected HEK-293T cells with this vector containing the AQP1 sequence truncated after each MSS. Glycosylation of the C-terminal tag was used to monitor its location relative to the ER lumen and consequently the membrane integration and orientation of successive MSSs. In contrast to previous studies our results indicate that AQP1 integrates into the ER membrane cotranslationally in intact HEK-293T cells. C1 NIDCR, Membrane Biol Sect, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Turner, RJ (reprint author), NIDCR, Membrane Biol Sect, Gene Therapy & Therapeut Branch, NIH, Bldg 10,Rm 1A01,10 Ctr Dr MSC 1190, Bethesda, MD 20892 USA. NR 23 TC 23 Z9 23 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 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 26 PY 2002 VL 277 IS 17 BP 15215 EP 15219 DI 10.1074/jbc.C100646200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 545EH UT WOS:000175203000108 PM 11884383 ER PT J AU Ramakrishnan, B Balaji, PV Qasba, PK AF Ramakrishnan, B Balaji, PV Qasba, PK TI Crystal structure of beta 1,4-galactosyltransferase complex with UDP-Gal reveals an oligosaccharide acceptor binding site SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE beta 1,4-galactosyltransferase; crystal structure; UDP-Gal binding; conformational changes; oligosaccharide binding site ID BETA-4-GALACTOSYLTRANSFERASE GENE FAMILY; ALPHA-LACTALBUMIN; CATALYTIC DOMAIN; GALACTOSYLTRANSFERASE; MECHANISM; GLYCOSYLTRANSFERASES; ASSOCIATION; GALACTOSE AB The crystal structure of the catalytic domain of bovine beta1,4-galactosyl-transferase (Gal-T1) co-crystallized with UDP-Gal and MnCl2 has been solved at 2.8 Angstrom resolution. The structure not only identifies galactose, the donor sugar binding site in Gal-T1, but also reveals an oligosaccharide acceptor binding site. The galactose moiety of UDP-Gal is found deep inside the catalytic pocket, interacting with Asp252, Gly292, Gly315, Glu317 and Asp318 residues. Compared to the native crystal structure reported earlier, the present UDP-Gal bound structure exhibits a large,, conformational change in residues 345-365 and a change in the side-chain orientation of Trp314. Thus, the binding of UDP-Gal induces a conformational change in Gal-T1, which not only creates the acceptor binding pocket for N-acetylglucosamine (GlcNAc) but also establishes the binding site for an extended sugar acceptor. The presence of a binding site that accommodates an extended sugar offers an explanation for the observation that an oligosaccharide with GlcNAc at the non-reducing end serves as a better acceptor than the monosaccharide, GlcNAc. Modeling studies using oligosaccharide acceptors indicate that a pentasaccharide, such as N-glycans with GlcNAc at their non-reducing ends, fits the site best. A sequence comparison of the human Gal-T family members indicates that although the binding site for the GlcNAc residue is highly conserved, the site that binds the extended sugar exhibits large variations. This is an indication that different Gal-T family members prefer different types of glycan acceptors with GlcNAc at their non-reducing ends. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 NCI, CCR, Lab Expt & Computat Biol, Struct Glycobiol Sect, Ft Detrick, MD 21702 USA. NCI, CCR, SAIC Frederick Inc,Intramural Res Support Program, Lab Expt & Computat Biol, Ft Detrick, MD 21702 USA. RP Qasba, PK (reprint author), NCI, CCR, Lab Expt & Computat Biol, Struct Glycobiol Sect, Ft Detrick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 36 TC 90 Z9 92 U1 1 U2 6 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD APR 26 PY 2002 VL 318 IS 2 BP 491 EP 502 DI 10.1016/S0022-2836(02)00020-7 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 549ZZ UT WOS:000175479300023 PM 12051854 ER PT J AU Barnes, DM Sykes, DB Miller, DS AF Barnes, DM Sykes, DB Miller, DS TI Mercuric chloride acting through Mg stimulates protein synthesis in Xenopus oocytes SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A LA English DT Article ID RAT ADIPOCYTES; INSULIN; TRANSPORT; CELLS; METALLOTHIONEIN; INDUCTION; MECHANISM; INVITRO; INVIVO; ZINC AB In Xenopus laevis oocytes, addition of HgCl2 (Hg) to the medium rapidly stimulated incorporation of [S-35]methionine (MET) into protein, increasing incorporation up to five-fold over control values. The action of inorganic mercury persisted after removal of Hg. Microinjection of HgCl, into oocytes maintained in buffer also increased MET incorporation. However, no such stimulation was found when Hg was microinjected into oocytes maintained under oil, suggesting that Hg action was dependent on a cell-medium interaction. Removing medium Mg2+ decreased insulin- and Hg-stimulated methionine incorporation. Increasing medium Mg2+, from 1 mM to 10 mM increased Hg-stimulated methionine incorporation twofold. Hypotonic swelling of oocytes stimulated hexose transport but inhibited protein synthesis. Together these data indicate that inorganic mercury activates translation in the oocyte through an Mg-dependent mechanism, possibly increased Mg2+ influx. C1 Univ Wisconsin, Dept Anim Sci, Madison, WI 53706 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Barnes, DM (reprint author), Univ Wisconsin, Dept Anim Sci, Madison, WI 53706 USA. NR 29 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1528-7394 J9 J TOXICOL ENV HEAL A JI J. TOXICOL. ENV. HEALTH PT A PD APR 26 PY 2002 VL 65 IS 8 BP 617 EP 629 DI 10.1080/152873902317349763 PG 13 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 545DQ UT WOS:000175201300004 PM 11991634 ER PT J AU Sundstrom, JM Hall, FS Stellar, JR Waugh, EJ AF Sundstrom, JM Hall, FS Stellar, JR Waugh, EJ TI Effects of isolation-rearing on intracranial self-stimulation reward of the lateral hypothalamus: Baseline assessment and drug challenges SO LIFE SCIENCES LA English DT Article DE isolation-rearing; reward; SCH-23390; raclopride; dopamine antagonists; MK-801; NMDA ID ACOUSTIC STARTLE RESPONSE; INDUCED ANHEDONIA MODEL; VENTRAL TEGMENTAL AREA; PREPULSE INHIBITION; NUCLEUS-ACCUMBENS; ADULT RATS; SOCIAL DEPRIVATION; LOCOMOTOR-ACTIVITY; BRAIN-STIMULATION; DOPAMINE AB There is evidence that isolation rearing produces down-regulation of the dopamine D2 receptor. Therefore, isolation rearing should also modify the effects of D2 antagonists on intracranial self-stimulation (ICSS) reward. This study investigated the effect of isolation rearing on ICSS reward, and modulation of that reward by SCH23390, Raclopride and MK-801. Sprague-Dawley rats were reared alone (isolates) or in pairs from day 21 postnatal to day 75 postnatal. At this time. all rats were implanted with monopolar stimulating electrodes in the lateral hypothalamus. The ICSS rate-frequency curve-shift method was used to assess reward and operant motor function at baseline and after administration of SCH-23390 (D1 antagonist: 0.02, 0.06, 0.2 mg/kg), Raclopride (D2 antagonist: 0.01. 0.025, 0.06 mg/kg), and MK-801 (non-competitive NMDA receptor antagonist: 0.1, 0.2 mk/kg). Isolation-reared rats displayed similar measures of both basal reward and motor function when compared to socially reared controls. Isolation-reared rats were subsensitive to the reward decreasing effects of Raclopride, Socially reared rats were observed to have more variant baseline reward measures, and could be divided into distinctly different groups with different basal reward function. Isolation-rearing down-regulates D2 function but does not affect basal reward function, but some unknown factor in the social rearing environment did have a substantial effect on basal reward function. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NIDA, Mol Neurobiol Branch, IRP, Baltimore, MD 21224 USA. Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. RP Hall, FS (reprint author), NIDA, Mol Neurobiol Branch, IRP, POB 5180,5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 NR 37 TC 9 Z9 9 U1 0 U2 2 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 APR 26 PY 2002 VL 70 IS 23 BP 2799 EP 2810 AR PII S0024-3205(02)01509-6 DI 10.1016/S0024-3205(02)01509-6 PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 564EB UT WOS:000176301100008 PM 12269384 ER PT J AU Hinnebusch, BJ Rudolph, AE Cherepanov, P Dixon, JE Schwan, TG Forsberg, A AF Hinnebusch, BJ Rudolph, AE Cherepanov, P Dixon, JE Schwan, TG Forsberg, A TI Role of Yersinia murine toxin in survival of Yersinia pestis in the midgut of the flea vector SO SCIENCE LA English DT Article ID PHOSPHOLIPID SYNTHASES; ESCHERICHIA-COLI; VIRULENCE; IDENTIFICATION; MUTAGENESIS; SUPERFAMILY; PLAGUE; FAMILY; MEMBER; LOCUS AB Transmission by flea bite is a relatively recent adaptation that distinguishes Yersinia pestis, the plague bacillus, from closely related enteric bacteria. Here, a plasmid-encoded phospholipase D (PLD), previously characterized as Yersinia murine toxin (Ymt), was shown to be required for survival of Y, pestis in the midgut of its principal vector, the rat flea Xenopsylla cheopis. Intracellular PLD activity appeared to protect Y. pestis from a cytotoxic digestion product of blood plasma in the flea gut. By enabling colonization of the flea midgut, acquisition of this PLD may have precipitated the transition of Y. pestis to obligate arthropod-borne transmission. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Univ Michigan, Sch Med, Dept Biol Chem, Ann Arbor, MI 48109 USA. Umea Univ, Dept Mol Biol, S-90187 Umea, Sweden. Swedish Def Res Agcy, Dept Med Countermeasures, S-90182 Umea, Sweden. RP Hinnebusch, BJ (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. NR 27 TC 186 Z9 200 U1 1 U2 25 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 APR 26 PY 2002 VL 296 IS 5568 BP 733 EP 735 DI 10.1126/science.1069972 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 546PD UT WOS:000175281700054 PM 11976454 ER PT J AU Dahmoush, L Hijazi, Y Barnes, E Stetler-Stevenson, M Abati, A AF Dahmoush, L Hijazi, Y Barnes, E Stetler-Stevenson, M Abati, A TI Adult T-cell leukemia/lymphoma - A cytopathologic, immunocytochemical, and flow cytometric study SO CANCER CYTOPATHOLOGY LA English DT Article; Proceedings Paper CT 90th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 03-09, 2001 CL ATLANTA, GEORGIA SP US & Canadian Acad Pathol DE adult T-cell leukemia/lymphoma (ATLL); cytology; immunocytochemistry; flow cytometry ID FINE-NEEDLE ASPIRATION; EUROPEAN-AMERICAN CLASSIFICATION; POLYMERASE-CHAIN-REACTION; NON-HODGKINS-LYMPHOMAS; RECURRENT LYMPHOMA; DIAGNOSIS; CYTOLOGY; BIOPSY; SUBCLASSIFICATION; LYMPHADENOPATHY AB BACKGROUND. Adult T-cell leukemia/lymphoma (ATLL) is a postthymic lympho-proliferative neoplasm of T cells caused by human T-cell lymphotropic virus (HTLV-1). Most cases are found in Japan, the Caribbean basin, and West Africa. DESIGN. To identify diagnostic parameters for cytology in this neoplasm, the authors under-took a retrospective review of all ATLL samples from 1990 to 2000. RESULTS. One hundred fourteen samples from 34 patients with the diagnosis of ATLL were reviewed: 80 cerebrospinal fluids, 7 pleural effusions, 4 bronchoalveolar lavages, 2 peritoneal effusions as well as fine-needle aspirations of 15 lymph nodes, 4 subcutaneous lesions, and 2 breast nodules. Twenty-one patients were women and 13 were men, with an age range of 30 to 71 years. Morphologically, 0 specimens were characterized by the presence of a polymorphous population of lymphocytes ranging from small bland-appearing lymphocytes to large atypical ones with bizarre, multilobulated nuclei (flower-like or clover leaf cells) with coarse chromatin and prominent nucleoli. The cytoplasm was deeply basophilic with occasional vacuoles. Immunocytochemistry was performed on 17 specimens from 14 patients. In all cases tested, tumor cells were immunoreactive for CD3, CD4, CD5, and CD25 and were nonimmunoreactive for CD7 and CD8. Flow cytometry was performed on 12 specimens from 9 patients. The tumor cells in all cases tested were positive for CD2, CD3, CD4, CD5, and CD25 and were negative for CD7. CONCLUSIONS. Despite the polymorphous nature of ATLL, diagnosis can be established by close attention to nuclear cytologic features in conjunction with ancillary studies such as immunocytochemistry and/or flow cytometry. C1 NCI, NIH, Sect Cytopathol, Bethesda, MD 20892 USA. Amer Med Labs, Chantilly, VA USA. NCI, NIH, Pathol Lab, Bethesda, MD 20892 USA. NCI, NIH, Sect Flow Cytometry, Bethesda, MD 20892 USA. RP Abati, A (reprint author), NCI, NIH, Sect Cytopathol, 10 Ctr Dr,Bldg 10,Room 2A19, Bethesda, MD 20892 USA. NR 38 TC 42 Z9 44 U1 1 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD APR 25 PY 2002 VL 96 IS 2 BP 110 EP 116 DI 10.1002/cncr.10480 PG 7 WC Oncology; Pathology SC Oncology; Pathology GA 542YD UT WOS:000175072500009 PM 11954028 ER PT J AU Olshan, AF Watson, MA Weissler, MC Bell, DA AF Olshan, AF Watson, MA Weissler, MC Bell, DA TI XRCC1 polymorphisms and head and neck cancer SO CANCER LETTERS LA English DT Article DE head and neck neoplasms; oral cancer; larynx cancer; genetic susceptibility; DNA repair; tobacco ID REPAIR GENE XRCC1; DNA-REPAIR; LUNG-CANCER; RISK; POLYMERASE; CARCINOMA; FREQUENCY; DAMAGE AB Inter-individual differences in DNA repair capacity have been demonstrated using a variety of phenotypic assays, including reduced repair among patients with squamous cell carcinoma of the head and neck (SCCHN). The XRCC1 DNA repair gene may facilitate DNA strand break and base excision repair. A recent case-control study of SCCHN reported associations with two polymorphisms of the XRM including the exon 6, 194Arg/Arg genotype and the exon 10, 399 Gln/Gln genotype. We conducted an analysis of these two XRM polymorphisms using data from a case-control study of SCCHN. Among white subjects, we found a weak elevation in risk associated with the Argl94Trp polymorphism [odds ratio (OR) = 1-3 95% confidence interval (0) = 0.6 - 2.9] and a decreased risk for the Arg399Gln polymorphism (OR = 0.6; CI = 0.4 - 1.1). We found a markedly decreased odds ratio for the Gln/Gln genotype among whites (OR = 0.1; CI = 0.04 - 0.6) and blacks (OR = 0.01; CI = 0.0004 - 0.3). We also found a suggestion of an interaction between the Argl94Trp and Arg399Gln polymorphisms and tobacco use. Additional epidemiologic and functional studies are needed to resolve the importance of these XRCCl polymorphisms in SCCHN. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Med, Dept Surg, Div ENT Head & Neck Surg, Chapel Hill, NC 27599 USA. Natl Inst Environm Hlth Sci, Lab Computat Biol & Risk Assessment, Res Triangle Pk, NC USA. RP Olshan, AF (reprint author), Univ N Carolina, Dept Epidemiol, CB 7435, Chapel Hill, NC 27599 USA. FU NCI NIH HHS [CA61188] NR 19 TC 83 Z9 87 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD APR 25 PY 2002 VL 178 IS 2 BP 181 EP 186 AR PII S0304-3835(01)00822-9 DI 10.1016/S0304-3835(01)00822-9 PG 6 WC Oncology SC Oncology GA 551VG UT WOS:000175582600009 PM 11867203 ER PT J AU Gawel, D Jonczyk, P Bialoskorska, M Schaaper, RM Fijalkowska, IJ AF Gawel, D Jonczyk, P Bialoskorska, M Schaaper, RM Fijalkowska, IJ TI Asymmetry of frameshift mutagenesis during leading and lagging-strand replication in Escherichia coli SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE frameshift mutagenesis; leading and lagging-strand replication; DNA replication fidelity; Escherichia coli ID POLYMERASE-III HOLOENZYME; SOS MUTATOR ACTIVITY; DNA-REPLICATION; MISMATCH REPAIR; IN-VITRO; FIDELITY; ERRORS; MUTATIONS; SPECIFICITY; CHROMOSOME AB Mutations in DNA, including frameshifts, may arise during DNA replication as a result of mistakes made by the DNA polymerase in copying the DNA template strands. In our efforts to better understand the factors that contribute to the accuracy of DNA replication, we have investigated whether frameshift mutations on the Escherichia coli chromosome occur differentially within the leading and lagging-strands of replication. The experimental system involves measurement of the reversion frequency for several defined lac frameshift alleles in pairs of strains in which the lac target is oriented in the two possible directions relative to the origin of chromosomal replication. Within these pairs any defined lac sequence will be subject to leading-strand replication in one orientation and to lagging-strand replication in the other. Fidelity differences between the two modes of replication can be observed as a differential lac reversion between the two strains. Our results, obtained with a series of lac alleles in a mismatch-repair-defective background, indicate that for at least some of the alleles there is indeed a difference in the fidelity of replication between the two modes of replication. (C) 2002 Elsevier Science B.V. All tights reserved. C1 Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland. NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Fijalkowska, IJ (reprint author), Polish Acad Sci, Inst Biochem & Biophys, Pawinskiego 5A, PL-02106 Warsaw, Poland. RI Fijalkowska, Iwona/I-7796-2016 NR 33 TC 24 Z9 24 U1 0 U2 3 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 APR 25 PY 2002 VL 501 IS 1-2 BP 129 EP 136 AR PII S0027-5107(02)00020-9 DI 10.1016/S0027-5107(02)00020-9 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 549QE UT WOS:000175455100013 PM 11934444 ER PT J AU Pittenger, C Huang, YY Paletzki, RF Bourtchouladze, R Scanlin, H Vronskaya, S Kandel, ER AF Pittenger, C Huang, YY Paletzki, RF Bourtchouladze, R Scanlin, H Vronskaya, S Kandel, ER TI Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory SO NEURON LA English DT Article ID LONG-TERM-MEMORY; ELEMENT-BINDING PROTEIN; MEDIATED GENE-EXPRESSION; LATE-PHASE; SYNAPTIC PLASTICITY; NUCLEAR TRANSLOCATION; TARGETED MUTATION; UP-REGULATION; MAP KINASE; POTENTIATION AB CREB is critical for long-lasting synaptic and behavioral plasticity in invertebrates. Its role in the mammalian hippocampus is less clear. We have interfered with CREB family transcription factors in region CA1 of the dorsal hippocampus. This impairs learning in the Morris water maze, which specifically requires the dorsal hippocampus, but not context conditioning, which does not. The deficit is specific to long-term memory, as shown in an object recognition task. Several forms of late-phase LTP are normal, but forskolin-induced and dopamine-regulated potentiation are disrupted. These experiments represent the first targeting of the dorsal hippocampus in genetically modified mice and confirm a role for CREB in hippocampus-dependent learning. Nevertheless, they suggest that some experimental forms of plasticity bypass the requirement for CREB. C1 Columbia Univ Coll Phys & Surg, Ctr Neurobiol & Behav, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Howard Hughes Med Inst, New York, NY 10032 USA. NINCDS, Mol Plast Sect, NIH, Bethesda, MD 20892 USA. RP Kandel, ER (reprint author), Columbia Univ Coll Phys & Surg, Ctr Neurobiol & Behav, 1051 Riverside Dr, New York, NY 10032 USA. RI Pittenger, Christopher/G-8402-2012 FU NIMH NIH HHS [MH 12956-01] NR 65 TC 309 Z9 321 U1 1 U2 13 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD APR 25 PY 2002 VL 34 IS 3 BP 447 EP 462 DI 10.1016/S0896-6273(02)00684-0 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 545JW UT WOS:000175214700015 PM 11988175 ER PT J AU Frey, SE Couch, RB Tacket, CO Treanor, JJ Wolff, M Newman, FK Atmar, RL Edelman, R Nolan, CM Belshe, RB AF Frey, SE Couch, RB Tacket, CO Treanor, JJ Wolff, M Newman, FK Atmar, RL Edelman, R Nolan, CM Belshe, RB CA Natl Inst Allergy Infect Dis Small TI Clinical responses to undiluted and diluted smallpox vaccine SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID VIRUS AB Background: To evaluate the potential to increase the supply of smallpox vaccine (vaccinia virus), we compared the response to vaccination with 10(8.1), 10(7.2), and 10(7.0) plaque-forming units (pfu) of vaccinia virus per milliliter. Methods: In this randomized, single-blind, prospective study, 680 adults who had not been previously immunized were inoculated intradermally with undiluted vaccine (mean titer, 10(8.1) pfu per milliliter), a 1:5 dilution, or a 1:10 dilution of vaccinia virus with use of a bifurcated needle, and the site was covered with a semipermeable dressing. Subjects were monitored for vesicle formation (an indicator of the success of vaccination) and adverse events for 56 days after immunization. Results: Success rates did not differ significantly among the groups and ranged from 97.1 to 99.1 percent after the first vaccination. Both the undiluted and diluted vaccines were reactogenic. In addition to the formation of pustules, common adverse events included the formation of satellite lesions, regional lymphadenopathy, fever, headache, nausea, muscle aches, fatigue, and chills consistent with the presence of an acute viral illness. Generalized and localized rashes, including two cases of erythema multiforme, were also observed. Conclusions: When given by a bifurcated needle, vaccinia virus vaccine can be diluted to a titer as low as 10(7.0) pfu per milliliter (approximately 10,000 pfu per dose) and induce local viral replication and vesicle formation in more than 97 percent of persons. C1 St Louis Univ, Hlth Sci Ctr, Sch Med,Dept Med,Div Infect Dis & Immunol, Natl Inst Allergy & Infect Dis,Vaccine & Treatmen, St Louis, MO 63110 USA. Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. Univ Rochester, Sch Med & Dent, Rochester, NY USA. Emmes Corp, Rockville, MD USA. RP Belshe, RB (reprint author), St Louis Univ, Hlth Sci Ctr, Sch Med,Dept Med,Div Infect Dis & Immunol, Natl Inst Allergy & Infect Dis,Vaccine & Treatmen, 3635 Vista Ave,FDT-8N, St Louis, MO 63110 USA. FU NCRR NIH HHS [M01-RR00188]; NIAID NIH HHS [N01-AI-65298, N01-AI-15448, N01-AI-45150, N01-AI-85342, N01-AI-45257, AI-45248] NR 16 TC 183 Z9 185 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 25 PY 2002 VL 346 IS 17 BP 1265 EP 1274 DI 10.1056/NEJMoa020534 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 544GX UT WOS:000175150800002 PM 11923490 ER PT J AU Frey, SE Newman, FK Cruz, J Shelton, WB Tennant, JM Polach, T Rothman, AL Kennedy, JS Wolff, M Belshe, RB Ennis, FA AF Frey, SE Newman, FK Cruz, J Shelton, WB Tennant, JM Polach, T Rothman, AL Kennedy, JS Wolff, M Belshe, RB Ennis, FA TI Dose-related effects of smallpox vaccine SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID VIRUS; BIOTERRORISM; RESPONSES; LYMPHOCYTES; MEMORY; ADULTS AB Background: We conducted a double-blind, randomized trial of three dilutions of vaccinia virus vaccine in previously unimmunized adults in order to assess the clinical success rates, humoral responses, and virus-specific activity of cytotoxic T cells and interferon-gamma-producing T cells. Methods: Sixty healthy adults were inoculated intradermally by bifurcated needle with undiluted vaccine (dose, 10(7.8))plaque-forming units [pfu] per milliliter), a 1:10 dilution (dose, 10(6.5) pfu per milliliter), or a 1:100 dilution (dose, 10(5.0) pfu per milliliter); there were 20 subjects in each group. The subjects were monitored with respect to vesicle formation (an indicator of successful vaccination), the viral titer at the time of peak lesion formation, antiviral antibodies, and cellular immune responses. Results: A vaccinia vesicle developed in 19 of the 20 subjects who received undiluted vaccine (95 percent), 14 of the 20 who received the 1:10 dilution (70 percent), and 3 of the 20 who received the 1:100 dilution (15 percent). One month after vaccination, 34 of 36 subjects with vesicles had antibody responses, as compared with only 1 of 24 subjects without clinical evidence of vaccinia virus replication. Vigorous cytotoxic T-cell and interferon-gamma responses occurred in 94 percent of subjects with vesicles, and a cytotoxic T-cell response occurred in only one subject without a vesicle. Conclusions: The vaccinia virus vaccine (which was produced in 1982 or earlier) still has substantial potency when administered by a bifurcated needle to previously unvaccinated adults. Diluting the vaccine reduces the rate of successful vaccination. The development of vesicular skin lesions after vaccination correlates with the induction of the antibody and T-cell responses that are considered essential for clearing vaccinia virus infections. C1 St Louis Univ, Hlth Sci Ctr, Sch Med,Dept Med,Div Infect Dis & Immunol, Natl Inst Allergy & Infect Dis,Vaccine & Treatmen, St Louis, MO 63110 USA. Univ Massachusetts, Sch Med, Ctr Infect Dis & Vaccine Res, Worcester, MA USA. Emmes Corp, Rockville, MD USA. RP Frey, SE (reprint author), St Louis Univ, Hlth Sci Ctr, Sch Med,Dept Med,Div Infect Dis & Immunol, Natl Inst Allergy & Infect Dis,Vaccine & Treatmen, 3635 Vista Ave,FDT-8N, St Louis, MO 63110 USA. FU NIAID NIH HHS [N01-AI-45250] NR 22 TC 148 Z9 149 U1 0 U2 6 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 25 PY 2002 VL 346 IS 17 BP 1275 EP 1280 DI 10.1056/NEJMoa013431 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 544GX UT WOS:000175150800003 PM 11923489 ER PT J AU Breman, JG Henderson, DA AF Breman, JG Henderson, DA TI Current concepts - Diagnosis and management of smallpox SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID VIRUS; ORTHOPOXVIRUS; CIDOFOVIR; PCR C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD USA. RP Breman, JG (reprint author), NIH, Fogarty Int Ctr, 16 Ctr Dr,MSC 6705,Bldg 16,Rm 214, Bethesda, MD 20892 USA. NR 49 TC 191 Z9 197 U1 0 U2 10 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 25 PY 2002 VL 346 IS 17 BP 1300 EP 1308 DI 10.1056/NEJMra020025 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 544GX UT WOS:000175150800008 PM 11923491 ER PT J AU Fauci, AS AF Fauci, AS TI Smallpox vaccination policy - The need for dialogue. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NIAID, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 14 TC 57 Z9 59 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 25 PY 2002 VL 346 IS 17 BP 1319 EP 1320 DI 10.1056/NEJM200204253461711 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 544GX UT WOS:000175150800010 PM 11923487 ER PT J AU Wexler, P AF Wexler, P TI Introduction to special issue (part II) on digital information and tools SO TOXICOLOGY LA English DT Editorial Material C1 Natl Lib Med, NIH, Toxicol & Environm Hlth Informat Program, Bethesda, MD 20894 USA. RP Wexler, P (reprint author), Natl Lib Med, NIH, Toxicol & Environm Hlth Informat Program, 8600 Rockville Pike, Bethesda, MD 20894 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD APR 25 PY 2002 VL 173 IS 1-2 BP 1 EP 1 AR PII S0300-483X(02)00018-5 DI 10.1016/S0300-483X(02)00018-5 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 551UX UT WOS:000175581400001 ER PT J AU Junghans, TB Sevin, IF Ionin, B Seifried, H AF Junghans, TB Sevin, IF Ionin, B Seifried, H TI Cancer information resources: digital and online sources SO TOXICOLOGY LA English DT Article DE cancer; online; digital ID TOXICOLOGY INFORMATION AB The Internet is becoming an increasingly important source of information on cancer. This article highlights major sites of credible information on cancer and describes the types of information each of these sites contains. Large directories that help point the visitor to additional cancer-related sites are described, as are searchable databases of information on cancer as a disease, its diagnosis, and treatment. Sources of information on chemical carcinogens, mechanistic studies, and applied cancer toxicology are also described. These Internet sources of cancer information address the needs of toxicologists, environmental and occupational health scientists, cancer researchers and clinicians, government regulators, the public, and cancer survivors and their caregivers. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Tech Resources Int Inc, Bethesda, MD 20817 USA. Walter Reed Army Inst Res, Dept Bacterial Dis, Silver Spring, MD 20910 USA. NCI, Nutr Sci Res Grp, Rockville, MD 20852 USA. RP Junghans, TB (reprint author), Tech Resources Int Inc, 6500 Rock Spring Dr,Suite 650, Bethesda, MD 20817 USA. FU NCI NIH HHS [N02-CB-07007] NR 17 TC 4 Z9 4 U1 0 U2 2 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 APR 25 PY 2002 VL 173 IS 1-2 BP 13 EP 34 AR PII S0300-483(02)00020-3 DI 10.1016/S0300-483X(02)00020-3 PG 22 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 551UX UT WOS:000175581400003 PM 11955682 ER PT J AU Portis, JL AF Portis, JL TI Perspectives on the role of endogenous human retroviruses in autoimmune diseases SO VIROLOGY LA English DT Review ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; VIRAL ENVELOPE GLYCOPROTEIN; DEPENDENT DIABETES-MELLITUS; ZEALAND BLACK MICE; MULTIPLE-SCLEROSIS; GENE-EXPRESSION; ANTIBODY REACTIVITY; AUTO-IMMUNITY; VIRUS; SUPERANTIGEN C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Portis, JL (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, 903 S 4th St, Hamilton, MT 59840 USA. EM jportis@nih.gov NR 44 TC 29 Z9 31 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD APR 25 PY 2002 VL 296 IS 1 BP 1 EP 5 DI 10.1066/viro.2002.1388 PG 5 WC Virology SC Virology GA 563FC UT WOS:000176244700001 PM 12036312 ER PT J AU Bharucha, DC Zhou, MS Nekhai, S Brady, JN Shukla, RR Kumar, A AF Bharucha, DC Zhou, MS Nekhai, S Brady, JN Shukla, RR Kumar, A TI A protein phosphatase from human T cells augments Tat transactivation of the human immunodeficiency virus type 1 long-terminal repeat SO VIROLOGY LA English DT Article DE HIV-1; Tat; RNA polymerase II; CTD; protein phosphatase 1; kinase ID RNA-POLYMERASE-II; HIGH-AFFINITY BINDING; HIV-1 TAT; P-TEFB; TRANSCRIPTION FACTOR; DOMAIN PHOSPHATASE; CYCLIN T1; IN-VITRO; PHOSPHORYLATION; ELONGATION AB HIV-1 Tat protein regulates viral gene expression by modulating the activity and association of cellular transcription factors with RNA polymerase II (RNAPII). Possible mechanisms include Tat-associated protein kinase(s) and phosphatase(s) that regulate phosphorylation of the C-terminal domain (CTD) of the large subunit of RNAPII Hypophosphorylated RNAPII (RNAPIIa) is recruited to promoters during formation of a preinitiation complex, whereas hyperphosphorylated RNAPII (RNAPIIo) is associated with the elongation complex. The role of phosphatases in maintaining the equilibrium between the two phosphorylated states of RNAPII, which is required for sustained transcriptional activation from the HIV-1 LTR, is not clear. In this study, we discuss the properties of a Tat-associated CTD phosphatase fractionated from Jurkat T cells. The Tat-associated protein phosphatase (TAPP) is related to the serine/threonine, type 1, protein phosphatase (PP1) family. TAPP dephosphorylates the hyperphosphorylated form of recombinant CTD specifically on serine 2, and augments Tat-mediated transcriptional transactivation of HIV-1 LTR in an in vitro transcription reaction. TAPP is associated with the transcription complex during the early initiation steps, and its release from the HIV-1 promoter coincides with the Tat-specific activation of CDK9. The results suggest a unique role of the Tat-associated phosphatase which regulates viral transcription by target-specific dephosphorylation of RNAPIl during the early stages of elongation. (C) 2002 Elsevier Science (USA). C1 George Washington Univ, Dept Biochem & Mol Biol, Med Ctr, Washington, DC 20037 USA. George Washington Univ, Med Ctr, Grad Program Mol & Cellular Oncol, Washington, DC 20037 USA. NCI, Virus Tumor Biol Sect, Ctr Canc Res, Bethesda, MD 20892 USA. RP George Washington Univ, Dept Biochem & Mol Biol, Med Ctr, 2300 I St NW, Washington, DC 20037 USA. EM akumar@gwu.edu FU NIAID NIH HHS [AI42491] NR 45 TC 19 Z9 20 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD APR 25 PY 2002 VL 296 IS 1 BP 6 EP 16 DI 10.1006/viro.2002.1438 PG 11 WC Virology SC Virology GA 563FC UT WOS:000176244700002 PM 12036313 ER PT J AU Campos-Olivas, R Aziz, R Helms, GL Evans, JNS Gronenborn, AM AF Campos-Olivas, R Aziz, R Helms, GL Evans, JNS Gronenborn, AM TI Placement of F-19 into the center of GB1: effects on structure and stability SO FEBS LETTERS LA English DT Article DE immunoglobulin G binding domain B1 of; streptococcal protein G; fluorine substitution; protein structure; nuclear magnetic resonance ID STREPTOCOCCAL PROTEIN-G; CONFORMATIONAL-CHANGES; NMR; SUBSTITUTION; DYNAMICS AB A structural and thermodynamic characterization of 5F-Trp-substituted immunoglobulin binding domain B1 of streptococcal protein G (GB1) was carried out by nuclear magnetic resonance and circular dichroism spectroscopy. A single fluorine reporter atom was positioned at the center of the three-dimensional structure, uniquely poised to be exploited for studying interior properties of this protein. We demonstrate that the introduction of 5F-Trp does not affect the global and local architecture of GB1 and has no influence on the thermodynamic stability. The favorable properties of the fluorinated GB1 render this molecule a desirable model system for the development of spectroscopic methodology and theoretical calculations. (C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Washington State Univ, Ctr NMR Spect, Pullman, WA 99164 USA. Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. RP Gronenborn, AM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 130, Bethesda, MD 20892 USA. RI Campos-Olivas, Ramon/L-9173-2014 OI Campos-Olivas, Ramon/0000-0002-5743-2221 FU NCRR NIH HHS [RR0631401, RR12948]; NIGMS NIH HHS [R01 GM43215] NR 14 TC 16 Z9 16 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD APR 24 PY 2002 VL 517 IS 1-3 BP 55 EP 60 AR PII S0014-5793(02)02577-2 DI 10.1016/S0014-5793(02)02577-2 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 545PE UT WOS:000175225600012 PM 12062409 ER PT J AU Solomon, D Davey, D Kurman, R Moriary, A O'Connor, D Prey, M Raab, S Sherman, M Wilbur, D Wright, T Young, N AF Solomon, D Davey, D Kurman, R Moriary, A O'Connor, D Prey, M Raab, S Sherman, M Wilbur, D Wright, T Young, N TI The 2001 Bethesda System - Terminology for reporting results of cervical cytology SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID INTERLABORATORY COMPARISON PROGRAM; CERVICOVAGINAL CYTOLOGY; ADENOCARCINOMA INSITU; SPECIMEN ADEQUACY; ENDOMETRIAL CELLS; UTERINE CERVIX; FOLLOW-UP; FEATURES; LESIONS AB Objectives The Bethesda 2001 Workshop was convened to evaluate and update the 1991 Bethesda System terminology for reporting the results of cervical cytology. A primary objective was to develop a new approach to broaden participation in the consensus process. Participants Forum groups composed of 6 to 10 individuals were responsible for developing recommendations for discussion at the workshop. Each forum group included at least 1 cytopathologist, cytotechnologist, clinician, and international representative to ensure a broad range of views and interests. More than 400 cytopathologists, cytotechnologists, histopathologists, family practitioners, gynecologists, public health physicians, epidemiologists, patient advocates, and attorneys participated in the workshop, which was convened by the National Cancer Institute and cosponsored by 44 professional societies. More than 20 countries were represented. Evidence Literature review, expert opinion, and input from an Internet bulletin board were all considered in developing recommendations. The strength of evidence of the scientific data was considered of paramount importance. Consensus Process Bethesda 2001 was a year-long iterative review process. An Internet bulletin board was used for discussion of issues and drafts of recommendations. More than 1000 comments were posted to the bulletin board over the course of 6 months. The Bethesda Workshop, held April 30-May 2, 2001, was open to the public. Postworkshop recommendations were posted on the bulletin board for a last round of critical review prior to finalizing the terminology. Conclusions Bethesda 2001 was developed with broad participation in the consensus process. The 2001 Bethesda System terminology reflects important advances in biological understanding of cervical neoplasia and cervical screening technology. C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Univ Kentucky, Med Ctr, Dept Pathol & Lab Med, Lexington, KY USA. Johns Hopkins Univ Hosp, Dept Gynecol & Obstet, Baltimore, MD 21287 USA. Johns Hopkins Univ Hosp, Dept Pathol, Baltimore, MD 21287 USA. AmeriPath Indiana, Indianapolis, IN USA. Clin Pathol Associates, Louisville, KY USA. Quest Diagnost Inc, St Louis, MO USA. Allegheny Hosp, Dept Pathol, Pittsburgh, PA USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Columbia Univ, Dept Pathol, New York, NY USA. Fox Chase Canc Ctr, Dept Pathol, Philadelphia, PA 19111 USA. RP Solomon, D (reprint author), EPN Room 2130,6130 Execut Blvd, Bethesda, MD 20892 USA. RI Manzotti, Grazia/C-5985-2008 NR 28 TC 1589 Z9 1731 U1 6 U2 24 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 APR 24 PY 2002 VL 287 IS 16 BP 2114 EP 2119 DI 10.1001/jama.287.16.2114 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 542ZK UT WOS:000175075700029 PM 11966386 ER PT J AU Andersen, PS Schuck, P Sundberg, EJ Geisler, C Karjalainen, K Mariuzza, RA AF Andersen, PS Schuck, P Sundberg, EJ Geisler, C Karjalainen, K Mariuzza, RA TI Quantifying the energetics of cooperativity in a ternary protein complex SO BIOCHEMISTRY LA English DT Article ID RECEPTOR-BETA-CHAIN; T-CELL ACTIVATION; CLASS-II; PEPTIDE-MHC; SACCHAROMYCES-CEREVISIAE; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; HOT-SPOTS; BINDING; SUPERANTIGEN AB The formation of complexes involving more than two proteins is critical for many cellular processes, including signal transduction, transcriptional control, and cytoskeleton remodeling. Energetically, these interactions cannot always be described simply by the additive effects of the individual binary reactions that make up the overall complex. This is due, in large part, to cooperative interactions between separate protein domains. Thus, a full understanding of multiprotein complexes requires the quantitative analysis of cooperativity. We have used surface plasmon resonance techniques and mathematical modeling to describe the energetics of cooperativity in a trimolecular protein complex. As a model system for quantifying cooperativity, we studied the ternary complex formed by the simultaneous interaction of a superantigen with major histocompatibility complex and T cell receptor, for which a structural model is available. This system exhibits positive and negative cooperativity, as well as augmentation of the temperature dependence of binding kinetics upon the cooperative interaction of individual protein components in the complex. Our experimental and theoretical analysis may be applicable to other systems involving cooperativity. C1 Univ Maryland, Inst Biotechnol, WM Keck Lab Struct Biol, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. Univ Copenhagen, Inst Med Microbiol & Immunol, DK-2200 Copenhagen N, Denmark. NIH, Div Bioengn & Phys Sci, ORS, Bethesda, MD 20892 USA. Basel Inst Immunol, CH-4005 Basel, Switzerland. RP Mariuzza, RA (reprint author), Univ Maryland, Inst Biotechnol, WM Keck Lab Struct Biol, Ctr Adv Res Biotechnol, 9600 Gudelsky Dr, Rockville, MD 20850 USA. RI Karjalainen, Klaus/A-2206-2011; OI Schuck, Peter/0000-0002-8859-6966 NR 41 TC 18 Z9 18 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD APR 23 PY 2002 VL 41 IS 16 BP 5177 EP 5184 DI 10.1021/bi0200209 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 545NG UT WOS:000175223400013 PM 11955066 ER PT J AU Bella, JN Palmieri, V Roman, MJ Liu, JE Welty, TK Lee, ET Fabsitz, RR Howard, BV Devereux, RB AF Bella, JN Palmieri, V Roman, MJ Liu, JE Welty, TK Lee, ET Fabsitz, RR Howard, BV Devereux, RB TI Mitral ratio of peak early to late diastolic filling velocity as a predictor of mortality in middle-aged and elderly adults - The strong heart study SO CIRCULATION LA English DT Article DE epidemiology; mortality; echocardiocyraphy; diastole; aging ID LEFT-VENTRICULAR MASS; CARDIOVASCULAR-DISEASE; AMERICAN-INDIANS; ECHOCARDIOGRAPHIC ASSESSMENT; SYSTOLIC FUNCTION; HYPERTROPHY; CONTRACTILITY; PATTERNS; PRESERVE; FAILURE AB Background-With aging, left ventricular filling tends to decrease in early diastole, reducing the mitral ratio of peak early to late diastolic filling velocity (E/A). However, the prognostic significance of low or high E/A in older adults remains C to be elucidated in population-based samples. Methods and Results-Doppler echocardiograms were analyzed in 3008 American Indian participants in the second Strong Heart Study examination who had no more than mild mitral or aortic regurgitation. Participants were followed for a mean of 3 years after Doppler echocardiography to assess risks of all-cause and cardiac death associated with E/A <0.6 or > 1.5: 2429 (81%) participants had normal E/A ratio, 490 (16%) had E/A <0.6, and 89 (3%) had E/A > 1.5. All-cause mortality was higher with E/A <0.6 or E/A >1.5 (12% and 13% versus 6%), as was cardiac mortality (4.5% and 6.5% versus 1.6% both P<0.001). Adjusting for age, sex, body mass index, systolic blood pressure, HDL and LDL cholesterol. smoking, hypertension, diabetes, coronary heart disease, left ventricular hypertrophy, and low ejection fraction (<40%), the relative risk of all-cause death with E/A >1.5 was 1.73 (95% CI, 0.99 to 3.03; P=0.05); the relative risk of cardiac death was 2.8 (95% CI, 1.19 to 6.75; P<0.05). E/A <0.6 was not independently associated with increased all-cause or cardiac mortality (P=0.19 and 0.31, respectively) after adjusting for covariates. Conclusions-In a population-based sample of middle-aged and elderly adults, mitral E/A >1.5 at baseline Doppler echocardiography is associated with 2-fold increased all-cause and 3-fold increased cardiac mortality independent of covariates; mitral E/A <0.6 was also associated with 2-fold increased all-cause and cardiac mortality but not independent of covariates. C1 Cornell Univ, Weill Med Coll, New York, NY USA. Aberdeen Area Tribal Chairmens Hlth Board, Rapid City, SD USA. Univ Oklahoma, Sch Publ Hlth Serv, Oklahoma City, OK USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Medstar Res Inst, Washington, DC USA. RP Bella, JN (reprint author), Bronx Lebanon Hosp Ctr, Albert Einstein Coll Med, Div Cardiol, 12th Floor,1650 Grand Concourse, Bronx, NY 10457 USA. OI Palmieri, Vittorio/0000-0003-3732-524X FU NCRR NIH HHS [M10-RR0047-34]; NHLBI NIH HHS [HL-41642, HL-41652, HL-41654] NR 27 TC 244 Z9 248 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD APR 23 PY 2002 VL 105 IS 16 BP 1928 EP 1933 DI 10.1161/01.CIR.0000015076.37047.D9 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 544UJ UT WOS:000175179800013 PM 11997279 ER PT J AU Goldstein, DS Holmes, CS Dendi, R Bruce, SR Li, ST AF Goldstein, DS Holmes, CS Dendi, R Bruce, SR Li, ST TI Orthostatic hypotension from sympathetic denervation in Parkinson's disease SO NEUROLOGY LA English DT Article ID MULTIPLE-SYSTEM ATROPHY; METAIODOBENZYLGUANIDINE MYOCARDIAL SCINTIGRAPHY; AUTONOMIC FUNCTION-TESTS; I-123 MIBG UPTAKE; SKIN-RESPONSE; PLASMA NOREPINEPHRINE; SKELETAL-MUSCLE; BLOOD-PRESSURE; CARDIAC UPTAKE; DYSFUNCTION AB Background: Patients with PD often have signs or symptoms of autonomic failure, including orthostatic hypotension. Cardiac sympathetic denervation occurs frequently in PD, but this has been thought to occur independently of autonomic failure. Methods: Forty-one patients with PI) (18 with and 23 without orthostatic hypotension) and 16 age-matched healthy volunteers underwent PET scanning to visualize sympathetic innervation after injection of 6-[F-18]fluorodopamine. Beat-to-beat blood pressure responses to the Valsalva maneuver were used to identify sympathetic neurocirculatory failure and plasma norepinephrine to indicate overall sympathetic innervation. Results: All patients with PD and orthostatic hypotension had abnormal blood pressure responses to the Valsalva maneuver and septal and lateral ventricular myocardial concentrations of 6-[F-18]fluorodopamine-derived radioactivity >2 SD below the normal mean. In contrast, only 6 of the 23 patients without orthostatic hypotension had abnormal Valsalva responses (p < 0.0001 compared with patients with orthostatic hypotension), and only 11 had diffusely decreased 6-[F-18]fluorodopamine-derived radioactivity in the left ventricular myocardium (p = 0.0004). Of the 12 remaining patients without orthostatic hypotension, 7 had locally decreased myocardial radioactivity. Supine plasma norepinephrine was lower in patients with than in those without orthostatic hypotension (1.40 +/- 0.15 vs 2.32 +/- 0.26 nmol/L, p = 0.005). 6-[F-18]fluorodopamine-derived radioactivity was less not only in the myocardium but also in the thyroid and renal cortex of patients with PI) than in healthy control subjects. Conclusions: In PD, orthostatic hypotension reflects sympathetic neurocirculatory failure from generalized sympathetic denervation. C1 NINCDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), NINCDS, Clin Neurocardiol Sect, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. NR 67 TC 124 Z9 126 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR 23 PY 2002 VL 58 IS 8 BP 1247 EP 1255 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 543QR UT WOS:000175113100018 PM 11971094 ER PT J AU Bradshaw, TD Chua, MS Browne, HL Trapani, V Sausville, EA Stevens, MFG AF Bradshaw, TD Chua, MS Browne, HL Trapani, V Sausville, EA Stevens, MFG TI In vitro evaluation of amino acid prodrugs of novel antitumour 2-(4-amino-3-methylphenyl)benzothiazoles SO BRITISH JOURNAL OF CANCER LA English DT Article DE 2-(4-aminopheryl)benzothiazole prodrug; CYPIAI ID IN-VITRO; BIOLOGICAL PROPERTIES; 2-(4-AMINOPHENYL)BENZOTHIAZOLES; BENZOTHIAZOLES; VIVO AB Novel 2-(4-aminophenyl)benzothiazoles possess highly selective, potent antitumour properties in vitro and in vivo. They induce and are biotransformed by cytochrome P450 (CYP) \A\ to putative active as well as inactive metabolites. Metal inactivation of the molecule has been thwarted by isosteric replacement of hydrogen with fluorine atoms at positions around the benzothiazole nucleus, The lipophilicity of these compounds presents limitations for drug formulation and bioavailability, To overcome this problem, water soluble prodrugs have been synthesised by conjugation of alanyl- and lysyl-amide hydrochloride salts to the exocyclic primary amine function of 2-(4-aminophenyl)benzothiazoles. The prodrugs retain selectivity with significant in vitro growth inhibitory potency against the same sensitive cell lines as their parent amine, but are inactive against cell lines inherently resistant to 2-(4-aminophenyl)benzothiazoles, Alanyl and lysyl prodrugs rapidly and quantitatively revert to their parent amine in sensitive and insensitive cell lines in vitro. Liberated parent compounds are sequestered and metabolised by sensitive cells only; similarly, CYP\A\ activity and protein expression are selectively induced in sensitive carcinoma cells. Amino acid prodrugs meet the criteria of aqueous solubility, chemical stability and quantitative reversion to parent molecule, and thus are suitable for in vivo preclinical evaluation. (C) 2002 Cancer Research UK. C1 Univ Nottingham, Sch Pharmaceut Sci, Canc Res Labs, Nottingham NG7 2RD, England. NCI, Dev Therapeut Program, Div Canc Treatment & Diagnosis, NIH, Frederick, MD 21702 USA. RP Bradshaw, TD (reprint author), Univ Nottingham, Sch Pharmaceut Sci, Canc Res Labs, Nottingham NG7 2RD, England. OI Trapani, Valentina/0000-0002-0259-6624 NR 17 TC 56 Z9 58 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD APR 22 PY 2002 VL 86 IS 8 BP 1348 EP 1354 DI 10.1038/sj/bjc/6600225 PG 7 WC Oncology SC Oncology GA 555NT UT WOS:000175800700026 PM 11953897 ER PT J AU Buda, C Burt, SK Cundari, TR Shenkin, PS AF Buda, C Burt, SK Cundari, TR Shenkin, PS TI De novo structural prediction of transition metal complexes: Application to technetium SO INORGANIC CHEMISTRY LA English DT Article ID CRYSTAL-STRUCTURE; SUPEROXIDE-DISMUTASE; CONTRAST AGENTS; SULFITE OXIDASE; LIGANDS; CHEMISTRY; NMR; SPECTROSCOPY; GEOMETRY; PYRIDINE AB De novo structural prediction of transition metal complexes is investigated. Technetium complexes are chosen given their importance in medical imaging and nuclear waste remediation and for the chemical diversity they display, A new conformational searching algorithm (LIGB) for transition metals is described that allows one to search for different conformational and geometric isomers within a single simulation. In the preponderance of cases, both conformational searching techniques (LIGB and high-temperature molecular dynamics/simulated annealing) provide comparable results, while LIGB is superior for macrocyclic complexes. A genetic algorithm-optimized PM3(tm) parametrization for Tc is compared with the standard implementation and found to yield a significant improvement in predictive ability for the most prevalent Tc structural motifs. The utility of a coupled molecular mechanics-semiempirical quantum mechanics protocol is demonstrated for very rapid, efficient, and effective de novo prediction of transition metal complex geometries. C1 Univ Memphis, Computat Res Mat Inst, Dept Chem, Memphis, TN 38152 USA. NCI, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. Schrodinger Inc, New York, NY 10036 USA. RP Cundari, TR (reprint author), Univ Memphis, Computat Res Mat Inst, Dept Chem, Memphis, TN 38152 USA. NR 55 TC 10 Z9 10 U1 2 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0020-1669 J9 INORG CHEM JI Inorg. Chem. PD APR 22 PY 2002 VL 41 IS 8 BP 2060 EP 2069 DI 10.1021/ic0109748 PG 10 WC Chemistry, Inorganic & Nuclear SC Chemistry GA 543PN UT WOS:000175110500012 PM 11952359 ER PT J AU Ho, GYF Knapp, M Freije, D Nelson, WG Smith, JR Carpten, JD Bailey-Wilson, JE Beaty, TH Petersen, G Xu, JF Kamensky, V Walsh, PC Isaacs, WB AF Ho, GYF Knapp, M Freije, D Nelson, WG Smith, JR Carpten, JD Bailey-Wilson, JE Beaty, TH Petersen, G Xu, JF Kamensky, V Walsh, PC Isaacs, WB TI Transmission/disequilibrium tests of androgen receptor and glutathione S-transferase pi variants in prostate cancer families SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE prostate cancer; androgen receptor; glutathione S-transferase pi; transmission disequilibrium test ID PARENTAL-GENOTYPE RECONSTRUCTION; CAG REPEAT; LINKAGE DISEQUILIBRIUM; GENETIC POLYMORPHISMS; RISK; ASSOCIATION; LOCUS; GSTP1; SUSCEPTIBILITY; MICROSATELLITE AB Population-based case-control studies have found relationships between risk of prostate cancer and genetic polymorphisms in the CAG repeat and GGC repeat of the X-linked androgen receptor gene (AR) as well as the autosomal gene coding for glutathione S-transferase pi (GSTPI). This family-based study utilized the transmission disequilibrium test to examine whether there was evidence that these polymorphisms could account for familial aggregation of prostate cancer. Seventy-nine North American pedigrees were studied. Most of these families had 3 or more affected first-degree relatives. Genotype information was obtained on 578 individuals. The reconstruction combined transmission disequilibrium test (RC-TDT) was used to test for linkage. There was no evidence of linkage to the CAG and GGC repeat sequences in the AR gene or the pentanucleotide (ATAAA) repeat in the GSTPI gene when each allele was analyzed separately or when alleles were grouped by repeat length. Our findings do not support the hypothesis that familial clustering of prostate cancer in high-risk families is attributable to these genetic variants. (C) 2002 Wiley-Liss. Inc. C1 Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY 10461 USA. Univ Bonn, Inst Med Biometry Informat & Epidemiol, Bonn, Germany. Johns Hopkins Med Inst, Dept Urol, Baltimore, MD USA. Johns Hopkins Med Inst, Ctr Oncol, Baltimore, MD 21205 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Mayo Clin, Rochester, MN USA. Wake Forest Univ, Sch Med, Ctr Genom, Winston Salem, NC USA. RP Ho, GYF (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Social Med, Belfer Bldg 1312, Bronx, NY 10461 USA. RI Smith, Jeff/C-3484-2012; OI Bailey-Wilson, Joan/0000-0002-9153-2920 FU NCI NIH HHS [CA58236, R01 CA64247] NR 26 TC 7 Z9 7 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 APR 20 PY 2002 VL 98 IS 6 BP 938 EP 942 DI 10.1002/ijc.10290 PG 5 WC Oncology SC Oncology GA 546XC UT WOS:000175300800022 PM 11948476 ER PT J AU Himmel, KL Bi, F Shen, HF Jenkins, NA Copeland, NG Zheng, Y Largaespada, DA AF Himmel, KL Bi, F Shen, HF Jenkins, NA Copeland, NG Zheng, Y Largaespada, DA TI Activation of Clg, a novel Dbl family guanine nucleotide exchange factor gene, by proviral insertion at Evi24, a common integration site in B cell and myeloid leukemias SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GTP-BINDING PROTEINS; RAS TRANSFORMATION; MESSENGER-RNA; RHO-GTPASE; CDC42; APOPTOSIS; RAC1; LYMPHOMAS; TRISTETRAPROLIN; PATHWAYS AB Retroviruses induce leukemia in inbred strains of mice by activating cellular proto-oncogenes and/or inactivating tumor suppressors. The proviral integration sites in these leukemias provide powerful genetic tags for disease gene identification. Here we show that Evi24, a common site of retroviral integration in AKXD B cell and BXH-2 myeloid leukemias, contains a novel Db1 family guanine nucleotide exchange factor gene. We have designated this gene Clg (common-site lymphoma/leukemia guanine nucleotide exchange factor). Proviral integrations on chromosome 7 at Evi24 are located 7.6-10.3 kb upstream of Clg and increased Clg expression 2-5-fold compared with leukemias lacking proviral integrations at Evi24. Clg contains Db1/pleckstrin homology domains with substantial sequence homology to many Rho family activators, including the transforming Dbl and Dbs/Ost oncogenes. Nucleotide exchange assays indicated that Clg specifically activated nucleotide exchange on Cdc42, but not RhoA or Rac1, in vitro. NIH 3T3 transfection studies showed that overexpression of full-length and carboxyl-terminally truncated forms of Clg morphologically transformed NIH 3T3 cells. This study and studies showing that the human homolog of EVI24 is located in a region of 19q13 frequently amplified in B cell lymphomas and pancreatic and breast cancers implicate Clg and Cdc42 activation in mouse and human cancers. C1 Univ Minnesota, Ctr Canc, Inst Human Genet, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. Univ Tennessee, Ctr Hlth Sci, Dept Mol Sci, Memphis, TN 38163 USA. NCI, Frederick Canc Res & Dev Ctr, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP Largaespada, DA (reprint author), Univ Minnesota, Ctr Canc, Inst Human Genet, Minneapolis, MN 55455 USA. EM larga002@tc.umn.edu RI Largaespada, David/C-9832-2014; Zheng, Yi/J-7235-2015 OI Zheng, Yi/0000-0001-7089-6074 FU NCI NIH HHS [CA09138, CA81051] NR 62 TC 15 Z9 18 U1 1 U2 1 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 APR 19 PY 2002 VL 277 IS 16 BP 13463 EP 13472 DI 10.1074/jbc.M110981200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 543HR UT WOS:000175096000018 PM 11839748 ER PT J AU Pommier, Y Kohlhagen, G Laco, GS Kroth, H Sayer, JM Jerina, DM AF Pommier, Y Kohlhagen, G Laco, GS Kroth, H Sayer, JM Jerina, DM TI Different effects on human topoisomerase I by minor groove and intercalated deoxyguanosine adducts derived from two polycyclic aromatic hydrocarbon diol epoxides at or near a normal cleavage site SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SOLUTION CONFORMATION; DNA DUPLEX; ANTICANCER DRUG; OPPOSITE DT; CAMPTOTHECIN; COMPLEXES; BASE; INHIBITORS; MECHANISM; SEQUENCE AB Topoisomerase I (top1) relieves supercoiling in DNA by forming transient covalent cleavage complexes. These cleavage complexes can accumulate in the presence of damaged DNA or anticancer drugs that either intercalate or lie in the minor groove. Recently we reported that covalent diol epoxide (DE) adducts of benzo[a]pyrene (BaP) at the exocyclic amino group of G(+1) block cleavage at a preferred cleavage site (similar toCTT-G(+1)G(+2)Asimilar to) and cause accumulation of cleavage products at remote sites. In the present study, we nave found that the 10S G(+2) adduct of Bal? DE, which lies toward the scissile bond in the minor groove, blocks normal cleavage, whereas the 10R isomer, which orients away from this bond, allows normal cleavage but blocks religation. In contrast to BaP, the pair of benzo[c] phenanthrene (BcPh) DE adducts at G(+2), which intercalate from the minor groove either between G(+1)/G(+2) or between G(+2)/A, allow normal cleavage but block religation. Both intercalated BcPh DE adducts at G(+1) suppress normal cleavage, as do both groove bound BaP DE adducts at this position. These studies demonstrate that these DE adducts provide a novel set of tools to study DNA topoisomerases and emphasize the importance of contacts between the minor groove and top1's catalytic site. C1 NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bldg 37,Rm 5068, Bethesda, MD 20892 USA. NR 38 TC 30 Z9 32 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 19 PY 2002 VL 277 IS 16 BP 13666 EP 13672 DI 10.1074/jbc.M200209200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 543HR UT WOS:000175096000044 PM 11832494 ER PT J AU Jain, A Karadag, A Fohr, B Fisher, LW Fedarko, NS AF Jain, A Karadag, A Fohr, B Fisher, LW Fedarko, NS TI Three SIBLINGs (small integrin-binding ligand, N-linked glycoproteins) enhance factor H's cofactor activity enabling MCP-like cellular evasion of complement-mediated attack SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MATRIX ACIDIC PHOSPHOPROTEIN; IMPERFECTA TYPE-II; BONE SIALOPROTEIN; SIALIC-ACID; OSTEOPONTIN; PROTEIN; GENE; SEQUENCE; CLONING; CELLS AB Previously we have shown that two members of the newly named SIBLING (small integrin-binding ligand, N-linked glycoproteins) family of proteins, bone sialoprotein, and osteopontin, bound first to a cell surface receptor and then to complement Factor H thereby blocking the lytic activity of the alternative pathway of complement. Another member of this family, dentin matrix protein 1, is shown in this paper to be very similar to osteopontin in that it can bind strongly to Factor H (K similar to 1 nm) and block the lytic activity through either the vitronectin receptor (alpha(V)beta(3) integrin) or CD44. Binding of Factor H to SIBLING localized to the cells surface was demonstrated by fluorescence-activated cell sorting. Extensive overlapping fragment analyses suggests that both dentin matrix protein I and osteopontin interact with cell surface CD44 through their amino termini. Similar fragments of bone sialoprotein, like the intact protein, did not functionally interact with CD44. All three proteins are shown to act in conjunction with Factor 1, a serum protease that, when complexed to appropriate cofactors, stops the lytic pathway by digesting the bound C3b in a series of proteolytic steps. These results show that at least three members of this family confer membrane cofactor protein-like activity (MCP or CD46) upon cells expressing RGD-binding integrins or CD44. The required order of the assembly of the complex suggests that this cofactor activity is limited to short diffusional distances. C1 Johns Hopkins Univ, Dept Med, Div Geriatr, Baltimore, MD 21224 USA. NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Fedarko, NS (reprint author), Rm 5A-64 JHAAC,5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. OI Fedarko, Neal/0000-0001-6055-6279 FU NCI NIH HHS [CA 87311] NR 36 TC 82 Z9 88 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 19 PY 2002 VL 277 IS 16 BP 13700 EP 13708 DI 10.1074/jbc.M110757200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 543HR UT WOS:000175096000048 PM 11825898 ER PT J AU Liang, XQ Wisniewski, D Strife, A Shivakrupa Clarkson, B Resh, MD AF Liang, XQ Wisniewski, D Strife, A Shivakrupa Clarkson, B Resh, MD TI Phosphatidylinositol 3-kinase and Src family kinases are required for phosphorylation and membrane recruitment of Dok-1 in c-Kit signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STEM-CELL FACTOR; CHRONIC MYELOGENOUS LEUKEMIA; PROTEIN-TYROSINE KINASE; PROGENITOR CELLS; JUXTAMEMBRANE REGION; HEMATOPOIETIC-CELLS; DOCKING PROTEIN; P62(DOK); RECEPTOR; BINDING AB Dok-1 is an adaptor protein that is a substrate for Bcr-Abl and other tyrosine protein kinases. The presence of pleckstrin homology and phosphotyrosine binding domains as well as multiple tyrosine phosphorylation sites suggests that Dok-1 is involved in protein-protein and/or protein-lipid interactions. Here we show that stimulation of Mo7 hematopoietic cells with c-Kit ligand (KL) induces phosphatidylinositol (PI) 3-kinase-dependent tyrosine phosphorylation and membrane recruitment of Dok-1. Addition of the K-Ras membrane-targeting motif to Dok-1 generated a constitutively membrane-bound Dok-1 protein whose tyrosine phosphorylation was independent of PI 3-kinase. Membrane localization of Dok-1 was required for its ability to function as a negative regulator of cell proliferation. Additional experiments revealed that Dok-1 associated with the juxtamembrane region and C-terminal tail of e-Kit. Lyn promoted phosphorylation of c-Kit and association of c-Kit and Dok-1. Both Lyn and Tec were capable of phosphorylating Dok-1. However, the use of primary bone marrow mast cells from normal and Lyn-deficient mice demonstrated that Lyn is required for KL-dependent Dok-1 tyrosine phosphorylation. Taken together, these data indicate that activation of PI 3-kinase by KL promotes binding of the Dok pleckstrin homology domain and Dok-1 recruitment to the plasma membrane where Dok-1 is phosphorylated by Src and/or Tec family kinases. C1 Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Therapeut Program, New York, NY 10021 USA. NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Basic Res Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Immunobiol Lab, Frederick, MD 21702 USA. RP Resh, MD (reprint author), Sloan Kettering Inst Canc Res, Cell Biol Program, 1275 York Ave,Box 143, New York, NY 10021 USA. FU NCI NIH HHS [P01 CA64593] NR 25 TC 40 Z9 44 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 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 19 PY 2002 VL 277 IS 16 BP 13732 EP 13738 DI 10.1074/jbc.M200277200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 543HR UT WOS:000175096000052 PM 11825908 ER PT J AU Silva-Neto, MAC Atella, GC Shahabuddin, M AF Silva-Neto, MAC Atella, GC Shahabuddin, M TI Inhibition of Ca2+/calmodulin-dependent protein kinase blocks morphological differentiation of Plasmodium gallinaceum zygotes to ookinetes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MALARIA PARASITE; TRYPANOSOMA-CRUZI; CA2+ CALMODULIN; CALCIUM; FALCIPARUM; CYTOSKELETON; MEMBRANE; PHOSPHORYLATION; CELLS; TRANSFORMATION AB Once ingested by mosquitoes, malaria parasites undergo complex cellular changes. These include zygote formation, transformation of zygote to ookinete, and differentiation from ookinete to oocyst. Within the oocyst, the parasite multiplies into numerous sporozoites. Modulators of intracellular calcium homeostasis A23187, MAPTAM, and TMB-8 blocked ookinete development as did the calmodulin (CaM) antagonists W-7 and calmidazolium. Ca2+/CaM-dependent protein kinase inhibitor KN-93 also blocked zygote elongation, while its ineffective analog KN-92 did not have such effect. In vitro both zygote and ookinete extracts efficiently phosphorylated autocamtide-2, a classic CaM kinase substrate, which could be blocked by calmodulin antagonists W-7 and calmidazolium and CaM kinase inhibitor KN-93. These results demonstrated the presence of calmodulin-dependent CaM kinase activity in the parasite. KN-93-treated parasites, however, expressed the ookinete-specific enzyme chitinase and the ookinete surface antigen Pgs28 normally, suggesting that the morphologically untransformed parasites are biochemically mature ookinetes. In mosquitoes, KN-93-treated parasites did not develop as oocysts, while KN-92-treated parasites produced similar numbers of oocysts as controls. These data suggested that in Plasmodium gallinaceum morphological development of zygote to ookinete, but not its biochemical maturation, relies on Ca2+/CaM-dependent protein kinase activity and demonstrated that the morphological differentiation is essential for the further development of the parasite in infected blood-fed mosquitoes. C1 NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Shahabuddin, M (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 4 Ctr Dr,Rm 4-B2-37, Bethesda, MD 20892 USA. RI Silva-Neto , Mario /C-1211-2013 OI Silva-Neto , Mario /0000-0003-2273-194X NR 47 TC 29 Z9 30 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 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 19 PY 2002 VL 277 IS 16 BP 14085 EP 14091 DI 10.1074/jbc.M107903200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 543HR UT WOS:000175096000096 PM 11827960 ER PT J AU Bewley, CA Louis, JM Ghirlando, R Clore, GM AF Bewley, CA Louis, JM Ghirlando, R Clore, GM TI Design of a novel peptide inhibitor of HIV fusion that disrupts the internal trimeric coiled-coil of gp41 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SIV GP41; ENVELOPE GLYCOPROTEINS; ACTIVE CONFORMATION; SYNTHETIC PEPTIDE; ATOMIC-STRUCTURE; VIRUS-INFECTION; TYPE-1 GP41; ENTRY; ECTODOMAIN; PROTEIN AB The pre-hairpin intermediate of gp41 from the human immunodeficiency virus (HIV) is the target for two classes of fusion inhibitors that bind to the C-terminal region or the trimeric coiled-coil of N-terminal helices, thereby preventing formation of the fusogenic trimer of hairpins. Using rational design, two 36-residue peptides, N36(Mut(e,g)) and N36(Mut(a,d)), were derived from the parent N36 peptide comprising the N-terminal helix of the gp41 ectodomain (residues 546-581 of HIV-1 envelope), characterized by analytical ultracentrifugation and CD, and assessed for their ability to inhibit HIV fusion using a quantitative vaccinia virus-based fusion assay. N36(Mut(e,g)) contains nine amino acid substitutions designed to disrupt interactions with the C-terminal region of gp41 while preserving contacts governing the formation of the trimeric coiled-coil. N36(Mut(a,d)) contains nine substitutions designed to block formation of the trimeric coiled-coil but retains residues that interact with the C-terminal region of gp41. N36(Mut(a,d)) is monomeric, is largely random coil, does not interact with the C34 peptide derived from the C-terminal region of gp41 (residues 628-661), and does not inhibit fusion. The trimeric coiled-coil structure is therefore a prerequisite for interaction with the C-terminal region of gp41. N36(Mut(e,g)) forms a monodisperse, helical trimer in solution, does not interact with C34, and yet inhibits fusion about 50-fold more effectively than the parent N36 peptide (IC50 -similar to308 nM versus similar to16 muM). These results indicate that N36(Mut(e,g)) acts by disrupting the homotrimeric coiled-coil of N-terminal helices in the pre-hairpin intermediate to form heterotrimers. Thus N36(Mut(e,g)) represents a novel third class of gp41-targeted HIV fusion inhibitor. A quantitative model describing the interaction of N36(Mut(e,g)) with the pre-hairpin intermediate is presented. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 8, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008; Ghirlando, Rodolfo/A-8880-2009 OI Clore, G. Marius/0000-0003-3809-1027; NR 30 TC 115 Z9 119 U1 0 U2 11 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 APR 19 PY 2002 VL 277 IS 16 BP 14238 EP 14245 DI 10.1074/jbc.M201453200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 543HR UT WOS:000175096000115 PM 11859089 ER PT J AU Chang, LC Bewley, CA AF Chang, LC Bewley, CA TI Potent inhibition of HIV-1 fusion by cyanovirin-N requires only a single high affinity carbohydrate binding site: Characterization of low affinity carbohydrate binding site knockout mutants SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE HIV-1 viral entry; surface envelope glycoprotein gpl20; high mannose oligosaccharides; NMR; dipolar couplings ID INACTIVATING PROTEIN; DIPOLAR COUPLINGS; GP120; CD4; CORECEPTOR; BLOCKING AB Cyanovirin-N (CVN) is a novel cyanobacterial protein that potently inhibits viral entry by human immunodeficiency viruses (HIV) via high affinity carbohydrate-mediated binding to the surface envelope glycoprotein gp120. Bearing C-2 pseudo-symmetry, CVN contains two carbohydrate binding sites of differing affinities located at opposite ends of the protein. CVN selectively binds with nanomolar affinity the mammalian high mannose oligosaccharides oligomannose-8 D1D3 and oligomannose-9, which also govern binding to gp120. At nanomolar concentrations CVN binds these oligosaccharides only through its high affinity site, while at micromolar to millimolar concentrations the oligosaccharides are bound through both sites leading to divalent protein-carbohydrate interactions. Similarly, two modes of binding to gp120 can be envisioned where CVN either binds gp120 solely through the high affinity site, or binds divalently using both carbohydrate binding sites. To determine the role of the low affinity site in binding to gp120, we sought to design a variant of CVN that lacks the low affinity carbohydrate binding site but retains a fully functional high affinity site. Thus, we constructed a series of CVN mutants possessing cumulative mutations in the low affinity site only, and characterized by NMR the overall structure and carbohydrate binding ability of each of these mutants. We demonstrate that carbohydrate binding by the low affinity site is completely absent in two mutants bearing three or four mutations (namely, m3-CVN = Lys3Asn, Glu23Ile, Asn93Ala; and m4-CVN = Lys3Asn, Thr7Ala, Glu23Ile, Asn93Ala), while the high affinity site binds the high affinity ligand Manalpha(1-2)Manalpha with a K-d value equal to that measured for CVN. Using an HIV-1 cell fusion assay, we show that all of the mutants inhibit HIV-1 fusion with nearly identical IC50 values as wild-type CVN. We interpret these results as indicating that the low affinity carbohydrate binding site of CVN is not necessary for high affinity binding to gp120, and HIV-1 fusion can therefore be blocked by monovalent protein-carbohydrate interactions. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 19 TC 36 Z9 36 U1 0 U2 3 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD APR 19 PY 2002 VL 318 IS 1 BP 1 EP 8 DI 10.1016/S0022-2836(02)00045-1 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 548MY UT WOS:000175392800001 PM 12054763 ER PT J AU Moscardini, M Pistello, M Bendinelli, M Ficheux, D Miller, JT Gabus, C Le Grice, SFJ Surewicz, WK Darlix, JL AF Moscardini, M Pistello, M Bendinelli, M Ficheux, D Miller, JT Gabus, C Le Grice, SFJ Surewicz, WK Darlix, JL TI Functional interactions of nucleocapsid protein of feline immunodeficiency virus and cellular prion protein with the viral RNA SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE FIV; nucleocapsid protein; reverse transcription; prion protein ID PROVIRAL DNA-SYNTHESIS; MURINE LEUKEMIA-VIRUS; MAJOR CORE PROTEIN; IN-VITRO; REVERSE-TRANSCRIPTASE; ANNEALING ACTIVITIES; BINDING-PROTEINS; MINUS-STRAND; ZINC-FINGER; NUCLEOPROTEIN COMPLEXES AB All lentiviruses and oncoretroviruses examined so far encode a major nucleic-acid binding protein (nucleocapsid or NC* protein), approximately 2500 molecules of which coat the dimeric RNA genome. Studies on HIV-1 and MoMuLV using in vitro model systems and in vivo have shown that NC protein is required to chaperone viral RNA dimerization and packaging during virus assembly, and proviral DNA synthesis by reverse transcriptase (RT) during infection. The human cellular prion protein (PrP), thought to be the major component of the agent causing transmissible spongiform encephalopathies (TSE), was recently found to possess a strong affinity for nucleic acids and to exhibit chaperone properties very similar to HIV-1 NC protein in the HIV-1 context in vitro. Tight binding of PrP to nucleic acids is proposed to participate directly in the prion disease process. To extend our understanding of lentiviruses and of the unexpected nucleic acid chaperone properties of the human prion protein, we set up an in vitro system to investigate replication of the feline immunodeficiency virus (FIV), which is functionally and phylogenetically distant from HIV-1. The results show that in the FIV model system, NC protein chaperones viral RNA dimerization, primer tRNA(Lys,3) annealing to the genomic primer-binding site (PBS) and minus strand DNA synthesis by the homologous FIV RT. FIV NC protein is able to trigger specific viral DNA synthesis by inhibiting self-priming of reverse transcription. The human prion protein was found to mimic the properties of FIV NC with respect to primer tRNA annealing to the viral RNA and chaperoning minus strand DNA synthesis. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Ecole Normale Super Lyon, INSERM ENS 412, LaboRetro, F-69364 Lyon, France. Univ Pisa, Dept Biomed, I-56127 Pisa, Italy. CNRS, IBCP, Lyon, France. NCI, HIV Drug Resistanc Program, Frederick, MD 21702 USA. Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA. RP Darlix, JL (reprint author), Ecole Normale Super Lyon, INSERM ENS 412, LaboRetro, F-69364 Lyon, France. NR 48 TC 28 Z9 28 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD APR 19 PY 2002 VL 318 IS 1 BP 149 EP 159 DI 10.1016/S0022-2836(02)00092-X PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 548MY UT WOS:000175392800013 PM 12054775 ER PT J AU Tran, H Brunet, A Grenier, JM Datta, SR Fornace, AJ DiStefano, PS Chiang, LW Greenberg, ME AF Tran, H Brunet, A Grenier, JM Datta, SR Fornace, AJ DiStefano, PS Chiang, LW Greenberg, ME TI DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein SO SCIENCE LA English DT Article ID CAENORHABDITIS-ELEGANS; DAMAGING AGENTS; GROWTH ARREST; LIFE-SPAN; EXPRESSION; INDUCTION; RESISTANCE; SIGNALS; DAF-16; FAMILY AB The signaling pathway from phosphoinositide 3-kinase to the protein kinase Akt controls organismal life-span in invertebrates and cell survival and proliferation in mammals by inhibiting the activity of members of the FOXO family of transcription factors. We show that mammalian FOXO3a also functions at the G(2) to M checkpoint in the cell cycle and triggers the repair of damaged DNA. By gene array analysis, FOXO3a was found to modulate the expression of several genes that regulate the cellular response to stress at the G(2)-M checkpoint. The growth arrest and DNA damage response gene Gadd45a appeared to be a direct target of FOXO3a that mediates part of FOXO3a's effects on DNA repair. These findings indicate that in mammals FOXO3a regulates the resistance of cells to stress by inducing DNA repair and thereby may also affect organismal life-span. C1 Harvard Univ, Childrens Hosp, Sch Med, Div Neurosci, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. Millennium Pharmaceut Inc, Cambridge, MA 02139 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Greenberg, ME (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Div Neurosci, Boston, MA 02115 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X FU NICHD NIH HHS [NIHP30-HD18655, P01-HD24926] NR 23 TC 520 Z9 540 U1 1 U2 16 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 APR 19 PY 2002 VL 296 IS 5567 BP 530 EP 534 DI 10.1126/science.1068712 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 544UE UT WOS:000175179400046 PM 11964479 ER PT J AU Walker, NJ AF Walker, NJ TI A technique whose time has come SO SCIENCE LA English DT Article ID POLYMERASE CHAIN-REACTION; PCR; AMPLIFICATION C1 NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Walker, NJ (reprint author), NIEHS, Environm Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. RI Walker, Nigel/D-6583-2012 OI Walker, Nigel/0000-0002-9111-6855 NR 16 TC 209 Z9 218 U1 2 U2 11 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 APR 19 PY 2002 VL 296 IS 5567 BP 557 EP + DI 10.1126/science.296.5567.557 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 544UE UT WOS:000175179400054 PM 11964485 ER PT J AU Cannon, RO AF Cannon, RO TI Perspective - Restenosis after angioplasty SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NHLBI, Bethesda, MD 20892 USA. RP Cannon, RO (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 10 Z9 11 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 18 PY 2002 VL 346 IS 16 BP 1182 EP 1183 DI 10.1056/NEJM200204183461602 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 542FT UT WOS:000175033400001 PM 11961145 ER PT J AU Arnold, EV Citro, ML Keefer, LK Hrabie, JA AF Arnold, EV Citro, ML Keefer, LK Hrabie, JA TI A nitric oxide-releasing polydiazeniumdiolate derived from acetonitrile SO ORGANIC LETTERS LA English DT Article ID CARBON AB [GRAPHIC] Acetonitrile, frequently used as a solvent in reactions of nitric oxide (NO) with amines and other nucleophiles to introduce the [N(O)NO](-)(diazeniumdiolate) functional group, has itself been shown to react with NO in the presence of strong base to yield methane trisdiazeniumdiolate (1), presumably via an intermediate trisdiazeniumdiolated imidate. Aqueous hydrolysis of I does not follow simple first-order kinetics and produces mixtures of NO and nitrous oxide in ratios that vary with solution pH. C1 NCI, IRSP, SAIC Frederick, Frederick, MD 21702 USA. NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Hrabie, JA (reprint author), NCI, IRSP, SAIC Frederick, Frederick, MD 21702 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01 CO-12400] NR 14 TC 10 Z9 10 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD APR 18 PY 2002 VL 4 IS 8 BP 1323 EP 1325 DI 10.1021/ol025624j PG 3 WC Chemistry, Organic SC Chemistry GA 541RM UT WOS:000174997600021 PM 11950353 ER PT J AU Durkin, ME Yuan, BZ Thorgeirsson, SS Popescu, NC AF Durkin, ME Yuan, BZ Thorgeirsson, SS Popescu, NC TI Gene structure, tissue expression, and linkage mapping of the mouse DLC-1 gene (Arhgap7) SO GENE LA English DT Article DE chromosome 8; promoter; Rho GAP; tumor suppressor gene ID HEPATOCELLULAR-CARCINOMA; C-MYC; RHO; PROTEINS; CANCER; DOMAIN; IDENTIFICATION; TRANSFORMATION; PROLIFERATION; LOCALIZATION AB DLC-1 (deleted in liver cancer 1) is a candidate tumor suppressor gene for hepatocellular carcinoma and other cancers. It is the human homologue of rat p122, which has been shown to function as a GTPase activating protein for RhoA, and it may be involved in signal transduction pathways regulating cell proliferation and adhesion. To establish an animal model for studying the regulation and function of DLC-1, we have undertaken the characterization of the mouse DLC-1 gene. Northern blot analysis shows that the mouse DLC-1 mRNA is widely expressed, with the highest levels in heart, liver, and lung. Mouse genomic clones that contain the entire DLC-1 gene of 47 kb were isolated. The mouse gene consists of 14 exons, and the structural organization is highly similar to that of the human gene. The promoter region of the mouse gene was GC-rich and contained potential binding sites for transcription factors SP1, GCF, and AP-2. A polymorphic microsatellite marker in intron 8 was used for mapping the gene (Arhgap7) to 20 cM on mouse chromosome 8 and for allelotyping of mouse liver tumor DNAs. Published by Elsevier Science B.V. C1 NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Durkin, ME (reprint author), NCI, Expt Carcinogenesis Lab, NIH, Bldg 37,Room 3C28, Bethesda, MD 20892 USA. NR 27 TC 18 Z9 20 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD APR 17 PY 2002 VL 288 IS 1-2 BP 119 EP 127 AR PII S0378-1119(02)00462-6 DI 10.1016/S0378-1119(02)00462-6 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 565MG UT WOS:000176373600014 PM 12034501 ER PT J AU Hawk, ET Viner, JL Dannenberg, A DuBois, RN AF Hawk, ET Viner, JL Dannenberg, A DuBois, RN TI COX-2 in cancer - A player that's defining the rules SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID DIFLUOROMETHYLORNITHINE; INHIBITION; PIROXICAM; POLYPOSIS; CELECOXIB; TOXICITY; MICE C1 NCI, Gastrointestinal & Canc Res Grp, Div Canc Prevent, EPN,NIH, Bethesda, MD 20892 USA. Cornell Univ, Weill Med Coll, New York, NY USA. Strang Canc Prevent Ctr, New York, NY USA. Vanderbilt Univ, Div Gastroenterol, Nashville, TN USA. RP Hawk, ET (reprint author), NCI, Gastrointestinal & Canc Res Grp, Div Canc Prevent, EPN,NIH, Suite 2141,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 17 TC 66 Z9 68 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD APR 17 PY 2002 VL 94 IS 8 BP 545 EP 546 PG 2 WC Oncology SC Oncology GA 542AV UT WOS:000175022000001 PM 11959883 ER PT J AU Rausch, JW Lener, D Miller, JT Julias, JG Hughes, SH Le Grice, SFJ AF Rausch, JW Lener, D Miller, JT Julias, JG Hughes, SH Le Grice, SFJ TI Altering the RNase H primer grip of human immunodeficiency virus reverse transcriptase modifies cleavage specificity SO BIOCHEMISTRY LA English DT Article ID MURINE LEUKEMIA-VIRUS; COLI RIBONUCLEASE HI; DNA STRAND TRANSFER; SEQUENCE FEATURES IMPORTANT; HIV-1 REVERSE; NUCLEOCAPSID PROTEIN; ESCHERICHIA-COLI; ANGSTROM RESOLUTION; POLYPURINE TRACT; CRYSTAL-STRUCTURE AB Recent crystallographic data suggest that conserved residues in the connection subdomain and C-terminal ribonuclease H (RNase H) domain of human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) contact the nascent DNA primer and modulate the trajectory of the template relative to the RNase H catalytic center. Within the RNase H domain, these residues include Thr473, Glu475, Lys476, Tyr501, and Ile505, while His539 and Asn474 interact with the scissile phosphate of the RNA template. Amino acid substitutions at several of these positions were evaluated in the context of hydrolysis of nonspecific RNA-DNA hybrids and substrates mimicking specific RNase H-mediated events. With the exception of mutant I505G, which exhibited a dimerization defect, Substituting alanine at positions 473-476 and 501 had minimal consequences for DNA synthesis on duplex and hybrid DNA and RNA substrates. In contrast, the efficiency with which most mutants catalyzed polymerization-independent RNase H cleavage was sharply reduced. This deficiency was more pronounced when mutant enzymes were challenged to process the (+) strand polypurine tract (PPT) primer from either (+) RNA or a PPT/(+) DNA RNA/DNA chimera. Reduced polymerization-independent RNase H activity also significantly influenced the rate of DNA strand transfer, suggesting the donor template must be reduced in size below 13 nt before this event proceeds. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Le Grice, SFJ (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. NR 56 TC 59 Z9 59 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 APR 16 PY 2002 VL 41 IS 15 BP 4856 EP 4865 DI 10.1021/bi015970t PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 541XX UT WOS:000175012900012 PM 11939780 ER PT J AU Lenfant, C AF Lenfant, C TI Clinical research skills development - A new approach SO CIRCULATION LA English DT Editorial Material DE editorials; research; funding; training C1 NHLBI, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Lenfant, C (reprint author), NHLBI, Dept Hlth & Human Serv, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 3 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD APR 16 PY 2002 VL 105 IS 15 BP 1751 EP 1752 DI 10.1161/01.CIR.0000014122.41950.10 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 543XK UT WOS:000175127700003 PM 11956111 ER PT J AU Sheps, DS McMahon, RP Becker, L Carney, RM Freedland, KE Cohen, JD Sheffield, D Goldberg, AD Ketterer, MW Pepine, CJ Raczynski, JM Light, K Krantz, DS Stone, PH Knatterud, GL Kaufmann, PG AF Sheps, DS McMahon, RP Becker, L Carney, RM Freedland, KE Cohen, JD Sheffield, D Goldberg, AD Ketterer, MW Pepine, CJ Raczynski, JM Light, K Krantz, DS Stone, PH Knatterud, GL Kaufmann, PG TI Mental stress-induced ischemia and all-cause mortality in patients with coronary artery disease - Results from the psychophysiological investigations of myocardial ischemia study SO CIRCULATION LA English DT Article DE coronary disease; ischemia; stress ID VASOMOTOR RESPONSE; PROGNOSTIC VALUE; HEART-DISEASE; INFARCTION; DEPRESSION; HOPELESSNESS; EXERCISE; DEATH; RISK; LIFE AB Background-Ischemia during laboratory mental stress tests has been linked to significantly higher rates of adverse cardiac events. Previous studies have not been designed to detect differences in mortality rates. Methods and Results-To determine whether mental stress-induced ischemia predicts death, we evaluated 196 patients from the Psychophysiological Investigations of Myocardial Ischemia (PIMI) study who had documented coronary artery disease and exercise-induced ischemia. Participants underwent bicycle exercise and psychological stress testing with radionuclide imaging. Cardiac function data and psychological test results were collected. Vital status was ascertained by telephone and by querying Social Security records 3.5 +/- 0.4 years and 5.2 +/- 0.4 years later. Of the 17 participants who had died, new or worsened wall motion abnormalities during the speech test were present in 40% compared with 19% of survivors (P=0.04) and significantly predicted death (rate ratio=3.0, 95% Cl, 1.04 to 8.36; P=0.04). Ejection fraction changes during the speech test were similar in patients who died and in survivors (P=0.9) and did not predict death even after adjusting for resting ejection fraction (P=0.63), which was similar in both groups (mean, 56.4 versus 59.7; P=0.24). Other indicators of ischemia during the speech test (ST-segment depression, chest pain) did not predict death, nor did psychological traits, hemodynamic responses to the speech test, or markers of the presence and severity of ischemia during daily life and exercise. Conclusions-In patients with coronary artery disease and exercise-induced ischemia, the presence of mental stress-induced ischemia predicts subsequent death. C1 Univ Florida, Coll Med, Malcom Randall Vet Affairs Med Ctr, Gainesville, FL USA. Dept Vet Affairs, Med Res Serv, Gainesville, FL USA. Univ Maryland, Baltimore, MD 21201 USA. Johns Hopkins Univ, Baltimore, MD USA. St Louis Univ, Hlth Sci Ctr, St Louis, MO 63103 USA. Henry Ford Hosp, Detroit, MI 48202 USA. Univ Alabama, Birmingham, AL USA. Univ N Carolina, Chapel Hill, NC USA. Brigham & Womens Hosp, Uniformed Serv Univ Hlth Sci, Boston, MA 02115 USA. Maryland Med Res Inst, Baltimore, MD USA. NHLBI, Bethesda, MD 20892 USA. RP Sheps, DS (reprint author), Univ Florida, Hlth Sci Ctr, Dept Med, Div Cardiovasc Med, POB 100277, Gainesville, FL 32610 USA. RI McMahon, Robert/C-5462-2009; Krantz, David/L-5364-2015; OI Krantz, David/0000-0002-1671-1355; Sheffield, David/0000-0001-9121-1783 FU NHLBI NIH HHS [HV18114, HV18119, HV18120, HV18121, HV28127] NR 26 TC 133 Z9 136 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD APR 16 PY 2002 VL 105 IS 15 BP 1780 EP 1784 DI 10.1161/01.CIR.0000014491.90666.06 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 543XK UT WOS:000175127700011 PM 11956119 ER PT J AU Baxa, U Speransky, V Steven, AC Wickner, RB AF Baxa, U Speransky, V Steven, AC Wickner, RB TI Mechanism of inactivation on prion conversion of the Saccharomyces cerevisiae Ure2 protein SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GREEN FLUORESCENT PROTEIN; GLUTATHIONE S-TRANSFERASES; IN-VITRO; NUCLEAR-LOCALIZATION; GENE-EXPRESSION; SCRAPIE PRION; YEAST URE2P; DOMAIN; BARNASE; DETERMINANT AB The [URE3] infectious protein (prion) of Saccharomyces cerevisiae is a self-propagating amyloid form of Ure2p. The C-terminal domain of Ure2p controls nitrogen catabolism by complexing with the transcription factor, Gln3p, whereas the asparagine-rich N-terminal ''prion'' domain is responsible for amyloid filament formation (prion conversion). On filament formation, Ure2p is inactivated, reflecting either a structural change in the C-terminal domain or steric blocking of its interaction with Gln3p. We fused the prion domain with four proteins whose activities should not be sterically impeded by aggregation because their substrates are very small: barnase, carbonic anhydrase, glutathione S-transferase, and green fluorescent protein. All formed amyloid filaments in vitro, whose diameters increased with the mass of the appended enzyme. The helical repeat lengths were consistent within a single filament but varied with the construct and between filaments from a single construct. CID data suggest that, in the soluble fusion proteins, the prion domain has no regular secondary structure, whereas earlier data showed that in filaments, it is virtually all beta-sheet. In filaments, the activity of the appended proteins was at most mildly reduced, when substrate diffusion effects were taken into account, indicating that they retained their native structures. These observations suggest that the amyloid content of these filaments is confined to their prion domain-containing backbones and imply that Ure2p is inactivated in [URE3] cells by a steric blocking mechanism. C1 NIAMSD, Struct Biol Lab, Bethesda, MD 20892 USA. NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIAMSD, Struct Biol Lab, Bethesda, MD 20892 USA. NR 66 TC 122 Z9 122 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 16 PY 2002 VL 99 IS 8 BP 5253 EP 5260 DI 10.1073/pnas.082097899 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543DX UT WOS:000175087000097 PM 11959975 ER PT J AU Ribeiro-Neto, F Urbani, J Lemee, N Lou, LG Altschuler, DL AF Ribeiro-Neto, F Urbani, J Lemee, N Lou, LG Altschuler, DL TI On the mitogenic properties of Rap1b: cAMP-induced G(1)/S entry requires activated and phosphorylated Rap1b SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DEPENDENT PROTEIN-KINASE; DOG THYROID-CELLS; CYCLIC-AMP; EXCHANGE FACTOR; DNA-SYNTHESIS; THYROGLOBULIN EXPRESSION; SIGNALING PATHWAY; RAS-P21 GTPASE; GENE-PRODUCT; AMINO-ACIDS AB We have shown that the small GTPase Rap1b, a protein known to antagonize the mitogenic and transforming activity of Ras, is endowed with both mitogenic and tumorigenic properties. Rap1b can be activated by cAMP, an intracellular message known to either stimulate or inhibit cell proliferation. The oncogenic property of Rap1b was revealed in a model system in which cAMP stimulates cell proliferation and was linked to Rap's ability to promote S phase entry. We have now tested the significance of the mitogenic action of Rap1b in a physiologically relevant model, the differentiated thyroid follicular cells, a system that requires thyroid-stimulating hormone (TSH), acting via cAMP, to mediate a full mitogenic response. Here we report that cAMP-dependent hormonal stimulation of DNA synthesis requires Rap1b in a manner dependent on its phosphorylation by protein kinase A. C1 Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15261 USA. NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Altschuler, DL (reprint author), Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15261 USA. FU NCI NIH HHS [R29 CA071649, R01 CA071649] NR 52 TC 49 Z9 50 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 APR 16 PY 2002 VL 99 IS 8 BP 5418 EP 5423 DI 10.1073/pnas.082122499 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543DX UT WOS:000175087000125 PM 11959997 ER PT J AU Ro, HS Song, S Lee, KS AF Ro, HS Song, S Lee, KS TI Bfa1 can regulate Tem1 function independently of Bub2 in the mitotic exit network of Saccharomyces cerevisiae SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Cdc15; two-component GAP; budding yeast ID GTPASE-ACTIVATING PROTEIN; SPINDLE-POLE BODIES; BUDDING-YEAST; CELL-CYCLE; FISSION YEAST; CHECKPOINT PATHWAY; GAP COMPLEX; KINASE; MITOSIS; SEPTATION AB In budding yeast, exit from mitosis is achieved by inactivation of Cdc28/Clb2 activity. Although it is not clear at present how mitotic exit is triggered, a growing body of evidence suggests that the Tem1 GTPase plays a critical role in mediating this pathway and that Bfa1 and Bub2 constitute a two-component GTPase-activating protein to negatively regulate Tem1. Here, we have demonstrated that introduction of bfa1Delta suppresses the growth defects associated with the cdc5-1 mutation significantly better than that of bub2Delta, suggesting that Bfa1 may have a previously uncharacterized role in this pathway. Overexpression of BFA1 efficiently arrested the cell cycle at postanaphase even in the absence of BUB2, whereas overexpression of BUB2 weakly induced mitotic arrest only in the presence of BFA1. Coimmunoprecipitation and in vitro binding studies indicate that Bfa1 binds strongly to Tem1 independently of Bub2. Provision of GDP+AlF4-, which mimics the GTPase transition state, enhanced the Bub2-Tem1 interaction both in vitro and in vivo. Interestingly, introduction of bfa1Delta, but not bub2Delta, greatly increased the interaction between Tem1 and Cdc15, a step that is thought to be critical for activating the mitotic exit network. Our data suggest that, in addition to its role as a putative, two-component GTPase-activating protein with Bub2, Bfa1 also can play a role in the regulation of mitotic exit by directly inhibiting the interaction between Tem1 and Cdc15 even in the absence of Bub2. C1 NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lee, KS (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 37,Room 3D25, Bethesda, MD 20892 USA. NR 35 TC 29 Z9 30 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 APR 16 PY 2002 VL 99 IS 8 BP 5436 EP 5441 DI 10.1073/pnas.062059999 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543DX UT WOS:000175087000128 PM 11959999 ER PT J AU Maeda, R Ishimura, A Mood, K Park, EK Buchberg, AM Daar, IO AF Maeda, R Ishimura, A Mood, K Park, EK Buchberg, AM Daar, IO TI Xpbx1b and Xmeis1b play a collaborative role in hindbrain and neural crest gene expression in Xenopus embryos SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NUCLEAR-LOCALIZATION; TRANSCRIPTION FACTOR; MYELOID LEUKEMIAS; PBX PROTEINS; HOX PROTEINS; EXTRADENTICLE; DROSOPHILA; ZEBRAFISH; MEIS; HOMOTHORAX AB Pbx1 is a homeodomain protein that functions in complexes with other homeodomain-containing proteins to regulate gene expression during embryogenesis and oncogenesis. Pbx proteins bind DNA cooperatively as heterodimers or higher order complexes with Meis family members and Hox proteins and are believed to specify cell identity during development. Here, we present evidence that Pbx1, in partnership with Meis1b, can regulate posterior neural markers and neural crest marker genes during Xenopus development. A Xenopus homolog of the Pbx1b homeodomain protein was isolated and shown to be expressed throughout embryogenesis. Xpbx1b expression overlaps with Xmeis1 in several areas, including the lateral neural folds, caudal branchial arch, hindbrain, and optic cup. When ectopically expressed, Xpbx1b can synergize with Xmeis1b to promote posterior neural and neural crest gene expression in ectodermal explants. Further, a physical interaction between these two homeodomain proteins is necessary for induction of these genes in embryonic tissue. In addition, coexpression of Xmeis1b and Xpbx1b leads to a prominent shift in the localization of Xmeis1b from the cytoplasm to the nucleus, suggesting that nuclear transport or retention of Xmeis1b may depend upon Xpbx1b. Finally, expression of a mutant construct in which Xpbx1b protein is fused to the repressor domain from Drosophila Engrailed inhibits posterior neural and neural crest gene expression. These data indicate that Xpbx1b and its partner, Xmeis1b, function in a transcriptional activation complex during hindbrain and neural crest development. C1 NCI, Regulat Cell Growth Lab, Frederick, MD 21702 USA. Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. RP Daar, IO (reprint author), NCI, Regulat Cell Growth Lab, Bldg 560 Room 22-3, Frederick, MD 21702 USA. OI Buchberg, Arthur/0000-0002-0543-5631; Daar, Ira/0000-0003-2657-526X NR 44 TC 35 Z9 37 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 APR 16 PY 2002 VL 99 IS 8 BP 5448 EP 5453 DI 10.1073/pnas.082654899 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543DX UT WOS:000175087000130 PM 11960001 ER PT J AU Lyons, SE Lawson, ND Lei, L Bennett, PE Weinstein, BM Liu, PP AF Lyons, SE Lawson, ND Lei, L Bennett, PE Weinstein, BM Liu, PP TI A nonsense mutation in zebrafish gata1 causes the bloodless phenotype in vlad tepes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; 5-AMINOLEVULINATE SYNTHASE GENE; ZINC-FINGER; DNA-BINDING; STEM-CELLS; DIFFERENTIATION; HEMATOPOIESIS; EXPRESSION; PROMOTER; IDENTIFICATION AB Wad tepes (vlt(m651)) is one of only five "bloodless" zebrafish mutants isolated through large-scale chemical mutagenesis screening. It is characterized by a severe reduction in blood cell progenitors and few or no blood cells at the onset of circulation. We now report characterization of the mutant phenotype and the identification of the gene mutated in vlt(m651). Embryos homozygous for the vlt(m651) mutation had normal expression of hematopoietic stem cell markers through 24 h postfertilization, as well as normal expression of myeloid and lymphoid markers. Analysis of erythroid development revealed variable expression of erythroid markers. Through positional and candidate gene cloning approaches we identified a nonsense mutation in the gata1 gene, 1015C --> T (Arg-339 --> Stop), in vlt(m651). The nonsense mutation was located C-terminal to the two zinc fingers and resulted in a truncated protein that was unable to bind DNA or mediate GATA-specific transactivation. A BAC clone containing the zebrafish gata1 gene was able to rescue the bloodless phenotype in vlt(m651). These results show that the vlt(m651) mutation is a previously uncharacterized gata I allele in the zebrafish. The vlt(m651) mutation sheds new light on Gata1 structure and function in vivo, demonstrates that Gata1 plays an essential role in zebrafish hematopoiesis with significant conservation of function between mammals and zebrafish, and offers a powerful tool for future studies of the hematopoietic pathway. C1 NHGRI, NIH, Bethesda, MD 20892 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Liu, PP (reprint author), NHGRI, NIH, 49 Convent Dr,Room 3A18, Bethesda, MD 20892 USA. RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X NR 43 TC 90 Z9 90 U1 2 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 16 PY 2002 VL 99 IS 8 BP 5454 EP 5459 DI 10.1073/pnas.082695299 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543DX UT WOS:000175087000131 PM 11960002 ER PT J AU Zhang, JZ Rosenberg, HF AF Zhang, JZ Rosenberg, HF TI Complementary advantageous substitutions in the evolution of an antiviral RNase of higher primates SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID EOSINOPHIL-DERIVED NEUROTOXIN; RESPIRATORY SYNCYTIAL VIRUS; AMINO-ACID-SEQUENCES; CATIONIC PROTEIN; RIBONUCLEASE SUPERFAMILY; RAPID EVOLUTION; GENE SUPERFAMILY; FAMILY; SELECTION; RECONSTRUCTION AB An improved understanding of the evolution of gene function at the molecular level may provide significant insights into the origin of biological novelty and adaptation. With the approach of ancestral protein reconstruction, we here address the question of how a dramatically enhanced ribonucleolytic activity and the related antiviral activity evolved in a recently duplicated ribonuclease (eosinophil-derived neurotoxin) gene of higher primates. We show that the mother gene of the duplicated genes had already possessed a weak antiviral activity before duplication. After duplication, substitutions at two interacting sites (Arg-64-->Ser and Thr-132-->Arg) resulted in a 13-fold enhancement of the ribonucleolytic activity of eosinophil-derived neurotoxin. These substitutions are also necessary for the potent antiviral activity, with contributions from additional amino acid changes at interacting sites. Our observation that a change in eosinophil-derived neurotoxin function occurs only when both interacting sites are altered indicates the importance of complementary substitutions in protein evolution. Thus, neutral substitutions are not simply "noises" in protein evolution, as many have thought. They may play constructive roles by setting the intramolecular microenvironment for further complementary advantageous substitutions, which can lead to improved or altered function. Overall, our study illustrates the power of the "paleomolecular biochemistry" approach in delineating the complex interplays of amino acid substitutions in evolution and in identifying the molecular basis of biological innovation. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. RP Zhang, JZ (reprint author), NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 54 TC 72 Z9 83 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 APR 16 PY 2002 VL 99 IS 8 BP 5486 EP 5491 DI 10.1073/pnas.072626199 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543DX UT WOS:000175087000137 PM 11917138 ER PT J AU McCarron, P Okasha, M McEwen, J Smith, GD AF McCarron, P Okasha, M McEwen, J Smith, GD TI Height in young adulthood and risk of death from cardiorespiratory disease: A prospective study of male former students of Glasgow University, Scotland SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cardiovascular diseases; cohort studies; coronary disease; mortality; neoplasms ID BODY-MASS INDEX; MIDDLE-AGED MEN; CARDIOVASCULAR-DISEASE; FOLLOW-UP; AORTIC-ANEURYSMS; HEART-DISEASE; ENERGY-INTAKE; MORTALITY; CHILDHOOD; CANCER AB To investigate the association between height in young, socially homogeneous males and cause-specific mortality, the authors conducted a prospective study of 8,361 male former students who underwent medical examinations while attending Glasgow University, Scotland, from 1948 to 1968. The mean age at examination was 20.5 (range, 16.1-30.0) years. The median follow-up time was 41.3 years. There were 863 deaths. In Cox proportional hazards modeling, there was no association between height and all-cause mortality with age-adjusted hazard ratios per 10-cm increase in height (hazard ratio = 0.92, 95% confidence interval: 0.83, 1.02). Height was inversely associated with all cardiovascular disease and coronary heart disease mortality, with hazard ratios per 10-cm increase in height of 0.78 (95% confidence interval: 0.66, 0.93) and 0.76 (95% confidence interval: 0.62, 0.93), respectively. Sizeable inverse associations with stroke and respiratory disease were also found, although these did not reach conventional levels of significance. There was no association with cancer or noncardiorespiratory disease mortality. There was a positive, although nonsignificant, association between height and mortality from aortic aneurysm. Controlling for confounding variables had little effect on these results. The findings suggest that factors operating in early life, and which influence height, also influence future cardiovascular health in men. C1 NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ Bristol, Dept Social Med, Bristol, Avon, England. Univ Glasgow, Dept Publ Hlth, Glasgow, Lanark, Scotland. RP McCarron, P (reprint author), Queens Univ Belfast, Dept Epidemiol & Publ Hlth, N Ireland Canc Registry, Mulhouse Bldg,Grosvenor Rd, Belfast BT12 6BJ, Antrim, North Ireland. OI Monsalve, Beatriz Elena/0000-0002-5994-866X; Davey Smith, George/0000-0002-1407-8314 NR 36 TC 54 Z9 56 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 15 PY 2002 VL 155 IS 8 BP 683 EP 687 DI 10.1093/aje/155.8.683 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 548PE UT WOS:000175396900001 PM 11943683 ER PT J AU McCarron, P Okasha, M McEwen, J Smith, GD AF McCarron, P Okasha, M McEwen, J Smith, GD TI McCarron et al. Respond to "Height-Cardiovascular disease relation": Are all risk factors equal? SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID CORONARY HEART-DISEASE; BLOOD-PRESSURE; ADOLESCENT TRIAL; SERUM-LIPIDS; HEALTH CATCH; MIDDLE-AGE; OBESITY; LIPOPROTEINS; INTERVENTION; ASSOCIATION C1 NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ Bristol, Dept Social Med, Bristol, Avon, England. Univ Glasgow, Dept Publ Hlth, Glasgow, Lanark, Scotland. RP McCarron, P (reprint author), Queens Univ Belfast, Dept Epidemiol & Publ Hlth, N Ireland Canc Registry, Mulhouse Bldg,Grosvenor Rd, Belfast BT12 6BJ, Antrim, North Ireland. OI Monsalve, Beatriz Elena/0000-0002-5994-866X NR 25 TC 11 Z9 11 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 15 PY 2002 VL 155 IS 8 BP 690 EP 691 DI 10.1093/aje/155.8.690 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 548PE UT WOS:000175396900003 PM 11943685 ER PT J AU Greendale, GA FitzGerald, G Huang, MH Sternfeld, B Gold, E Seeman, T Sherman, S Sowers, M AF Greendale, GA FitzGerald, G Huang, MH Sternfeld, B Gold, E Seeman, T Sherman, S Sowers, M TI Dietary soy isoflavones and bone mineral density: Results from the Study of Women's Health Across the Nation SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE bone density; cohort studies; diet; genistein; isoflavones; menopause; soybeans; women ID FOOD FREQUENCY QUESTIONNAIRE; ESTROGEN-RECEPTOR-BETA; BREAST-CANCER INCIDENCE; FATTY-ACID INTAKE; PHYTO-ESTROGENS; HIP FRACTURE; PHYTOESTROGENS; BENEFITS; DATABASE; ALPHA AB Isoflavones are naturally occurring selective estrogen receptor modulators, with potential bone protective effects. To study the relation between soy isoflavone intake and bone mineral density (BMD), the authors analyzed baseline data from the Study of Women's Health Across the Nation, a US community-based cohort study of women aged 42-52 years. Their 1996-1997 analysis included African-American (n = 497), Caucasian (n = 1,003), Chinese (n = 200), and Japanese (n = 227) participants. Genistein and daidzein intakes were highly correlated (r = 0.98); therefore, analyses were conducted by using genistein. Median intakes of genistein (measured in micrograms/day) by African Americans and Caucasians were too low to pursue relational analyses further. For Chinese and Japanese women, median genistein intakes were 3,511 and 7,151 mug/day, respectively. Ethnic-specific, linear models were used to predict BMD as a function of energy-adjusted tertile of intake, controlled for relevant covariates. For Chinese women, no association between genistein and BMD was found. Premenopausal, but not perimenopausal, Japanese women whose intakes were greater had higher spine and femoral neck BMD. Adjusted mean spinal BMD of those in the highest tertile of intake was 7.7% greater than that of women in the lowest tertile (p = 0.02); femoral neck BMD was 12% greater in the highest versus the lowest tertile (p < 0.0001). C1 Univ Calif Los Angeles, Sch Med, Div Geriatr, Los Angeles, CA 90095 USA. New England Res Inst, Watertown, MA 02172 USA. Kaiser Permanente, Div Res, Oakland, CA USA. Univ Calif Davis, Sch Med, Dept Epidemiol & Prevent Med, Davis, CA 95616 USA. NIA, NIH, Bethesda, MD 20892 USA. Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. RP Greendale, GA (reprint author), Univ Calif Los Angeles, Sch Med, Div Geriatr, 10945 Le Conte Ave,Suite 2339, Los Angeles, CA 90095 USA. FU NIA NIH HHS [U01 AG12535, U01 AG12495, U01 AG12505, U01 AG12553, U01 AG12554]; NINR NIH HHS [U01 NR04061]; PHS HHS [U01 A12539] NR 39 TC 91 Z9 93 U1 2 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 15 PY 2002 VL 155 IS 8 BP 746 EP 754 DI 10.1093/aje/155.8.746 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 548PE UT WOS:000175396900011 PM 11943693 ER PT J AU Koch, CA Chrousos, GP Chandra, R Evangelista, RS Gilbert, JC Nobuhara, K Zhuang, ZP Vortmeyer, AO AF Koch, CA Chrousos, GP Chandra, R Evangelista, RS Gilbert, JC Nobuhara, K Zhuang, ZP Vortmeyer, AO TI Two-hit model for tumorigenesis of nevoid basal cell carcinoma (Gorlin) syndrome-associated hepatic mesenchymal tumor SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Letter ID ENDOCRINE NEOPLASIA TYPE-1; ANGIOFIBROMAS C1 NINCDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Pathol, Washington, DC 20010 USA. Childrens Natl Med Ctr, Dept Pediat Surg, Washington, DC 20010 USA. RP Vortmeyer, AO (reprint author), NINCDS, Surg Neurol Branch, NIH, Bldg 10,Rm 5D37, Bethesda, MD 20892 USA. RI Koch, Christian/A-4699-2008; OI Koch, Christian/0000-0003-3127-5739; Koch, Christian/0000-0003-0678-1242 NR 12 TC 5 Z9 5 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD APR 15 PY 2002 VL 109 IS 1 BP 74 EP 76 DI 10.1002/ajmg.10301 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 536MB UT WOS:000174702900013 PM 11932998 ER PT J AU Peebles, RS Hashimoto, K Morrow, JD Dworski, R Collins, RD Hashimoto, Y Christman, JW Kang, KH Jarzecka, K Furlong, J Mitchell, DB Talati, M Graham, BS Sheller, JR AF Peebles, RS Hashimoto, K Morrow, JD Dworski, R Collins, RD Hashimoto, Y Christman, JW Kang, KH Jarzecka, K Furlong, J Mitchell, DB Talati, M Graham, BS Sheller, JR TI Selective cyclooxygenase-1 and-2 inhibitors each increase allergic inflammation and airway hyperresponsiveness in mice SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE airway hyperresponsiveness; cyclooxygenase; IL-1 3; ovalbumin ID INHALED PGE(2); INDUCED BRONCHOCONSTRICTION; STIMULATED RELEASE; CYTOKINE SECRETION; PROSTAGLANDIN E(2); ASTHMA; IL-4; INTERLEUKIN-13; LYMPHOCYTES; CHEMOKINES AB Nonselective cyclooxygenase (COX) inhibition during allergic sensitization with ovalbumin in a murine model leads to an increase in the Type 2 cytokines interleukin-5 (IL-5) and IL-13; however, the effect of selective COX-1 and COX-2 inhibitors on these cytokines is unknown. We found that COX-1 protein was constitutively expressed in lung tissue. Expression of COX-1 protein did not increase with ovalbumin sensitization, but expression of COX-2 protein did. Ovalbumin-sensitized mice treated with either selective COX-1 inhibitor SC58560 (OVA-COX-1 inhibitor) or selective COX-2 inhibitor SC58236 (OVA-COX-2 inhibitor) had significantly greater airway hyperresponsiveness (p < 0.05) and higher levels of IL-13 (p < 0.05) in lung supernatants than did untreated mice that were ovalbumin sensitized (OVA). Lung mRNA levels for the chemokine receptors CCR1 through CCR5 (expressed on eosinophils, basophils, lymphocytes, and dendritic cells) were increased in the OVA-COX-2 inhibitor and OVA-indomethacin groups. We conclude that in the BALB/c mouse, COX inhibition with either a COX-1 or COX-2 inhibitor during allergen sensitization augments production of IL-13 and increases airway hyperresponsiveness. C1 Vanderbilt Univ, Med Ctr, Ctr Lung Res, Sch Med,Dept Med, Nashville, TN 37215 USA. Vanderbilt Univ, Sch Med, Dept Pathol, Nashville, TN 37215 USA. NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Peebles, RS (reprint author), Vanderbilt Univ, Med Ctr, Ctr Lung Res, Sch Med,Dept Med, T-1217 MCN, Nashville, TN 37215 USA. FU NCI NIH HHS [CA 77839]; NHLBI NIH HHS [K08-HL03730]; NIAID NIH HHS [R01-AI-45512]; NIDDK NIH HHS [DK 26657, DK 48831]; NIGMS NIH HHS [GM 15431] NR 34 TC 82 Z9 82 U1 0 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD APR 15 PY 2002 VL 165 IS 8 BP 1154 EP 1160 DI 10.1164/rccm.2106025 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 542CX UT WOS:000175026900024 PM 11956061 ER PT J AU Mittal, A Leikina, E Bentz, J Chernomordik, LV AF Mittal, A Leikina, E Bentz, J Chernomordik, LV TI Kinetics of influenza hemagglutinin-mediated membrane fusion as a function of technique SO ANALYTICAL BIOCHEMISTRY LA English DT Article ID CELL-CELL FUSION; OCTADECYLRHODAMINE DEQUENCHING ASSAY; TRANSMEMBRANE DOMAIN; COILED COILS; EARLY-STAGE; VIRUS-CELL; FLUORESCENCE; LIPIDS; PORE; PH AB Reliable techniques are required to evaluate the plausibility of proposed membrane fusion mechanisms. Here we have studied the kinetics of establishing the lipidic connection between hemagglutinin-expressing cells (HA-cells) and red blood cells (RBC) labeled with octadecylrhodamine, R18, using three different experimental approaches: (1) the most common approach of monitoring the rate of the R18 de-quenching in a cuvette with a suspension of RBC/HA-cell complexes; (2) video fluorescence microscopy (VFM) to detect the waiting times before the onset of R18 redistribution, not dequenching, for each RBC attached to an adherent HA-cell; and (3) a new approach based on blockage of RBC fusion to an adherent HA-cell at different time points by lysophosphatidylcholine (LPC), so that only the cell pairs which, at the time of LPC application, had fused or were irreversibly committed to fusion contributed to the final extent of lipid mixing. The LPC blockage and VFM gave very similar estimates for the fusion kinetics, with LPC monitoring also those sites committed to the lipid mixing process. In contrast, R18 dequenching in the cuvette was much slower, i.e., it monitors a much later stage of dye redistribution. C1 Drexel Univ, Dept Biosci & Biotechnol, Philadelphia, PA 19104 USA. NICHHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Chernomordik, LV (reprint author), Bldg 10,Room 10D04,10 Ctr Dr,MSC 1855, Bethesda, MD 20892 USA. RI Mittal, Aditya/E-3087-2010 OI Mittal, Aditya/0000-0002-4030-0951 NR 38 TC 14 Z9 14 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD APR 15 PY 2002 VL 303 IS 2 BP 145 EP 152 DI 10.1006/abio.2002.5590 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 544TT UT WOS:000175177800005 PM 11950214 ER PT J AU Hicks, JE Drinkard, B Sunmers, RM Rider, LG AF Hicks, JE Drinkard, B Sunmers, RM Rider, LG TI Decreased aerobic capacity in children with juvenile dermatomyositis SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article DE juvenile dermatomyositis; inflammatory myopathies; aerobic capacity; exercise ID IDIOPATHIC INFLAMMATORY MYOPATHIES; VALIDATED DISEASE-ACTIVITY; POLYMYOSITIS/DERMATOMYOSITIS PATIENTS; DAMAGE INDEXES; GAS-EXCHANGE; EXERCISE; MUSCLE; CHILDHOOD; ABNORMALITIES; POLYMYOSITIS AB Objective. To determine whether patients with juvenile dermatomyositis (DM) have limited aerobic capacity compared with healthy controls. Methods. Fourteen juvenile DM patients with inactive to moderately active, stable disease (age range 7-17 years) and 14 age- and sex-matched controls performed a maximal exercise test using a cycle ergometer. Oxygen uptake and power were measured at peak exercise (VO2peak and W-peak, respectively) and at anaerobic threshold (AT and W-AT). Juvenile DM disease activity and damage were also assessed. Results. Patients with juvenile DM had significantly reduced VO2peak (19.6 ml O-2/kg/minute in juvenile DM versus 31.1 ml O-2/kg/minute in controls), peak heart rate (166 versus 184 beats per minute), W-peak (1.6 versus 2.7 watts/kg), AT (11.1 versus 18.0 ml O-2/kg/minute) and W-AT (0.6 versus 1.4 watts/kg), compared to controls (P less than or equal to 0.05 for each). Aerobic exercise parameters correlated with physician global disease activity and damage, T1-weighted magnetic resonance imaging, and Childhood Myositis Assessment Scale scores (r(s) = 0.58 - 0.82, P less than or equal to 0.05). Conclusion. Patients with juvenile DM with a range of disease activity have a decreased aerobic and work capacity compared to healthy children. Aerobic exercise limitation in juvenile DM correlates best with measures of disease damage (global damage assessment, T1-weighted magnetic resonance imaging, and disease duration). Aerobic exercise testing may be valuable in the assessment of physical endurance, and aerobic training may be indicated as part of the therapeutic regimen in myositis patients with inactive to moderately active, stable disease. C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. NIAMS, Arthrit & Rheumatism Branch, NIH, Bethesda, MD USA. US FDA, Ctr Biol Evaluat & Res, Div Monoclonal Antibodies, Bethesda, MD USA. RP Drinkard, B (reprint author), NIH, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 65235, Bethesda, MD 20892 USA. OI Rider, Lisa/0000-0002-6912-2458 NR 37 TC 27 Z9 27 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 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD APR 15 PY 2002 VL 47 IS 2 BP 118 EP 123 DI 10.1002/art1.10237 PG 6 WC Rheumatology SC Rheumatology GA 540UN UT WOS:000174948100004 PM 11954004 ER PT J AU Brennan, MT Sankar, V Leakan, RA Kleiner, D Atkinson, JC Wilkinson, WE Baum, BJ Pillemer, SR AF Brennan, MT Sankar, V Leakan, RA Kleiner, D Atkinson, JC Wilkinson, WE Baum, BJ Pillemer, SR TI Risk factors for positive minor salivary gland biopsy findings in Sjogren's syndrome and dry mouth patients SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article DE Sjogren's syndrome; biopsy; immunoglobulins; diagnostic tests ID CLASSIFICATION; ASSOCIATION; XEROSTOMIA; FEATURES; CRITERIA; SICCA AB Objective. To investigate risk factors for positive minor salivary gland biopsy results in Sjogren's syndrome (SS) and dry mouth patients. Methods. A total of 289 patients with dry mouth symptoms were evaluated. Potential risk factors for positive minor salivary gland biopsy results (>1 focus of lymphocytes) were studied in 2 phases. In phase 1, predictor variable candidates were identified for the test study (phase 2). Odds ratios were calculated for predictor variables. Results. IgG, IgA, keratoconjunctivitis sicca, and sex, identified as the best predictor variables from phase 1 data, were included in a logistic regression model using phase 2 data. Only IgG demonstrated association with biopsy results (chi(2) = 20.4, P = 0.0001). An elevated IgG level (>1,482 mg/dl) had a high specificity (97% and 97%), high positive predictive value (PPV) (97% and 97%), but poor sensitivity (40% and 45%) in predicting positive biopsy results and SS, respectively. Conclusion. Elevated serum IgG levels best predicted a positive biopsy result and SS with high PPV and specificities. C1 NIDCR, NIH, Bethesda, MD USA. NIH, Clin Ctr Nursing, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Maryland, Baltimore, MD 21201 USA. Duke Univ, Med Ctr, Durham, NC USA. RP Brennan, MT (reprint author), Carolinas Med Ctr, Dept Oral Med, 1000 Blythe Blvd,MEB-409, Charlotte, NC 28232 USA. OI Kleiner, David/0000-0003-3442-4453 NR 19 TC 16 Z9 16 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD APR 15 PY 2002 VL 47 IS 2 BP 189 EP 195 DI 10.1002/art1.10219 PG 7 WC Rheumatology SC Rheumatology GA 540UN UT WOS:000174948100013 PM 11954013 ER PT J AU van der Heijde, D Simon, L Smolen, J Strand, V Sharp, J Boers, M Breedveld, F Weisman, M Weinblatt, M Rau, R Lipsky, P AF van der Heijde, D Simon, L Smolen, J Strand, V Sharp, J Boers, M Breedveld, F Weisman, M Weinblatt, M Rau, R Lipsky, P TI How to report radiographic data in randomized clinical trials in rheumatoid arthritis: Guidelines from a roundtable discussion SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article ID PROGRESSION C1 Univ Hosp Maastricht, Dept Internal Med, Div Rheumatol, NL-6202 AZ Maastricht, Netherlands. Harvard Univ, Sch Med, Boston, MA USA. Univ Vienna, Vienna Gen Hosp, Vienna, Austria. Stanford Univ, San Francisco, CA USA. Univ Washington, Sch Med, Seattle, WA USA. Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. Leiden Univ, Med Ctr, Leiden, Netherlands. Univ Calif Los Angeles, Los Angeles, CA USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Evangel Fachkrankenhaus, Ratingen, Germany. NIAMSD, NIH, Bethesda, MD 20892 USA. RP van der Heijde, D (reprint author), Univ Hosp Maastricht, Dept Internal Med, Div Rheumatol, POB 5800, NL-6202 AZ Maastricht, Netherlands. NR 13 TC 89 Z9 89 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 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD APR 15 PY 2002 VL 47 IS 2 BP 215 EP 218 DI 10.1002/art1.10181 PG 4 WC Rheumatology SC Rheumatology GA 540UN UT WOS:000174948100017 PM 11954017 ER PT J AU Shimizu, C Fuda, H Lee, YC Strott, CA AF Shimizu, C Fuda, H Lee, YC Strott, CA TI Transcriptional regulation of human 3 '-phosphoadenosine 5 '-phosphosulphate synthase 2 SO BIOCHEMICAL JOURNAL LA English DT Article DE adenosine 5 '-phosphosulphate kinase; ATP-sulphurylase; sulphoconjugation; sulphonation ID GENE-EXPRESSION REGULATION; REPRESS TRANSCRIPTION; MOLECULAR-CLONING; SP-FAMILY; ACTIVATION; PROMOTER; DOMAINS; PROTEIN; KINASE; SYNTHETASE AB Sulphonation is a fundamental process that is essential for normal growth and development as well as maintenance of the internal milieu. The universal sulphonate donor molecule essential for all sulphoconjugation reactions is adenosine 3'-phosphate 5'-phosphosulphate (PATS), which is produced from ATP and inorganic sulphate by the action of bifunctional PAPS synthase. There are two isozymes encoded by genes located on chromosome 4 (PAPS synthase 1) and chromosome 10 (PAPS synthase 2). The promoter for PAPS synthase 2 contains neither a TATAAA nor a CCAAT box, although a consensus initiator motif is present. Three human cell lines were used to examine promoter activity after transfection with various lengths of the 5'-flanking region of the PAPS synthase 2 gene fused to a reporter gene. Proximal promoter activity was located between bp - 84 and bp - 124 upstream of the purported transcription start site. This region contains two GC/GT boxes that are essential for full promoter activity, as indicated by deletion analysis and supported further by mutagenesis. A nuclear extract of SW13 cells, which highly express PAIRS synthase 2, contained proteins that bound to probes possessing promoter-specific GC/GT boxes. Furthermore, the presence of specificity protein (Sp) 1, Sp2 and Sp3 proteins in the nuclear extract was confirmed by supershift analysis. Co-transfection experiments using SL2 cells yielded additional support for the involvement of Sp1 in transcriptional regulation of the PAPS synthase 2 gene; the involvement of Sp2 and/or Sp3 remains to be clarified further. C1 NICHHD, Sect Steroid Regulat, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Strott, CA (reprint author), NICHHD, Sect Steroid Regulat, Endocrinol & Reprod Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 30 TC 6 Z9 6 U1 0 U2 0 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD APR 15 PY 2002 VL 363 BP 263 EP 271 DI 10.1042/0264-6021:3630263 PN 2 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 545BH UT WOS:000175196000007 PM 11931653 ER PT J AU Qian, SY Chen, YR Deterding, LJ Fann, YC Chignell, CF Tomer, KB Mason, RP AF Qian, SY Chen, YR Deterding, LJ Fann, YC Chignell, CF Tomer, KB Mason, RP TI Identification of protein-derived tyrosyl radical in the reaction of cytochrome c and hydrogen peroxide: characterization by ESR spin-trapping, HPLC and MS SO BIOCHEMICAL JOURNAL LA English DT Article DE ESI mass spectrometry; on-line HPLC/ESR; radical identification; tandem mass spectrometry ID TANDEM MASS-SPECTROMETRY; FAST-ATOM-BOMBARDMENT; LIQUID-CHROMATOGRAPHY; LIPID-PEROXIDATION; MITOCHONDRIAL GENERATION; SOYBEAN LIPOXYGENASE; SUPEROXIDE-DISMUTASE; RESONANCE DETECTION; HEART-MITOCHONDRIA; ADDUCTS AB The reaction of cytochrome e and H2O2 is known to form a protein-centred radical that can be detected with the spin trap 2-methyl-2-nitrosopropane (MNP). To characterize the MNP/tyrosyl adduct structure that had previously been determined incorrectly [Barr, Gunther, Deterding, Tomer and Mason (1996) J. Biol. Chem. 271, 15498-15503], we eliminated unreasonable structure models by ESR studies with a series of C-13-labelled tyrosines, and photochemically synthesized an authentic MNP/tyrosyl adduct that has its trapping site on the C-3 position of the tyrosine phenyl ring. The observation of the identical ESR spectra for this radical adduct from the UV irradiation of 3-iodotyrosine and the adduct from the cytochrome c reaction demonstrated that the radical trapping site of MNP/tyrosyl is located on the equivalent C-3/C-5 positions instead of the C-1 position, as was proposed by Barr et al. In an on-line HPLC/ESR system, an identical retention time (17.7 min) was observed for the ESR-active HPLC peak of the MNP/tyrosyl adduct from the following three reactions: (i) the tyrosine oxidation via horseradish peroxidase/H2O2; (ii) UV irradiation of 3-iodo-tyrosine and (iii) the reaction of cytochrome c with H2O2. This result demonstrated that the radical adducts of all three reactions are most probably the same. The mass spectrometric analysis of the HPLC fractions from reactions (i) and (ii) showed an ion at m/z 267 attributed to the MNP/tyrosyl adduct. We conclude that the cytochrome c-derived tyrosyl radical was trapped by MNP, leading to a persistent radical adduct at the C-3/C-5 positions of the tyrosine phenyl ring. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Qian, SY (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Tomer, Kenneth/E-8018-2013 NR 38 TC 51 Z9 53 U1 1 U2 7 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD APR 15 PY 2002 VL 363 BP 281 EP 288 DI 10.1042/0264-6021:3630281 PN 2 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 545BH UT WOS:000175196000009 PM 11931655 ER PT J AU Wan, WS DePetrillo, PB AF Wan, WS DePetrillo, PB TI Ritonavir inhibition of calcium-activated neutral proteases SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE calpain; enzyme inhibitors; ritonavir; PC12 cell; HIV protease ID CALPAIN INHIBITOR; CASPASE-3 ACTIVATION; NEURONAL DAMAGE; PC12 CELLS; APOPTOSIS; ISCHEMIA; INJURY; RAT; PROTEOLYSIS; MDL-28170 AB Calpains (EC 3.4.22.17) are intracellular calcium-activated cysteine proteases that mediate tissue injury following post-ischemic and post-traumatic stress. Both human HIV protease and calpains share a similar secondary structure, where the active site is flanked by hydrophobic regions. The present study demonstrates that ritonavir, a hydrophobic HIV protease inhibitor, also inhibits calpain activity. In PC12 cell extracts assayed for calpain at maximal activity (2 mM calcium), ritonavir exhibited competitive inhibition with a K-i of 11 +/- 7.0 muM Experiments with purified enzymes showed inhibition for both m- and mu-calpain isoforms (m-calpain, K-i = 9.2 +/- 1.2 muM; mu-calpain, K-i = 5.9 +/- 1.4 muM). Ritonavir also inhibited calcium-stimulated calpain activity in PC12 cells in situ. These results suggest that ritonavir or analogues of the drug should be investigated as cytoprotective agents in conditions where cell death or injury is mediated via calpain activation. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NIAAA, Clin Studies Lab, Unit Clin & Biochem Pharmacol, Div Intramural Clin & Biochem Res,NIH, Bethesda, MD 20892 USA. RP DePetrillo, PB (reprint author), NIAAA, Clin Studies Lab, Unit Clin & Biochem Pharmacol, Div Intramural Clin & Biochem Res,NIH, 10-3C103,10 Ctr Dr MSC 1256, Bethesda, MD 20892 USA. NR 25 TC 22 Z9 24 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 APR 15 PY 2002 VL 63 IS 8 BP 1481 EP 1484 AR PII S0006-2952(02)00907-3 DI 10.1016/S0006-2952(02)00907-3 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 566GY UT WOS:000176419600012 PM 11996889 ER PT J AU Miller, FG Rosenstein, DL Roca, CA AF Miller, FG Rosenstein, DL Roca, CA TI Independent capacity assessment in psychiatric research SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIH, CC Bioeth, Bethesda, MD 20892 USA. NIMH, OCD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 8 BP 2S EP 3S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400005 ER PT J AU McDougle, C Scahill, L McCracken, JT Aman, MG Tierney, E Arnold, E Vitiello, B AF McDougle, C Scahill, L McCracken, JT Aman, MG Tierney, E Arnold, E Vitiello, B TI Therapeutic use of atypical antipsychotic in children with autism SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 Indiana Univ, Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90024 USA. Kennedy Krieger Inst, Dept Psychiat, Baltimore, MD USA. Ohio State Univ, Dept Psychiat, Sunbury, OH USA. NIMH, Div Serv & Intervent Res, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 9 BP 3S EP 3S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400006 ER PT J AU Pine, DS AF Pine, DS TI Mood disorders and the developing brain: What can MRI teach us? SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 21 BP 7S EP 7S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400018 ER PT J AU Pine, DS AF Pine, DS TI Examining developmental relationships among attention, memory, neural function, and HPA activity SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 20 BP 7S EP 7S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400017 ER PT J AU Lipska, BK Halim, N Weinberger, DR AF Lipska, BK Halim, N Weinberger, DR TI Transient disconnection of the hippocampus in the neonatal rat as a model of schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, CBDB, IRP, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 25 BP 9S EP 9S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400022 ER PT J AU Rapoport, JL Vidal, C Thompson, P Gogtay, N Toga, A AF Rapoport, JL Vidal, C Thompson, P Gogtay, N Toga, A TI Dynamic pattern of accelerated gray matter loss in childhood onset schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA 90024 USA. RI Gogtay, Nitin/A-3035-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 30 BP 10S EP 10S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400027 ER PT J AU Guido, GKW Meltzer, CC Price, J Drevets, WC Greer, P Mathis, C Kaye, WH AF Guido, GKW Meltzer, CC Price, J Drevets, WC Greer, P Mathis, C Kaye, WH TI Alterations of 5HT1A and 2A receptors persist after recovery from anorexia and bulimia nervosa SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15260 USA. NIMH, Mood & Anxiety Disorders Imaging Sect, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 33 BP 11S EP 11S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400030 ER PT J AU Bremner, JD Vythilingam, M Vermetten, E McGlashan, T Southwick, SM Charney, DS AF Bremner, JD Vythilingam, M Vermetten, E McGlashan, T Southwick, SM Charney, DS TI Neural correlates of memory for emotional words in abuserelated PTSD SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 Emory Univ, Sch Med, Atlanta, GA USA. NIMH, Mood & Anxiety Disorders Res Program, Bethesda, MD 20892 USA. Yale Univ, Sch Med, New Haven, CT USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 40 BP 14S EP 14S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400037 ER PT J AU Bertolino, A Altamura, M Brudaglio, F Sciota, D Blasi, G Bellomo, A Antonucci, N Callicott, JH Scarabino, T Weinberger, DR Nardini, M AF Bertolino, A Altamura, M Brudaglio, F Sciota, D Blasi, G Bellomo, A Antonucci, N Callicott, JH Scarabino, T Weinberger, DR Nardini, M TI Specific relationship between N-acetylaspartate levels in dorsolateral prefrontal cortex and working memory in schizophreniform disorder SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. IRCCSS, Dept Neuroradiol, Foggia, Italy. Univ Bari, Dept Psychiat & Neurol Sci, I-70121 Bari, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 52 BP 18S EP 18S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400049 ER PT J AU Du, J Choudhuri, R Manji, HK AF Du, J Choudhuri, R Manji, HK TI Internalization of ionotropic glutamate receptors glur1 and glur2/3 in response to dexamethasone in cultured hippocampal neuron SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 89 BP 30S EP 30S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400085 ER PT J AU Konstantinidis, A Stastny, J Neumeister, A Winkler, D Thierry, N Hilger, E Heiden, A Praschak-Rieder, N Willeit, M Kasper, S AF Konstantinidis, A Stastny, J Neumeister, A Winkler, D Thierry, N Hilger, E Heiden, A Praschak-Rieder, N Willeit, M Kasper, S TI Gender differences in wintersad outpatients SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 Univ Vienna, Dept Gen Psychiat, Vienna, Austria. NIMH, Mood & Anxiety Disorders Res Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 95 BP 32S EP 32S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400091 ER PT J AU Gray, NA Du, J Yuan, PX Chen, G Manji, H AF Gray, NA Du, J Yuan, PX Chen, G Manji, H TI Chronic treatment with moodstabilizers increases synapsin phosphorylation in rat hippocampus SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, Mol Pathophysiol Lab, Detroit, MI USA. RI Chen, Guang/A-2570-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 102 BP 34S EP 35S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400098 ER PT J AU Vythilingam, M Vermetten, E Anderson, E Norris, S Staib, L Bronen, R Charney, DS Bremner, JD AF Vythilingam, M Vermetten, E Anderson, E Norris, S Staib, L Bronen, R Charney, DS Bremner, JD TI Hippocampal volume in patients with major depression without childhood trauma SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Cent Mil Hosp, Utrecht, Netherlands. Yale Univ, Sch Med, New Haven, CT USA. Emory Univ, Sch Med, Atlanta, GA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 101 BP 34S EP 34S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400097 ER PT J AU Gould, TD Du, J Yuan, P Chen, G Manji, HK AF Gould, TD Du, J Yuan, P Chen, G Manji, HK TI Evidence suggesting activation of the Wnt signaling pathway in rat brain after lithium and valproic acid administration SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 Natl Inst Hlth, Lab Mol Pathophysiol, Bethesda, MD USA. Wayne State Univ, Mol Pathophysiol Program, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 117 BP 39S EP 39S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400112 ER PT J AU O'Donnell, P Lewis, BL Weinberger, DR Lipska, BK AF O'Donnell, P Lewis, BL Weinberger, DR Lipska, BK TI Neonatal hippocampal damage alters physiological response properties to VTA stimulation in the adult rat prefrontal cortex SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 Albany Med Coll, Ctr Neuropharmacol & Neurosci, Albany, NY USA. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 180 BP 61S EP 61S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400174 ER PT J AU Sanacora, G Berman, RM Zimolo, Z Cappiello, A Charney, DS AF Sanacora, G Berman, RM Zimolo, Z Cappiello, A Charney, DS TI Combining yohimbine and fluoxetine in the treatment of depression SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, New Haven, CT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 201 BP 68S EP 68S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400195 ER PT J AU Tohen, M Baker, RW Altshuler, L Zarate, CA Suppes, T Ketter, TA Risser, RC Juliar, BE Luther, MF Gilmore, JA AF Tohen, M Baker, RW Altshuler, L Zarate, CA Suppes, T Ketter, TA Risser, RC Juliar, BE Luther, MF Gilmore, JA TI Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: A 47-week study SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat, Belmont, MA 02178 USA. Univ Calif Los Angeles, Neuropsychiat Inst & Hosp, Los Angeles, CA 90024 USA. NIMH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX USA. Stanford Univ, Stanford, CA 94305 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 208 BP 70S EP 70S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400202 ER PT J AU Sharrief, AZ Harrington, ME Burton, F AF Sharrief, AZ Harrington, ME Burton, F TI Circadian gene expression linked to compulsive behaviors: Differential effects of transgenic manipulation and cocaine administration on Per1 expression SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Smith Coll, Dept Psychol, Northampton, MA 01063 USA. Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 237 BP 80S EP 80S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400231 ER PT J AU Smith, MJ Jean-Mary, J Grafman, J Murphy, DL Wassermann, EM AF Smith, MJ Jean-Mary, J Grafman, J Murphy, DL Wassermann, EM TI Abnormal cortical excitability in motor learning in OCD SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NINCDS, Brain Stimulat Unit, Bethesda, MD 20892 USA. NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 239 BP 81S EP 81S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400233 ER PT J AU Castellanos, FX Sharp, W Giedd, JN Greenstein, DK Gottesman, R Rapoport, JL AF Castellanos, FX Sharp, W Giedd, JN Greenstein, DK Gottesman, R Rapoport, JL TI Anatomic brain MRI in monozygotic twins discordant for Attention deficit hyperactivity disorder (ADHD) SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NYU, Sch Med, Ctr Child Study, New York, NY USA. NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 246 BP 83S EP 83S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400240 ER PT J AU Little, JT Ketter, TA Kimbrell, TA Dunn, RT Benson, BE Willis, MW Luckenbaugh, DA Post, RM AF Little, JT Ketter, TA Kimbrell, TA Dunn, RT Benson, BE Willis, MW Luckenbaugh, DA Post, RM TI Pretreatment regional cerebral metabolism and antidepressant response to bupropion and venlafaxine SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 257 BP 87S EP 87S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400251 ER PT J AU Malhotra, AK Egan, M Lipsky, RH Bilder, RM Goldberg, TE AF Malhotra, AK Egan, M Lipsky, RH Bilder, RM Goldberg, TE TI The COMT Val158Met polymorphism and human cognitive function SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 Hillside Hosp, Glen Oaks, NY 11004 USA. NIMH, CBDB, Bethesda, MD 20892 USA. NIAAA, Lab Neurogenet, Rockville, MD 20852 USA. Nathan S Kline Inst Psychiat Res, CABI, Orangeburg, NY 10962 USA. RI Bilder, Robert/A-8894-2008 OI Bilder, Robert/0000-0001-5085-7852 NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 278 BP 95S EP 95S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400267 ER PT J AU Pine, DS AF Pine, DS TI Psychobiology of stress in children SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 282 BP 96S EP 96S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400270 ER PT J AU Bowley, MP Drevets, WC Ongur, D Price, JL AF Bowley, MP Drevets, WC Ongur, D Price, JL TI Low glial numbers in the amygdala and entorhinal cortex in mood disorders SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 Washington Univ, Sch Med, St Louis, MO USA. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 287 BP 97S EP 98S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400275 ER PT J AU Charney, DS AF Charney, DS TI Biology of PTSD in adults SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 285 BP 97S EP 97S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400273 ER PT J AU Berman, KF Schmidt, P Meyer-Lindenberg, A Olsen, RK Danaceau, M Weinberger, DR Rubinow, D AF Berman, KF Schmidt, P Meyer-Lindenberg, A Olsen, RK Danaceau, M Weinberger, DR Rubinow, D TI Brain imaging studies of the effects of gonadal steroids on human neural function SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Unit Integrat Neuroimaging, NIH, IRP, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, NIH, IRP, Bethesda, MD 20892 USA. NIMH, Behav Endocrinol Branch, NIH, IRP, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 292 BP 99S EP 99S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400280 ER PT J AU Lopez, JF Higley, JD AF Lopez, JF Higley, JD TI The effect of early experience on brain corticosteroid and serotonin receptors in rhesus monkeys SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 Univ Michigan, Psychiat & Mental Hlth Res Inst, Ann Arbor, MI 48109 USA. NIAAA, Clin Studies Lab, Primate Unit, Bethesda, MD USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 294 BP 100S EP 100S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400282 ER PT J AU Weickert, CS Tomascovick-Crook, E Herman, MM Hyde, TM Kleinman, JE AF Weickert, CS Tomascovick-Crook, E Herman, MM Hyde, TM Kleinman, JE TI Estrogen receptor in schizophrenia: In the wrong place at the right time SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 293 BP 100S EP 100S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400281 ER PT J AU Drevets, WC Thase, M Frank, E Price, JC Mathis, C Kupfer, DJ AF Drevets, WC Thase, M Frank, E Price, JC Mathis, C Kupfer, DJ TI Serotonin type-1A receptor imaging in unipolar and bipolar depression SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Mol Imaging Branch, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 300 BP 102S EP 102S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400288 ER PT J AU Callicott, JH Egan, MF Goldberg, TE Dryden, EA Verchinski, BA Kolachana, B Fera, F Coppola, R Mattay, VS Weinberger, DR AF Callicott, JH Egan, MF Goldberg, TE Dryden, EA Verchinski, BA Kolachana, B Fera, F Coppola, R Mattay, VS Weinberger, DR TI COMT Val(108/158)Met polymorphism effects DLPFC efficiency in healthy individuals SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, CBDB, NIH, Bethesda, MD 20892 USA. NIH, LDRR, CC, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 308 BP 105S EP 105S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400296 ER PT J AU Sokolov, BP Polesskaya, OO AF Sokolov, BP Polesskaya, OO TI Mechanisms of differential expression of the "C" and "T" alleles of the 5-HT2A receptor gene. Possible role for allele specific methylation SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIDA, Mol Neuropsychiat Sect, NIH, Baltimore, MD USA. NIDA, Mol Neurobiol Branch, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 349 BP 119S EP 119S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400337 ER PT J AU Wilson, J Kupfer, DJ Thase, M Bogers, W Greer, P Drevets, WC AF Wilson, J Kupfer, DJ Thase, M Bogers, W Greer, P Drevets, WC TI Ventral striatal metabolism is increased in depression, and decreases with treatment SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 358 BP 122S EP 123S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400346 ER PT J AU Chen, G Einat, H Yuan, P Manji, HK AF Chen, G Einat, H Yuan, P Manji, HK TI Evidence for the involvement of the MAPK/ERK signaling pathway in mood modulation SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, LMP, Detroit, MI USA. NIMH, Unit Mol Neurotherapeut, LMP, MAP,NIH, Bethesda, MD 20892 USA. RI Chen, Guang/A-2570-2017 NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 368 BP 126S EP 126S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400356 ER PT J AU Coryell, WH Fyer, AJ Pine, DS AF Coryell, WH Fyer, AJ Pine, DS TI Characteristics of individuals at high risk for panic disorder SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Bethesda, MD 20892 USA. Columbia Univ, New York, NY USA. Univ Iowa, Iowa City, IA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 371 BP 127S EP 127S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400359 ER PT J AU Einat, H Chen, G Manji, HK AF Einat, H Chen, G Manji, HK TI Does the ERK map kinase signaling cascade play a role in the pathophysiology and treatment of bipolar disorder? SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. RI Chen, Guang/A-2570-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 376 BP 128S EP 128S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400364 ER PT J AU Khin, NA Buerger, K Wagner, J Bauer, L Geraci, M Cannon-Spoor, E Hampel, H Sunderland, T AF Khin, NA Buerger, K Wagner, J Bauer, L Geraci, M Cannon-Spoor, E Hampel, H Sunderland, T TI Circulating levels of interleukin-6, IL-6sR and gp130 in Traumatic Grief SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Geriatr Psychiat Branch, Bethesda, MD 20892 USA. Univ Munich, Dept Psychiat, D-8000 Munich, Germany. NIH, Dept Nursing, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 405 BP 138S EP 138S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400393 ER PT J AU Yao, JK Hibbeln, JR Thomas, EA Glen, L Mahadik, SP Peet, M AF Yao, JK Hibbeln, JR Thomas, EA Glen, L Mahadik, SP Peet, M TI Arachidonic acid signaling in schizophrenia: Pathophysiological and treament implications SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 VA Pittsburgh Healthcare Syst, Med Res Serv, Pittsburgh, PA USA. VA Pittsburgh Healthcare Syst, Dept Psychiat, Pittsburgh, PA USA. Western Psychiat Inst & Clin, Pittsburgh, PA USA. NIAAA, Lab Memb Biochem & Biophys, NIH, Rockville, MD USA. Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. Craig Dunain Hosp, Highland Psychiat Res Grp, Inverness, Scotland. Med Coll Georgia, Dept Psychiat & Hlth Behav, Augusta, GA 30912 USA. No Gen Hosp, Dept Psychiat, Sheffield S5 7AU, S Yorkshire, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 431 BP 147S EP 148S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400414 ER PT J AU Greenhill, LL Fisher, P Mosholder, A Heiligenstein, J Vitiello, B AF Greenhill, LL Fisher, P Mosholder, A Heiligenstein, J Vitiello, B TI Approaches to standardizing safety data collection in pediatric psychopharmacology SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 Columbia Univ, New York State Psychiat Inst, New York, NY USA. US FDA, Div Neuropharmacol Drug Prod, Rockville, MD 20857 USA. Lilly Corp Ctr, Global Neurosci, Indianapolis, IN USA. NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 432 BP 148S EP 148S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400415 ER PT J AU Manji, H Zhou, R Rohlff, C Chen, G AF Manji, H Zhou, R Rohlff, C Chen, G TI Genomic studies identify novel targets for the long term actions of mood stabilizers SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. Oxford Glycosci, Oxford, England. RI Chen, Guang/A-2570-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 439 BP 150S EP 150S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400422 ER PT J AU Winterer, G AF Winterer, G TI Schizophrenia: Reduced signal-to-noise ratio and impaired phase-locking during information processing SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Clin Brain Disorder Branch, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 445 BP 151S EP 152S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400428 ER PT J AU Innis, RB Hargreaves, R Charney, DS AF Innis, RB Hargreaves, R Charney, DS TI Pet studies of CNS neurokinin-1 (NK-1) receptors in living human brain SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Bethesda, MD 20892 USA. Merck & Co Inc, Merck Res Labs, W Point, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 454 BP 155S EP 155S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400437 ER PT J AU Drevets, WC Thase, M Bogers, W Phil, G David, KJ AF Drevets, WC Thase, M Bogers, W Phil, G David, KJ TI Glucose metabolic correlates of depression severity and antidepressant treatment response SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Mol Imaging Branch, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 513 BP 176S EP 176S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400496 ER PT J AU Neumeister, A Stastny, J Konstantinidis, A Kasper, S Schwarz, MJ Vitouch, O Rosenthal, NE AF Neumeister, A Stastny, J Konstantinidis, A Kasper, S Schwarz, MJ Vitouch, O Rosenthal, NE TI Effects of monoamine depletion on immune parameters in remitted depressed patients SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Univ Vienna, Dept Gen Psychiat, Vienna, Austria. Univ Munich, Dept Neurochem, Munich, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 519 BP 178S EP 178S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400502 ER PT J AU Zhou, R Damschroder-Williams, PJ Yuan, P Chen, G Manji, HK AF Zhou, R Damschroder-Williams, PJ Yuan, P Chen, G Manji, HK TI Valproate, an anticonvulsant and mood-stablizing agent suppresses death genes and induces cell survival genes SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. WSU, Detroit, MI USA. RI Chen, Guang/A-2570-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 539 BP 185S EP 185S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400522 ER PT J AU Gould, TD Li, JL Yuan, PX Chen, G Manji, HK AF Gould, TD Li, JL Yuan, PX Chen, G Manji, HK TI Postmortem interval alters phosphoprotein and total protein levels in the rat frontal cortex and hippocampus SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. Wayne State Univ, Mol Pathophysiol Program, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 547 BP 187S EP 188S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400529 ER PT J AU Linker, G Mirza, N Manetti, G Sunderland, T AF Linker, G Mirza, N Manetti, G Sunderland, T TI Fine-needle, negative-pressure lumbar puncture: A safe technique for collecting CSF SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Geriatr Psychiat Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 SU S MA 574 BP 197S EP 198S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 541JA UT WOS:000174980400556 ER PT J AU Bartzokis, G Beckson, M Lu, PH Edwards, N Bridge, P Mintz, J AF Bartzokis, G Beckson, M Lu, PH Edwards, N Bridge, P Mintz, J TI Brain maturation may be arrested in chronic cocaine addicts SO BIOLOGICAL PSYCHIATRY LA English DT Article DE brain; aging; maturation; cocaine; addiction; white matter; myelin; gray matter; frontal lobe; temporal lobe ID CEREBRAL BLOOD-FLOW; MAGNETIC-RESONANCE; WHITE-MATTER; GRAY-MATTER; ALZHEIMERS-DISEASE; IN-VIVO; ABUSERS; MRI; AGE; CORTEX AB Background: Animal and human newborn studies suggest that exposure to cocaine in utero delays glial maturation and white matter myelination. Postmortem data show that in the frontal and temporal lobes, white matter myelination continues into middle age. Recent magnetic resonance imaging (MRI) data have confirmed continued white matter volume increase in these regions, reaching a maximum at age 47. Methods: Thirty-seven male cocaine dependent (CD) and 52 normal control subjects between ages 19 and 47 were evaluated with MRI. Coronal images focused on the frontal and temporal lobes were acquired using pulse sequences that maximized gray/white matter contrast. Results: Highly significant positive correlations between white matter volume and age were observed in both the frontal and temporal lobes of the control group (r = .52, p = .0001 and r = .54, p = .0001, respectively); however, CD subjects did not demonstrate any age-related increase in white matter volume of the frontal (r = -.001; p = .99) and temporal (r = -.07; p = .67) lobes in this age range. Conclusions: The age-related expansion in white matter volume occurring in normal control subjects was absent in CD subjects. The findings suggest that in adults, cocaine dependence may arrest normal white matter maturation in the frontal and temporal lobes of addicts who continue using cocaine. (C) 2002 Society of Biological Psychiatry. C1 Cent Arkansas Vet Healthcare Syst, Little Rock, AR USA. Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. Greater Los Angeles VA Healthcare Syst, Los Angeles, CA USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90024 USA. NIDA, Med Dev Div, Rockville, MD USA. RP Bartzokis, G (reprint author), 710 Westwood Plaza,Room 2-238, Los Angeles, CA 90095 USA. RI Bartzokis, George/K-2409-2013 FU NIDA NIH HHS [1Y01 DA 50038]; NIMH NIH HHS [MH 51928] NR 50 TC 56 Z9 56 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 BP 605 EP 611 AR PII S0006-3223(02)01315-X DI 10.1016/S0006-3223(02)01315-X PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 540XN UT WOS:000174956300001 PM 11955460 ER PT J AU Stine, SM Southwick, SM Petrakis, IL Kosten, TR Charney, DS Krystal, JH AF Stine, SM Southwick, SM Petrakis, IL Kosten, TR Charney, DS Krystal, JH TI Yohimbine-induced withdrawal and anxiety symptoms in opioid-dependent patients SO BIOLOGICAL PSYCHIATRY LA English DT Article DE methadone; noradrenergic; opioid; yohimbine; hormone; HPA axis ID METHADONE-MAINTAINED PATIENTS; LOCUS COERULEUS NEURONS; COCAINE ABUSE; OPIATE-WITHDRAWAL; CHRONIC MORPHINE; M-CHLOROPHENYLPIPERAZINE; PSYCHIATRIC-DIAGNOSIS; DESIPRAMINE TREATMENT; CORTISOL-LEVELS; BETA-ENDORPHIN AB Background: Alteration in noradrenergic regulation as well as alteration in the hypothalamic-pituitary-adrenal (HPA) axis have been associated with opioid dependence and acute abstinence symptoms. Methods: This double-blind, placebo-controlled study evaluated subjective, physiologic, and biochemical responses to yohimbine (.4 mg/kg, IV) in eight patients receiving methadone and compared results to those from a pool of nine healthy volunteers. All subjects were compared for panic anxiety symptom scale (PASS) scores, systolic and diastolic blood pressure, heart rate, plasma 3-methoxy-4 hydroxyphenethyleneglycol (MHPG), and cortisol. Results: Yohimbine elicited objective and subjective opioid withdrawal and elevated craving for opioid drugs in methadone patients. Significant yohimbine effects were seen across the combined subject group for PASS, physiologic measures, MHPG, and cortisol. Methadone patients had lower baseline MHPG levels. Methadone group interactions with yohimbine were seen for systolic blood pressure and cortisol levels. Conclusions: Methadone-maintained patients are sensitive to the postsynaptic effects of noradrenergic-facilitating medications, experiencing greater physiologic and psychological symptoms, including an increase in craving. The effect on cortisol supports the above conclusion and is consistent with HPA axis perturbation in opioid dependence as reported in other studies and extends these observations to stable methadone-maintained patients. Medications that increase synaptic noradrenaline should be used with care in opioid-dependent patients. (C) 2002 Society of Biological Psychiatry. C1 Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, Detroit, MI 48207 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. VA Med Ctr, Psychiat Serv, West Haven, CT USA. NIMH, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20892 USA. RP Stine, SM (reprint author), Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, 2761 E Jefferson Ave, Detroit, MI 48207 USA. OI Stine, Susan/0000-0001-5426-4448 FU NIAAA NIH HHS [1K02 AA 00261]; NIDA NIH HHS [P50 DA 04060, P50 DA 09250] NR 64 TC 68 Z9 68 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2002 VL 51 IS 8 BP 642 EP 651 AR PII S0006-3223(01)01292-6 DI 10.1016/S0006-3223(01)01292-6 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 540XN UT WOS:000174956300005 PM 11955464 ER PT J AU Wilson, WH Grossbard, ML Pittaluga, S Cole, D Pearson, D Drbohlav, N Steinberg, SM Little, RF Janik, J Gutierrez, M Raffeld, M Staudt, L Cheson, BD Longo, DL Harris, N Jaffe, ES Chabner, BA Wittes, R Balis, F AF Wilson, WH Grossbard, ML Pittaluga, S Cole, D Pearson, D Drbohlav, N Steinberg, SM Little, RF Janik, J Gutierrez, M Raffeld, M Staudt, L Cheson, BD Longo, DL Harris, N Jaffe, ES Chabner, BA Wittes, R Balis, F TI Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy SO BLOOD LA English DT Article ID NON-HODGKINS-LYMPHOMA; PROGNOSTIC-SIGNIFICANCE; INTERMEDIATE-GRADE; PROMACE-CYTABOM; DRUG-RESISTANCE; DOXORUBICIN; THERAPY; TRIAL; VINCRISTINE; INTENSITY AB We hypothesized that incremental improvements in the cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) chemotherapy regimen through optimization of drug selection, schedule, and pharmacokinetics would improve outcome in patients with large B-cell lymphomas. A prospective multi-institutional study of administration of etoposide, vincristine, and doxorubicin for 96 hours with bolus doses of cyclophosphamide and oral prednisone (EPOCH therapy) was done in 50 patients with previously untreated large B-cell lymphomas. The doses of etoposide, doxorubicin, and cyclophosphamide were adjusted 20% each cycle to achieve a nadir absolute neutrophil count below 0.5 x 10(9)/L. The median age of the patients was 46 years (range, 20-88 years); 24% were older than 60 years; and 44% were at high-intermediate or high risk according to International Prognostic Index (IPI) criteria. There was a complete response in 92% of patients, and at the median follow-up time of 62 months, the progression-free survival (PFS) and overall survival (OS) rates were 70% and 73%, respectively. Neither IPI risk factors nor the index itself was associated with response, PFS, or OS. Doses were escalated in 58% of cycles, and toxicity levels were tolerable. Significant inverse correlations were observed between dose intensity and age for all adjusted agents, and drug clearance of doxorubicin and free etoposide was also inversely correlated with age (r = -0.54 and P-2 = .08 and r = -0.45 and P-2 = .034, respectively). Free-etoposide clearance increased significantly during successive cycles (P-2 = .015). Lymphomas with proliferation of at least 80% had somewhat lower progression and those expressing bcl-2 had significantly higher progression (P-2 = .04). Expression of bcl-2 may discriminate the recently described activated B-like from germinal-center B-like large-cell lymphomas and provide important pathobiologic and prognostic information. Dose-adjusted EPOCH may produce more cell kill than CHOP-based regimens. Dynamic dose adjustment may overcome inadequate drug concentrations, particularly in younger patients, and compensate for increased drug clearance overtime. (C) 2002 by The American Society of Hematology. C1 NCI, Canc Res Ctr, Med Branch, Bethesda, MD 20892 USA. Holy Cross Hosp, Ft Lauderdale, FL USA. St Lukes Roosevelt Hosp, New York, NY 10025 USA. Beth Israel Med Ctr, New York, NY 10003 USA. NIA, Baltimore, MD 21224 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Wilson, WH (reprint author), NCI, Canc Res Ctr, Med Branch, Bldg 10,Room 12N-226,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 45 TC 125 Z9 130 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 15 PY 2002 VL 99 IS 8 BP 2685 EP 2693 DI 10.1182/blood.V99.8.2685 PG 9 WC Hematology SC Hematology GA 539JJ UT WOS:000174866500007 PM 11929754 ER PT J AU Salvucci, O Yao, L Villalba, S Sajewicz, A Pittaluga, S Tosato, G AF Salvucci, O Yao, L Villalba, S Sajewicz, A Pittaluga, S Tosato, G TI Regulation of endothelial cell branching morphogenesis by endogenous chemokine stromal-derived factor-1 SO BLOOD LA English DT Article ID HEMATOPOIETIC PROGENITOR CELLS; GROWTH-FACTOR; BONE-MARROW; FACTOR-I; RECEPTOR CXCR4; FUNCTIONAL EXPRESSION; BASEMENT-MEMBRANE; B-CELLS; ANGIOGENESIS; LOCALIZATION AB The chemokine stromal-derived factor-1 (SDF-1) and its unique receptor, CXCR4, are required for normal cardiovascular development, but a critical role for SDF-1 In postnatal vascular remodeling and the mechanisms underlying SDF-1/CXCR-4 vasculogenesis are unclear. Here we show that SDF-1 is expressed by the vascular endothellum from selected healthy and tumor tissues. In vitro, primary endothelial cells constitutively express SDF-1 that is detected in the cytoplasm, on the cell surface, and in the culture supernatant. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) increase SDF-1 expression In endothelial cells. In functional studies, pertussis toxin and antibodies to SDF-1 or CXCR-4 disrupt extracellular matrix-dependent endothelial cell tube formation In vitro. This morphogenic process Is associated with time-dependent modulation of surface CXCR-4 expression that changes from being diffuse to being polarized and subsequently lost. In vivo, pertussis toxin and neutralizing antibodies directed at SDF-1 inhibit growth factor-dependent neovascularization. These results indicate that SDF-1/CXCR-4 identifies VEGF and bFGF-regulated autocrine signaling systems that are essential regulators of endothelial cell morphogenesis and angiogenesis. (C) 2002 by The American Society of Hematology. C1 NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Salvucci, O (reprint author), NCI, Expt Transplantat & Immunol Branch, Bldg 10,Rm 12N226,MSC 1907, Bethesda, MD 20892 USA. NR 56 TC 242 Z9 277 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 15 PY 2002 VL 99 IS 8 BP 2703 EP 2711 DI 10.1182/blood.V99.8.2703 PG 9 WC Hematology SC Hematology GA 539JJ UT WOS:000174866500009 PM 11929756 ER PT J AU Okamoto, Y Douek, DC McFarland, RD Koup, RA AF Okamoto, Y Douek, DC McFarland, RD Koup, RA TI Effects of exogenous interleukin-7 on human thymus function SO BLOOD LA English DT Article ID BONE-MARROW TRANSPLANTATION; T-CELL DEVELOPMENT; RECEPTOR-GAMMA-CHAIN; SEVERE COMBINED IMMUNODEFICIENCY; NATURAL-KILLER-CELLS; IMMUNE RECONSTITUTION; DENDRITIC CELLS; IN-VIVO; DEFICIENT MICE; GROWTH-FACTOR AB Immune reconstitution is a critical component of recovery after treatment of human immunodeficiency virus (HIV) infection, cancer chemotherapy, and hematopoietic stem cell transplantation. The ability to enhance T-cell production would benefit such treatment. We examined the effects of exogenous interleukin-7 (IL-7) on apoptosis, proliferation, and the generation of T-cell receptor rearrangement excision circles (TRECs) in human thymus. Quantitative polymerase chain reaction demonstrated that the highest level of TRECs (14 692 copies/10 000 cells) was present in the CD1a(+)CD3(-)CD4(+)CD8(+) stage in native thymus, suggesting that TREC generation occurred following the cellular division in this subpopulation. In a thymic organ culture system, exogenous IL-7 increased the TREC frequency in fetal as well as infant thymus, indicating increased T-cell receptor (TCR) rearrangement. Although this increase could be due to the effect of IL-7 to increase thymocyte proliferation and decrease apoptosis of immature CD3(-) cells, the in vivo experiments using NOD/LtSz-scid mice given transplants of human fetal thymus and liver suggested that IL-7 can also directly enhance TREC generation. Our results provide compelling evidence that IL-7 has a direct effect on increasing TCR-alphabeta rearrangement and indicate the potential use of IL-7 for enhancing de novo naive T-cell generation in immunocompromised patients. (C) 2002 by The American Society of Hematology. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Dept Expt Transplantat & Immunol, Med Branch, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Koup, RA (reprint author), NIAID, Vaccine Res Ctr, NIH, Rm 3502,40 Convent Dr, Bethesda, MD 20892 USA. NR 71 TC 102 Z9 105 U1 1 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 15 PY 2002 VL 99 IS 8 BP 2851 EP 2858 DI 10.1182/blood.V99.8.2851 PG 8 WC Hematology SC Hematology GA 539JJ UT WOS:000174866500028 PM 11929775 ER PT J AU Wojda, U Noel, P Miller, JL AF Wojda, U Noel, P Miller, JL TI Fetal and adult hemoglobin production during adult erythropoiesis: coordinate expression correlates with cell proliferation SO BLOOD LA English DT Article ID GLOBIN GENE-EXPRESSION; HUMAN ERYTHROID-CELLS; PERIPHERAL-BLOOD; TRANSPLANTATION; MATURATION; INDUCTION; COLONIES; LOCUS AB The design and evaluation of therapies for the sickle cell and beta-thalassemia syndromes rely on our understanding of hemoglobin accumulation during human erythropoiests. Here we report direct measurements of hemoglobin composition and messenger RNA (mRNA) levels In cultured CD34(+) cells and correlate those measurements with studies of freshly obtained bone marrow samples. Hemoglobin levels in differentiating cells were also compared with morphologic, immunophenotypic, and cell cycle assessments. A population of large preproerythroblasts was first identified within 24 hours and became the dominant population by day 5. The transition from proerythroblast to basophilic normoblast occurred later, from days 7 to 9, and correlated with a peak of 74.1% +/- 3.9% of the cells in the S phase of cell cycle. Orthochromatic normoblasts were the dominant and final cell type by day 13. High-performance liquid chromatography-based quantitation of fetal (HbF) and adult (HbA) hemoglobin and real-time polymerase chain reaction globin mRNA quantitation demonstrated a coordinate rise in the accumulation of both proteins and mRNA among these developmentally staged populations. Quantitative analyses on freshly sorted bone marrow populations demonstrated a similar rising pattern with p-globin and HbA as the dominant species at both early and late stages of differentiation. We found no evidence for HbF dominant populations or switching during differentiation in adult cells. Instead, rapid Increases In both HbF (heterocellular) and HbA (pancellular) content were observed, which coincided with the apex in cell cycling and the proerythroblast-basophilic normoblast transition. Based on these measurements, we conclude that HbF and HbA content are regulated with the rate of proliferation during adult erythropoiesis. (Blood. 2002;99: 3005-3013). (C) 2002 by The American Society of Hematology. C1 NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. NIH, Dept Lab Med, Hematol Serv, Bethesda, MD USA. RP Miller, JL (reprint author), NIDDKD, Biol Chem Lab, NIH, Bldg 10,Rm 9B17, Bethesda, MD 20892 USA. RI Wojda, Urszula/M-6079-2015 OI Wojda, Urszula/0000-0002-4525-2004 NR 34 TC 62 Z9 64 U1 1 U2 11 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 15 PY 2002 VL 99 IS 8 BP 3005 EP 3013 PG 9 WC Hematology SC Hematology GA 539JJ UT WOS:000174866500046 PM 11929793 ER PT J AU Luo, J Zha, S Gage, WR Dunn, TA Hicks, JL Bennett, CJ Ewing, CN Platz, EA Ferdinandusse, S Wanders, RJ Trent, JM Isaacs, WB De Marzo, AM AF Luo, J Zha, S Gage, WR Dunn, TA Hicks, JL Bennett, CJ Ewing, CN Platz, EA Ferdinandusse, S Wanders, RJ Trent, JM Isaacs, WB De Marzo, AM TI alpha-Methylacyl-CoA racemase: A new molecular marker for prostate cancer SO CANCER RESEARCH LA English DT Article ID EXPRESSION; CARCINOMA AB Identification of genes that are dysregulated in association with prostate carcinogenesis can provide disease markers and clues relevant to disease etiology. Of particular interest as candidate markers of disease are those genes that are frequently overexpressed. In this study, we describe a gene, alpha-methylacyl-CoA racemase (AMACR), whose expression is consistently up-regulated in prostate cancer. Analysis of mRNA levels of AMACR revealed an average up-regulation of similar to9 fold in clinical prostate cancer specimens compared with normal. Western blot and immunohistochemical analysis confirms the up-regulation at the protein level and localizes the enzyme predominantly to the peroxisomal compartment of prostate cancer cells. A detailed immunohistochemical analysis of samples from 168 primary prostate cancer cases using both standard slides and tissue microarrays demonstrates that both prostate carcinomas and the presumed precursor lesion (high-grade prostatic intraepithelial neoplasia) consistently scored significantly higher than matched normal prostate epithelium; 88% of the carcinomas had a staining score higher than the highest score observed for any sample of normal prostate epithelium. Both untreated metastases (n = 32 patients) and hormone refractory prostate cancers (n = 14 patients) were generally strongly positive for AMACR. To extend the utility of this marker for prostate cancer diagnosis, we combined staining for cytoplasmic AMACR with staining for the nuclear protein, P63, a basal cell marker in the prostate that is absent in prostate cancer. In a simple assay that can be useful for the diagnosis of prostate cancer on both biopsy and surgical specimens, combined staining for p63 and AMACR resulted in a staining pattern that greatly facilitated the identification of malignant prostate cells. The enzyme encoded by the AMACR gene plays a critical role in peroxisomal beta oxidation of branched chain fatty acid molecules. These observations could have important epidemiological and preventive implications for prostate cancer, as the main sources of branched chain fatty acids are dairy products and beef, the consumption of which has been associated with an increased risk for prostate cancer in multiple studies. On the basis of its consistency and magnitude of cancer cell-specific expression, we propose AMACR as an important new marker of prostate cancer and that its use in combination with p63 staining will form the basis for an improved staining method for the identification of prostate carcinomas. Furthermore, the absence of AMACR staining in the vast majority of normal tissues coupled with its enzymatic activity makes AMACR the ideal candidate for development of molecular probes for the noninvasive identification of prostate cancer by imaging modalities. C1 Johns Hopkins Univ, Sch Med, Brady Urol Inst, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Univ Amsterdam, Acad Med Ctr, Emma Childrens Hosp, Dept Pediat, NL-1105 AZ Amsterdam, Netherlands. RP Isaacs, WB (reprint author), Johns Hopkins Univ Hosp, Marburg 115,600 N Wolfe St, Baltimore, MD 21287 USA. FU NCI NIH HHS [CA 58236, CA 78588] NR 27 TC 360 Z9 398 U1 2 U2 24 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 APR 15 PY 2002 VL 62 IS 8 BP 2220 EP 2226 PG 7 WC Oncology SC Oncology GA 543ML UT WOS:000175105700004 PM 11956072 ER PT J AU Russell, JS Raju, U Gumin, GJ Lang, FF Wilson, DR Huet, T Tofilon, PJ AF Russell, JS Raju, U Gumin, GJ Lang, FF Wilson, DR Huet, T Tofilon, PJ TI Inhibition of radiation-induced nuclear factor-kappa B activation by an anti-Ras single-chain antibody fragment: Lack of involvement in radiosensitization SO CANCER RESEARCH LA English DT Article ID TUMOR-CELL LINES; SIGNAL-TRANSDUCTION PATHWAY; IONIZING-RADIATION; INTRACELLULAR EXPRESSION; MEDIATED EXPRESSION; NECROSIS-FACTOR; K-RAS; TRANSFORMATION; RESISTANCE; ONCOGENES AB We have shown previously that the transduction of a number of human tumor cell lines with an adenovirus (AV1Y28) expressing a single-chain antibody fragment (scFv) directed against Ras proteins results in radio-sensitization. Because Ras is involved in the regulation or a number of transcription factors, we have determined the effects of this adenovirus on the activation of nuclear factor-kappaB (NF-kappaB), a radiation-responsive transcription factor associated with cell survival. In U251 human glioma cells. radiation-induced NF-kappaB was significantly attenuated by prior transduction of the anti-Ras scFv adenovirus. This effect appeared to involve an inhibition of IkappaB kinase activity and IkappaBalpha phosphorylation. Inhibitors to the Ras effectors mitogen-activated protein kinase kinase, phosphatidylinositol 3-kinase, and p38, however, did not reduce radiation-induced NF-kappaB. Whereas AV1Y28 inhibited NF-kappaB activation by hydrogen peroxide and ferricyanide, it had no effect of tumor necrosis factor-alpha-induced NF-kappaB activation. These results are consistent with a novel Ras-dependent, oxidant-specific signaling pathway mediating the activation of NF-kappaB. In additional cell lines radiosensitized by AV1Y28, radiation-induced NF-kappaB activation was also inhibited by the anti-Ras scFv, whereas in cell lines not radiosensitized. radiation did not activate NF-kappaB. This correlation suggested that AV1Y28-mediated radiosensitization involved the inhibition of radiation-induced NF-kappaB activation. However, inhibition of NF-kappaB activation via the expression of a dominant-negative form of IkappaBalpha in U251 cells had no effect on radiation-induced cell killing and did not influence AV1Y28-mediated radiosensitization. Therefore, whereas AV1Y28 inhibits radiation-induced NF-kappaB activation, this process does not appear to play a direct role in its radiosensitizing actions. C1 NCI, Radiat Oncol Sci Program, Mol Radiat Therapy Branch, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Exptl Radiat Oncol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA. Introgen Therapeut Inc, Houston, TX 77054 USA. Aventis Pharmaceut, Hayward, CA 94540 USA. RP Tofilon, PJ (reprint author), NCI, Radiat Oncol Sci Program, Mol Radiat Therapy Branch, EPN-6015A,6130 Execut Blvd,MSC 7440, Bethesda, MD 20892 USA. NR 47 TC 37 Z9 40 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 APR 15 PY 2002 VL 62 IS 8 BP 2318 EP 2326 PG 9 WC Oncology SC Oncology GA 543ML UT WOS:000175105700022 PM 11956090 ER PT J AU Skotheim, RI Monni, O Mousses, S Fossa, SD Kallioniemi, OP Lothe, RA Kallioniemi, A AF Skotheim, RI Monni, O Mousses, S Fossa, SD Kallioniemi, OP Lothe, RA Kallioniemi, A TI New insights into testicular germ cell tumorigenesis from gene expression profiling SO CANCER RESEARCH LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; FOCAL ADHESION KINASE; ESOPHAGEAL-CARCINOMA; PROSTATE-CANCER; FACTOR-RECEPTOR; BREAST-CANCER; TUMORS; GRB7; ASSOCIATION; PROTEIN AB We have shown recently that about half of the human TGCTs(3) reveal DNA copy number increases affecting two distinct regions on chromosome arm 17q. To identify, potential target genes with elevated expressions attributable to the extra copies, we constructed a cDNA microarray containing 636 genes and expressed sequence tags from chromosome 17. The expression patterns of 14 TGCTs, 1 carcinoma in situ, and 3 normal testis samples were examined, all with known chromosome 17 copy numbers. The growth factor receptor-bound protein 7 (GRB7) and junction plakoglobin (JUP) were the two most highly overexpressed genes in the TGCTs. GRB7 is tightly linked to ERBB2 and is coamplified and coexpressed with this gene in several cancer types. Interestingly, the expression levels of ERBB2 were not elevated in the TGCTs, suggesting that GRB7 might be the target for the increased DNA copy number in TGCTs. Because of the limited knowledge of altered gene expression in the development of TGCTs, we also examined the expression levels of 512 additional genes located throughout the genome. Several genes novel to testicular tumorigenesis were consistently up- or down-regulated, including, overexpression POV1, MYCL1, MYBL2, MXI1, and DNMT2. Additionally of the proto-oncogenes CCND2 and MYCN were confirmed from the literature. The overexpressions were for some of the target genes closely associated to either seminoma or nonseminoma TGCTs, and hierarchical cluster analysis of the gene expression data effectively distinguished among the known histological subtypes. In summary, this focused functional genomic characterization of TGCTs has lead to the identification of new gene targets associated with a common genomic rearrangement as well as other genes with potential importance to testicular tumorigenesis. C1 Norwegian Radium Hosp, Dept Genet, Canc Res Inst, N-0310 Oslo, Norway. Norwegian Radium Hosp, Dept Genet, Canc Res Inst, N-0310 Oslo, Norway. Norwegian Radium Hosp, Dept Radiotherapy & Oncol, N-0310 Oslo, Norway. Biomed Helsinki, Biomed Biochip Ctr, FIN-00290 Helsinki, Finland. NHGRI, Canc Genet Brach, NIH, Bethesda, MD 20892 USA. Univ Tampere, Inst Med Technol, Canc Genet Lab, FIN-33520 Tampere, Finland. Tampere Univ Hosp, FIN-33520 Tampere, Finland. RP Norwegian Radium Hosp, Dept Genet, Canc Res Inst, N-0310 Oslo, Norway. EM rlothe@radium.uio.no RI Kallioniemi, Olli/H-5111-2011; Kallioniemi, Olli/H-4738-2012; OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Anne/0000-0003-3552-8158 NR 55 TC 122 Z9 127 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD APR 15 PY 2002 VL 62 IS 8 BP 2359 EP 2364 PG 6 WC Oncology SC Oncology GA 543ML UT WOS:000175105700029 PM 11956097 ER PT J AU Heselmeyer-Haddad, K Chaudhri, N Stoltzfus, P Cheng, JC Wilber, K Morrison, L Auer, G Ried, T AF Heselmeyer-Haddad, K Chaudhri, N Stoltzfus, P Cheng, JC Wilber, K Morrison, L Auer, G Ried, T TI Detection of chromosomal aneuploidies and gene copy number changes in fine needle aspirates is a specific, sensitive, and objective genetic test for the diagnosis of breast cancer SO CANCER RESEARCH LA English DT Article ID FLUORESCENCE INSITU HYBRIDIZATION; COMPARATIVE GENOMIC HYBRIDIZATION; TUMORS; VISUALIZATION; AMPLIFICATION; ABERRATIONS AB Fine needle aspiration cytology is central to the evaluation of clinically or mammographically detected suspicious lesions of the breast. On the basis of results from studies of >500 breast cancers by comparative genomic hybridization we have developed protocols and designed probe sets that allow one to visualize recurrent chromosomal aneuploidies, amplification of oncogenes, and deletion of tumor suppressor genes directly in cytological preparations using multicolor fluorescence in situ hybridization. The fluorescence in situ hybridization probes are specific for chromosome arm 1q, the c-MYC and HER2 oncogenes, the tumor suppressor gene p53 and, as controls for chromosome ploidy of each cell, the centromeres of chromosomes 8, 10, and 17. Application of these diagnostic mixtures to 20 invasive breast cancers, 7 mastopathias, and 2 fibroadenomas demonstrates that a highly sensitive, specific, and objective diagnosis of breast cancer is now possible on cytological preparations obtained by minimally invasive fine needle aspiration. C1 NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Karolinska Inst, Ctr Canc, S-17176 Stockholm, Sweden. Vysis Inc, Downers Grove, IL 60515 USA. RP Ried, T (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, 50 S Dr,Bldg 50,Room 1306, Bethesda, MD 20892 USA. NR 21 TC 24 Z9 25 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 APR 15 PY 2002 VL 62 IS 8 BP 2365 EP 2369 PG 5 WC Oncology SC Oncology GA 543ML UT WOS:000175105700030 PM 11956098 ER PT J AU Kopp, JB Falloon, J Filie, A Abati, A King, C Hortin, GL Mican, JM Vaughan, E Miller, KD AF Kopp, JB Falloon, J Filie, A Abati, A King, C Hortin, GL Mican, JM Vaughan, E Miller, KD TI Indinavir-associated interstitial nephritis and urothelial inflammation: Clinical and cytologic findings SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID INHIBITOR-INDUCED UROLITHIASIS; ACUTE-RENAL-FAILURE; NEPHROLITHIASIS; NEPHROPATHY; INSUFFICIENCY; ABNORMALITIES; CRYSTALLURIA; RITONAVIR; PYURIA AB The objective of the present study was to characterize the genitourinary syndromes that accompany indinavir-associated pyuria. Of 23 indinavir-treated patients with persistent pyuria, 4 had isolated interstitial nephritis, 10 had both interstitial nephritis and urothelial inflammation, 7 had isolated urothelial inflammation, and 2 had pyuria with nonspecific urinary tract inflammation. A total of 21 patients had multinucleated histiocytes identified by cytologic testing of urine specimens. Urine abnormalities resolved in all 20 patients who stopped receiving indinavir therapy. Pyuria continued in the 3 patients who continued receiving indinavir. Six patients had elevated serum creatinine levels, which returned to baseline levels when indinavir was discontinued. In conclusion, indinavir-associated pyuria was frequently associated with evidence of interstitial nephritis and/or urothelial inflammation, multinucleated histiocytes were commonly present in urine specimens, and cessation of indinavir therapy was associated with prompt resolution of urine abnormalities. C1 NIDDKD, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NIAID, Off Clin Director, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Clin Pathol, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Kopp, JB (reprint author), NIDDKD, Kidney Dis Sect, NIH, 10-3N116, Bethesda, MD 20892 USA. OI Kopp, Jeffrey/0000-0001-9052-186X NR 30 TC 29 Z9 33 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD APR 15 PY 2002 VL 34 IS 8 BP 1122 EP 1128 DI 10.1086/339486 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 534UW UT WOS:000174608500013 PM 11915002 ER PT J AU Schnizlein-Bick, CT Mandy, FF O'Gorman, MRG Paxton, H Nicholson, JKA Hultin, LE Gelman, RS Wilkening, CL Livnat, D AF Schnizlein-Bick, CT Mandy, FF O'Gorman, MRG Paxton, H Nicholson, JKA Hultin, LE Gelman, RS Wilkening, CL Livnat, D TI Use of CD45 gating in three and four-color flow cytometric immunophenotyping: Guideline from the national institute of allergy and infectious diseases, division of AIDS SO CYTOMETRY LA English DT Article DE HIV; CD45 gating; three-color immunophenotyping; four-color immunophenotyping; single-platform immunophenotyping ID LYMPHOCYTE-T SUBSETS; SINGLE-PLATFORM; PERIPHERAL-BLOOD; CELL SUBSETS; IMMUNODEFICIENCY; ABSOLUTE; COUNTS; NUMBERS; CD4(+); VARIABILITY C1 NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46204 USA. Hlth Canada, Ottawa, ON, Canada. Northwestern Univ, Sch Med, Dept Pediat, Chicago, IL 60611 USA. Childrens Mem Hosp, Chicago, IL 60614 USA. Pan Bio Indx Inc, Baltimore, MD USA. Natl Ctr Infect Dis, Atlanta, GA USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. RP Livnat, D (reprint author), NIAID, Div Aids, NIH, 67008 Rockledge Dr,Room 5207, Bethesda, MD 20892 USA. FU NIAID NIH HHS [N01 AI 95356, U01 AI 38855] NR 27 TC 33 Z9 36 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 0196-4763 J9 CYTOMETRY JI Cytometry PD APR 15 PY 2002 VL 50 IS 2 BP 46 EP 52 DI 10.1002/cyto.10073 PG 7 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 546QL UT WOS:000175284800002 PM 12116345 ER PT J AU Cooper, ER Charurat, M Mofenson, L Hanson, IC Pitt, J Diaz, C Hayani, K Handelsman, E Smeriglio V Hoff, R Blattner, W AF Cooper, ER Charurat, M Mofenson, L Hanson, IC Pitt, J Diaz, C Hayani, K Handelsman, E Smeriglio, V Hoff, R Blattner, W CA Women & Infants Transmission Study TI Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV-1; antiretrovirals; perinatal transmission; combination therapy ID HUMAN-IMMUNODEFICIENCY-VIRUS; MOTHER-TO-CHILD; VERTICAL TRANSMISSION; ZIDOVUDINE TREATMENT; VIRAL PHENOTYPE; INFECTED WOMEN; CLINICAL-TRIAL; TYPE-1 HIV-1; RISK-FACTORS; RNA AB Context: The Women and Infants Transmission Study is a prospective natural history study that has been enrolling HIV-1-infected pregnant women and their infants since 1989. Objective: To evaluate the impact of different antiretroviral regimens on perinatal HIV-1 transmission at the population level. Design: Prospective cohort study. Plasma HIV-1 RNA levels were serially measured in 1542 HIV-1-infected women with singleton live births between January 1990 and June 2000. Main Outcome Measure: HIV-1 status of the infant. Results: HIV-1 transmission was 20.0% (95% confidence internal [CI]. 16.1%-23.9%) for 396 women who not receiving prenatal antiretroviral therapy: 10.4% (95% CI. 8.2%-12.6%) for 710 receiving zidovudine monotherapy: 3.8% (95% CI, 1.1%-6.5%) for 186 receiving dual antiretroviral therapy with no or one highly active drug (Multi-ART): and 1.2% (95% CI, 0-2.5%) for 250 receiving highly active antiretroviral therapy (HAART). Transmission also varied by maternal delivers HIV RNA level: 1.0% for <400: 5.3% for 400 to 3499: 9.3% for 3500 to 9999: 14.7% for 10,000 to 29,999: and 23.4% for >30,000 copies/mL (p = .0001 for trend). The odds of transmission increased 2.4-fold (95% CL 1.7-3.5) for emery log, increase in delivery viral load, In multivariate analyses adjusting for maternal viral load. duration of therapy, and other factors. the odds ratio for transmission for women receiving Multi-ART and HAART compared with those receiving ZDV monotherapy was 0.30 (95% Cl. 0.09-1.02) and 0.27 (95% CL 0.08-0.94). respectively. Conclusion: Levels of HIV-1 RNA at delivery and prenatal antiretroviral therapy were independently associated with transmission. The protective effect of therapy increased with the complexity and duration of the regimen. HAART was associated with the lowest rates of transmission. C1 Boston Univ, Sch Med, Maxwell Finland Lab Infect Dis, Boston Med Ctr, Boston, MA 02118 USA. Inst Human Virol, Baltimore, MD USA. Natl Inst Hlth, Natl Inst Child Hlth & Human Dev, Rockville, MD USA. Baylor Coll Med, Houston, TX 77030 USA. Columbia Univ, Coll Phys & Surg, New York, NY USA. Univ Puerto Rico, San Juan, PR 00936 USA. SUNY, Brooklyn, NY USA. Univ Illinois, Rockford, IL USA. Natl Inst Drug Abuse, Natl Inst Hlth, Rockville, MD USA. Natl Inst Allergy & Infect Dis, NIH, Rockville, MD USA. RP Cooper, ER (reprint author), Boston Univ, Sch Med, Maxwell Finland Lab Infect Dis, Boston Med Ctr, 774 Albany St Suite 506, Boston, MA 02118 USA. EM ercooper@bu.edu OI Mofenson, Lynne/0000-0002-2818-9808 NR 33 TC 600 Z9 638 U1 1 U2 22 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD APR 15 PY 2002 VL 29 IS 5 BP 484 EP 494 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 543YB UT WOS:000175129700009 PM 11981365 ER PT J AU Ward, Y Yap, SF Ravichandran, V Matsumura, F Ito, M Spinelli, B Kelly, K AF Ward, Y Yap, SF Ravichandran, V Matsumura, F Ito, M Spinelli, B Kelly, K TI The GTP binding proteins Gem and Rad are negative regulators of the Rho-Rho kinase pathway SO JOURNAL OF CELL BIOLOGY LA English DT Article DE Gem; Rad; Rho kinase; myosin light chain; neuroblastoma ID ACTIN STRESS FIBERS; FOCAL ADHESIONS; ROCK-I; CYTOSKELETAL REORGANIZATION; TRANSCRIPTIONAL ACTIVATION; CELLULAR-TRANSFORMATION; SERINE/THREONINE KINASE; MLC PHOSPHORYLATION; MYOSIN PHOSPHATASE; FAMILY AB The cytoskeletal changes that alter cellular morphogenesis and motility depend upon a complex interplay among molecules that regulate actin, myosin, and other cytoskeletal components. The Rho family of GTP binding proteins are important upstream mediators of cytoskeletal organization. Gem and Rad are members of another family of small GTP binding proteins (the Rad, Gem, and Kir family) for which biochemical functions have been mostly unknown. Here we show that Gem and Rad interface with the Rho pathway through association with the Rho effectors, Rho kinase (ROK) alpha and beta. Gem binds ROKbeta independently of RhoA in the ROKbeta coiled-coil region adjacent to the Rho binding domain. Expression of Gem inhibited ROKbeta-mediated phosphorylation of myosin light chain and myosin phosphatase, but not LIM kinase, suggesting that Gem acts by modifying the substrate specificity of ROKbeta. Gem or Rad expression led to cell flattening and neurite extension in N1E-115 neuroblastoma cells. In interference assays, Gem opposed ROKbeta- and Rad opposed ROKalpha-mediated cell rounding and neurite retraction. Gem did not oppose cell rounding initiated by ROKbeta containing a deletion of the Gem binding region, demonstrating that Gem binding to ROKbeta is required for the effects observed. In epithelial or fibroblastic cells, Gem or Rad expression resulted in stress fiber and focal adhesion disassembly. In addition, Gem reverted the anchorage-independent growth and invasiveness of Dbl-transformed fibroblasts. These results identify physiological roles for Gem and Rad in cytoskeletal regulation mediated by ROK. C1 NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Rutgers State Univ, Dept Mol Biol & Biochem, Piscataway, NJ 08855 USA. Mie Univ, Sch Med, Dept Internal Med 1, Tsu, Mie 5148507, Japan. RP Kelly, K (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bldg 10,Room 3B43, Bethesda, MD 20892 USA. OI Matsumura, Fumio/0000-0002-8204-153X FU NCI NIH HHS [CA42742, R01 CA042742, R37 CA042742] NR 54 TC 124 Z9 131 U1 0 U2 2 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 APR 15 PY 2002 VL 157 IS 2 BP 291 EP 302 DI 10.1083/jcb.200111026 PG 12 WC Cell Biology SC Cell Biology GA 566KF UT WOS:000176426700010 PM 11956230 ER PT J AU Sateren, WB Trimble, EL Abrams, J Brawley, O Breen, N Ford, L McCabe, M Kaplan, R Smith, M Ungerleider, R Christian, MC AF Sateren, WB Trimble, EL Abrams, J Brawley, O Breen, N Ford, L McCabe, M Kaplan, R Smith, M Ungerleider, R Christian, MC TI How sociodemographics, presence of oncology specialists, and hospital cancer programs affect accrual to cancer treatment trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BREAST-CANCER; SOCIOECONOMIC-STATUS; PROSTATE-CANCER; UNITED-STATES; HEALTH; SURVIVAL; RACE; BLACK; WHITE; PREVENTION AB Purpose : We chose to examine the impact of socioeconomic factors an accrual to National Cancer Institute (NCI)-sponsored cancer treatment trials. Patients and Methods: We estimated the geographic and demographic cancer burden in the United States and then identified 24,332 patients accrued to NCI-sponsored cancer treatment trials during a 12-month period. Next, we examined accrual by age, sex, geographic residence, health insurance status, health maintenance organization market penetration, several proxy measures of socioeconomic status, the availability of an oncologist, and the presence of a hospital with an approved multidisciplinary cancer program. Results: Pediatric patients were accrued to clinical trials at high levels, whereas after adolescence, only a small percentage of cancer patients were enrolled onto clinical trials. There were few differences by sex. Black males as well as Asian-American and Hispanic adults were accrued to clinical trials at lower rates than white cancer patients of the same age. Overall, the highest observed accrual was in suburban counties. Compared with the United States population, patients enrolled onto clinical trials were significantly less likely to be uninsured and more like to have Medicare health insurance. Geographic areas with higher socioeconomic levels had higher levels of clinical trial accruals. The number of oncologists and the presence of approved cancer programs both were significantly associated with increased accrual to clinical trials. Conclusion: We must work to increase the number of adults who enroll onto trials, especially among the elderly. Ongoing partnership with professional societies may be an effective approach to strengthen accrual to clinical trials. (C) 2002 by American Society of Clinical Oncology. C1 NCI, Bethesda, MD 20982 USA. Walter Reed Army Inst Res, Rockville, MD USA. RP Trimble, EL (reprint author), NCI, 6130 Execut Blvd,Suite 7025,MSC 7436, Bethesda, MD 20982 USA. NR 30 TC 267 Z9 268 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 15 PY 2002 VL 20 IS 8 BP 2109 EP 2117 DI 10.1200/JCO.2002.08.056 PG 9 WC Oncology SC Oncology GA 544JR UT WOS:000175154900023 PM 11956272 ER PT J AU Costa, C Barber, DF Fodor, WL AF Costa, C Barber, DF Fodor, WL TI Human NK cell-mediated cytotoxicity triggered by CD86 and Gal alpha 1,3-Gal is inhibited in genetically modified porcine cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; BABOON CARDIAC TRANSPLANTS; ACUTE VASCULAR REJECTION; T-CELL; ENDOTHELIAL-CELLS; COSTIMULATORY MOLECULES; XENOGRAFT REJECTION; TRANSGENIC PIG; HUMAN CD59; ACTIVATION AB Delayed xenograft rejection is a major hurdle that needs to be addressed to prolong graft survival in pig-to-primate xenotransplantation. NK cell activation has been implicated in delayed xenograft rejection. Both Ab-dependent and independent mechanisms are responsible for the high susceptibility of porcine cells to human NK cell-mediated cytotoxicity. Previous reports demonstrated a role of Galalpha1,3-Gal Ag in triggering the Ab-independent responses. We hypothesize that expression or CD80 and/or CD86 on porcine cells may also play a role in NK cell activation as human NK cells express a variant of CD28. Our initial analysis showed that porcine endothelial cells and fibroblasts express CD86, but not CD80. Genetic engineering of these cells to express hCD152-hCD59, a chimeric molecule designed to block CD86 in cis, was accompanied by a reduction in susceptibility to human NK cell-mediated cytotoxicity. The use of a specific anti-porcine CD86-blocking Ab and the NK92 and YTS cell lines further confirmed the involvement of CD86 in triggering NK cell-mediated lysis of porcine cells. Maximal protection was achieved when hCD152-hCD59 was expressed in H transferase-transgenic cells, which show reduced Galalpha1,3-Gal expression. In this work, we describe two mechanisms of human NK cell-mediated rejection of porcine cells and demonstrate that genetically modified cells resist Ab-independent NK cell-mediated cytotoxicity. C1 Alexion Pharmaceut, Dept Mol Sci, Cheshire, CT 06410 USA. NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Fodor, WL (reprint author), Alexion Pharmaceut, Dept Mol Sci, 352 Knotter Dr, Cheshire, CT 06410 USA. RI Barber, Domingo/G-1257-2010 OI Barber, Domingo/0000-0001-8824-5405 NR 59 TC 25 Z9 26 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 APR 15 PY 2002 VL 168 IS 8 BP 3808 EP 3816 PG 9 WC Immunology SC Immunology GA 540DJ UT WOS:000174913300018 PM 11937533 ER PT J AU Zhou, XY Yashiro-Ohtani, Y Nakahira, M Park, WR Abe, R Hamaoka, T Naramura, M Gu, H Fujiwara, H AF Zhou, XY Yashiro-Ohtani, Y Nakahira, M Park, WR Abe, R Hamaoka, T Naramura, M Gu, H Fujiwara, H TI Molecular mechanisms underlying differential contribution of CD28 versus non-CD28 costimulatory molecules to IL-2 promoter activation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; T-CELL ACTIVATION; MESSENGER-RNA STABILITY; SIGNAL-TRANSDUCTION; GENE-EXPRESSION; LYMPHOCYTES-T; C-REL; INTERLEUKIN-2 EXPRESSION; PROLIFERATIVE RESPONSES; MONOCLONAL-ANTIBODIES AB T cell costimulation via CD28 and other (non-CD28) costimulatory molecules induces comparable levels of [H-3]TdR incorporation, but fundamentally differs in the contribution to IL-2 production. In this study, we investigated the molecular basis underlying the difference between CD28 and non-CD28 costimulation for IL-2 gene expression. Resting T cells from a mutant mouse strain generated by replacing the IL-2 gene with a cDNA encoding green fluorescent protein were stimulated with a low dose of anti-CD3 plus anti-CD28 or anti-non-CD28 (CD5 or CD9) mAbs. CD28 and non-CD28 costimulation capable of inducing potent [H-3]TdR uptake resulted in high and marginal levels of green fluorescent protein expression, respectively, indicating their differential IL-2 promoter activation. CD28 costimulation exhibited a time-dependent increase in the binding of transcription factors to the NF-AT and NF-kappaB binding sites and the CD28-responsive element of the IL-2 promoter, whereas non-CD28 costimulation did not. Particularly, a striking difference was observed for the binding of NF-kappaB to CD28-responsive element and the NF-kappaB binding site. Decreased NF-kappaB activation in non-CD28 costimulation resulted from the failure to translocate a critical NF-kappaB member, c-Rel, to the nuclear compartment due to the lack of IkappaBbeta inactivation. These observations suggest that unlike CD28 costimulation, non-CD28 costimulation fails to sustain IL-2 promoter activation and that such a failure is ascribed largely to the defect in the activation of c-Rel/NF-kappaB. C1 Osaka Univ, Grad Sch Med, Dept Oncol C6, Suita, Osaka 5650871, Japan. Sci Univ Tokyo, Res Inst Biol Sci, Chiba, Japan. NIAID, Immunol Lab, NIH, Rockville, MD 20892 USA. RP Fujiwara, H (reprint author), Osaka Univ, Grad Sch Med, Dept Oncol C6, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. NR 56 TC 35 Z9 35 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 APR 15 PY 2002 VL 168 IS 8 BP 3847 EP 3854 PG 8 WC Immunology SC Immunology GA 540DJ UT WOS:000174913300023 PM 11937538 ER PT J AU Gao, XP Standiford, TJ Rahman, A Newstead, M Holland, SM Dinauer, MC Liu, QH Malik, AB AF Gao, XP Standiford, TJ Rahman, A Newstead, M Holland, SM Dinauer, MC Liu, QH Malik, AB TI Role of NADPH oxidase in the mechanism of lung neutrophil sequestration and microvessel injury induced by gram-negative sepsis: Studies in p47(phox-/-) and gp91(phox-/-) mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; MACROPHAGE INFLAMMATORY PROTEIN-2; TUMOR-NECROSIS-FACTOR; IN-VIVO; HOST-DEFENSE; MOUSE MODEL; KLEBSIELLA PNEUMONIA; BACTERIAL CLEARANCE; DEPENDENT MECHANISM; ADHESION MOLECULES AB We addressed the role of O-2 generated by the NADPH oxidase complex in the mechanism of polymorphonuclear leukocyte (PMN) 2 accumulation and transalveolar migration and lung microvascular injury. Studies were made in mice lacking the p47(phox) and gp91(phox) subunits of NADPH oxidase (p47(phox-/-) and gp91(phox-/-)) in which PMN are incapable of the respiratory burst. The mice were challenged i.p. with live Escherichia coli to induce sepsis. We observed time-dependent increases in PMN sequestration and migration from 1 to 6 h after challenge with 2 x 10(8) E. coli. The responses in knockout mice were greater post-E. coli challenge compared with control mice; i.e., transalveolar PMN migration post-E. coli challenge increased by similar to50% in the null mice above values in wild type. The increased PMN infiltration was associated with decreased lung bacterial clearance. The generation of the chemoattractant macrophage-inflammatory protein-2 in lung tissue was greater in NADPH oxidase-defective mice after E. coli challenge than control mice; moreover, macrophage-inflammatory protein-2 Ab pretreatment prevented the PMN infiltration. We also observed that E. coli failed to increase lung microvascular permeability in p47(phox-/-) and gp91(phox-/-) mice despite the greater lung PMN sequestration. Thus, O-2(radical anion) production is required for the induction of sepsis-induced lung inicrovascular injury. We conclude that NADPH oxidase-derived O-2(radical anion) generation has an important bactericidal role, such that an impairment in bacterial clearance in NADPH oxidase-defective mice results in increased chemokine generation and lung tissue PMN infiltration. C1 Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USA. Univ Michigan, Sch Med, Dept Med, Div Pulm & Crit Care Med, Ann Arbor, MI 48109 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. RP Malik, AB (reprint author), Univ Illinois, Coll Med, Dept Pharmacol, 835 S Wolcott Ave M-C 868, Chicago, IL 60612 USA. FU NHLBI NIH HHS [HL60678, HL27601, HL45638, HL57243, P50HL60289] NR 49 TC 132 Z9 133 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 APR 15 PY 2002 VL 168 IS 8 BP 3974 EP 3982 PG 9 WC Immunology SC Immunology GA 540DJ UT WOS:000174913300039 PM 11937554 ER PT J AU Belkaid, Y Von Stebut, E Mendez, S Lira, R Caler, E Bertholet, S Udey, MC Sacks, D AF Belkaid, Y Von Stebut, E Mendez, S Lira, R Caler, E Bertholet, S Udey, MC Sacks, D TI CD8(+) T cells are required for primary immunity in C57BL/6 mice following low-dose, intradermal challenge with Leishmania major SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MHC CLASS-I; CUTANEOUS LEISHMANIASIS; DENDRITIC CELLS; INSITU CHARACTERIZATION; MEDIATED-IMMUNITY; LANGERHANS CELLS; DEFICIENT MICE; NATURAL MODEL; FETAL SKIN; INFECTION AB Standard murine models of cutaneous leishmaniasis, involving s.c. inoculation of large numbers of Leishmania major promastigotes, have not supported an essential role for CD8(+) T cells in the control of primary infection. Recently, a L major model combining two main features of natural transmission, low parasite dose and inoculation into a dermal site, has been established in resistant C57BL/6 mice. In the present studies, C57BL/6 mice with CD8(+) T cell deficiencies, including CD8(-/-) and CD8-depleted mice, failed to control the growth of L. major following inoculation of 100 metacyclic promastigotes into the ear dermis. The resulting dermal pathology was minor and delayed. Lesion formation in wild-type mice was coincident with the killing of parasites in the inoculation site. Both events were associated with the accumulation of CD8(+) T lymphocytes in the skin and with the capacity of CD8(+) T cells recovered from draining lymph nodes or infected dermis to release IFN-gamma following coculture with infected dendritic cells. Reconstitution of resistance to L. major in RAG(-/-) mice using T cells from naive donors was optimal when both CD4(+) and CD8(+) T cells were transferred. Primed CD8(+) T lymphocytes obtained from C57BL/6 mice during the acute stage of infection were able to mediate both pathology and immunity when transferred alone. The low dose, intradermal challenge model reveals that CD8(+) T cells play an essential role in both pathogenesis of and immunity to primary infection with L. major in the skin. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NCI, Dermatol Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Sacks, D (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 4-126,4 Ctr Dr MSC 0425, Bethesda, MD 20892 USA. NR 52 TC 191 Z9 194 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 15 PY 2002 VL 168 IS 8 BP 3992 EP 4000 PG 9 WC Immunology SC Immunology GA 540DJ UT WOS:000174913300041 PM 11937556 ER PT J AU Nguyen, DH Taub, D AF Nguyen, DH Taub, D TI CXCR4 function requires membrane cholesterol: Implications for HIV infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SMALL-MOLECULE INHIBITOR; CHEMOKINE RECEPTORS; CORECEPTOR; ENTRY; PALMITOYLATION; MICRODOMAINS; LESTR/FUSIN; PREVENTS; LIGAND; SDF-1 AB HIV requires cholesterol and lipid rafts on target cell membranes for infection. To elucidate a possible mechanism, we determined that cholesterol extraction by hydroxypropyl-beta-cyclodextrin (BCD) inhibits stromal cell-derived factor 1alpha (SDF-1alpha) binding to CXCR4 on T cell lines and PBMCs. Intracellular calcium responses to SDF-1alpha, as well as receptor internalization, were impaired in treated T cells. Loss in ligand binding is likely due to conformational changes in CXCR4 and not increased sensitivity to internalization. SDF-1alpha binding and calcium responses were effectively restored by reloading cholesterol. Immunofluorescence microscopy revealed that SDF-1alpha binding occurred in lipid raft microdomains that contained GM1. CXCR4 surface expression, on the other hand, only partially colocalized with GM1. HIV-1(IIIB) infection assays confirmed the functional loss of CXCR4 in the cell lines tested, Sup-T1 and CEM-NKR-CCR5. These data suggest that cholesterol is essential for CXCR4 conformation and function and that lipid rafts may play a regulatory role in SDF-1alpha signaling. C1 NIA, NIH, Ctr Gerontol Res, Baltimore, MD 21224 USA. RP Taub, D (reprint author), 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 21 TC 151 Z9 152 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 15 PY 2002 VL 168 IS 8 BP 4121 EP 4126 PG 6 WC Immunology SC Immunology GA 540DJ UT WOS:000174913300057 PM 11937572 ER PT J AU Moss, WJ Ryon, JJ Monze, M Cutts, F Quinn, TC Griffin, DE AF Moss, WJ Ryon, JJ Monze, M Cutts, F Quinn, TC Griffin, DE TI Suppression of human immunodeficiency virus replication during acute measles SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 37th Annual Meeting of the Infectious-Diseases-Society-of-America CY NOV 18-21, 1999 CL PHILADELPHIA, PENNSYLVANIA SP Infect Dis Soc Amer ID HIV-INFECTED INFANTS; T-CELL ACTIVATION; IMMUNE ACTIVATION; DISEASE PROGRESSION; TYPE-1 REPLICATION; VIRAL REPLICATION; SERUM LEVELS; PROGNOSTIC-SIGNIFICANCE; UNCOMPLICATED DISEASE; INFLUENZA VACCINATION AB To determine the effect of measles virus coinfection on plasma human immunodeficiency virus (HIV) RNA levels, a prospective study of hospitalized children with measles was conducted between January 1998 and October 2000 in Lusaka, Zambia. Plasma HIV RNA levels were measured during acute measles and 1 month after hospital discharge. The median plasma HIV RNA level in 33 children with measles who were followed longitudinally was 5339 copies/mL at study entry, 60, 121 copies/mL at hospital discharge, and 387, 148 copies/mL at 1-month follow-up. The median plasma HIV RNA level in children without acute illness was 228,454 copies/mL. Plasma levels of immune activation markers were elevated during the period of reduced plasma HIV RNA. Plasma levels of several potential HIV suppressive factors also were elevated during acute measles. HIV replication is transiently suppressed during acute measles at a time of intense immune activation. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Teaching Hosp, Virol Lab, Lusaka, Zambia. London Sch Hyg & Trop Med, Dept Infect & Trop Dis, London WC1, England. RP Moss, WJ (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, 615 N Wolfe St,Rm E5132, Baltimore, MD 21205 USA. FU NIAID NIH HHS [AI 23047] NR 66 TC 53 Z9 56 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD APR 15 PY 2002 VL 185 IS 8 BP 1035 EP 1042 DI 10.1086/340027 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 536XH UT WOS:000174726800006 PM 11930312 ER PT J AU Yabe, T Samuels, I Schwartz, JP AF Yabe, T Samuels, I Schwartz, JP TI Bone morphogenetic proteins BMP-6 and BMP-7 have differential effects on survival and neurite outgrowth of cerebellar granule cell neurons SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE cerebellar granule cell neurons; bone morphogenetic protein-6; bone morphogenetic protein-7; survival; neurite outgrowth ID ENHANCES DENDRITIC GROWTH; EPITHELIUM-DERIVED FACTOR; OSTEOGENIC PROTEIN-1; SYMPATHETIC NEURONS; MESSENGER-RNA; RODENT BRAIN; EXPRESSION; INVOLVEMENT; APOPTOSIS; RECEPTORS AB The bone morphogenetic proteins (BMPs) play an inductive role in the generation of cerebellar granule cells embryonically. Therefore, we chose to look at their effects on cerebellar granule cell survival and differentiation postnatally. The cells express mRNA for both BMP-6 and BMP-7, as well as for the receptors BMPRIA and BMPRII, demonstrating that the postnatal cells have the ability to form the heterodimer receptors needed to respond to BMPs. BMP-7 promotes cell survival, with a maximal effect at 10 ng/ml, whereas tenfold more BMP-6 is needed: Both were active over the course of 8 days in culture. In addition, both BMPs were able to protect the neurons against death from induced apoptosis (exposure to serum-free, low-potassium medium) or exposure to glutamate. However, only BMP-6 could stimulate neurite outgrowth, measured with a neurofilament ELISA, an effect that was seen over the first 6 days in culture. These results, taken together with others in the literature, suggest that the BMPs have strong neurotrophic effects that are both neuron specific and BMP specific. Published 2002 Wiley-Liss, Inc(dagger). C1 NINCDS, NTFS, Neurotroph Factors Sect, NIH, Bethesda, MD 20892 USA. RP Schwartz, JP (reprint author), NINCDS, NTFS, Neurotroph Factors Sect, NIH, Bldg 36,Room 4A31, Bethesda, MD 20892 USA. NR 35 TC 50 Z9 53 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 APR 15 PY 2002 VL 68 IS 2 BP 161 EP 168 DI 10.1002/jnr.10210 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 537YH UT WOS:000174786900005 PM 11948661 ER PT J AU Zheng, H Covey, JM Tosca, PJ Turner, N Chan, KK AF Zheng, H Covey, JM Tosca, PJ Turner, N Chan, KK TI Chiral high-performance liquid chromatographic analysis of the enantiomers of XK469, a new antitumor agent, in plasma and urine SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE chiral HPLC; XK469; (+/-)-2-[4-(7-Chloro-2-quinoxaliny) oxy]phenoxy propionic acid ID ACID AB XK469 (NSC697887), (+/-)-2-[4-(7-Chloro-2-quinoxaliny)oxy]-phenoxy propionic acid, an analog of the herbicide Assure(R), which possesses antitumor activity, especially against murine solid tumors and human xenografts, has recently been found to be the first topoisomerase IIbeta poison. Both R(+) and S(-) isomers are cytotoxic, although the R-isomer is more potent. A chiral high-performance liquid chromatography (HPLC) assay that utilizes Chirobiotic T column for the measurement of enantiomers of XK469 in plasma has been developed with a limit of quantitation (LOQ) of 0.2 mug/ml using a 0.2 ml plasma sample. Chloroqinoxaline sulfonamide (CQS) was used as the internal standard and the assay has been validated in rat plasma. The within-run coefficient of variations (CVs) were 5.9, 5.0, and 3.1% for the S-isomer and 8.1, 4.2, 6.4% for R(+)-XK469 at 0.2, 1, and 2 mug/ml, respectively. The between-run CVs were 10.5, 5.3, and 1.9% for S(-)- and 10.9, 6.3, and 3.6% for R(+)-XK469. Using this chiral assay, a plasma concentration time data of R( +)-,S( -)-XK469 in a Fischer 344 rat receiving i.v. dosing of S(-)X K469 at 10 mg/kg was monitored. S(-)XK469 was found to be significantly converted to the R-enantiomer in circulation even when the S-enantiomer was administered. The predominant inversion from S(-)- to R( +)XK469 was also observed in the mouse and dog plasma. In the rat, the plasma concentration-time profiles for both isomers follow two compartmental pharmacokinetics with the t(1/2beta) for the R-enantiomer slightly longer and the clearance of the S-enantiomer higher than the R-enantiomer. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Ohio State Univ, Coll Pharm & Med, Columbus, OH 43210 USA. NCI, Toxicol & Pharmacol Branch, Rockville, MD 20852 USA. Battelle Mem Inst, Columbus, OH 43201 USA. RP Chan, KK (reprint author), Ohio State Univ, Coll Pharm & Med, 410 W 12th Ave, Columbus, OH 43210 USA. FU NCI NIH HHS [CM-87028, CM-57201] NR 13 TC 6 Z9 6 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD APR 15 PY 2002 VL 28 IS 2 BP 287 EP 294 AR PII S0731-7085(01)00566-0 DI 10.1016/S0731-7085(01)00566-0 PG 8 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 546DH UT WOS:000175256300011 PM 11929671 ER PT J AU Khiroug, SS Harkness, PC Lamb, PW Sudweeks, SN Khiroug, L Millar, NS Yakel, JL AF Khiroug, SS Harkness, PC Lamb, PW Sudweeks, SN Khiroug, L Millar, NS Yakel, JL TI Rat nicotinic ACh receptor alpha 7 and beta 2 subunits co-assemble to form functional heteromeric nicotinic receptor channels SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID ACETYLCHOLINE-RECEPTORS; HIPPOCAMPAL-NEURONS; BUNGAROTOXIN RECEPTORS; DISTINCT SUBTYPES; GANGLION NEURONS; XENOPUS-LAEVIS; INTERNEURONS; BRAIN; ACTIVATION; OOCYTES AB Rat hippocampal interneurons express diverse subtypes of functional nicotinic acetylcholine receptors (nAChRs), including alpha7-containing receptors that have properties unlike those expected for homomeric alpha7 nAChRs. We previously reported a strong correlation between expression of the alpha7 and of the beta2 subunits in individual neurons. To explore whether co-assembly of the alpha7 and beta2 subunits might occur, these subunits were co-expressed in Xenopus oocytes and the functional properties of heterologously expressed nAChRs were characterized by two-electrode voltage clamp. Co-expression of the beta2 subunit, both wild-type and mutant forms, with the alpha7 subunit significantly slowed the rate of nAChR desensitization and altered the pharmacological properties. Whereas ACh, carbachol and choline were full or near-full agonists for homomeric alpha7 receptor channels, both carbachol and choline were only partial agonists in oocytes expressing both alpha7 and beta2 subunits. In addition the EC(50) values for all three agonists significantly increased when the beta2 subunit was co-expressed with the alpha7 subunit. Co-expression with the beta2 subunit did not result in any significant change in the current-voltage curve. Biochemical evidence for the co-assembly of the alpha7 and beta2 subunits was obtained by co-immunoprecipitation of these subunits from transiently transfected human embryonic kidney (TSA201) cells. These data provide direct biophysical and molecular evidence that the nAChR alpha7 and beta2 subunits co-assemble to form a functional heteromeric nAChR with functional and pharmacological properties different from those of homomeric alpha7 channels. This co-assembly may help to explain nAChR channel diversity in rat hippocampal interneurons, and perhaps in other areas of the nervous system. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. UCL, Dept Pharmacol, London WC1E 6BT, England. RP Yakel, JL (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233,F2-08,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM yakel@niehs.nih.gov NR 42 TC 140 Z9 142 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD APR 15 PY 2002 VL 540 IS 2 BP 425 EP 434 DI 10.1113/jphysiol.2001.013847 PG 10 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 546FN UT WOS:000175262900003 PM 11956333 ER PT J AU Kaelin-Lang, A Luft, AR Sawaki, L Burstein, AH Sohn, YH Cohen, LG AF Kaelin-Lang, A Luft, AR Sawaki, L Burstein, AH Sohn, YH Cohen, LG TI Modulation of human corticomotor excitability by somatosensory input SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID HUMAN MOTOR CORTEX; TRANSCRANIAL MAGNETIC STIMULATION; ELECTRICAL-STIMULATION; INTRACORTICAL CONNECTIONS; CORTICAL EXCITABILITY; DEPENDENT PLASTICITY; SENSORY STIMULATION; BRAIN-STIMULATION; COIL ORIENTATION; STROKE PATIENTS AB In humans, somatosensory stimulation results in increased corticomotoneuronal excitability to the stimulated body parts. The purpose of this study was to investigate the underlying mechanisms. We recorded motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) from abductor pollicis brevis (APB), first dorsal interosseous (FDI), and abductor digiti minimi (ADM) muscles. MEP amplitudes, recruitment curves (RC), intracortical inhibition (ICI), intracortical facilitation (ICF), resting (rMT) and active motor thresholds (aMT) were recorded before and after a 2-h period of ulnar nerve electrical stimulation at the wrist. Somatosensory input was monitored by recording somatosensory evoked potentials. To differentiate excitability changes at cortical vs. subcortical sites, we recorded supramaximal peripheral M-responses and MEN to brainstem electrical stimulation (BES). In order to investigate the involvement of GABAergic mechanisms, we studied the influence of lorazepam (LZ) (a GABA(A) receptor agonist) relative to that of dextromethorphan (DM) (an NMDA receptor antagonist) and placebo in a double-blind design. We found that somatosensory stimulation increased MEP amplitudes to TMS only in the ADM, confirming a previous report. This effect was blocked by LZ but not by either DM or placebo and lasted between 8 and 20 min in the absence of (i) changes in MEN elicited by BES, (ii) amplitudes of early somatosensory-evoked potentials or (iii) M-responses. We conclude that somatosensory stimulation elicited a focal increase in corticomotoneuronal excitability that outlasts the stimulation period and probably occurs at cortical sites. The antagonistic effect of LZ supports the hypothesis of GABAergic involvement as an operating mechanism. C1 NINCDS, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA. NIH, Clin Ctr Pharm Dept, Clin Pharmacokinet Res Lab, Bethesda, MD 20892 USA. NINCDS, NIH, Human Motor Control Sect, Bethesda, MD 20892 USA. RP Cohen, LG (reprint author), NINCDS, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC1428, Bethesda, MD 20892 USA. NR 59 TC 201 Z9 203 U1 1 U2 5 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD APR 15 PY 2002 VL 540 IS 2 BP 623 EP 633 DI 10.1113/jphysiol.2001.012801 PG 11 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 546FN UT WOS:000175262900018 PM 11956348 ER PT J AU Serrano, J Alonso, D Fernandez, AP Encinas, JM Lopez, JC Castro-Blanco, S Fernandez-Vizarra, P Richart, A Santacana, M Uttenthal, LO Bentura, ML Martinez-Murillo, R Martinez, A Cuttitta, F Rodrigo, J AF Serrano, J Alonso, D Fernandez, AP Encinas, JM Lopez, JC Castro-Blanco, S Fernandez-Vizarra, P Richart, A Santacana, M Uttenthal, LO Bentura, ML Martinez-Murillo, R Martinez, A Cuttitta, F Rodrigo, J TI Adrenomedullin in the central nervous system SO MICROSCOPY RESEARCH AND TECHNIQUE LA English DT Article DE adrenomedullin; brain; spinal cord; hypoxia; ischemia; immunohistochemistry; electron microscopy ID GENE-RELATED PEPTIDE; SMOOTH-MUSCLE CELLS; IMMUNOREACTIVE ADRENOMEDULLIN; HYPOTENSIVE PEPTIDE; ENDOTHELIAL-CELLS; CALCITONIN-GENE; RAT ADRENOMEDULLIN; SUPRAOPTIC NUCLEI; MESSENGER-RNA; HUMAN PLASMA AB Adrenomedullin (AM) is a novel vasodilator peptide first purified from human pheochromocytoma by tracing its capacity to stimulate cAMP production in platelets, AM immunoreactivity is widely distributed in the central nervous system (CNS) and in the rat has been demonstrated by immunohistochemical techniques to be present in many neurons throughout the brain and spinal cord, as well as in some vascular endothelial cells and perivascular glial cells. Electron microscopy shows that the immunoreactivity is located mainly in the neuronal cytoplasm, but also occurs in the cell nucleus in some cells of the caudate putamen and olfactory tubercle. Biochemical analyses suggest that higher molecular forms, presumably precursor forms, may predominate over fully processed AM in some brain areas. The expression of AM immunoreactivity is increased in cortical neurons, endothelial cells, and perivascular processes after a simulation of ischemia by oxygen and glucose deprivation. Immunohistochemical, electrophysiological, and pharmacological studies suggest that AM in the CNS can act as a neurotransmitter, neuromodulator, or neurohormone, or as a cytoprotective factor in ischemic/hypoxic conditions, in addition to its vasodilator role. (C) 2002 Wiley-Liss, Inc. C1 CSIC, Inst Cajal, Dept Neuroanatomy & Cell Biol, E-28002 Madrid, Spain. NCI, Dept Cell & Canc Biol, NIH, Bethesda, MD 20892 USA. RP Rodrigo, J (reprint author), CSIC, Inst Cajal, Dept Neuroanatomy & Cell Biol, Avenida Doctor Arce 37, E-28002 Madrid, Spain. RI Encinas, Juan/E-3625-2010; Fernandez-Vizarra, Paula/H-5588-2012; Martinez, Alfredo/A-3077-2013; Martinez-Murillo, Ricardo/K-7596-2014; Lopez Ramos, Juan Carlos/K-9336-2014; OI Fernandez-Vizarra, Paula/0000-0002-0322-6844; Martinez, Alfredo/0000-0003-4882-4044; Martinez-Murillo, Ricardo/0000-0003-3657-3890; Lopez Ramos, Juan Carlos/0000-0003-0943-8802; Encinas, Juan Manuel/0000-0002-0402-972X NR 52 TC 34 Z9 43 U1 0 U2 7 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1059-910X J9 MICROSC RES TECHNIQ JI Microsc. Res. Tech. PD APR 15 PY 2002 VL 57 IS 2 BP 76 EP 90 DI 10.1002/jemt.10053 PG 15 WC Anatomy & Morphology; Biology; Microscopy SC Anatomy & Morphology; Life Sciences & Biomedicine - Other Topics; Microscopy GA 541CF UT WOS:000174967100002 PM 11921358 ER PT J AU Calvo, A Abasolo, I Jimenez, N Wang, Z Montuenga, L AF Calvo, A Abasolo, I Jimenez, N Wang, Z Montuenga, L TI Adrenomedullin and proadrenomedullin N-terminal 20 peptide in the normal prostate and in prostate carcinoma SO MICROSCOPY RESEARCH AND TECHNIQUE LA English DT Article DE prostate; neuroendocrine; amidation; prostate cancer; androgens ID RAT VENTRAL PROSTATE; NEUROENDOCRINE CELLS; GUINEA-PIG; EXPRESSION; ANDROGEN; CANCER; GENE; GROWTH; DIFFERENTIATION; TISSUE AB There is increasing evidence for the important role played by regulatory peptides in the physiology of the normal and neoplastic prostate. Adrenomedullin (AM) and pro-adrenomedullin N-terminal 20 peptide (PAMP) are recently discovered regulatory peptides widely expressed in the normal prostate and in prostate carcinoma. AM is produced in secretory, stroma, and endothelial cells and in neurons of the prostate ganglia. PAMP is only produced by neuroendocrine cells, The expression of AM m-RNA is regulated by androgens in the rat prostate. The number of neuroendocrine cells expressing PAMP is increased in prostate carcinoma after androgen deprivation, which shows that this peptide could regulate androgen-independent prostate tumor growth. However, the roles of AM and PAMP in the normal prostate and in prostate carcinoma are yet to be elucidated. (C) 2002 Wiley-Liss, Inc. C1 Univ Navarra, Dept Hist & Pathol, Pamplona, Spain. Northwestern Univ, Med Sch, Dept Urol, Chicago, IL USA. RP Calvo, A (reprint author), NCI, Lab Cell Regulat & Carcinogensis, NCI, Bethesda, MD 20892 USA. RI Abasolo, Ibane/H-7741-2012; Jimenez, Nuria/C-6374-2012 OI Abasolo, Ibane/0000-0001-5970-6276; NR 37 TC 7 Z9 7 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1059-910X J9 MICROSC RES TECHNIQ JI Microsc. Res. Tech. PD APR 15 PY 2002 VL 57 IS 2 BP 98 EP 104 DI 10.1002/jemt.10056 PG 7 WC Anatomy & Morphology; Biology; Microscopy SC Anatomy & Morphology; Life Sciences & Biomedicine - Other Topics; Microscopy GA 541CF UT WOS:000174967100004 PM 11921360 ER PT J AU Cuttitta, F Pio, R Garayoa, M Zudaire, E Julian, M Elsasser, TH Montuenga, LM Martinez, A AF Cuttitta, F Pio, R Garayoa, M Zudaire, E Julian, M Elsasser, TH Montuenga, LM Martinez, A TI Adrenomedullin functions as an important tumor survival factor in human carcinogenesis SO MICROSCOPY RESEARCH AND TECHNIQUE LA English DT Article DE cancer; apoptosis; angiogenesis; hypoxia; growth factor ID ANGIOGENIC FACTOR ADRENOMEDULLIN; INDUCIBLE FACTOR 1-ALPHA; RAT ENDOTHELIAL-CELLS; CIRCULATING ADRENOMEDULLIN; HYPOTENSIVE PEPTIDE; FACTOR-H; FACTOR-I; PLASMA ADRENOMEDULLIN; GENE-EXPRESSION; HEART-FAILURE AB Adrenomedullin (AM) is a pluripotent regulatory peptide initially isolated from a human pheochromocytoma (adrenal tumor) and subsequently shown to play a critical role in cancer cell division, tumor neovascularization, and circumvention of programmed cell death, thus it is an important tumor cell survival factor underlying human carcinogenesis. A variety of neural and epithelial cancers have been shown to produce abundant amounts of AM, Recent findings have implicated elevation of serum AM with the onset of malignant expression. In addition, patients with tumors producing high levels of this peptide have a poor prognostic clinical outcome. Given that most human epithelial cancers display a microenvironment of reduced oxygen tension, it is interesting to note that AM and several of its receptors are upregulated during hypoxic insult. The existence of such a regulatory pathway has been implicated as the basis for the overexpression of AM/AM-R in human malignancies, thereby generating a subsequent autocrine/paracrine growth advantage for the tumor cell. Furthermore, AM has been implicated as a potential immune suppressor substance, inhibiting macrophage function and acting as a newly identified negative regulator of the complement cascade, protective properties which may help cancer cells to circumvent immune surveillance. Hence, AM's traditional participation in normal physiology (cited elsewhere in this issue) can be extended to a primary player in human carcinogenesis and may have clinical relevance as a biological target for the intervention of tumor progression. Published 2002 Wiley-Liss, Inc.(dagger). C1 NCI, Ctr Canc Res, Cell & Canc Biol Branch, Bethesda, MD 20892 USA. Univ Navarra, Biochem Dept, Pamplona, Spain. Univ Navarra, Dept Biochem, Pamplona, Spain. Univ Navarra, Cellular & Pathol Dept, Pamplona, Spain. USDA, Growth Biol Lab, Beltsville, MD 20705 USA. RP Cuttitta, F (reprint author), NCI, Ctr Canc Res, Cell & Canc Biol Branch, Bldg 10 Rm 12N226, Bethesda, MD 20892 USA. RI Martinez, Alfredo/A-3077-2013; Pio, Ruben/F-5353-2017 OI Martinez, Alfredo/0000-0003-4882-4044; Pio, Ruben/0000-0002-6831-6111 NR 89 TC 54 Z9 58 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 1059-910X J9 MICROSC RES TECHNIQ JI Microsc. Res. Tech. PD APR 15 PY 2002 VL 57 IS 2 BP 110 EP 119 DI 10.1002/jemt.10059 PG 10 WC Anatomy & Morphology; Biology; Microscopy SC Anatomy & Morphology; Life Sciences & Biomedicine - Other Topics; Microscopy GA 541CF UT WOS:000174967100006 PM 11921362 ER PT J AU Sokhansanj, BA Rodrigue, GR Fitch, JP Wilson, DM AF Sokhansanj, BA Rodrigue, GR Fitch, JP Wilson, DM TI A quantitative model of human DNA base excision repair. I. mechanistic insights SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN APURINIC/APYRIMIDINIC ENDONUCLEASE; POLYMERASE-BETA; SUBSTRATE-SPECIFICITY; MATHEMATICAL-MODEL; ABASIC SITE; ACTIVE-SITE; PROTEIN; GLYCOSYLASE; PATHWAY; DAMAGE AB Base excision repair (BER) is a multistep process involving the sequential activity of several proteins that cope with spontaneous and environmentally induced mutagenic and cytotoxic DNA damage. Quantitative kinetic data on single proteins of BER have been used here to develop a mathematical model of the BER pathway. This model was then employed to evaluate mechanistic issues and to determine the sensitivity of pathway throughput to altered enzyme kinetics. Notably, the model predicts considerably less pathway throughput than observed in experimental in vitro assays. This finding, in combination with the effects of pathway cooperativity on model throughput, supports the hypothesis of cooperation during abasic site repair and between the apurinic/apyrimidinic (AP) endonuclease, Ape1, and the 8-oxoguanine DNA glycosylase, Ogg1. The quantitative model also predicts that for 8-oxoguanine and hydrolytic AP site damage, short-patch Polbeta-mediated BER dominates, with minimal switching to the long-patch subpathway. Sensitivity analysis of the model indicates that the Polbeta-catalyzed reactions have the most control over pathway throughput, although other BER reactions contribute to pathway efficiency as well. The studies within represent a first step in a developing effort to create a predictive model for BER cellular capacity. C1 Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA 94551 USA. Univ Calif Davis, Coll Engn, Dept Appl Sci, Davis, CA 95616 USA. Univ Calif Davis, Ctr Canc, Dept Radiat Oncol, Sacramento, CA 95817 USA. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 66 TC 55 Z9 56 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR 15 PY 2002 VL 30 IS 8 BP 1817 EP 1825 DI 10.1093/nar/30.8.1817 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 538CW UT WOS:000174797300015 PM 11937636 ER PT J AU Foley, DJ Monjan, A Masaki, K Redline, S AF Foley, DJ Monjan, A Masaki, K Redline, S TI Severe sleep-disordered breathing is not associated with screening for dementia in elderly Japanese-American men SO SLEEP LA English DT Meeting Abstract C1 Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Hawaii, Honolulu, HI 96822 USA. NIA, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 1 U2 1 PU AMER ACAD SLEEP MEDICINE PI ROCHESTER PA 6301 BANDEL RD, STE 101, ROCHESTER, MN 55901 USA SN 0161-8105 J9 SLEEP JI Sleep PD APR 15 PY 2002 VL 25 SU S MA 656 BP A463 EP A464 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 540KB UT WOS:000174927200657 ER PT J AU Gottlieb, DJ Schulman, DA Nam, BH D'Agostino, RA Kannel, WA AF Gottlieb, DJ Schulman, DA Nam, BH D'Agostino, RA Kannel, WA TI Sleep duration predicts mortality: The Framingham Study SO SLEEP LA English DT Meeting Abstract C1 Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. NHLBI, Framingham Heart Dis Epidemiol Study, Bethesda, MD USA. NR 0 TC 6 Z9 6 U1 0 U2 2 PU AMER ACAD SLEEP MEDICINE PI ROCHESTER PA 6301 BANDEL RD, STE 101, ROCHESTER, MN 55901 USA SN 0161-8105 J9 SLEEP JI Sleep PD APR 15 PY 2002 VL 25 SU S MA 143 BP A108 EP A108 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 540KB UT WOS:000174927200145 ER PT J AU Gruber, R Sadeh, A AF Gruber, R Sadeh, A TI Sleep and neurobehavioral functioning in children with Attention Deficit Hyperactivity Disorder SO SLEEP LA English DT Meeting Abstract C1 NIMH, Bethesda, MD 20892 USA. Tel Aviv Univ, Dept Psychol, IL-69978 Tel Aviv, Israel. RI Sadeh, Avi/K-5392-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD SLEEP MEDICINE PI ROCHESTER PA 6301 BANDEL RD, STE 101, ROCHESTER, MN 55901 USA SN 0161-8105 J9 SLEEP JI Sleep PD APR 15 PY 2002 VL 25 SU S MA 073 BP A54 EP A54 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 540KB UT WOS:000174927200075 ER PT J AU Lin, L Wisor, J Shiba, T Yanai, M Vitaterna, M Takahashi, J Dugovic, C Uhl, G Nishino, S Mignot, E AF Lin, L Wisor, J Shiba, T Yanai, M Vitaterna, M Takahashi, J Dugovic, C Uhl, G Nishino, S Mignot, E TI Hypocretin/orexin content in the mouse brain: The effect of circadian time, age and genetic background SO SLEEP LA English DT Meeting Abstract C1 Stanford Univ, Ctr Narcolepsy & Sleep Disorder, Stanford, CA 94305 USA. Tohoku Univ, Sch Med, Sendai, Miyagi 980, Japan. Northwestern Univ, Evanston, IL 60208 USA. NIDA, Mol Neurobiol Branch, IRP, NIH, Lexington, KY USA. RI Takahashi, Joseph/E-8482-2012 OI Takahashi, Joseph/0000-0003-0384-8878 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD SLEEP MEDICINE PI ROCHESTER PA 6301 BANDEL RD, STE 101, ROCHESTER, MN 55901 USA SN 0161-8105 J9 SLEEP JI Sleep PD APR 15 PY 2002 VL 25 SU S MA 012 BP A8 EP A9 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 540KB UT WOS:000174927200014 ER PT J AU Sanchez, M Huitron-Resendiz, S Wills, DN Gallegos, RA Chesebro, B Oldstone, MB Criado, JR Henriksen, SJ AF Sanchez, M Huitron-Resendiz, S Wills, DN Gallegos, RA Chesebro, B Oldstone, MB Criado, JR Henriksen, SJ TI Power spectral analysis of cortical EEG in mice devoid of PRP SO SLEEP LA English DT Meeting Abstract ID PROTEIN C1 Scripps Res Inst, Dept Neuropharmacol, La Jolla, CA USA. NIH, Rocky Mt Labs, Hamilton, MT USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD SLEEP MEDICINE PI ROCHESTER PA 6301 BANDEL RD, STE 101, ROCHESTER, MN 55901 USA SN 0161-8105 J9 SLEEP JI Sleep PD APR 15 PY 2002 VL 25 SU S MA 571 BP A406 EP A407 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 540KB UT WOS:000174927200573 ER PT J AU Bokesch, HR Stull, AC Pannell, LK McKee, TC Boyd, MR AF Bokesch, HR Stull, AC Pannell, LK McKee, TC Boyd, MR TI A new pentacyclic sulfated hydroquinone from the marine sponge Haliclona sp. SO TETRAHEDRON LETTERS LA English DT Article DE pentacyclic sulfated hydroquinone; marine natural product; Haliclona ID AKA ADOCIA SP; TOXICLONA-TOXIUS; TRITERPENE AB A new pentacyclic sulfated hydroquinone, phuklona sulfate. has been isolated from the marine sponge Haliclona sp. collected near Phuket Island. Thailand. The structure was elucidated by a variety of spectroscopic methods including 1D and 2D NMR experiments. Phuklona sulfate contains a novel triterpenoid carbon skeleton linked to a sulfated hydroquinone moeity. Published by Elsevier Science Ltd. C1 NCI, Mol Targets Drug Discovery Program, Ctr Canc Res, Frederick, MD 21702 USA. SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Boyd, MR (reprint author), NCI, Mol Targets Drug Discovery Program, Ctr Canc Res, Frederick, MD 21702 USA. NR 13 TC 7 Z9 8 U1 2 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 APR 15 PY 2002 VL 43 IS 16 BP 3079 EP 3081 AR PII S0040-4039(02)00355-6 DI 10.1016/S0040-4039(02)00355-6 PG 3 WC Chemistry, Organic SC Chemistry GA 545TP UT WOS:000175233900050 ER PT J AU Staub, C Hardy, VB Chapin, RE Harris, MW Johnson, L AF Staub, C Hardy, VB Chapin, RE Harris, MW Johnson, L TI The hidden effect of estrogenic/antiandrogenic methoxychlor on spermatogenesis SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE methoxychlor; oral exposure; germ cell; Sertoli cell; rat ID SERTOLI-CELL POPULATION; DAILY SPERM PRODUCTION; REPRODUCTIVE-TRACT; TESTICULAR SIZE; RATS; STALLIONS; NUMBER; DDT; AGE; SPERMATOGONIA AB Perinatal and juvenile oral treatment of rats with methoxychlor (MXC) only during development reduces testicular size and Sertoli cell number in those animals as adults. The objectives were to determine if MXC administered orally reduces numbers of spermatogonia and daily sperm production that parallel reduction in Sertoli cell number and if germ cell degeneration rate or function of individual Sertoli cells was also affected. Rat dams were gavaged with MXC at 0, 5, 50, or 150 mg/kg/day for the week before and after they gave birth. Resulting male pups (14-16 per group) then were dosed directly from postnatal day 7 to 42. Testes were fixed in Bouin's fixative, postfixed in osmium tetroxide, and embedded in Epon. Sections of 0.5 and 20 mum were evaluated stereologically. Across dose groups, body weight was not affected, but testicular weight was significantly reduced in a dose-dependent fashion. Spermatogenic potential based on number of spermatogonia and number of spermatids per testis was significantly reduced by treatment. There was no adverse effect on daily sperm production per gram of parenchyma based on spermatids; however, the number of spermatogonia per gram was reduced. The ratio of spermatid number per spermatogonia was higher in the MXC-treated groups. This difference indicated that the testis can compensate for the treatment-induced reduction in number of spermatogonia by reducing degeneration of their progeny. However, the reduced number of Sertoli cells prevented the compensation from recovering the daily sperm production per testis totally. Given that endocrine disruptors like MXC can induce compensation during spermatogenesis, it may reduce the ability of the testis to compensate during subsequent exposures. (C) 2002 Elsevier Science (USA). C1 Texas A&M Univ, Ctr Environm & Rural Hlth, Dept Vet Anat & Publ Hlth, College Stn, TX 77843 USA. NIEHS, Reprod Toxicol Grp, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Johnson, L (reprint author), Texas A&M Univ, Ctr Environm & Rural Hlth, Dept Vet Anat & Publ Hlth, College Stn, TX 77843 USA. OI Chapin, Robert/0000-0002-5997-1261 FU NICHD NIH HHS [N01 HD 83281]; NIEHS NIH HHS [T32 ES 07273, N01 ES 15307] NR 41 TC 16 Z9 16 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD APR 15 PY 2002 VL 180 IS 2 BP 129 EP 135 DI 10.1006/taap.2002.9369 PG 7 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 547ZQ UT WOS:000175363500008 PM 11969380 ER PT J AU Storek, J Joseph, A Dawson, MA Douek, DC Storer, B Maloney, DG AF Storek, J Joseph, A Dawson, MA Douek, DC Storer, B Maloney, DG TI Factors influencing T-lymphopoiesis after allogeneic hematopoietic cell transplantation SO TRANSPLANTATION LA English DT Article ID BONE-MARROW TRANSPLANTATION; THYMIC FUNCTION; RECONSTITUTION AB In adult recipients of allogeneic, hematopoietic cell transplants (HCT) studied at 1 year after grafting, there was a significant correlation between the counts of T cell receptor excision circle (TREC) -containing CD4 T cells (presumed recent thymic emigrants) and the counts of total T cells (r=0.65, P<0.001). Thus, the reconstitution of CD4 T cell pool depends on T cell generation from hematopoietic stem cells (T-lymphopoiesis). We evaluated factors that could affect T-lymphopoiesis. Low TREC-containing CD4 T cell counts were associated with older patient age (r=-0.41, P=0.01) but not with donor age, graft type (marrow vs. blood stem cells), CD34 cell dose, conditioning (with vs. without irradiation), acute graft-versus-host disease (aGVHD), or chronic graft-versus-host disease (cGVHD) in multivariate analysis. We conclude that patient age is the primary determinant of CD4 T-lymphopoiesis after allogeneic HCT. C1 Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Washington, Seattle, WA 98195 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Dept Expt Transplantat & Immunol, Med Branch, NIH, Bethesda, MD 20892 USA. RP Storek, J (reprint author), D1-100,1100 Fairview Ave N, Seattle, WA 98109 USA. FU NCI NIH HHS [CA68496, CA18029, CA18221]; NHLBI NIH HHS [HL69710]; NIAID NIH HHS [AI46108] NR 14 TC 71 Z9 75 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD APR 15 PY 2002 VL 73 IS 7 BP 1154 EP 1158 DI 10.1097/00007890-200204150-00026 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 547ZY UT WOS:000175364100026 PM 11965050 ER PT J AU Ometto, L De Forni, D Patiri, F Trouplin, V Mammano, F Giacomet, V Giaquinto, C Douek, D Koup, R De Rossi, A AF Ometto, L De Forni, D Patiri, F Trouplin, V Mammano, F Giacomet, V Giaquinto, C Douek, D Koup, R De Rossi, A TI Immune reconstitution in HIV-1-infected children on antiretroviral therapy: role of thymic output and viral fitness SO AIDS LA English DT Article DE HIV-1; children; antiretroviral therapy; thymus; viral replication ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; IN-VIVO; PROTEASE INHIBITORS; HIV-1 INFECTION; VIROLOGICAL RESPONSES; DIFFERENTIAL TROPISM; TYPE-1 INFECTION; REPLICATION; HAART AB Objective To investigate the role of thymic output and viral fitness in immune reconstitution in HIV-1-infected children on antiretroviral therapy. Methods Thymic output was studied by measuring levels of T-cell receptor rearrangement excision circles (TREC) in peripheral blood lymphocytes, using a real-time quantitative PCR assay. Recombinant viruses containing pre-therapy or post-therapy HIV-1 protease domains were evaluated for viral infectivity in a quantitative single-cycle assay. Results Eighteen HIV-1-infected children who showed a significant increase in CD4 T-cell count after therapy were studied; HIV-1 plasma viraemia was substantially suppressed in 12 children (virological responders), but not in the other six (virological non-responders). TREC were quantified at baseline, and sequentially during the first 12 months of therapy. Both virological responders and non-responders showed an increase in TREC levels that was inversely correlated with baseline TREC and CD4 T cell counts. Changes in TREC positively correlated with CD4 T-cell count increases in virological responders, but not in non-responders; moreover, the ratios between TREC and CD4 T-cell count increases were higher in non-responders than in responders, suggesting a persistence of peripheral CD4 T-cell loss in the former. Drug-resistant viruses with reduced replicative capacity were documented in three out of six non-responders. Conclusions These findings indicate that recovery of thymic function is a pivotal event in immune reconstitution, and suggest that CD4 T-cell increase despite persistent viraemia is sustained by a continuous thymic output that compensates peripheral CD4 T-cell depletion which might be slowed down by emerging viruses with reduced fitness. (C) 2002 Lippincott Williams Wilkins. C1 Univ Padua, Dept Oncol & Surg Sci, Oncol Sect, AIDS Reference Ctr, I-35128 Padua, Italy. INSERM U552, Lab Rech Antivirale, Paris, France. NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Univ Padua, Dept Paediat, Padua, Italy. RP De Rossi, A (reprint author), Univ Padua, Dept Oncol & Surg Sci, Oncol Sect, AIDS Reference Ctr, Via Gattamelata 64, I-35128 Padua, Italy. RI De Rossi, Anita/L-3128-2015; Virginie, Trouplin/P-5650-2016; OI De Rossi, Anita/0000-0001-6435-7509; Mammano, Fabrizio/0000-0002-9193-7696 NR 49 TC 56 Z9 56 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD APR 12 PY 2002 VL 16 IS 6 BP 839 EP 849 DI 10.1097/00002030-200204120-00003 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 544NZ UT WOS:000175167900003 PM 11919485 ER PT J AU Han, ZZ Xiong, CY Mori, T Boyd, MR AF Han, ZZ Xiong, CY Mori, T Boyd, MR TI Discovery of a stable dimeric mutant of cyanovirin-N (CV-N) from a T7 phage-displayed CV-N mutant library SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE cyanovirin-N; CV-N; anti-HIV; phage display; T7 phage; monomer; dimer ID VIRUS-INACTIVATING PROTEIN; GP120 ENVELOPE GLYCOPROTEIN; RANDOM MUTAGENESIS; PROLINE RESIDUES; BINDING-SITES; AFFINITY; TYPE-1; PCR; CD4; CYANOBACTERIUM AB Mutant proteins with altered properties can be useful probes for investigating structure, ligand binding sites, mechanisms of action, and physicochemical attributes of the corresponding wild-type proteins of interest. In this report, we illuminate properties of mutants of the potent HIV-inactivating protein, cyanovirin-N (CV-N), selected by construction of a mutant library by error-prone polymerase chain reaction and affinity-based screening using T7 phage display technology. After three rounds of biopanning, two phage-displayed, one-point mutants of CV-N, Ser52Pro and Ala77Thr, were isolated. After the elucidation of biological activities of the mutants displayed on phage as well as the Escherichia coli-expressed, purified mutant proteins, we subsequently subjected the mutants to analyses by native PAGE and size-exclusion chromatography. We found that the Ser52Pro mutant not only was active against HIV but also existed exclusively as a dimer in solution. This was in marked contrast to the wildtype CV-N, which exists in solution predominantly as the monomer. The Ser52Pro mutant provides a novel model for further investigations of the folding mechanism as well as structure-activity requirements for CV-N's antiviral properties. (C) 2002 Elsevier Science (USA). C1 NCI, Ctr Canc Res, Mol Targets Drug Discovery Program, Frederick, MD 21702 USA. RP Boyd, MR (reprint author), NCI, Ctr Canc Res, Mol Targets Drug Discovery Program, Frederick, MD 21702 USA. NR 48 TC 20 Z9 20 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE 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 APR 12 PY 2002 VL 292 IS 4 BP 1036 EP 1043 DI 10.1006/bbrc.2002.6741 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 544QP UT WOS:000175171800038 PM 11944919 ER PT J AU Hwang, YS Seo, JJ Cha, SW Lee, HS Lee, SY Roh, DH Kung, HF Kim, J Park, MJ AF Hwang, YS Seo, JJ Cha, SW Lee, HS Lee, SY Roh, DH Kung, HF Kim, J Park, MJ TI Antimorphic PV.1 causes secondary axis by inducing ectopic organizer SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE antimorphic PV.1; BMP-4; PV.1; ectopic organizer; homeobox; loss-of-function; dorsoventral axis; Xenopus laevis embryo; secondary axis; ventralization ID BONE MORPHOGENETIC PROTEIN-4; XENOPUS HOMEOBOX GENE; SPEMANN ORGANIZER; MESODERM; EMBRYOS; INDUCTION; BMP-4; LAEVIS; VENTRALIZATION; REQUIREMENT AB Xenopus homeobox gene, PV.1 ventralizes activin-induced dorsal mesoderm and inhibits neuralization of ectoderm. in animal cap when overexpressed. Here we generated PV.1/engrailed fusion construct (N-PV1-EnR) to perform loss-of-function study for this transcription factor. N-PV1-EnR showed an extremely antimorphic effect, causing a partial secondary embryonic axis when expressed at ventral marginal zone of blastula. In ventral marginal zone cells, this chimeric protein induced organizer genes and suppressed ventral markers mimicking those effects reported for dominant negative BMP-4 receptor (DNBR). Moreover, N-PV1-EnR rescued the ventralized embryos caused by the ectopic dorsal expression of PV.1 but not by that of Xvent-2. These results suggested that PV.1 functions at downstream of BMP-4 as a ventralizing effector which acts separately from Xvent-2 and the dominant negative effect gained by this specific mutant is applicable for the further studies of BMP-4 downstream pathway. (C) 2002 Elsevier Science (USA). C1 Kyungpook Natl Univ, Sch Med, Dept Anat, Jung Gu, Taegu 700422, South Korea. Hallym Univ, Coll Med, Dept Biochem, Chunchon, South Korea. Univ Hong Kong, Inst Mol Biol, Hong Kong, Hong Kong, Peoples R China. NIDDKD, Lab Biochem & Genet, Bethesda, MD 20892 USA. RP Park, MJ (reprint author), Kyungpook Natl Univ, Sch Med, Dept Anat, Jung Gu, Dongin Dong 101, Taegu 700422, South Korea. RI Lee, Hyun-Shik/G-3555-2011 NR 29 TC 6 Z9 7 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD APR 12 PY 2002 VL 292 IS 4 BP 1081 EP 1086 DI 10.1006/bbrc.2002.6740 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 544QP UT WOS:000175171800045 PM 11944926 ER PT J AU Saito, S Goodarzi, AA Higashimoto, Y Noda, Y Lees-Miller, SP Appella, E Anderson, CW AF Saito, S Goodarzi, AA Higashimoto, Y Noda, Y Lees-Miller, SP Appella, E Anderson, CW TI ATM mediates phosphorylation at multiple p53 sites, including Ser(46), in response to ionizing radiation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-DAMAGE; P53-DEPENDENT APOPTOSIS; KINASE; ACTIVATION; TRANSACTIVATION; CHECKPOINT; INHIBITION; CASCADE AB The p53 tumor suppressor protein preserves genome integrity by regulating growth arrest and apoptosis in response to DNA damage. In response to ionizing radiation (111), ATM, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of Ser(15) and (indirectly) Ser(20). Here we show that phosphorylation of p53 on Ser(46), a residue important for p53 apoptotic activity, as well as on Ser(9), in response to IR also is dependent on the ATM protein kinase. IR-induced phosphorylation at Ser(46) was inhibited by wortmannin, a phosphatidylinositol 3-kinase inhibitor, but not PD169316, a p38 MAPK inhibitor. p53 C-terminal acetylation at Lys(320) and Lys(382), which may stabilize p53 and activate sequence-specific DNA binding, required Ser15 phosphorylation by ATM and was enhanced by phosphorylation at nearby residues including Ser(6), Ser(9), and Thr(18). These observations, together with the proposed role of Ser(46) phosphorylation in mediating apoptosis, suggest that ATM is involved in the initiation of p53-dependent apoptosis after IR in human lymphoblastoid cells. C1 Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. NCI, NIH, Cell Biol Lab, Bethesda, MD 20892 USA. Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB T2N 1N4, Canada. RP Anderson, CW (reprint author), Brookhaven Natl Lab, Dept Biol, 50 Bell Ave, Upton, NY 11973 USA. NR 35 TC 152 Z9 154 U1 1 U2 7 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 APR 12 PY 2002 VL 277 IS 15 BP 12491 EP 12494 DI 10.1074/jbc.C200093200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 542GZ UT WOS:000175036300002 PM 11875057 ER PT J AU Kaul, S Blackford, JA Cho, SY Simons, SS AF Kaul, S Blackford, JA Cho, SY Simons, SS TI Ubc9 is a novel modulator of the induction properties of glucocorticoid receptors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TYROSINE AMINOTRANSFERASE GENE; UBIQUITIN-CONJUGATING ENZYME; LIGAND-BINDING DOMAIN; ANDROGEN RECEPTOR; SUMO-1 MODIFICATION; TRANSCRIPTIONAL ACTIVITY; ESTROGEN-RECEPTOR; PROMOTER-CONTEXT; RESPONSE ELEMENT; AGONIST ACTIVITY AB The EC50 of agonists and the partial agonist activity of antagonists are crucial parameters for steroid hormone control of gene expression and endocrine therapies. These parameters have been shown to be modulated by a naturally occurring cis-acting element, called the glucocorticoid modulatory element (GME) that binds two proteins, GMEB-1 and -2. We now present evidence that the GMEBs contact Ubc9, which is the mammalian homolog of a yeast E2 ubiquitin-conjugating enzyme. Ubc9 also binds to glucocorticoid receptors (GRs). Ubc9 displays no intrinsic transactivation activity but modifies both the absolute amount of induced gene product and the fold induction by GR. With high concentrations of GR, added Ubc9 also reduces the EC50 of agonists and increases the partial agonist activity of antagonists in a manner that is independent of the ability of Ubc9 to transfer SUMO-1 (small ubiquitin-like modifier-1) to proteins. This new activity of Ubc9 requires only the ligand binding domain of GR and part of the hinge region. Interestingly, Ubc9 modulation of full-length GR transcriptional properties can be seen in the absence of a GME. This, though, is consistent with the GME acting by increasing the local concentration of Ubc9, which then activates a previously unobserved target in the transcriptional machinery. With high concentrations of Ubc9 and GR, Ubc9 binding to GR appears to be sufficient to permit Ubc9 to act independently of the GME. C1 NIDDK, Steroid Hormones Sect, LCMB, NIH, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDK, Steroid Hormones Sect, LCMB, NIH, Bldg 8,Rm B2A-07, Bethesda, MD 20892 USA. NR 62 TC 68 Z9 68 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 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 12 PY 2002 VL 277 IS 15 BP 12541 EP 12549 DI 10.1074/jbc.M112330200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 542GZ UT WOS:000175036300010 PM 11812797 ER PT J AU Marchand, C Zhang, XC Pais, GCG Cowansage, K Neamati, N Burke, TR Pommier, Y AF Marchand, C Zhang, XC Pais, GCG Cowansage, K Neamati, N Burke, TR Pommier, Y TI Structural determinants for HIV-1 integrase inhibition by beta-diketo acids SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STRAND TRANSFER; DNA; COMPLEXES; BINDING; TARGET AB Among all the HIV-1 integrase inhibitors, the beta-diketo acids (DKAs) represent a major lead in anti-HIV-1 integrase drug design. These derivatives inhibit the integration reaction in vitro with a strong specificity for the 3'-end joining step. They are also antiviral and inhibit integration in vivo. The aim of the present study has been to investigate the molecular interactions between DKAs and HIV-1 integrase. We have compared 5CITEP with one of the most potent DKAs reported by the Merck group (L-708,906) and found that 5CITEP inhibits 3'-processing at concentrations where L-708,906 is only active on strand transfer. We also report a novel bifunctional DKA derivative that inhibits 3'-processing even more effectively than 5CITEP. The interactions of these inhibitors with the viral DNA donor ends have been studied by performing experiments with oligonucleotides containing defined modifications. We propose that the bifunctional DKA derivative binds to both the acceptor and donor sites of HIV-1 integrase, whereas the monofunctional L-708,906 derivative binds selectively to the acceptor site. C1 NCI, NIH, Ctr Canc Res, Mol Pharmacol Lab, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Med Chem Lab, Frederick, MD 21702 USA. Univ So Calif, Coll Pharm, Los Angeles, CA 90089 USA. RP Pommier, Y (reprint author), NCI, NIH, Ctr Canc Res, Mol Pharmacol Lab, Bldg 37,Rm 5065, Bethesda, MD 20892 USA. RI Burke, Terrence/N-2601-2014; Marchand, Christophe/D-8559-2016 NR 17 TC 103 Z9 115 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 12 PY 2002 VL 277 IS 15 BP 12596 EP 12603 DI 10.1074/jbc.M110758200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 542GZ UT WOS:000175036300016 PM 11805103 ER PT J AU Vann, LR Payne, SG Edsall, LC Twitty, S Spiegel, S Milstien, S AF Vann, LR Payne, SG Edsall, LC Twitty, S Spiegel, S Milstien, S TI Involvement of sphingosine kinase in TNF-alpha-stimulated tetrahydrobiopterin biosynthesis in C6 glioma cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GTP CYCLOHYDROLASE-I; NITRIC-OXIDE SYNTHASE; NECROSIS-FACTOR-ALPHA; SIGNAL-REGULATED KINASE; HUMAN ENDOTHELIAL-CELLS; FUNCTIONAL-CHARACTERIZATION; MOLECULAR-CLONING; EXPRESSION; 1-PHOSPHATE; CERAMIDE AB In C6 glioma cells, the sphingolipid second messenger ceramide potentiates expression of inducible nitric-oxide synthase (iNOS) induced by tumor necrosis factor a (TNF-alpha) without affecting GTP cyclohydrolase I (GT-PCH), the rate-limiting enzyme in the biosynthesis of 6(R)-5,6,7,8-tetrahydrobiopterin (BH4), a cofactor required for iNOS activity. TNF-alpha also stimulates sphingosine kinase, the enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate (SPP), a further metabolite of ceramide. Several clones of C6 cells, expressing widely varying levels of sphingosine kinase, were used to examine the role of SPP in regulation of GTPCH and BH4 biosynthesis. Overexpression of sphingosine kinase, with concomitant increased endogenous SPP levels, potentiated the effect of TNF-alpha on GTPCH expression and activity and BH4 biosynthesis. In contrast, enforced expression of sphingosine kinase had no effect on iNOS expression or NO formation. Furthermore, N,N-dimethylsphingosine, a potent sphingosine kinase inhibitor, completely eliminated the increased GTPCH activity and expression induced by TNF-alpha. Surprisingly, we found that, although C6 cells can secrete SPP, which is enhanced by TNF-alpha, treatment of C6 cells with exogenous SPP or dihydro-SPP had no affect on BH4 biosynthesis. However, both SPP and dihydro-SPP markedly stimulated ERK 1/2 in C6 cells, which express cell surface SPP receptors. Interestingly, although this ERK activation was blocked by PD98059, which also reduced cellular proliferation induced by enforced expression of sphingosine kinase, PD98059 had no effect on GTPCH activity. Collectively, these results suggest that only intracellularly generated SPP plays a role in regulation of GTPCH and BH4 levels. C1 NIMH, LCMR, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. RP Milstien, S (reprint author), NIMH, LCMR, NIH, Bldg 36,Rm 2A-11, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA 61774]; NIGMS NIH HHS [GM 43880] NR 52 TC 48 Z9 51 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 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 12 PY 2002 VL 277 IS 15 BP 12649 EP 12656 DI 10.1074/jbc.M109111200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 542GZ UT WOS:000175036300022 PM 11815603 ER PT J AU Yu, Q He, M Lee, NH Liu, ET AF Yu, Q He, M Lee, NH Liu, ET TI Identification of Myc-mediated death response pathways by microarray analysis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-CYCLE ARREST; C-MYC; INDUCED APOPTOSIS; CDNA MICROARRAY; GENE-EXPRESSION; DNA-DAMAGE; GROWTH; P53; INDUCTION; FIBROBLASTS AB To understand the mechanisms of Myc-mediated apoptosis induced by DNA damage, we have characterized the death kinetics of three Rat-1 fibroblast cell lines that either overexpress Myc or lack Myc and their parental wild-type cells following exposure to the DNA-damaging agent VP-16, and we monitored the changes in gene expression using microarray. We have identified three groups of genes whose expressions are distinctly regulated during this process. One cluster (Cluster A) revealed a VP-16-dependent but Myc-independent induction of a set of genes that is not linked to the apoptotic response. Two other gene clusters, however, were associated with VP-16-induced apoptosis. Cluster 13, which includes p53-responsive genes, was associated with the temporal onset of apoptosis but accounted for only the basal apoptosis. However, Cluster C, which includes c-jun, was highly regulated by Myc and appeared to be critical to mounting the maximal apoptotic response in Myc-expressing cells. Furthermore, the Myc level dropped sharply following VP-16 exposure, which varied inversely with the induction of Cluster C genes, suggesting Myc normally represses their transcription. Thus, we have proposed that removal of Myc-mediated repression of apoptotic signals, combined with Myc-associated acceleration of the p53 responsive pathway, results in complete and rapid cell death following DNA damage. C1 NCI, Ctr Adv Technol, Canc Res Ctr, NIH, Gaithersburg, MD 20877 USA. Inst Genom Res, Rockville, MD 20850 USA. RP Liu, ET (reprint author), Natl Univ Singapore, Genome Inst Singapore, 1 Res Link,IMA Bldg04-01, Singapore 117604, Singapore. RI Liu, Edison/C-4141-2008 NR 44 TC 20 Z9 20 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 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 12 PY 2002 VL 277 IS 15 BP 13059 EP 13066 DI 10.1074/jbc.M111403200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 542GZ UT WOS:000175036300073 PM 11821411 ER PT J AU Zhou, TJ Kurnasov, O Tomchick, DR Binns, DD Grishin, NV Marquez, VE Osterman, AL Zhang, H AF Zhou, TJ Kurnasov, O Tomchick, DR Binns, DD Grishin, NV Marquez, VE Osterman, AL Zhang, H TI Structure of human nicotinamide/nicotinic acid mononucleotide adenylyltransferase - Basis for the dual substrate specificity and activation of the oncolytic agent tiazofurin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NMN ADENYLYLTRANSFERASE; HUMAN PLACENTA; NAD; CRYSTALLOGRAPHY; BIOSYNTHESIS; CONSERVATION; CONSEQUENCES; METABOLISM; RESISTANCE; ANALOGS AB Nicotinamide/nicotinate mononueleotide (NMN/ NaMN)adenylyltransferase (NMNAT) is an indispensable enzyme in the biosynthesis of NAD(+) and NADP(+). Human NMNAT displays unique dual substrate specificity toward both NMN and NaMN, thus flexible in participating in both de novo and salvage pathways of NAD synthesis. Human NMNAT also catalyzes the rate-limiting step of the metabolic conversion of the anticancer agent tiazofurin to its active form tiazofurin adenine dinucleotide (TAD). The tiazofurin resistance is mainly associated with the low NMNAT activity in the cell. We have solved the crystal structures of human NMNAT in complex with NAD, deamido-NAD, and a non-hydrolyzable TAD analogue beta-CR2-TAD. These complex structures delineate the broad substrate specificity of the enzyme toward both NAIN and NaMN and reveal the structural mechanism for adenylation of tiazofurin nucleotide. The crystal structure of human NMNAT also shows that it forms a barrel-like hexamer with the predicted nuclear localization signal sequence located on the outside surface of the barrel, supporting its functional role of interacting with the nuclear transporting proteins, The results from the analytical ultracentrifugation studies are consistent with the formation of a hexamer in solution under certain conditions. C1 Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dallas, TX 75390 USA. Integrated Genom Inc, Chicago, IL 60612 USA. NCI, Frederick Canc Res & Dev Ctr, Med Chem Lab, Frederick, MD 21702 USA. RP Zhang, H (reprint author), Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA. OI Tomchick, Diana/0000-0002-7529-4643 FU NIGMS NIH HHS [GM 63689-01] NR 33 TC 56 Z9 58 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 12 PY 2002 VL 277 IS 15 BP 13148 EP 13154 DI 10.1074/jbc.M111469200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 542GZ UT WOS:000175036300084 PM 11788603 ER PT J AU Garcia-Diaz, M Bebenek, K Sabariegos, R Dominguez, O Rodriguez, J Kirchhoff, T Garcia-Palomero, E Picher, AJ Juarez, R Ruiz, JF Kunkel, TA Blanco, L AF Garcia-Diaz, M Bebenek, K Sabariegos, R Dominguez, O Rodriguez, J Kirchhoff, T Garcia-Palomero, E Picher, AJ Juarez, R Ruiz, JF Kunkel, TA Blanco, L TI DNA polymerase lambda, a novel DNA repair enzyme in human cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE EXCISION-REPAIR; CRYSTAL-STRUCTURES; BETA; PROTEIN; IDENTIFICATION; PURIFICATION; MUTAGENESIS; EXPRESSION; FIDELITY; BINDING AB DNA polymerase lambda (pol lambda) is a novel family X DNA polymerase that has been suggested to play a role In meiotic recombination and DNA repair. The recent demonstration of an intrinsic 5'-deoxyribose-5-phosphate lyase activity in pol lambda supports a function of this enzyme in base excision repair. However, the biochemical properties of the polymerization activity of this enzyme are still largely unknown. We have cloned and purified human pol lambda to homogeneity in a soluble and active form, and we present here a biochemical description of its polymerization features. In support of a role in DNA repair, pol lambda inserts nucleotides in a DNA template-dependent manner and is processive in small gaps containing a 5'-phosphate group. These properties, together with its nucleotide insertion fidelity parameters and lack of proofreading activity, indicate that pol lambda is a novel beta-like DNA polymerase. However, the high affinity of polk lambda for dNTPs (37-fold over pol beta) is consistent with its possible involvement in DNA, transactions occurring under low cellular levels of dNTPs. This suggests that, despite their similarities, pol beta and pol lambda have nonredundant in vivo functions. C1 UAM, CSIC, Ctr Biol Mol Severo Ochoa, Madrid 28049, Spain. NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Blanco, L (reprint author), UAM, CSIC, Ctr Biol Mol Severo Ochoa, Madrid 28049, Spain. RI Sabariegos, Rosario/K-5169-2014; Ruiz, Jose F./A-1651-2015; Blanco, Luis/I-1848-2015; OI Sabariegos, Rosario/0000-0003-3005-7588; Ruiz, Jose F./0000-0002-0039-3524; Kirchhoff, Tomas/0000-0002-9055-2364 NR 42 TC 141 Z9 147 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 12 PY 2002 VL 277 IS 15 BP 13184 EP 13191 DI 10.1074/jbc.M111601200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 542GZ UT WOS:000175036300088 PM 11821417 ER PT J AU Liu, QR Zhang, PW Zhen, QX Walther, D Wang, XB Uhl, GR AF Liu, QR Zhang, PW Zhen, QX Walther, D Wang, XB Uhl, GR TI KEPI, a PKC-dependent protein phosphatase I inhibitor regulated by morphine. SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MU-OPIOID RECEPTOR; KINASE-C PKC; PHOSPHOLIPASE-C; HUMAN NEUROBLASTOMA; DOWN-REGULATION; SMOOTH-MUSCLE; ALPHA-ISOFORM; DARPP-32; PHOSPHORYLATION; EXPRESSION AB cDNAs encoding KEPI, a novel protein kinase C (PKC) -potentiated inhibitory protein for type 1 Ser/Thr protein phosphatase (PP1), were identified. They were found among morphine-regulated brain mRNAs identified using subtracted differential display techniques. Full-length rat, mouse, and human cDNA and genomic sequences were elucidated with library screening and data base searching. Rat, mouse, and human KEPI cDNAs encode 164-165 amino acid proteins with calculated isoelectric points of 5.2. Each species' amino acid sequence contains consensus sequences for phosphorylation by PKC ((KVTVK)-V-72), protein kinase A (RKLS154), and casein kinase H ((SSRE)-S-43, (SEEE)-E-120). Multiple KEPI N-terminal myristoylation consensus sites provide potential regions for membrane anchoring. Subcellular fractionation and Western analyses revealed that most KEPI immunoreactivity was associated with P2 and P3 membrane-enriched fractions and little in cytosolic fractions. 2.6-kb KEPI mRNAs were detected in brain, especially in the cerebral cortex and hippocampus, and in heart and skeletal muscle. Brain KEPI mRNA was up-regulated by both acute and chronic morphine treatments. The human KEPI gene contains four exons extending over more than 100 kb of genomic sequence on 6q24-q25, near the mu opiate receptor gene. These sequences displayed sufficient homology with the porcine PP1 inhibitor CPI-17 that we asked whether KEPI could share the ability of CPI-17 to modulate PP1 activity in a PKC-dependent fashion. Recombinant mouse KEPI is phosphorylated by PKC with a K-m of 2.6 mum and a t(1/2), of 20 min. Phospho-KEPI inhibits PP1alpha with an IC50 of 2.7 nM, a potency more than 600-fold greater than that displayed by unphosphorylated KEPI. Neither phosphonor dephospho-KEPI inhibits protein phosphatase 2A. Up-regulation of KEPI expression by morphine, an agonist at PKC-regulating G-protein-coupled mu receptors, provides a novel signaling paradigm in which the half-lives of serine/threonine phosphorylation events can be influenced by activities at G(i)/G(o)-coupled receptors that modulate KEPI expression, KEPI phosphorylation, and KEPI regulation of PP1 activity. C1 NIDA, Mol Neurobiol Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Uhl, GR (reprint author), NIDA, Mol Neurobiol Branch, Intramural Res Program, POB 5180,5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Liu, Qing-Rong/A-3059-2012 OI Liu, Qing-Rong/0000-0001-8477-6452 NR 49 TC 40 Z9 44 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 12 PY 2002 VL 277 IS 15 BP 13312 EP 13320 DI 10.1074/jbc.M107558200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 542GZ UT WOS:000175036300102 PM 11812771 ER PT J AU Yang, LJ Beard, WA Wilson, SH Broyde, S Schlick, T AF Yang, LJ Beard, WA Wilson, SH Broyde, S Schlick, T TI Polymerase beta simulations suggest that Arg258 rotation is a slow step rather than large subdomain motions per se SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE human DNA polymerase beta; dynamics simulations; fidelity; closed state; open state ID HUMAN DNA-POLYMERASE; TARGETED MOLECULAR-DYNAMICS; HIV-1 REVERSE-TRANSCRIPTASE; STATE KINETIC-ANALYSIS; NUCLEOTIDE INCORPORATION; CRYSTAL-STRUCTURES; ACTIVE-SITE; LANGEVIN DYNAMICS; I KLENOW; CONFORMATIONAL TRANSITION AB The large-scale opening motion of mammalian DNA polymerase P is followed at atomic resolution by dynamic simulations that link crystal "closed" and "open" conformations. The closing/opening conformational change is thought to be key to the ability of polymerases to choose a correct nucleotide (through "induced fit") and hence maintain DNA repair synthesis fidelity. Corroborating available structural and kinetic measurements, our studies bridge static microscopic crystal structures with macroscopic kinetic data by delineating a specific sequence, Phe272 ring flip large thumb movement, Arg258 rotation with release of catalytic Mg2+, together with estimated time-scales, that suggest the Arg258 rearrangement as a limiting factor of large subdomain motions. If Similarly slow in the closing motion, this conformational change might be restricted further when an incorrect nucleotide binds and thus play a role in pol beta's selectivity for the correct nucleotide. These results suggest new lines of experimentation in the study of polymerase mechanisms (e.g. enzyme mutants), which should provide further insights into mechanisms of error discrimination and DNA synthesis fidelity. (C) 2002 Elsevier Science Ltd. C1 NYU, Dept Chem, New York, NY 10012 USA. NYU, Courant Inst Math Sci, New York, NY 10012 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. NYU, Dept Biol, New York, NY 10003 USA. RP Schlick, T (reprint author), NYU, Dept Chem, 251 Mercer St, New York, NY 10012 USA. FU NCI NIH HHS [CA75449, CA28038]; NIGMS NIH HHS [R01 GM55164] NR 91 TC 66 Z9 66 U1 1 U2 3 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD APR 12 PY 2002 VL 317 IS 5 BP 651 EP 671 DI 10.1006/jmbi.2002.5450 PG 21 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 545EA UT WOS:000175202300002 PM 11955015 ER PT J AU Wang, HB Chanas, B Ghanayem, BI AF Wang, HB Chanas, B Ghanayem, BI TI Effect of methacrylonitrile on cytochrome P-450 2E1 (CYP2E1) expression in male F344 rats SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A LA English DT Article ID OLFACTORY TOXICITY; MESSENGER-RNA; NASAL-MUCOSA; METABOLISM; INDUCTION; LIVER; ACETONE; MICE; ETHANOL; BETA,BETA'-IMINODIPROPIONITRILE AB Tissue-specific induction of cytochrome P-450s (CYP) Followed by increased in situ bioactivation may contribute to chemical-induced site-specific toxicity. In rats, methacrylonitrile (MAN) is metabolized by cytochrome P-450 2E1 (CYP2E1) to acetone, which is eliminated along with parent MAN in breath. Gavage administration of MAN to rats causes olfactory epithelial damage and liver enlargement. it was hypothesized that treatment of rats with MAN may result in differential expression of CYP2E1 in tissues leading to tissue-specific toxicity via increased in situ formation of cytotoxic MAN metabolites. In this study, male F344 rats received 60 mg MAN/kg and were sacrificed 6, 12, or 24 h after a single dose, or 24 h after 7 consecutive daily doses. Liver, lung, and nasal tissues were collected. Reverse-transcription polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemical staining were used to assess CYP2E1 expression and localization, and chlorzoxazone hydroxylation was used as a measure of CYP2E1 catalytic activity. Present results showed that CYP2E1 mRNA was increased in lung and nasal tissues with minimal effects in liver of MAN-treated rats. Induction of CYP2E1 protein expression was detected in lung. CYP2E1 activity was higher in liver and lung microsomes from MAN-treated rats when compared to control animals. To compare the effects of MAN and acetone, male F344 rats received a single acetone dose (5 ml/kg) by gavage. After 12 h, acetone treatment resulted in a significant increase in the levels of CYP2E1 mRNA and protein in lung and nasal tissues, with no obvious change noted in the liver. Overall, these data suggest that administration of MAN to rats causes increased expression of CYP2E1 in lung, liver, and nasal tissues. These results also show that acetone induces the expression of CYP2E1 at both the mRNA and protein levels in rat nasal and lung tissues, In conclusion, MAN increased the expression of CYP2E1, and this effect varied as a function of time, length of exposure, and tissue examined. While the damage in the olfactory mucosa due to MAN treatment may not be explained by the observed induction of CYP2E1, it is possible that other CYPs may play a role in the in situ bioactivation of MAN. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Ghanayem, BI (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233 MD B3-10, Res Triangle Pk, NC 27709 USA. NR 41 TC 7 Z9 8 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1528-7394 J9 J TOXICOL ENV HEAL A JI J. TOXICOL. ENV. HEALTH PT A PD APR 12 PY 2002 VL 65 IS 7 BP 523 EP 537 DI 10.1080/15287390252807984 PG 15 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 537RR UT WOS:000174773800004 PM 11939710 ER PT J AU Fidani, L Compton, D Hardy, J Petersen, RC Tangalos, E Mirtsou, V Goulas, A De Vrieze, FW AF Fidani, L Compton, D Hardy, J Petersen, RC Tangalos, E Mirtsou, V Goulas, A De Vrieze, FW TI No association between the lipoprotein lipase S447X polymorphism and Alzheimer's disease SO NEUROSCIENCE LETTERS LA English DT Article DE Alzheimer's disease; lipoprotein lipase; polymorphism; genetics ID APOLIPOPROTEIN-E; GENETIC ASSOCIATION; LRP GENE; POPULATION; RISK AB Results from various genetic association studies of the lipoprotein lipase (LPL) S447X polymorphism and Alzheimer's disease (AD), range from a statistically significant negative association of clinically examined patients to a non-significant but consistent trend for under-representation of the X447 allele in neuropathologically confirmed subjects. In this report we have compared the distribution of the above polymorphism in an independent group of clinically diagnosed AD patients, including a subgroup where the disease was pathologically confirmed, and a spousal control group. No statistically significant differences emerged from this comparison. We conclude that LPL cannot be a major factor in pathogenesis of AD. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Thessaloniki, Dept Gen Biol, Sch Med, GR-54006 Thessaloniki, Greece. Univ Thessaloniki, Dept Pharmacol, Sch Med, GR-54006 Thessaloniki, Greece. Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. UCL, Reta Lila Weston Inst Neurol Studies, London WC2, England. Inst Neurol, Dept Mol Pathogenesis, London WC2, England. Mayo Clin, Dept Community Med, Rochester, MN 55055 USA. Mayo Clin, Dept Neurol, Rochester, MN 55055 USA. RP Fidani, L (reprint author), Univ Thessaloniki, Dept Gen Biol, Sch Med, GR-54006 Thessaloniki, Greece. RI Hardy, John/C-2451-2009 NR 17 TC 18 Z9 18 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD APR 12 PY 2002 VL 322 IS 3 BP 192 EP 194 AR PII S0304-3940(02)00098-8 DI 10.1016/S0304-3940(02)00098-8 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 538HQ UT WOS:000174809800014 PM 11897170 ER PT J AU Freed, EO AF Freed, EO TI Virology: Rafting with Ebola SO SCIENCE LA English DT Editorial Material ID LIPID RAFTS; VIRUS; GLYCOPROTEINS C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Freed, EO (reprint author), NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 11 TC 10 Z9 11 U1 1 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 APR 12 PY 2002 VL 296 IS 5566 BP 279 EP 279 DI 10.1126/science.1070868 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 541TJ UT WOS:000175000300038 PM 11951027 ER PT J AU Matzinger, P AF Matzinger, P TI The danger model: A renewed sense of self SO SCIENCE LA English DT Article ID DELTA T-CELLS; VERSUS-HOST DISEASE; RECOGNITION; NONSELF; INDUCTION; REJECTION; TOLERANCE; RECEPTOR; FAMILY; CD14 C1 NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Matzinger, P (reprint author), NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. NR 51 TC 2220 Z9 2369 U1 10 U2 128 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 APR 12 PY 2002 VL 296 IS 5566 BP 301 EP 305 DI 10.1126/science.1071059 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 541TJ UT WOS:000175000300043 PM 11951032 ER PT J AU Runyon, SP Peddi, S Savage, JE Roth, BL Glennon, RA Westkaemper, RB AF Runyon, SP Peddi, S Savage, JE Roth, BL Glennon, RA Westkaemper, RB TI Geometry-affinity relationships of the selective serotonin receptor ligand 9-(aminomethyl)-9,10-dihydroanthracene SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CONFORMATION; MODEL AB With the exception of its two aromatic rings and basic nitrogen atom, 9-(aminomethyl)-9,10-dihydroanthracene (AMDA; 1) is remarkably devoid of the pharmacophore features usually associated with high-affinity receptor ligands such as the heteroatom hydrogen bonding features of the endogenous ligand serotonin. AMDA does contain a phenylethylamine skeleton within a tricyclic ring system, and the presence of the second aromatic group is necessary for optimal receptor affinity. The structural requirements for the binding of AMDA at 5-HT2A receptors were investigated with respect to the geometric relationship between the two aromatic rings. It appears that the geometry of the AMDA parent is in the optimal range for fold angle between aromatic moieties. Evaluation of conformationally constrained derivatives of AMDA suggests that a chain extended trans, gauche form is most likely responsible for high affinity. C1 Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, Richmond, VA 23298 USA. Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Psychiat, Cleveland, OH 44106 USA. NIMH, Psychoact Drug Screening Program, Bethesda, MD 20892 USA. RP Westkaemper, RB (reprint author), Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, POB 980540, Richmond, VA 23298 USA. RI Roth, Bryan/F-3928-2010 FU NIDA NIH HHS [DA01642]; NIMH NIH HHS [MH01366, MH57969, MH57635] NR 32 TC 9 Z9 9 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD APR 11 PY 2002 VL 45 IS 8 BP 1656 EP 1664 DI 10.1021/jm010354g PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 538ZH UT WOS:000174844600012 PM 11931619 ER PT J AU Misra, A Blair, M Stuart, C Ozarowski, A Casas-Finet, JR Maki, AH AF Misra, A Blair, M Stuart, C Ozarowski, A Casas-Finet, JR Maki, AH TI Phosphorescence and optically detected magnetic resonance of polynucleotide complexes of tryptophan- and 5-methyltryptophan-containing peptide stereoisomers SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID TRIPLET-STATE PROPERTIES; SINGLE-STRANDED POLYNUCLEOTIDES; DNA-BINDING-PROTEIN; D-AMINO ACIDS; NUCLEIC-ACIDS; AROMATIC RESIDUES; DIASTEREOMERIC TRIPEPTIDES; DEOXYRIBONUCLEIC-ACID; POLY(ADENYLIC ACID); F-19 NMR AB Phosphorescence and optically detected magnetic resonance (ODMR) measurements of tryptophan (W) and 5-methyltryptophan (MeW) triplet states are reported in stereoisomeric peptide complexes with polynucleotides. The peptide diastereomers KWK, K(MeW)K, KGWK, and KGWGK in which the W or MeW are either D Or L and the lysine (K) is L have been prepared and their complexes with poly(deoxythymidylic) acid (poly dT), poly(inosinic) acid (poly 1), and poly(uridylic) acid (poly U) have been studied. Complex formation with polynucleotide results in a phosphorescence redshift and reduction of the zero field splitting D value of W or MeW that varies with polynucleotide, the length and sequence of the peptide, and with the diastereomer. In addition, the kinetic parameters of the triplet state show considerable variation between complexes. These results are discussed in terms of the stereochemistry of peptide bonding to the single stranded polynucleotide and differing types of aromatic amino acid-base interaction: intercalation, aromatic stacking, and edge-to-face contact. Our results are consistent with binding of the peptide to helical regions of the polynucleotide in a single-stranded helical beta-sheet structure in which alternating side chains of an all L oliogopeptide face inward toward the bases and outward from the helix. The orientation is determined by the N-terminal lysine that binds in a stereospecific manner to DNA phosphates through its alpha- and epsilon-amino groups. This model resembles one originally proposed by Gabbay et al. [Gabbay, E. J.; Adawadkar, P. D.; Wilson, W. D. Biochemistry 1976, 15, 146; Gabbay, E. J.; Adawadkar, P. D.; Kapicak, L.; Pearce, S.; Wilson, W. D. Biochemistry 1976, 15, 152] for peptide binding to duplex DNA. C1 Univ Calif Davis, Dept Chem, Davis, CA 95616 USA. NCI, Frederick Canc Res & Dev Ctr, AIDS Vaccine Program, SAIC Ferderick, Frederick, MD 21702 USA. RP Maki, AH (reprint author), Univ Calif Davis, Dept Chem, Davis, CA 95616 USA. NR 60 TC 5 Z9 5 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD APR 11 PY 2002 VL 106 IS 14 BP 3735 EP 3741 DI 10.1021/jp013879t PG 7 WC Chemistry, Physical SC Chemistry GA 542AW UT WOS:000175022100031 ER PT J AU Lu, XF Matsuzawa, M Hikosaka, O AF Lu, XF Matsuzawa, M Hikosaka, O TI A neural correlate of oculomotor sequences in supplementary eye field SO NEURON LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; PRESUPPLEMENTARY MOTOR AREAS; MEMORY-GUIDED SACCADES; NEURONAL-ACTIVITY; TEMPORAL ORGANIZATION; MOVEMENTS; HAND; COORDINATION; ACTIVATION; CORTEX AB Complex learned motor sequences can be composed of a combination of a small number of elementary actions. To investigate how the brain represents such sequences, we devised an oculomotor sequence task in which the monkey had to choose the target solely by the sequential context, not by the current stimulus combination. We found that many neurons in the supplementary eye field (SEF) became active with a specific target direction (D neuron) or a specific target/distractor combination (C neuron). Furthermore, such activity was often selective for one among several sequences that included the combination (S neuron). These results suggest that the SEF contributes to the generation of saccades in many learned sequences. C1 Juntendo Univ, Sch Med, Dept Physiol, Tokyo 1138421, Japan. RP Hikosaka, O (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50, Bethesda, MD 20892 USA. NR 30 TC 67 Z9 67 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD APR 11 PY 2002 VL 34 IS 2 BP 317 EP 325 DI 10.1016/S0896-6273(02)00657-8 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 541GE UT WOS:000174976200016 PM 11970872 ER PT J AU Begg, CB Riedel, ER Bach, PB Kattan, MW Schrag, D Warren, JL Scardino, PT AF Begg, CB Riedel, ER Bach, PB Kattan, MW Schrag, D Warren, JL Scardino, PT TI Variations in morbidity after radical prostatectomy. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HOSPITAL VOLUME; RETROPUBIC PROSTATECTOMY; PANCREATIC RESECTION; COMPLICATION RATES; COLORECTAL-CANCER; BREAST-CANCER; OUTCOMES; MORTALITY; SURVIVAL; SURGERY AB Background: Recent studies of surgery for cancer have demonstrated variations in outcomes among hospitals and among surgeons. We sought to examine variations in morbidity after radical prostatectomy for prostate cancer. Methods: We used the Surveillance, Epidemiology, and End Results-Medicare linked data base to evaluate health-related outcomes after radical prostatectomy. The rates of postoperative complications, late urinary complications (strictures or fistulas 31 to 365 days after the procedure), and long-term incontinence (more than 1 year after the procedure) were inferred from the Medicare claims records of 11,522 patients who underwent prostatectomy between 1992 and 1996. These rates were analyzed in relation to hospital volume and surgeon volume (the number of procedures performed at individual hospitals and by individual surgeons, respectively). Results: Neither hospital volume nor surgeon volume was significantly associated with surgery-related death. Significant trends in the relation between volume and outcome were observed with respect to postoperative complications and late urinary complications. Postoperative morbidity was lower in very-high-volume hospitals than in low-volume hospitals (27 percent vs. 32 percent, P=0.03) and was also lower when the prostatectomy was performed by very-high-volume surgeons than when it was performed by low-volume surgeons (26 percent vs. 32 percent, P<0.001). The rates of late urinary complications followed a similar pattern. Results for long-term preservation of continence were less clear-cut. In a detailed analysis of the 159 surgeons who had a high or very high volume of procedures, wide surgeon-to-surgeon variations in these clinical outcomes were observed, and they were much greater than would be predicted on the basis of chance or observed variations in the case mix. Conclusions: In men undergoing prostatectomy, the rates of postoperative and late urinary complications are significantly reduced if the procedure is performed in a high-volume hospital and by a surgeon who performs a high number of such procedures. C1 Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, Hlth Outcomes Res Grp, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Urol, New York, NY 10021 USA. NCI, Appl Res Branch, Bethesda, MD 20892 USA. RP Begg, CB (reprint author), Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, Hlth Outcomes Res Grp, 1275 York Ave,Box 44, New York, NY 10021 USA. NR 39 TC 524 Z9 534 U1 0 U2 8 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 11 PY 2002 VL 346 IS 15 BP 1138 EP 1144 DI 10.1056/NEJMsa011788 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 539PX UT WOS:000174880600007 PM 11948274 ER PT J AU Zhuang, Z Song, F Martin, BM Dunaway-Mariano, D AF Zhuang, Z Song, F Martin, BM Dunaway-Mariano, D TI The YbgC protein encoded by the ybgC gene of the tol-pal gene cluster of Haemophilus influenzae catalyzes acyl-coenzyme A thioester hydrolysis SO FEBS LETTERS LA English DT Article DE tol-pal operon; thioesterase; Haemophilus influenzae; YbgC; bacterial cell envelope; peptidoglycan AB This paper examines the catalytic function of the protein YbgC, encoded by the ybgC gene of the tol-pal gene cluster in Haemophilus influenzae. The YbgC protein, a homologue of the Pseudomonas sp. strain CBS3 4-hydroxybenzoyl-coenzyme A thioesterase, conserves the active site Asp residue associated with thioesterase activity. The H. influenzae ybgC gene was cloned and overexpressed in Escherichia coli. The recombinant protein was purified and tested for thioesterase activity towards acyl-CoA and acyl-N-acetylcysteamine thioesters. The YbgC protein catalyzes the hydrolysis of short chain aliphatic acyl-CoA thioesters, while the D18N YbgC mutant protein (prepared to serve as a control) does not. (C) 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies. C1 Univ New Mexico, Dept Chem, Albuquerque, NM 87131 USA. NIMH, Clin Neurosci Branch, Bethesda, MD 20892 USA. RP Dunaway-Mariano, D (reprint author), Univ New Mexico, Dept Chem, Albuquerque, NM 87131 USA. FU NIGMS NIH HHS [GM28688] NR 7 TC 20 Z9 20 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD APR 10 PY 2002 VL 516 IS 1-3 BP 161 EP 163 DI 10.1016/S0014-5793(02)02533-4 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 544TU UT WOS:000175178000033 PM 11959124 ER PT J AU Colbert, LH Hartman, TJ Tangrea, JA Pietinen, P Virtamo, J Taylor, PR Albanes, D AF Colbert, LH Hartman, TJ Tangrea, JA Pietinen, P Virtamo, J Taylor, PR Albanes, D TI Physical activity and lung cancer risk in male smokers SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE exercise; physical activity; lung cancer; smoking AB We examined the association between physical activity and lung cancer in a prospective cohort of 27,087 male smokers, ages 50-69 years, enrolled in the Alpha-Tocopherol, Beta Carotene Cancer Prevention (ATBC) Study. After an average of 10 years of follow-up, 1,442 lung cancer cases were diagnosed. Cox proportional hazards models were used to estimate the relative risk (1111) and 95% confidence intervals (CI) of lung cancer associated with self-reported occupational and leisure-time activity, adjusted for age, supplement group, body mass index, cigarettes smoked daily, years of smoking, education, energy intake and vegetable intake. There were no associations between occupational, leisure-time or combined categories of physical activity with lung cancer risk; however, age appeared to modify the effect of leisure-time activity (p = 0.02). Within increasing quartiles of age, the RRs (Cl) for men active in leisure time compared to sedentary men were 0.77 (0.54-1.09), 0.74 (0.57-0.95), 1.09 (0.89-1.33) and 1.03 (0.88-1.21). These data suggest that among smokers, neither occupational nor leisure-time activity is associated with lung cancer risk. There may, however, be some modest risk reduction associated with leisure activity among younger smokers. Published 2002 Wiley-Liss, Inc. C1 NCI, Canc Res Ctr, Bethesda, MD 20892 USA. Penn State Univ, Dept Nutr, University Pk, PA 16802 USA. Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Colbert, LH (reprint author), 7201 Wisconsin Ave,Suite 3C-309, Bethesda, MD 20892 USA. RI Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [CN-45035, N01-CN-45165] NR 14 TC 29 Z9 30 U1 1 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD APR 10 PY 2002 VL 98 IS 5 BP 770 EP 773 DI 10.1002/ijc.10156 PG 4 WC Oncology SC Oncology GA 531KC UT WOS:000174413700019 PM 11920649 ER PT J AU Davidson, JRT Gadde, KM Fairbank, JA Krishnan, RR Califf, RM Binanay, C Parker, CB Pugh, N Hartwell, TD Vitiello, B Ritz, L Severe, J Cole, JO de Battista, C Doraiswamy, PM Feighner, JP Keck, P Kelsey, J Lin, KM Londborg, PD Nemeroff, CB Schatzberg, AF Sheehan, DV Srivastava, RK Taylor, L Trivedi, MH Weisler, RH AF Davidson, JRT Gadde, KM Fairbank, JA Krishnan, RR Califf, RM Binanay, C Parker, CB Pugh, N Hartwell, TD Vitiello, B Ritz, L Severe, J Cole, JO de Battista, C Doraiswamy, PM Feighner, JP Keck, P Kelsey, J Lin, KM Londborg, PD Nemeroff, CB Schatzberg, AF Sheehan, DV Srivastava, RK Taylor, L Trivedi, MH Weisler, RH CA Hypericum Depression Trial Study G TI Effect of Hypericum perforatum (St John's wort) in major depressive disorder - A randomized controlled trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID DOUBLE-BLIND; MODERATE DEPRESSION; CLINICAL-TRIALS; PLACEBO; EFFICACY; EXTRACT; AMITRIPTYLINE; METAANALYSIS; SERTRALINE; IMIPRAMINE AB Context Extracts of Hypericum perforatum (St John's wort) are widely used for the treatment of depression of varying severity. Their efficacy in major depressive disorder, however, has not been conclusively demonstrated. Objective To test the efficacy and safety of a well-characterized H perforatum extract (L1-160) in major depressive disorder. Design and Setting Double-blind, randomized, placebo-controlled trial conducted in 12 academic and community psychiatric research clinics in the United States. Participants Adult outpatients (n=340) recruited between December 1998 and June 2000 with major depression and a baseline total score on the Hamilton Depression Scale (HAM-D) of at least 20. Interventions Patients were randomly assigned to receive H perforatum, placebo, or sertraline (as an active comparator) for 8 weeks. Based on clinical response, the daily dose of H perforatum could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg. Responders at week 8 could continue blinded treatment for another 18 weeks. Main Outcome Measures Change in the HAM-D total score from baseline to 8 weeks; rates of full response, determined by the HAM-D and Clinical Global Impressions (CGI) scores. Results On the 2 primary outcome measures, neither sertraline nor H perforatum was significantly different from placebo. The random regression parameter estimate for mean (SE) change in HAM-D total score from baseline to week 8 (with a greater decline indicating more improvement) was-9.20 (0.67) (95% confidence interval [CI], -10.51 to -7.89) for placebo vs -8.68 (0.68) (95% CI, -10.01 to -7.35) for H perforatum (P=.59) and -10.53 (0.72) (95% CI, -11.94 to -9.12) for sertraline (P=.18). Full response occurred in 31.9% of the placebo-treated patients vs 23.9% of the H perforatum-treated patients (P=.21) and 24.8% of sertraline-treated patients (P=.26). Sertraline was better than placebo on the CGI improvement scale (P=.02), which was a secondary measure in this study. Adverse-effect profiles for H perforatum and sertraline differed relative to placebo. Conclusion This study fails to support the efficacy of H perforatum in moderately severe major depression. The result may be due to low assay sensitivity of the trial, but the complete absence of trends suggestive of efficacy for H perforatum is noteworthy. C1 Duke Univ, Med Ctr, Coordinating Ctr, Durham, NC 27710 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NIMH, Bethesda, MD 20892 USA. Harvard Univ, McLean Hosp, Sch Med, Belmont, MA 02178 USA. Stanford Univ, Palo Alto, CA 94304 USA. Duke Univ, Med Ctr, Durham, NC 27708 USA. Feighner Res Inst, San Diego, CA USA. Univ Cincinnati, Cincinnati, OH 45221 USA. Emory Univ, Sch Med, Atlanta, GA 30303 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. Summit Res Network, Seattle, WA USA. Univ S Florida, Tampa, FL 33612 USA. Eastside Comprehens Med Serv, New York, NY USA. Dean Fdn, Madison, WI USA. Univ Wisconsin, Madison, WI 53706 USA. Univ Texas, SW Med Ctr, Dallas, TX 75235 USA. RP Davidson, JRT (reprint author), Duke Univ, Med Ctr, Coordinating Ctr, Box 3812, Durham, NC 27710 USA. RI Fairbank, John/F-8972-2013 OI Fairbank, John/0000-0003-2604-7256 NR 33 TC 272 Z9 273 U1 2 U2 21 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 APR 10 PY 2002 VL 287 IS 14 BP 1807 EP 1814 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 539QJ UT WOS:000174881700033 ER PT J AU Nicholas, GM Kovac, P Bewley, CA AF Nicholas, GM Kovac, P Bewley, CA TI Total synthesis and proof of structure of mycothiol bimane SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article C1 NIDDK, Labs Biiorgan Chem & Med Chem, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDK, Labs Biiorgan Chem & Med Chem, NIH, Bethesda, MD 20892 USA. NR 13 TC 33 Z9 33 U1 0 U2 7 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 APR 10 PY 2002 VL 124 IS 14 BP 3492 EP 3493 DI 10.1021/ja017891a PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 538ZJ UT WOS:000174844700006 PM 11929223 ER PT J AU Austin, C Boehm, M Tooze, SA AF Austin, C Boehm, M Tooze, SA TI Site-specific cross-linking reveals a differential direct interaction of class 1, 2, and 3 ADP-ribosylation factors with adaptor protein complexes 1 and 3 SO BIOCHEMISTRY LA English DT Article ID IMMATURE SECRETORY GRANULES; GTP-DEPENDENT INTERACTION; MAMMALIAN-CELLS; SYNTHETIC LIPOSOMES; DIFFERENT DOMAINS; PLASMA-MEMBRANE; CLATHRIN; GOLGI; VESICLE; FAMILY AB We have used a site-specific photo-cross-linking approach to identify direct interactions between clathrin adaptor protein (AP)(1) complexes and small GTPases of the ADP-ribosylation factor (ARF) family and to explore the specificity of this interaction on immature secretory granule (ISG) membranes. ISG membranes are a well-characterized, highly enriched preparation of membranes that has previously been shown to have the membrane-associated factors for ARF1 recruitment that are not present on artificial liposomes. All three classes of ARF proteins could be recruited to ISG membranes, displaying differential requirements for GTPgammaS. We found that ARF1, ARF5, and ARF6 interacted directly with the beta1-adaptin subunit of AP-1 in the presence of GTPgammaS. Furthermore, we observed a direct interaction between the switch 1 region of ARF1I and the N-terminal trunk domains of gamma- and beta1-adaptin. In addition, both ARF1 and ARF6 but not ARF5 interacted directly with the beta3- and delta-adaptin subunits of AP-3. No interaction was observed between AP-2 and any of the ARF proteins. Our results delineate the specificity and provide evidence of a direct interaction between different ARF proteins and the AP complexes AP-1 and AP-3 on natural ISG membranes and show that residues in the switch 1 region of ARF proteins can selectively bind to the trunk domains of these complexes. C1 Canc Res UK London Res Inst, Secretory Pathways Lab, London WC2A 3PX, England. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Tooze, SA (reprint author), Canc Res UK London Res Inst, Secretory Pathways Lab, 44 Lincolns Inn Fields, London WC2A 3PX, England. NR 30 TC 39 Z9 40 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 APR 9 PY 2002 VL 41 IS 14 BP 4669 EP 4677 DI 10.1021/bi016064j PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 539JN UT WOS:000174866900019 PM 11926829 ER PT J AU Fox, C Polak, JF Chazaro, I Cupples, A Wolf, P D'Agostine, R O'Donnell, CJ AF Fox, C Polak, JF Chazaro, I Cupples, A Wolf, P D'Agostine, R O'Donnell, CJ TI Carotid intimal medical thickness is a heritable phenotype: The Framingham heart study SO CIRCULATION LA English DT Meeting Abstract C1 NHLBI, Framingham Heart Study, Framingham, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Boston Univ, Boston, MA 02215 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 0009-7322 J9 CIRCULATION JI Circulation PD APR 9 PY 2002 VL 105 IS 14 MA 26 BP E90 EP E91 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 541MA UT WOS:000174987300035 ER PT J AU Gardin, JM Permanenta, K Schreiner, P Loria, CM Wong, ND AF Gardin, JM Permanenta, K Schreiner, P Loria, CM Wong, ND TI Relation of echo cardiographic left ventricular mass, geometry, stress, and left atrial dimension with coronary calcium 10 years later in young adults: The CARDIA study SO CIRCULATION LA English DT Meeting Abstract C1 St Johns Hosp, Detroit, MI USA. Kaiser Permanente, Oakland, CA USA. Northwestern Univ, Chicago, IL 60611 USA. Univ Minnesota, Minneapolis, MN USA. NHLBI, NIH, Bethesda, MD 20892 USA. Univ Calif Irvine, Irvine, CA 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 0009-7322 J9 CIRCULATION JI Circulation PD APR 9 PY 2002 VL 105 IS 14 MA 14 BP E88 EP E88 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 541MA UT WOS:000174987300023 ER PT J AU Henry, JC Thach, C Polak, NJ Chaves, P Hopkins, J Sutton-Tyrell, K Manolio, T Herrington, D Kuller, L Psaty, B Price, T Cushman, M AF Henry, JC Thach, C Polak, NJ Chaves, P Hopkins, J Sutton-Tyrell, K Manolio, T Herrington, D Kuller, L Psaty, B Price, T Cushman, M TI C-reactive protein, internal carotid intima media thickness, and incident ischemic in the elderly: The Cardiovascular Health Study SO CIRCULATION LA English DT Meeting Abstract C1 Henry Ford Syst, Detroit, MI USA. Merck Res Lab, Princeton, NJ USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Johns Hopkins Univ, Baltimore, MD USA. NHLBI, Bethesda, MD 20892 USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Washington, Seattle, WA 98195 USA. Univ Maryland, Washington, DC USA. Univ Vermont, Burlington, VT 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 0009-7322 J9 CIRCULATION JI Circulation PD APR 9 PY 2002 VL 105 IS 14 MA 90 BP E102 EP E102 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 541MA UT WOS:000174987300097 ER PT J AU Liu, K Steffes, MW Colangelo, L Gapstur, SM Loria, C AF Liu, K Steffes, MW Colangelo, L Gapstur, SM Loria, C TI Clustering of the insulin resistance syndrome (IRS) risk factors in young adults and the presence of coronary calcium 15 years later: The CARDIA study SO CIRCULATION LA English DT Meeting Abstract C1 Northwestern Univ, Sch Med, Chicago, IL 60611 USA. Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. NHLBI, 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 0009-7322 J9 CIRCULATION JI Circulation PD APR 9 PY 2002 VL 105 IS 14 MA 159 BP E115 EP E115 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 541MA UT WOS:000174987300162 ER PT J AU Loria, CM Detrano, R Liu, K Lewis, CE Sidney, S Permanente, K Schreiner, P Williams, OD Hulley, S Bild, D AF Loria, CM Detrano, R Liu, K Lewis, CE Sidney, S Permanente, K Schreiner, P Williams, OD Hulley, S Bild, D TI Sex and race differences in prevalence and predictors of early coronary calcification: The CARDIA study SO CIRCULATION LA English DT Meeting Abstract C1 NHLBI, Bethesda, MD 20892 USA. Harbor UCLA Med Ctr, Torrance, CA 90509 USA. Northwestern Univ, Chicago, IL 60611 USA. Univ Alabama, Birmingham, AL USA. Kaiser Permanente, Oakland, CA USA. Univ Minnesota, Minneapolis, MN USA. Univ Calif San Francisco, San Francisco, CA 94143 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 0009-7322 J9 CIRCULATION JI Circulation PD APR 9 PY 2002 VL 105 IS 14 MA 24 BP E90 EP E90 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 541MA UT WOS:000174987300033 ER PT J AU Mozaffarian, D Kumanyika, SK Lemaitre, RN Siscovick, DS Olson, J AF Mozaffarian, D Kumanyika, SK Lemaitre, RN Siscovick, DS Olson, J TI Consumption of cereal fiber, fruit fiber, and vegetable fiber and the risk of incident cardiovascular disease in older adults: The cardiovascular health study SO CIRCULATION LA English DT Meeting Abstract C1 Vet Affairs HSRD Program, CV Hlth Res Unit, Seattle, WA USA. Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Washington, CV Hlth Res Unit, Seattle, WA 98195 USA. NHLBI, NIH, DECA, EBP, Bethesda, MD 20892 USA. Univ Washington, CV Hlth Res Unit, Seattle, WA 98195 USA. RI Mozaffarian, Dariush/B-2276-2008 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 0009-7322 J9 CIRCULATION JI Circulation PD APR 9 PY 2002 VL 105 IS 14 MA 9 BP E87 EP E87 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 541MA UT WOS:000174987300018 ER PT J AU North, K Williams, K Best, L Lee, E Howard, B Welty, T Fabsitz, R MacCluer, JW AF North, K Williams, K Best, L Lee, E Howard, B Welty, T Fabsitz, R MacCluer, JW TI Genetic factors underlying the metabolic syndrome in American Indians: The Strong Heart Family Study SO CIRCULATION LA English DT Meeting Abstract C1 SW Fdn Biomed Res, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX 78285 USA. Missouri Breaks Ind Res, Timber Lake, SD USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. MedStar Res Inst, Washington, DC USA. Aberdeen Area Tribal Chairmens Hlth Board, Rapid City, SD USA. NHLBI, 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 0009-7322 J9 CIRCULATION JI Circulation PD APR 9 PY 2002 VL 105 IS 14 MA 29 BP E91 EP E91 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 541MA UT WOS:000174987300038 ER PT J AU Shlipak, MG Fried, LF Psaty, B Crump, C Manolio, TA Tracy, RP Bleyer, AJ Furberg, CD AF Shlipak, MG Fried, LF Psaty, B Crump, C Manolio, TA Tracy, RP Bleyer, AJ Furberg, CD TI Elevated inflammatory and pro-coagulant biomarkers in elderly persons with renal insufficiency SO CIRCULATION LA English DT Meeting Abstract C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Washington, Seattle, WA 98195 USA. NHLBI, Bethesda, MD 20892 USA. Univ Vermont, Colchester, VT USA. Wake Forest Univ, Bowman Gray Med Ctr, Winston Salem, NC 27109 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 0009-7322 J9 CIRCULATION JI Circulation PD APR 9 PY 2002 VL 105 IS 14 MA 72 BP E99 EP E99 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 541MA UT WOS:000174987300079 ER PT J AU Wong, ND Schreiner, PJ Jacobs, D Hilner, J Loria, CM AF Wong, ND Schreiner, PJ Jacobs, D Hilner, J Loria, CM TI Relation of baseline and longitudinal changes in lipids over 15 years with coronary artery calcium: The CARDIA study SO CIRCULATION LA English DT Meeting Abstract C1 Univ Calif Irvine, Irvine, CA USA. Univ Minnesota, Minneapolis, MN USA. Univ Alabama, Birmingham, AL USA. NHLBI, 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 0009-7322 J9 CIRCULATION JI Circulation PD APR 9 PY 2002 VL 105 IS 14 MA 15 BP E88 EP E88 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 541MA UT WOS:000174987300024 ER PT J AU Omelchenko, MV Makarova, KS Koonin, EV AF Omelchenko, MV Makarova, KS Koonin, EV TI Recurrent intragenomic recombination leading to sequence homogenization during the evolution of the lipoyl-binding domain SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE lipoyl-binding domain; protein evolution; intragenomic recombination; sequence homogenization; duplication ID DEHYDROGENASE MULTIENZYME COMPLEXES; GENE CONVERSION; TUF GENES; MOLECULAR CHARACTERIZATION; PROTEIN SEQUENCES; ZYMOMONAS-MOBILIS; ENZYME-SYSTEM; GENERATION; IDENTIFICATION; PURIFICATION AB The lipoyl-binding domain is often present, in one or several copies, in the E2 subunit and, less often, in the E1 and E3 subunits of 2-oxo acid dehydrogenase complexes. Phylogenetic analysis shows evidence of multiple, independent intragenomic recombination events between different versions of the lipoyl-binding domain in various bacteria and eukaryotic mitochondria, leading to homogenization of the sequences of the lipoyl-binding domain within the same enzymatic complex in several bacterial lineages. This appears to be the first case of sequence homogenization at the level of an individual domain in prokaryotes. (C) 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Microbiological Societies. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Pathol, Bethesda, MD 20814 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. NR 26 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1097 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD APR 9 PY 2002 VL 209 IS 2 BP 255 EP 260 AR PII S0378-1097(02)00517-7 PG 6 WC Microbiology SC Microbiology GA 558JJ UT WOS:000175962300018 PM 12007814 ER PT J AU Gratepanche, S Menage, S Touati, D Wintjens, R Delplace, P Fontecave, M Masset, A Camus, D Dive, D AF Gratepanche, S Menage, S Touati, D Wintjens, R Delplace, P Fontecave, M Masset, A Camus, D Dive, D TI Biochemical and electron paramagnetic resonance study of the iron superoxide dismutase from Plasmodium falciparum SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Plasmodium falciparum; malaria; iron superoxide dismutase ID X-RAY STRUCTURE; PROPIONIBACTERIUM-SHERMANII; HYDROGEN-PEROXIDE; ESCHERICHIA-COLI; PORPHYROMONAS-GINGIVALIS; PROTEIN MOIETY; FE-SUPEROXIDE; MANGANESE; SITE; MN AB Recombinant iron-containing superoxide dismutase (Fe-SOD) from Plasmodium falciparum was produced in a SOD-deficient strain of Escherichia coli, purified and characterised. The enzyme is a dimer, which contains 1.7 Fe equivalents and is sensitive to hydrogen peroxide (H2O2). Electron paramagnetic resonance (EPR) analysis showed two different signals, reflecting the presence of two different types of high-spin Fe sites with different symmetries. The role of the W71 residue during inactivation by H2O2 of the P. falciparum Fe-SOD was studied by site-directed mutagenesis. First, the W71V mutation led to a change in the relative proportion of the two Fe-based EPR signals. Second, the mutant protein was almost as active as the wild-type (WT) protein but more sensitive to heat inactivation. Third, resistance to H2O2. was only slightly increased indicating that W71 was marginally responsible for the sensitivity of Fe-SOD to H2O2, A molecular model of the subunit was designed to assist in interpretation of the results. The fact that the parasite SOD does not belong to classes of SOD present in humans may provide a novel approach for the design of antimalarial drugs. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Inst Pasteur, INSERM, U547, F-59019 Lille, France. NIAID, Parasit Dis Lab, Growth & Dev Sect, NIH, Bethesda, MD 20892 USA. Univ Grenoble 1, CNRS, UMR 5047, DBMS CB,Cea Grenoble, F-38054 Grenoble, France. Univ Paris 06, Inst Jacques Monod, F-75251 Paris 05, France. Univ Paris 07, Inst Jacques Monod, F-75251 Paris 05, France. Inst Pasteur, CNRS, UMR 8525, F-59019 Lille, France. Serv Parasitol Mycol, F-59000 Lille, France. RP Dive, D (reprint author), Inst Pasteur, INSERM, U547, 1 Rue Prof Calmette,BP 245, F-59019 Lille, France. NR 57 TC 24 Z9 27 U1 1 U2 3 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 APR 9 PY 2002 VL 120 IS 2 BP 237 EP 246 AR PII S0166-6851(02)00004-X DI 10.1016/S0166-6851(02)00004-X PG 10 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 541CH UT WOS:000174967300008 PM 11897129 ER PT J AU Miller, LH Hudson-Taylor, D Gamain, B Saul, AJ AF Miller, LH Hudson-Taylor, D Gamain, B Saul, AJ TI Definition of the minimal domain of CIDR1 alpha of Plasmodium falciparum PfEMP1 for binding CD36 SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE CD36; CIDR1; PfEMP1; Plasmodium falciparum; receptor ID INTERCELLULAR-ADHESION MOLECULE-1; ERYTHROCYTE-MEMBRANE PROTEIN-1; CHONDROITIN SULFATE-A; IDENTIFICATION; ADHERENCE; RECEPTOR; THROMBOSPONDIN; MALARIA C1 NIAID, Malaria Vaccine Dev Unit, NIH, Rockville, MD 20852 USA. RP Miller, LH (reprint author), NIAID, Malaria Vaccine Dev Unit, NIH, Twinbrook 1,5640 Fishers Lane, Rockville, MD 20852 USA. RI Saul, Allan/I-6968-2013 OI Saul, Allan/0000-0003-0665-4091 NR 13 TC 11 Z9 11 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 APR 9 PY 2002 VL 120 IS 2 BP 321 EP 323 AR PII S0166-6851(02)00011-7 DI 10.1016/S0166-6851(02)00011-7 PG 3 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 541CH UT WOS:000174967300019 PM 11897140 ER PT J AU Volpato, S Guralnik, JM Fried, LP Remaley, AT Cappola, AR Launer, LJ AF Volpato, S Guralnik, JM Fried, LP Remaley, AT Cappola, AR Launer, LJ TI Serum thyroxine level and cognitive decline in euthyroid older women SO NEUROLOGY LA English DT Article ID MINI-MENTAL-STATE; ALZHEIMERS-DISEASE; THYROID-HORMONES; COMMUNITY; HYPOTHYROIDISM; ASSOCIATION; HEALTH; ADULTS; INDEX AB Background: Clinical and subclinical hypothyroidism is associated with cognitive impairment, Objective: This study investigated the association between thyroxine (T-4) and thyroid-stimulating hormone (TSH) level and change over time in cognitive performance in a sample of older women with normal thyroid gland function. Methods: T-4 and TSH were measured at baseline in 628 women (greater than or equal to65 years) enrolled in the Women's Health and Aging Study, a community-based study of physically impaired women. Cognitive function was assessed at baseline and after 1, 2, and 3 years, using the Mini-Mental State Examination (MMSE), Incident cognitive decline was defined as a decrease of more than one point/year in MMSE score between baseline and the end of the follow-up. The analysis included 464 subjects with normal thyroid gland function with a baseline and at least one follow-up MMSE. Results: At baseline there was no association between T-4 and TSH level and cognitive function. In longitudinal analysis, adjusting for age, race, level of education, and other covariates, compared with women in the highest T-4 tertile (8.1 to 12.5 mug/dL), those in the lowest tertile (4.5 to 6.5 mug/dL) had a greater decline in MMSE score (-0.25 point/year vs -0.12 point/year; p = 0.04). A total of 95 women (20.5%) had cognitive decline during the study period (mean MMSE decline, 5.5 points). Compared with women in the highest T-4 tertile, those in the lowest tertile had a twofold risk of cognitive decline (adjusted relative risk, 1.97; 95% CI, 1.10 to 3.50). The results were not modified by baseline cognitive and physical function. There was no association between baseline TSH level and change in cognitive function. Conclusions: In older women, low T-4 levels, within the normal range, were associated with a greater risk of cognitive decline over a 3-year period. Thyroid hormone levels may contribute to cognitive impairment in physically impaired women. C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Epidemiol, Baltimore, MD 21205 USA. NIH, Ctr Clin, Dept Clin Pathol, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. Univ Ferrara, Dept Clin & Expt Med, I-44100 Ferrara, Italy. RP Volpato, S (reprint author), NIA, Lab Epidemiol Demog & Biometry, 7201 Wisconsin Ave,Room 3C-309, Bethesda, MD 20892 USA. RI VOLPATO, STEFANO/H-2977-2014 OI VOLPATO, STEFANO/0000-0003-4335-6034 NR 33 TC 67 Z9 72 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR 9 PY 2002 VL 58 IS 7 BP 1055 EP 1061 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 539JC UT WOS:000174865900013 PM 11940692 ER PT J AU Crawford, FC Vanderploeg, RD Freeman, MJ Singh, S Waisman, M Michaels, L Abdullah, L Warden, D Lipsky, R Salazar, A Mullan, MJ AF Crawford, FC Vanderploeg, RD Freeman, MJ Singh, S Waisman, M Michaels, L Abdullah, L Warden, D Lipsky, R Salazar, A Mullan, MJ TI APOE genotype influences acquisition and recall following traumatic brain injury SO NEUROLOGY LA English DT Article ID APOLIPOPROTEIN-E; HEAD-INJURY AB APOE has been demonstrated to influence traumatic brain injury (TBI) outcome. The relationship between APOE genotype and memory following TBI was examined in 110 participants in the Defense and Veterans' Head Injury Program. Memory performance was worse in those who had an APOE epsilon4 allele (n = 30) than those who did not (n = 80), whereas genotype groups did not differ on demographic or injury variables or on measures of executive functioning. These data support a specific role for the APOE protein in memory outcome following TBI, and suggest an APOE isoform-specific effect on neuronal repair processes. C1 Univ S Florida, Roskamp Inst, Tampa, FL 33613 USA. James A Haley Vet Hosp, Tampa, FL 33612 USA. Def & Vet Head Injury Program, Tampa, FL USA. Walter Reed Army Med Ctr, Def & Vet Head Injury Program, Washington, DC 20307 USA. NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Crawford, FC (reprint author), Univ S Florida, Roskamp Inst, 3515 E Fletcher Ave, Tampa, FL 33613 USA. OI Mullan, Michael/0000-0002-1473-7527; Lipsky, Robert/0000-0001-7753-1473 NR 10 TC 119 Z9 120 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR 9 PY 2002 VL 58 IS 7 BP 1115 EP 1118 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 539JC UT WOS:000174865900027 PM 11940706 ER PT J AU Kanaya, AM Harris, F Volpato, S Perez-Stable, EJ Harris, T Bauer, DC AF Kanaya, AM Harris, F Volpato, S Perez-Stable, EJ Harris, T Bauer, DC TI Association between thyroid dysfunction and total cholesterol level in an older biracial population - The health, aging and body composition study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID SUBCLINICAL HYPOTHYROIDISM; SERUM THYROTROPIN; DISEASE; LIPIDS; HYPERTHYROIDISM; HYPERLIPIDEMIA; PREVALENCE; ANTIBODIES; COMMUNITY; THYROXINE AB Background: Thyroid dysfunction increases with age. Less is known about the prevalence of thyroid disease in older black adults and whether an association between thyroid function and serum cholesterol level exists, as in older white adults. Methods: A cross-sectional study of 2799 well functioning white and black participants, aged 70 to 79 years, were recruited for a population-based study. Participants underwent thyrotropin, free thyroxine, and total cholesterol testing; a medical history; and physical measurements. Results: Among the entire cohort, 94% were euthyroid based on biochemical testing results. Approximately 10% were taking thyroid hormones. Subclinical hypothyroidism was the most prevalent disorder (3.1% of all participants not taking thyroid hormones), but black men and women had lower rates of this condition than white men and women. After excluding those taking thyroid or lipid medication and adjusting for potential confounders, an elevated thyrotropin level (>5.5 mIU/mL) was associated with a 9 mg/dL (0.23 mmol/L) higher cholesterol level, and a suppressed thyrotropin level (<0.35 mIU/mL) was associated with a 19 mg/dL (0.49 mmol/L) lower cholesterol level. Conclusion: Healthy community-dwelling older black adults have a lower prevalence of thyroid dysfunction compared with older white adults, but the association between increased thyrotropin and increased cholesterol levels is similar in both races. C1 Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Prevent Sci Grp, San Francisco, CA 94143 USA. Univ Calif San Francisco, Ctr Aging Diverse Communities, San Francisco, CA 94143 USA. Univ Calif San Francisco, Med Effectiveness Res Ctr Diverse Populat, San Francisco, CA 94143 USA. NIA, NIH, Bethesda, MD 20892 USA. RP Kanaya, AM (reprint author), Univ Calif San Francisco, Dept Med, Div Gen Internal Med, 1701 Divisadero St,Suite 554, San Francisco, CA 94143 USA. RI VOLPATO, STEFANO/H-2977-2014 OI VOLPATO, STEFANO/0000-0003-4335-6034 FU BHP HRSA HHS [1D08PE50109-01]; NIA NIH HHS [N01-AG-6-2102, N01-AG-6-2103, N01-AG-6-2106]; PHS HHS [556198] NR 25 TC 60 Z9 65 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD APR 8 PY 2002 VL 162 IS 7 BP 773 EP 779 DI 10.1001/archinte.162.7.773 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 537XK UT WOS:000174784800005 PM 11926850 ER PT J AU Schernhammer, ES Michaud, DS Leitzmann, MF Giovannucci, E Colditz, GA Fuchs, CS AF Schernhammer, ES Michaud, DS Leitzmann, MF Giovannucci, E Colditz, GA Fuchs, CS TI Gallstones, cholecystectomy, and the risk for developing pancreatic cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE pancreatic cancer; gallstones; cholecystectomy; risk factors; prospective cohort study ID COHORT; GROWTH AB We examined the relation between gallstones, cholecystectomy, and the development of pancreatic cancer in the Nurses' Health Study and the Health Professionals Follow-up Study. Among 104 856 women and 48 928 men without cancer at baseline, we documented 349 cases of pancreatic cancer during up to 16 years of follow-up. Participants were classified according to a history of gallstones or cholecystectomy. The age-adjusted relative risk of pancreatic cancer following cholecystectomy or diagnosis of gallstones was 1.31 (95% Cl, 0.93 - 1.83). However, adjustment for other pancreatic cancer risk factors attenuated the association (RR= 1.11, 95% Cl, 0.78 - 1.56); this risk did not increase with increasing time following cholecystectomy or gallstones. Gallstones or cholecystectomy do not appear to be significant risk factors for pancreatic cancer. (C) 2002 Cancer Research UK. C1 Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. KFJ Spital, Ludwig Boltzmann Inst Appl Canc Res, Vienna, Austria. NCI, Nutr Epidemiol Branch, Rockville, MD 20852 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Ctr Canc Prevent, Boston, MA USA. Dana Farber Harvard Canc Ctr, Program Epidemiol, Boston, MA USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Schernhammer, ES (reprint author), Channing Labs, 181 Longwood Ave, Boston, MA 02115 USA. RI Michaud, Dominique/I-5231-2014; Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NCI NIH HHS [CA 86102, CA 40356, CA 55075, CA/ES62984, CA87969, P01 CA055075, P01 CA087969, R01 CA040356, R01 CA086102] NR 22 TC 25 Z9 25 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD APR 8 PY 2002 VL 86 IS 7 BP 1081 EP 1084 DI 10.1038/sj/bjc/6600193 PG 4 WC Oncology SC Oncology GA 550GV UT WOS:000175496000013 PM 11953853 ER PT J AU Korn, EL McShane, LM Troendle, JF Rosenwald, A Simon, R AF Korn, EL McShane, LM Troendle, JF Rosenwald, A Simon, R TI Identifying pre-post chemotherapy differences in gene expression in breast tumours: a statistical method appropriate for this aim SO BRITISH JOURNAL OF CANCER LA English DT Article DE cluster analysis; doxorubicin; gene expression; microarray; multiple comparisons; statistical methods ID CANCER; PATTERNS; CELLS AB Although widely used for the analysis of gene expression microarray data, cluster analysis may not be the most appropriate statistical technique for some study aims. We demonstrate this by considering a previous analysis of microarray data obtained on breast tumour specimens, many of which were paired specimens from the same patient before and after chemotherapy. Reanalysing the data using statistical methods that appropriately utilise the paired differences for identification of differentially expressed genes, we find 17 genes that we can confidently identify as more. expressed after chemotherapy than before. These findings were not reported by the original investigators who analysed the data using cluster analysis techniques. (C) 2002 Cancer Research UK. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. NICHHD, Biometry & Math Stat Branch, Bethesda, MD 20892 USA. NCI, Metab Branch, Bethesda, MD 20892 USA. RP Korn, EL (reprint author), NCI, Biometr Res Branch, EPN-8128, Bethesda, MD 20892 USA. NR 12 TC 15 Z9 15 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD APR 8 PY 2002 VL 86 IS 7 BP 1093 EP 1096 DI 10.1038/sj/bjc/6600216 PG 4 WC Oncology SC Oncology GA 550GV UT WOS:000175496000015 PM 11953855 ER PT J AU Kuratomi, Y Nomizu, M Tanaka, K Ponce, ML Komiyama, S Kleinman, HK Yamada, Y AF Kuratomi, Y Nomizu, M Tanaka, K Ponce, ML Komiyama, S Kleinman, HK Yamada, Y TI Laminin gamma 1 chain peptide, C-16 (KAFDITYVRLKF), promotes migration, MMP-9 secretion, and pulmonary metastasis of B16-F10 mouse melanoma cells SO BRITISH JOURNAL OF CANCER LA English DT Article DE laminin; peptide; metastasis; migration; adhesion ID AMINO-ACID-SEQUENCE; A-CHAIN; ALPHA-1 CHAIN; PLASMINOGEN-ACTIVATOR; SYNTHETIC PEPTIDES; BINDING SEQUENCES; IKVAV SEQUENCE; IV COLLAGENASE; BETA-1 CHAIN; IDENTIFICATION AB Laminin-1, a heterotrimer of alpha1, beta1, and gamma1 chains specific to basement membrane, promotes cell adhesion and migration, proteinase secretion and metastases of tumour cells. Several active sites or) the g I chain have been found to promote B16 - F10 melanoma lung colonisation and here we have determined whether additional tumour promoting sites exist on the beta1 and gamma1 chains. Recently, we have identified novel cell adhesive peptides derived from laminin beta1 and gamma1 chains by systematic screening of synthetic peptides. Nine beta1 peptides and seven gamma1 peptides active for cell adhesion were tested for their effects on experimental pulmonary metastases of B16 - F10 mouse melanoma cells in vivo. The most active adhesive peptide derived from the gamma1 chain globular domain, C-16 (KAFDITYVRLKF), significantly enhanced pulmonary metastases of B16 - F10 cells, whereas no other peptides showed enhancement. C-16 also stimulated migration of B16 - F10 cells in the Boyden chamber assay in vitro. Furthermore, C-16 significantly induced the production of MMP-9 from B16 - F10 cells. These results suggest that this specific laminin gamma1 chain peptide has a metastasis-promoting activity and might be a new molecular, target of anti-cancer treatment. (C) 2002 Cancer Research UK. C1 Kyushu Univ, Dept Otorhinolaryngol, Fac Med, Higashi Ku, Fukuoka 8128582, Japan. NIH, Craniofacial Dev Biol & Regenerat Branch, Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. Hokkaido Univ, Grad Sch Environm Earth Sci, Sapporo, Hokkaido 0600810, Japan. Kyushu Univ, Fac Med, Dept Orthoped, Higashi Ku, Fukuoka 8128582, Japan. RP Kuratomi, Y (reprint author), Kyushu Univ, Dept Otorhinolaryngol, Fac Med, Higashi Ku, 3-1-1 Maidashi, Fukuoka 8128582, Japan. NR 43 TC 45 Z9 46 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD APR 8 PY 2002 VL 86 IS 7 BP 1169 EP 1173 DI 10.1038/sj/bjc/6600187 PG 5 WC Oncology SC Oncology GA 550GV UT WOS:000175496000027 PM 11953867 ER PT J AU Ress, NB Donnelly, KC George, SE AF Ress, NB Donnelly, KC George, SE TI The effect of pentachlorophenol on DNA adduct formation in p53 wild-type and knockout mice exposed to benzo[a]pyrene SO CANCER LETTERS LA English DT Article DE benzo[a]pyrene; pentachlorophenol; transgenic animal model; p53 protein; DNA adduct ID ABNORMALITIES; SENSITIVITY; ACTIVATION; INDUCTION; MOUSE AB Previous studies have shown that pentachlorophenol (PCP) has both potentiative and antagonistic effects on the genotoxicity of benzo[a]pyrene (B[a]P). It has been suggested that these effects are due to inhibition and/or induction of enzymes involved in the biotransformation of B[a]P [Carcinogenesis 16 (1995) 2643]. However, B[a]P [J. Biol. Chem. 274 (1999) 35240] and a metabolite of PCP, tetrachlorohydroquinone (TCHQ) [Chem. Biol. Interact. 105 (1997) 11, induce p53 protein synthesis in vitro. To investigate this effect further, C57BL/6Tac trp53 +/+ (wild-type, WT) and C57BL/6Tac trp53 -/- (knockout, KO) mice were exposed to 55 mug B[a]P/g BW alone or in combination with 25 mug/g PCP. Hepatic and lung DNA were analyzed for the major B[a]P DNA adduct, 7R,8S,9S-trihydroxy-10R-(N-2-2'-deoxyguanosyl)-7,8,9,10-tetrahydro-B[a]P (BPDE-N(2)G) and other minor adducts using the P-32-postlabeling assay. BPDE-N(2)G adducts were detected in all animals exposed to B[a]P. Similar adduct levels were observed in WT mice exposed to 55 mug/g B[a]P compared with KO mice exposed to B[a]P alone or in combination with PCP. Interestingly, hepatic and lung BPDE-N(2)G adducts were decreased in WT mice exposed to B[a]P with PCP (P < 0.05). Total DNA adducts in the liver (P < 0.05) were also decreased in WT mice exposed to B[a]P and PCP. Total DNA adducts in either hepatic or lung DNA isolated from KO mice were not different in mice treated with PCP and B [a]P. These results suggest that the decrease in BPDE-N(2)G adducts observed in WT mice may be a result of p53 accumulation or induction of repair pathways in response to damage induced by PCP. Published by Elsevier Science Ireland Ltd. C1 Texas A&M Univ, Dept Vet Anat & Publ Hlth, College Stn, TX USA. US EPA, Div Environm Carcinogenesis, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. RP Ress, NB (reprint author), NIEHS, NIH, 111 Alexander Dr,MD E1-03, Res Triangle Pk, NC 27711 USA. FU NIEHS NIH HHS [P42ES04917-10] NR 20 TC 5 Z9 5 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 APR 8 PY 2002 VL 178 IS 1 BP 11 EP 17 AR PII S0304-3835(01)00810-2 DI 10.1016/S0304-3835(01)00810-2 PG 7 WC Oncology SC Oncology GA 576GQ UT WOS:000176995500002 PM 11849736 ER PT J AU Berezhkovskii, AM Pustovoit, MA Bezrukov, SM AF Berezhkovskii, AM Pustovoit, MA Bezrukov, SM TI Effect of binding on particle number fluctuations in a membrane channel SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID ESCHERICHIA-COLI; TRANSPORT; NOISE; LAMB AB Transport of solutes through membrane channels produces additional noise in the channel ion current because the number of solute molecules in the channel fluctuates. We obtain a general expression for the power spectral density of these fluctuations in a cylindrical channel in the presence of a binding site of arbitrary strength. The expression shows how the spectral density transforms from that in the case of no-binding to the Lorentzian spectral density corresponding to the strong-binding limit. Brownian dynamics simulations confirm our analytical results. (C) 2002 American Institute of Physics. C1 NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. St Petersburg Nucl Phys Inst, Gatchina 188350, Russia. NIH, CIT, Math & Stat Comp Lab, Bethesda, MD 20892 USA. RP Berezhkovskii, AM (reprint author), NICHHD, Lab Phys & Struct Biol, NIH, Bldg 9,Room 1E-122, Bethesda, MD 20892 USA. RI Pustovoit, Mark/B-5249-2008 NR 15 TC 15 Z9 15 U1 0 U2 0 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD APR 8 PY 2002 VL 116 IS 14 BP 6216 EP 6220 DI 10.1063/1.1458935 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 535FH UT WOS:000174634200034 ER PT J AU Strickland, JA Foureman, GL AF Strickland, JA Foureman, GL TI US EPA's acute reference exposure methodology for acute inhalation exposures SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article; Proceedings Paper CT Conference on Issues and Applications in Toxicology and Risk Assessment CY APR 23-26, 2001 CL FAIRBORN, OHIO SP USAF, Toxicol, USA, Toxicol, USN, Toxicol, Natl Ctr Environm Assessment, Off Res & Dev, US EPA, Natl Inst Environm Hlth Sci, Food & Drug Adm, Div Toxicol, ATSDR, Natl Res Counil & Natl Acad Sci DE acute inhalation toxicity; health risk assessment; toxicity value; hydrogen sulfide; hexachlorocyclopentadiene ID HYDROGEN-SULFIDE INHALATION; EXERCISING MEN; HEALTHY-MEN; RATS; WOMEN; RESPONSES; LUNGS AB The US Environmental Protection Agency (EPA) National Center for Environmental Assessment is engaged in the development of a methodology for Agency use to perform risk assessments for non-cancer effects due to acute inhalation exposures. The methodology will provide general guidance for deriving chemical-specific acute exposure benchmarks called acute reference exposures (AREs). Chemical-specific AREs are analogous to reference concentrations (RfCs) for chronic non-cancer effects and will be incorporated in chemical-specific files in the US EPA's Integrated Risk Information System (IRIS) as they are developed and reviewed. AREs will have wide applicability in assessing the potential health risks of accidental and routine acute releases of chemicals to the environment. The proposed methodology for ARE development provides a framework for choosing an optimal derivation approach, depending on the type of data available, from the no-observed-adverse-effect level (NOAEL), benchmark concentration (BMC), or categorical regression approaches. Uncertainty factors are applied to the point of departure, determined by one of the recommended approaches, to derive the ARE. Due to the capability to use more exposure-response information than the NOAEL approach allows, exposure-response analyses such as BMC and categorical regression are favored as methods to develop the point of departure when the available database will support such analyses. The NOAEL approach is suitable when the data are insufficient to support exposure-response modeling. Applications of the proposed ARE methodology are illustrated by the derivation of example AREs for hydrogen sulfide and hexachlorocyclopentadiene, which showcase the categorical regression and NOAEL approaches, respectively. In addition, a recent review of the proposed ARE methodology by the US EPA Risk Assessment Forum is discussed. (C) 2002 Elsevier Science B.V. All rights reserved. C1 US EPA, Natl Ctr Environm Assessment, Res Triangle Pk, NC 27711 USA. RP Strickland, JA (reprint author), NIEHS, Integrated Lab Syst Inc, POB 12233 EC 17, Res Triangle Pk, NC 27709 USA. NR 32 TC 9 Z9 10 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD APR 8 PY 2002 VL 288 IS 1-2 BP 51 EP 63 AR PII S0048-9697(01)01114-7 DI 10.1016/S0048-9697(01)01114-7 PG 13 WC Environmental Sciences SC Environmental Sciences & Ecology GA 544BJ UT WOS:000175138100007 PM 12013548 ER PT J AU Daly, JW AF Daly, JW TI Award address - Amphibian skin: A remarkable source of biologically active arthropod alkaloids. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDK, Bioorgan Chem Lab, Sect Pharmacodynam, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 130-MEDI BP A110 EP A110 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296800645 ER PT J AU Gabrielsen, B Ferguson, S Cragg, GM AF Gabrielsen, B Ferguson, S Cragg, GM TI National Cancer Institute - Natural Products Repository - A resource for drug development. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Technol Transfer Branch, Fairview Ctr, Frederick, MD 21701 USA. NCI, Dev Therapeut Program, Frederick, MD 21701 USA. NIH, Off Technol Transfer, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 008-MEDI BP A88 EP A88 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296800524 ER PT J AU Kalish, H Bryant, LH Frank, JA Yordanov, AT Brechbiel, MW AF Kalish, H Bryant, LH Frank, JA Yordanov, AT Brechbiel, MW TI Synthesis and evaluation of novel Gd(III) calix[4]arene based MR contrast agents. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Lab Diagnost Radiol Res, Ctr Clin, Bethesda, MD 20892 USA. NIH, Radiat Oncol Branch, Radioimmune & Inorgan Chem, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 465-INOR BP A76 EP A77 PN 2 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296800465 ER PT J AU Katoch-Rouse, R Pavlova, OA Mukhin, AG Kimes, AS Horti, AG AF Katoch-Rouse, R Pavlova, OA Mukhin, AG Kimes, AS Horti, AG TI Synthesis and structure-activity relationships of diarylpyrazole ligands as potential targets for positron emission tomography studies of central cannabinoid receptors. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDA, Neuroimaging Branch, Intramural Res Program, NIH,Brain Imaging Sect, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 014-MEDI BP A89 EP A89 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296800530 ER PT J AU Kim, HS Barak, D Harden, TK Boyer, JL Jacobson, KA AF Kim, HS Barak, D Harden, TK Boyer, JL Jacobson, KA TI Acyclic and cyclopropyl analogues of adenosine bisphosphate antagonists of the P2Y1 receptor: Structure-activity relationships and receptor docking. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. NIDDK, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Med, Chapel Hill, NC 27515 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 024-MEDI BP A91 EP A91 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296800540 ER PT J AU Yordanov, AT Yamada, K Krishna, M Russo, A Yoo, J English, S Mitchell, J Brechbiel, MW AF Yordanov, AT Yamada, K Krishna, M Russo, A Yoo, J English, S Mitchell, J Brechbiel, MW TI Acyl-protected hydroxylamines as spin label generators for EPR brain imaging. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH,Ctr Canc Res, Bethesda, MD 20892 USA. NIH, Radiat Biol Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 41-MEDI BP A94 EP A95 PN 2 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296800557 ER PT J AU Zhu, XX Yu, QS Culter, RG Mattson, M Greig, NH AF Zhu, XX Yu, QS Culter, RG Mattson, M Greig, NH TI Design and synthesis of novel neuroprotective agents. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Neurosci Lab, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 012-MEDI BP A89 EP A89 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296800528 ER PT J AU Cardona, CM Gawley, RE AF Cardona, CM Gawley, RE TI Synthesis of a dendritic receptor attached to solid support. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ Miami, Dept Chem, Coral Gables, FL 33124 USA. Univ Miami, NIEHS Marine & Freshwater Biomed Sci Ctr, Coral Gables, FL 33124 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 242-ORGN BP B210 EP B210 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296801165 ER PT J AU Choi, YS Strazewski, P Marquez, VE AF Choi, YS Strazewski, P Marquez, VE TI The synthesis of a conformationally locked aminonucleoside analogue of the antibiotic puromycin. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Med Chem Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. Univ Lyon 1, Lab Syntheses Biomol, Lyon, France. RI Choi, Yongseok/F-8375-2012 OI Choi, Yongseok/0000-0002-3622-3439 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 217-ORGN BP B206 EP B206 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296801140 ER PT J AU Luzzio, FA Figg, WD Mayorov, AV Kruger, EA Thomas, EM AF Luzzio, FA Figg, WD Mayorov, AV Kruger, EA Thomas, EM TI Synthesis and antiangiogenic activity of 2-deoxygenated analogs and 6'-deoxygenated metabolic analogs of thalidome SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ Louisville, Louisville, KY 40292 USA. NCI, Med Branch, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 185-MEDI BP B129 EP B129 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296800700 ER PT J AU Senderowicz, AM AF Senderowicz, AM TI Preclinical and clinical development of CDK inhibitors. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Mol Therapeut Unit, Oral Pharyngeal Canc Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 252-MEDI BP B141 EP B141 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296800760 ER PT J AU Wang, XZ Yao, ZJ Burke, T AF Wang, XZ Yao, ZJ Burke, T TI An efficient synthesis of a constrained phosphotyrosine analogue. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Med Chem Lab, NIH, Ft Detrick, MD 21702 USA. RI Yao, Zhu-Jun/E-7635-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 226-ORGN BP B207 EP B207 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296801149 ER PT J AU Yoshimura, Y Moon, HR Marquez, VE AF Yoshimura, Y Moon, HR Marquez, VE TI An enatioselective synthesis of bicyclo[3.1.0]hexane carbocyclic nucleoside: A practical access to a guanosine derivative through lipase-mediated kinetic resolution. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Ctr Canc Res, Med Chem Lab, Ft Detrick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 109-ORGN BP B189 EP B189 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296801032 ER PT J AU Burt, SK Abashkin, YG Wang, Y Topol, IA AF Burt, SK Abashkin, YG Wang, Y Topol, IA TI Studies on phosphate hydrolysis in aqueous and protein environments. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Adv Biomed Comp Ctr, Ft Detrick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 163-PHYS BP C44 EP C44 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296801611 ER PT J AU Dimitriadis, EK Horkay, F Maresca, J Kachar, B Chadwick, RS AF Dimitriadis, EK Horkay, F Maresca, J Kachar, B Chadwick, RS TI Method for determination of the elastic modulus of thin polymer gels using the atomic force microscope. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Div Bioengn & Phys Sci, Bethesda, MD 20892 USA. NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. NIDCD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 083-POLY BP C113 EP C113 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296802050 ER PT J AU Gordon, DJ Tycko, R Meredith, SC AF Gordon, DJ Tycko, R Meredith, SC TI Increasing the amphiphilicity of an amyloidgenic peptide changes the beta-strand orientation in the fibril from antiparallel to parallel. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA. NIH, Lab Chem Phys, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 064-PHYS BP C29 EP C29 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296801513 ER PT J AU Horkay, F Haselkorn, K Tasaki, I Basser, PJ AF Horkay, F Haselkorn, K Tasaki, I Basser, PJ TI Swelling kinetics of polyacrylate gel beads in physiological salt solutions. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. St Louis Univ, Dept Biomed Engn, St Louis, MO 63103 USA. RI Basser, Peter/H-5477-2011 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 105-POLY BP C116 EP C116 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296802071 ER PT J AU Horkay, F Basser, PJ Hecht, AM Geissler, E AF Horkay, F Basser, PJ Hecht, AM Geissler, E TI Small-angle neutron scattering from strongly charged polyacrylate hydrogels in physiological salt solutions. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. Univ Grenoble 1, Lab Spectrometrie Phys, CNRS UMR 5588, F-38041 Grenoble, France. RI Basser, Peter/H-5477-2011 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 039-POLY BP C107 EP C107 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296802006 ER PT J AU Ling, H Boudsocq, F Woodgate, R Yang, W AF Ling, H Boudsocq, F Woodgate, R Yang, W TI Crystal structure of a Y-family DNA polymerase in action: A mechanism for error-prone and lesion-bypass replication. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 166-PHYS BP C44 EP C44 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296801614 ER PT J AU Stan, G Thirumalai, D Brooks, BR AF Stan, G Thirumalai, D Brooks, BR TI Computational studies of chaperonin-mediated protein folding. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NHLBI, Lab Biophys Chem, NIH, Bethesda, MD 20892 USA. Univ Maryland, Inst Phys Sci & Technol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 077-PHYS BP C31 EP C31 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296801526 ER PT J AU Tycko, R AF Tycko, R TI Probing the structure of amyloid fibrils with solid state NMR. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Chem Phys Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 021-PHYS BP C22 EP C22 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296801470 ER PT J AU Weiss, MA Petkova, A Wan, ZL Chu, YC Nakagawa, S Dong, J Carey, P Katsoyannis, PG Tycko, R AF Weiss, MA Petkova, A Wan, ZL Chu, YC Nakagawa, S Dong, J Carey, P Katsoyannis, PG Tycko, R TI Structural studies of insulin fibrils. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Case Western Reserve Univ, Dept Biochem, Sch Med, Cleveland, OH 44106 USA. Lab Chem Phys, NIH, Bethesda, MD USA. Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 107-PHYS BP C36 EP C36 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296801556 ER PT J AU Wickner, RB Edskes, HK Roberts, BT Pierce, MM Baxa, U Ross, E Brachmann, A Speransky, VV Steven, AC AF Wickner, RB Edskes, HK Roberts, BT Pierce, MM Baxa, U Ross, E Brachmann, A Speransky, VV Steven, AC TI The [URE3] prion of yeast is a heritable amyloidosis. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RI Brachmann, Andreas/I-2241-2013 OI Brachmann, Andreas/0000-0001-7980-8173 NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 019-PHYS BP C21 EP C21 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296801468 ER PT J AU Wilson, SH AF Wilson, SH TI On the mechanism of base recognition for incoming nucleotide in the DNA polymerase beta active site. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIEHS, Struct Biol Lab, NIH, Durham, NC 27707 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 164-PHYS BP C44 EP C44 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CE UT WOS:000176296801612 ER PT J AU Brooks, BR Woodcock, HL Cheatham, TE Wu, XW AF Brooks, BR Woodcock, HL Cheatham, TE Wu, XW TI Examining complex processes and reactions: The Replica/Path method. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Univ Georgia, Dept Chem, Athens, GA 30602 USA. Univ Utah, Dept Med Chem, Salt Lake City, UT 84112 USA. RI Woodc, Henry/D-9275-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 57-COMP BP U472 EP U472 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CD UT WOS:000176296702615 ER PT J AU Haley, MA Panyutin, IV Panyutin, IG Chuang, EJ Neumann, RD AF Haley, MA Panyutin, IV Panyutin, IG Chuang, EJ Neumann, RD TI Molecular cloning of a triplex-forming sequence to a plasmid vector. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Carroll Coll, Dept Biol, Waukesha, WI 53186 USA. Carroll Coll, Dept Chem, Waukesha, WI 53186 USA. NIH, Warren G Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 356-CHED BP U213 EP U213 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CD UT WOS:000176296701097 ER PT J AU Qasba, PK Ramakrishnan, B Balaji, PV AF Qasba, PK Ramakrishnan, B Balaji, PV TI Oligosaccharide binding site of beta 1,4-galactosyltransferases (Gal-Ts) defined by docking various glycan substrates in the binding site. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, LECB, CCR, NIH, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 217-COMP BP U496 EP U496 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CD UT WOS:000176296702774 ER PT J AU Schuck, P Gilligan, JJ Abrantes, M Magone, MT Yergey, AL AF Schuck, P Gilligan, JJ Abrantes, M Magone, MT Yergey, AL TI A new sample handling technique for SPR biosensing with small sample volumes and long contact times and the combination with mass spectrometry. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Div Bioengn & Phys Sci, ORS, Bethesda, MD 20892 USA. NICHHD, Sect Metab Anal & Mass Spectrometry, LCMB, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Ophthalmol, Washington, DC 20057 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 002-ANYL BP U63 EP U63 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CD UT WOS:000176296700261 ER PT J AU Sheeley, DM AF Sheeley, DM TI Detailed characterization of protein glycosylation using a combined approach of nanoscale data-dependent LC/MS/MS and MS/MS of methylated oligosaccharides. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Natl Ctr Res Resources, Div Biomed Technol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 085-CARB BP U114 EP U114 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CD UT WOS:000176296700541 ER PT J AU Tabor, DC AF Tabor, DC TI Strategies for preparing underrepresented biomedical scientists. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Natl Inst Gen Med Sci, Minor Biomed Res Support Branch, Div Minor Opportunities Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 017-CHED BP U166 EP U166 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CD UT WOS:000176296700758 ER PT J AU Yan, SQ Nicklaus, MC Blumberg, PM Marquez, VE AF Yan, SQ Nicklaus, MC Blumberg, PM Marquez, VE TI Homology modeling and discovery of ligands via virtual screening with protein kinase C zeta. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Frederick Canc Res & Dev Ctr, NIH, Frederick, MD 21702 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 143-COMP BP U485 EP U485 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 564CD UT WOS:000176296702700 ER PT J AU Yang, Y Nicklaus, MC AF Yang, Y Nicklaus, MC TI Anti-HIV drug design based on a model of HIV-1 integrase complexed with viral DNA. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD APR 7 PY 2002 VL 223 MA 224-COMP BP U497 EP U498 PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 564CD UT WOS:000176296702781 ER PT J AU Longenecker, G Thyagarajan, T Nagineni, CN Flanders, KC Factor, V Miller, G Ward, JM Nalca, A Rangnekar, VM Thorgeirsson, S Kulkarni, AB AF Longenecker, G Thyagarajan, T Nagineni, CN Flanders, KC Factor, V Miller, G Ward, JM Nalca, A Rangnekar, VM Thorgeirsson, S Kulkarni, AB TI Endocrine expression of the active form of TGF-beta 1 in the TGF-beta 1 null mice fails to ameliorate lethal phenotype SO CYTOKINE LA English DT Article DE autoimmunity; cytokine therapy; glomerulonephritis; inflammation; TGF-beta 1 ID TRANSFORMING GROWTH FACTOR-BETA-1; GROWTH-FACTOR-BETA-1 KNOCKOUT MOUSE; BETA TGF-BETA; IN-VIVO; TRANSGENIC MICE; INFLAMMATION; DISEASE; SKIN; RATS; THROMBOSPONDIN-1 AB TGF-beta1 null mice die by 3 to 4 weeks of age due to a severe autoimmune-mediated multifocal inflammation resulting in multi-organ failure. To assess the therapeutic potential of circulating levels of active TGF-beta1, we generated mice with endocrine expression of active TGF-beta1 on a TGF-beta1 null background (TGF-beta1 ((-/-/TG))) by crossing TGF-beta1((+/-)) mice with transgenic mice (TG) that express recombinant TGF-beta1 specifically in the liver and secrete it in the blood. The TGF-beta1 ((-/-/TG)) mice exhibit a survival profile similar to the TGF-beta1 ((-/-)) mice indicating a failure to rescue the lethal phenotype. However, serum TGF-beta1 levels in the TGF-beta1 ((-/-/TG)) mice were restored to near normal levels with expression in all the tissues, notably in the kidney and spleen. Histopathology showed reduced inflammation in the target tissues, especially in the heart. Interestingly, unlike TGF-beta1 ((-/-)) mice, the TGF-beta1 ((-/-/TG)) mice have glomerulonephritis in their kidneys similar to the TG mice. Thus, the phenotype of TGF-beta1 ((-/-/TG)) animal model indicates the potential role of circulating active-TGF-beta1 in reducing inflammation, but its failure to rescue lethality in TGF-beta1 null mice indicates a critical autocrine role of TGF-beta1. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Natl Inst Dent & Craniofacial Res, Funct Genom Unit & Gene Targeting Facil, NIH, Bethesda, MD 20892 USA. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NIH, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Natl Canc Inst, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NIH, Vet Resources Program, Off Director, Bethesda, MD 20892 USA. Natl Canc Inst, Vet & Tumor Pathol Sect, Off Lab Sci, NIH, Ft Detrick, MD 21702 USA. Univ Kentucky, Dept Radiat Med, Lexington, KY 40536 USA. RP Kulkarni, AB (reprint author), Natl Inst Dent & Craniofacial Res, Funct Genom Unit & Gene Targeting Facil, NIH, Bldg 10,Room 529, Bethesda, MD 20892 USA. NR 53 TC 15 Z9 16 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD APR 7 PY 2002 VL 18 IS 1 BP 43 EP 50 DI 10.1006/cyto.2002.1025 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 575LG UT WOS:000176947300006 PM 12090759 ER PT J AU Issaq, HJ Veenstra, TD Conrads, TP Felschow, D AF Issaq, HJ Veenstra, TD Conrads, TP Felschow, D TI The SELDI-TOF MS approach to proteomics: Protein profiling and biomarker identification SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID MASS-SPECTROMETRY AB The need for methods to identify disease biomarkers is underscored by the survival-rate of patients diagnosed at early stages of cancer progression. Surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) is a novel approach to biomarker discovery that combines two powerful techniques: chromatography and mass spectrometry. One of the key features of SELDI-TOF MS is its ability to provide a rapid protein expression profile from a variety of biological and clinical samples. It has been used for biomarker identification as well as the study of protein-protein, and protein-DNA interaction. The versatility of SELDI-TOF MS has allowed its use in projects ranging from the identification of potential diagnostic markers for prostate, bladder, breast, and ovarian cancers and Alzheimer's disease, to the study of biomolecular interactions and the characterization of posttranslational modifications. In this minireview we discuss the application of SELDI-TOF MS to protein biomarker discovery and profiling. C1 NCI, SAIC Frederick Inc, Frederick, MD 21702 USA. Ciphergen Biosyst Inc, Fremont, CA 94555 USA. RP Issaq, HJ (reprint author), NCI, SAIC Frederick Inc, POB B,Bldg 469,Room 155, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 20 TC 381 Z9 441 U1 5 U2 40 PU ACADEMIC PRESS INC ELSEVIER SCIENCE 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 APR 5 PY 2002 VL 292 IS 3 BP 587 EP 592 DI 10.1006/bbrc.2002.6678 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 538YK UT WOS:000174842600001 PM 11922607 ER PT J AU Yokochi, T Robertson, KD AF Yokochi, T Robertson, KD TI Preferential methylation of unmethylated DNA by mammalian de novo DNA methyltransferase Dnmt3a SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STEADY-STATE KINETICS; EMBRYONIC STEM-CELLS; DE-NOVO; CYTOSINE-5 METHYLTRANSFERASES; POSTTRANSLATIONAL MODIFICATIONS; INSECT CELLS; MECHANISM; EXPRESSION; SITES; PURIFICATION AB DNA methylation is an epigenetic modification of DNA. There are currently three catalytically active mammalian DNA methyltransferases, DNMT1, -3a, and -3b. DNMT1 has been shown to have a preference for hemimethylated DNA and has therefore been termed the maintenance methyltransferase. Although previous studies on DNMT3a and -3b revealed that they act as functional enzymes during development, there is little biochemical evidence about how new methylation patterns are established and maintained. To study this mechanism we have cloned and expressed Dnmt3a using a baculovirus expression system. The substrate specificity of Dnmt3a and molecular mechanism of its methylation reaction were then analyzed using a novel and highly reproducible assay. We report here that Dnmt3a is a true de novo methyltransferase that prefers unmethylated DNA substrates more than 3-fold to hemimethylated DNA. Furthermore, Dnmt3a binds DNA nonspecifically, regardless of the presence of CpG dinucleotides in the DNA substrate. Kinetic analysis supports an Ordered Bi Bi mechanism for Dnmt3a, where DNA binds first, followed by S-adenoSyl-L-methionine. C1 NCI, Epigenet Gene Regulat & Canc Sect, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Robertson, KD (reprint author), NCI, Epigenet Gene Regulat & Canc Sect, Lab Receptor Biol & Gene Express, NIH, Bldg 41,Rm B602, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA84535-01] NR 64 TC 94 Z9 108 U1 0 U2 12 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 APR 5 PY 2002 VL 277 IS 14 BP 11735 EP 11745 DI 10.1074/jbc.M106590200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 539AC UT WOS:000174846400019 PM 11821381 ER PT J AU Odersky, A Panyutin, IV Panyutin, IG Schunck, C Feldmann, E Goedecke, W Neumann, RD Obe, G Pfeiffer, P AF Odersky, A Panyutin, IV Panyutin, IG Schunck, C Feldmann, E Goedecke, W Neumann, RD Obe, G Pfeiffer, P TI Repair of sequence-specific I-125-induced double-strand breaks by nonhomologous DNA end joining in mammalian cell-free extracts SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHROMOSOMAL-ABERRATIONS; RESTRICTION ENDONUCLEASES; ENZYMATIC RESTRICTION; XENOPUS-LAEVIS; RECOMBINATION; MECHANISMS; I-125; TRIPLEX; OLIGONUCLEOTIDES; POLYMERASES AB In mammalian cells, nonhomologous DNA end joining (NHEJ) is considered the major pathway of double-strand break (DSB) repair. Rejoining of DSB produced by decay of I-125 positioned against a specific target site in plasmid DNA via a triplex-forming oligonucleotide (TFO) was investigated in cell-free extracts from Chinese hamster ovary cells. The efficiency and quality of NHEJ of the "complex" DSB induced by the I-125-TFO was compared with that of "simple" DSB induced by restriction enzymes. We demonstrate that the extracts are indeed able to rejoin I-125-TFO-induced DSB, although at approximately 10-fold decreased efficiency compared with restriction enzyme-induced DSB. The resulting spectrum of junctions is highly heterogeneous exhibiting deletions (1-30 bp), base pair substitutions, and insertions and reflects the heterogeneity of DSB induced by the I-125-TFO within its target site. We show that NHEJ of I-125-TFO-induced DSB is not a random process that solely depends on the position of the DSB but is driven by the availability of microhomology patches in the target sequence. The similarity of the junctions obtained with the ones found in vivo after I-125-TFO-mediated radiodamage indicates that our in vitro system may be a useful tool to elucidate the mechanisms of ionizing radiation-induced mutagenesis and repair. C1 Univ Essen Gesamthsch, Inst Genet, FB9, D-45117 Essen, Germany. NIH, Warren G Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20854 USA. RP Pfeiffer, P (reprint author), Univ Essen Gesamthsch, Inst Genet, FB9, S05 T04 B26,Univ St 5, D-45117 Essen, Germany. NR 50 TC 24 Z9 26 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 5 PY 2002 VL 277 IS 14 BP 11756 EP 11764 DI 10.1074/jbc.M111304200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 539AC UT WOS:000174846400021 PM 11821407 ER PT J AU Chiapperino, D Kroth, H Kramarczuk, IH Sayer, JM Masutani, C Hanaoka, F Jerina, DM Cheh, AM AF Chiapperino, D Kroth, H Kramarczuk, IH Sayer, JM Masutani, C Hanaoka, F Jerina, DM Cheh, AM TI Preferential misincorporation of purine nucleotides by human DNA polymerase eta opposite benzo[a]pyrene 7,8-diol 9,10-epoxide deoxyguanosine adducts SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GUANINE PHOSPHORIBOSYLTRANSFERASE GENE; TEMPLATE-PRIMER JUNCTION; PRONE LESION BYPASS; XERODERMA-PIGMENTOSUM; SOLUTION CONFORMATION; NUCLEOSIDE ADDUCTS; THYMINE DIMER; V-79 CELLS; MUTATIONS; REPLICATION AB Human DNA polymerase eta was used to copy four stereoisomeric deoxyguanosine (dG) adducts derived from benzo[a]pyrene 7,8-diol 9,10-epoxide (diastereomer with the 7-hydroxyl group and epoxide oxygen trans (BaP DE-2)). The adducts, formed by either cis or trans epoxide ring opening of each enantiomer of BaP DE-2 by N-2 of dG, were placed at the fourth nucleotide from the 5'-end in two 16-mer sequence contexts, 5'similar toCG*Asimilar to and 5'similar toGG*T. poleta was remarkably error prone at all four diol epoxide adducts, preferring to misincorporate G and A at frequencies 3- to more than 50-fold greater than the frequencies for T or the correct C, although the highest rates were 60-fold below the rate of incorporation of C opposite a non-adducted G. Anti to syn rotation of the adducted base, consistent with previous NMR data for a BaP DE-2 dG adduct placed just beyond a primer terminus, provides a rationale for preferring purine misincorporation. Extension of purine misincorporations occurred preferentially, but extension beyond the adduct site was weak with V-max/K-m values generally 10-fold less than for misincorporation. Mostly A was incorporated opposite (+)-BaP DE-2 dG adducts, which correlates with published observations that G --> T is the most common type of mutation that (+)-BaP DE-2 induces in mammalian cells. C1 NIDDK, Lab Bioorgan Chem, Bethesda, MD 20892 USA. American Univ, Dept Chem, Washington, DC 20016 USA. Japan Sci & Technol Corp, Core Res Evolut Sci & Technol, Wako, Saitama 3510198, Japan. RIKEN, Wako, Saitama 3510198, Japan. Osaka Univ, Inst Mol & Cellular Biol, Suita, Osaka 5650871, Japan. RP Cheh, AM (reprint author), NIDDK, Lab Bioorgan Chem, Bethesda, MD 20892 USA. RI Masutani, Chikahide/I-6160-2014 NR 57 TC 66 Z9 68 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 5 PY 2002 VL 277 IS 14 BP 11765 EP 11771 DI 10.1074/jbc.M112139200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 539AC UT WOS:000174846400022 PM 11821420 ER PT J AU Pero, SC Oligino, L Daly, RJ Soden, AL Liu, C Roller, PP Li, P Krag, DN AF Pero, SC Oligino, L Daly, RJ Soden, AL Liu, C Roller, PP Li, P Krag, DN TI Identification of novel non-phosphorylated ligands, which bind selectively to the SH2 domain of Grb7 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STRUCTURE-BASED DESIGN; PHAGE DISPLAY LIBRARIES; GROWTH-FACTOR RECEPTOR; FOCAL ADHESION KINASE; SRC HOMOLOGY-2 DOMAIN; HIGH-AFFINITY LIGANDS; PEPTIDE LIBRARIES; GRB2-SH2 DOMAIN; ESOPHAGEAL-CARCINOMA; TYROSINE KINASE AB Grb7 is an adapter-type signaling protein, which is recruited via its SH2 domain to a variety of receptor tyrosine kinases (RTKs), including ErbB2 and ErbB3. It is overexpressed in breast, esophageal, and gastric cancers, and may contribute to the invasive potential of cancer cells. Molecular interactions involving Grb7 therefore provide attractive targets for therapeutic intervention. We have utilized phage display random peptide libraries as a source of small peptide ligands to the SH2 domain of Grb7. Screening these libraries against purified Grb7 SH2 resulted in the identification of Grb7-binding peptide phage clones that contained a nonphosphorylated Tyr-X-Asn (YXN) motif. The tyrosine-phosphorylated form of this motif is characteristic of Grb7 SH2 domain binding sites identified in RTKs and other signaling proteins such as Shc. Peptides that are non-phosphorylated have greater potential in the development of therapeutics because of the instability of a phosphate group in vivo. Using a biased library approach with this conserved YXN motif, we identified seven different peptide phage clones, which bind specifically to the SH2 domain of Grb7. These peptides did not bind to the SH2 domain of Grb2 (which also selects for Asn at py(+2)) or Grb14, a closely related family member. The cyclic structure of the peptides was required to bind to the Grb7 SH2 domain. Importantly, the synthetic Grb7-binding peptide G7-18 in cell lysates was able to specifically inhibit the association of Grb7 with the ErbB family of RTKs, in particular ErbB3, in a dose-dependent manner. These peptides will be useful in the development of targeted molecular therapeutics for cancers overexpressing Grb7 and in the development of Grb7-specific inhibitors to gain a complete understanding of the physiological role of Grb7. C1 Univ Vermont, Sch Med, Dept Surg, Burlington, VT 05405 USA. Univ Vermont, Sch Med, Vermont Canc Ctr, Burlington, VT 05405 USA. St Vincents Hosp, Garvan Inst Med Res, Canc Res Program, Sydney, NSW 2010, Australia. NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. RP Krag, DN (reprint author), Univ Vermont, Sch Med, Dept Surg, Given Med Bldg,Rm E309, Burlington, VT 05405 USA. RI Daly, Roger/C-8179-2009; OI Daly, Roger/0000-0002-5739-8027 FU NCI NIH HHS [R01 CA087790, U01 CA665121] NR 73 TC 62 Z9 62 U1 1 U2 11 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 APR 5 PY 2002 VL 277 IS 14 BP 11918 EP 11926 DI 10.1074/jbc.M111816200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 539AC UT WOS:000174846400042 PM 11809769 ER PT J AU Riese, MJ Goehring, UM Ehrmantraut, ME Moss, J Barbieri, JT Aktories, K Schmidt, G AF Riese, MJ Goehring, UM Ehrmantraut, ME Moss, J Barbieri, JT Aktories, K Schmidt, G TI Auto-ADP-ribosylation of Pseudomonas aeruginosa ExoS SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GTP-BINDING PROTEINS; EXOENZYME-S; EUKARYOTIC CELLS; TERMINAL DOMAIN; RHO GTPASES; RIBOSYLTRANSFERASE; RAS; HYDROLYSIS; EXPRESSION AB Pseudomonas aeruginosa Exoenzyme S (ExoS) is a bifunctional type-III cytotoxin. The N terminus possesses a Rho GTPase-activating protein (GAP) activity, whereas the C terminus comprises an ADP-ribosyltransferase domain. We investigated whether the ADP-ribosyltransferase activity of ExoS influences its GAP activity. Although the ADP-ribosyltransferase activity of ExoS is dependent upon FAS, a 14-3-3 family protein, factor-activating ExoS (FAS) had no influence on the activity of the GAP domain of ExoS (ExoS-GAP). In the presence of NAD and FAS, the GAP activity of full-length ExoS was reduced about 10-fold, whereas NAD and FAS did not affect the activity of the ExoS-GAP fragment. Using [P-32]NAD, ExoS-GAP was identified as a substrate of the ADP-ribosyltransferase activity of ExoS. Site-directed mutagenesis revealed that auto-ADP-ribosylation of Arg-146 of ExoS was crucial for inhibition of GAP activity in vitro. To reveal the auto-ADP-ribosylation of ExoS in intact cells, tetanolysin was used to produce pores in the plasma membrane of Chinese hamster ovary (CHO) cells to allow the intracellular entry of [32p]NAD, the substrate for ADP-ribosylation. After a 3-h infection of CHO cells with Pseudomonas aeruginosa, proteins of 50 and 25 kDa were preferentially ADP-ribosylated. The 50-kDa protein was determined to be auto-ADP-ribosylated ExoS, whereas the 25-kDa protein appeared to represent a group of proteins that included Ras. C1 Univ Freiburg, Inst Expt, D-79104 Freiburg, Germany. Univ Freiburg, Klin Pharmakol & Toxikol, D-79104 Freiburg, Germany. Med Coll Wisconsin, Milwaukee, WI 53226 USA. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Aktories, K (reprint author), Univ Freiburg, Inst Expt, Albertstr 25, D-79104 Freiburg, Germany. FU PHS HHS [A1-30162] NR 31 TC 37 Z9 38 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 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 5 PY 2002 VL 277 IS 14 BP 12082 EP 12088 DI 10.1074/jbc.M109039200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 539AC UT WOS:000174846400064 PM 11821389 ER PT J AU Joseloff, E Cataisson, C Aamodt, H Ocheni, H Blumberg, P Kraker, AJ Yuspa, SH AF Joseloff, E Cataisson, C Aamodt, H Ocheni, H Blumberg, P Kraker, AJ Yuspa, SH TI Src family kinases phosphorylate protein kinase C delta on tyrosine residues and modify the neoplastic phenotype of skin keratinocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SIGNAL-TRANSDUCTION PATHWAY; GROWTH-FACTOR RECEPTOR; HIGH-AFFINITY RECEPTOR; PKC-DELTA; TRANSEPITHELIAL PERMEABILITY; DIFFERENTIATION MARKERS; EPIDERMAL-KERATINOCYTES; INDUCED APOPTOSIS; EPITHELIAL-CELLS; TUMOR PROMOTION AB Protein kinase C delta (PKC delta) is tyrosine-phosphorylated and catalytically inactive in mouse keratinocytes transformed by a ras oncogene. In several other model systems, Src kinases are upstream regulators of PKC delta. To examine this relationship in epidermal carcinogenesis, v-ras transformed mouse keratinocytes were treated with a selective Src kinase inhibitor (PD 173958). PD 173958 decreased autophosphorylation of Src, Fyn, and Lyn kinases and prevented tyrosine phosphorylation of the Src kinase substrate p120. PD 173958 also prevented PKC delta tyrosine phosphorylation and activated PKC delta as detected by membrane translocation. Expression of keratinocyte differentiation markers increased in PD 173958-treated v-ras-keratinocytes, and fluid-filled domes emerged, indicative of tight junction formation. Antisense PKC delta or bryostatin 1 inhibited dome formation, while overexpression of PKC delta in the presence of PD 173958 enhanced the formation of domes. Plasmids encoding phenylalanine mutants of PKC delta tyrosine residues 64 and 565 induced domes in the absence of PD 173958, while phenylalanine mutants of tyrosine residues 52, 155, and 187 were inactive. Thus, Src kinase mediated post-translational modification of PKC delta on specific tyrosine residues in ras-transformed mouse keratinocytes inactivates PKC delta and contributes to alterations in the differentiated phenotype and tight junction formation associated with neoplasia. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Pfizer Global Res & Dev, Canc Pharmacol, Ann Arbor Labs, Ann Arbor, MI 48105 USA. RP Yuspa, SH (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res, 37 Convent Dr,MSC-4255,Bldg 37,Rm 3B25, Bethesda, MD 20892 USA. NR 53 TC 63 Z9 64 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 5 PY 2002 VL 277 IS 14 BP 12318 EP 12323 DI 10.1074/jbc.M111618200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 539AC UT WOS:000174846400094 PM 11812791 ER PT J AU Chikumi, H Fukuhara, S Gutkind, JS AF Chikumi, H Fukuhara, S Gutkind, JS TI Regulation of G protein-linked guanine nucleotide exchange factors for Rho, PDZ-RhoGEF, and LARG by tyrosine phosphorylation - Evidence of a role for focal adhesion kinase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HETEROTRIMERIC G-PROTEINS; VAV PROTOONCOGENE PRODUCT; GTPASE-ACTIVATING PROTEIN; JUN NH2-TERMINAL KINASE; SERUM RESPONSE ELEMENT; DBL ONCOGENE PRODUCT; COUPLED RECEPTORS; CELLULAR-TRANSFORMATION; LYSOPHOSPHATIDIC ACID; DEPENDENT ACTIVATION AB A recently identified family of guanine nucleotide exchange factors for Rho that includes PDZ-RhoGEF, LARG, and p115RhoGEF exhibits a unique structural feature consisting in the presence of area of similarity to regulators of G protein signaling (RGS). This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha12 and Galpha(13) to Rho. Recently available data suggest, however, that tyrosine kinases can regulate the ability of G protein-coupled receptors (GPCRs) to stimulate Rho, although the underlying molecular mechanisms are still unknown. Here, we found that the activation of thrombin receptors endogenously expressed in HEK-293T cells leads to a remarkable increase in the levels of GTP-bound Rho within 1 min (11-fold) and a more limited but sustained activation (4-fold) thereafter, which lasts even for several hours. Interestingly, tyrosine kinase inhibitors did not affect the early phase of Rho activation, immediately after thrombin addition, but diminished the levels of GTP-bound Rho during the delayed phase. As thrombin receptors stimulate focal adhesion kinase (FAK) potently, we explored whether this non-receptor tyrosine kinase participates in the activation of Rho by GPCRs. We obtained evidence that FAR can be activated by thrombin, Galpha(12), Galpha(13), and Galpha(q) through both Rho-dependent and Rho-independent mechanisms and that PDZ-RhoGEF and LARG can in turn be tyrosine-phosphorylated through FAK in response to thrombin, thereby enhancing the activation of Rho in vivo. These data indicate that FAK may act as a component of a positive feedback loop that results in the sustained activation of Rho by GPCRs, thus providing evidence of the existence of a novel biochemical route by which tyrosine kinases may regulate the activity of Rho through the tyrosine phosphorylation of RGL-containing RhoGEFs. C1 NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), NIDCR, Oral & Pharyngeal Canc Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009 NR 58 TC 122 Z9 122 U1 2 U2 6 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 APR 5 PY 2002 VL 277 IS 14 BP 12463 EP 12473 DI 10.1074/jbc.M108504200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 539AC UT WOS:000174846400113 PM 11799111 ER PT J AU Nemukhin, AV Grigorenko, BL Bochenkova, AV Topol, IA Burt, SK AF Nemukhin, AV Grigorenko, BL Bochenkova, AV Topol, IA Burt, SK TI A QM/MM approach with effective fragment potentials applied to the dipeptide-water structures SO JOURNAL OF MOLECULAR STRUCTURE-THEOCHEM LA English DT Article DE QM/MM method; dipeptide-water structures; effective fragment potentials ID L-ALANINE N'-METHYLAMIDE; SIMULATIONS; SOLVATION; FORMAMIDE; CHEMISTRY; MOLECULES; SOLVENT; SPECTRA; MODEL AB An application of the hybrid quantum mechanical and molecular mechanical (QM/MM) model to calculations of the structures of the hydrogen-bonded complex of the dipeptide N-acetyl-L-alanine N'-methylamide with water molecules is described. This particular approach is essentially based on the effective fragment potential theory [J. Phys. Chem. A 105 (2001) 293]. We discuss both options in the QM/MM treatment of the system, considering once the dipeptide as a quantum part and water molecules as a MM subsystem, and vice versa, taking the dipeptide as a collection of effective fragments, while water molecules constitute a QM part. The first method is realized in the GAMESS program, in the second case a new version, combining quantum chemical and molecular mechanical packages is required. Our approach assumes that the MM subsystem is viewed as a flexible composition of effective fragments while fragment-fragment interactions are replaced by the MM force fields. It is shown that these QM/MM models correctly describe the conformational properties of dipeptide, namely, the changes in the backbone angles phi and psi due to complexation with water. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NCI, SAIC Frederick, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119899, Russia. RP Topol, IA (reprint author), NCI, SAIC Frederick, Adv Biomed Comp Ctr, POB B, Frederick, MD 21702 USA. RI Nemukhin, Alexander/P-9662-2015; Bochenkova, Anastasia/G-2090-2015 OI Bochenkova, Anastasia/0000-0003-4101-3564 NR 25 TC 30 Z9 30 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-1280 J9 J MOL STRUC-THEOCHEM JI Theochem-J. Mol. Struct. PD APR 5 PY 2002 VL 581 BP 167 EP 175 AR PII S0166-1280(01)00755-2 DI 10.1016/S0166-1280(01)00755-2 PG 9 WC Chemistry, Physical SC Chemistry GA 554FH UT WOS:000175723200016 ER PT J AU Farrer, M Skipper, L Berg, M Bisceglio, G Hanson, M Hardy, J Adam, A Gwinn-Hardy, K Aasly, J AF Farrer, M Skipper, L Berg, M Bisceglio, G Hanson, M Hardy, J Adam, A Gwinn-Hardy, K Aasly, J TI The Tau H1 haplotype is associated with Parkinson's disease in the Norwegian population SO NEUROSCIENCE LETTERS LA English DT Article DE Tau; genetics; Parkinson's disease; case-control study; epidemiology ID LEWY BODIES; SYNUCLEIN; DEMENTIA; GENE AB We investigated the association of Parkinson's disease (PD) with tau gene H1 haplotypes in the Norwegian population. In a sample of 96 unrelated PD cases and 68 control subjects, we observed an increased risk of PD for persons with the tau H1 haplotype (odds ratio = 5.52; 95% confidence interval: 2.64-11.10; P = 2.17 X 10(-6)). Findings provide evidence that tau participates in the PD pathogenic process and demonstrate the value of isolated populations in mapping complex traits. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Trondheim Hosp, Dept Neurol, N-7006 Trondheim, Norway. Mayo Clin, Lab Familial Movement Disorders, Jacksonville, FL 32224 USA. NIA, Neurogenet Lab, Bethesda, MD 20892 USA. NINCDS, Bethesda, MD 20892 USA. RP Aasly, J (reprint author), Univ Trondheim Hosp, Dept Neurol, N-7006 Trondheim, Norway. RI Hardy, John/C-2451-2009 FU NINDS NIH HHS [NS40256] NR 20 TC 53 Z9 53 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD APR 5 PY 2002 VL 322 IS 2 BP 83 EP 86 AR PII S0304-3940(02)00106-4 DI 10.1016/S0304-3940(02)00106-4 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 539CV UT WOS:000174852900004 PM 11958849 ER PT J AU Kelley, BS Chang, LC Bewley, CA AF Kelley, BS Chang, LC Bewley, CA TI Engineering an obligate domain-swapped dimer of cyanovirin-N with enhanced anti-HIV activity SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID INACTIVATING PROTEIN; CRYSTAL-STRUCTURE; GP120 C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 20 TC 34 Z9 35 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 APR 3 PY 2002 VL 124 IS 13 BP 3210 EP 3211 DI 10.1021/ja025537m PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 538BD UT WOS:000174793400010 PM 11916396 ER PT J AU Yu, XD Guo, ZS Marcu, MG Neckers, L Nguyen, DM Chen, GA Schrump, DS AF Yu, XD Guo, ZS Marcu, MG Neckers, L Nguyen, DM Chen, GA Schrump, DS TI Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228 SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HISTONE DEACETYLASE INHIBITORS; MAP KINASE PATHWAY; ADENOCARCINOMA CELLS; ANTITUMOR-ACTIVITY; SODIUM-BUTYRATE; TRICHOSTATIN-A; IN-VITRO; ACETYLATION; APOPTOSIS; CYCLE AB Background: Histone deacetylases (HDACs) modulate chromatin structure by regulating acetylation of core histone proteins. HDAC inhibitors, such as depsipeptide FR901228 (FK228), induce growth arrest and apoptosis in a variety of human cancer cells by mechanisms that cannot be attributed solely to histone acetylation. This study evaluated the mechanisms by which FK228 mediates apoptosis in non-small-cell lung cancer (NSCLC) cells. Methods: Proliferation and apoptosis were assessed in a panel of NSCLC cell lines that vary in the expression of the growth-regulating proteins p53, pRb, and K-Ras treated with a clinically relevant dose of FK228 (25 ng/mL). Western blot and immunoprecipitation techniques were used to analyze expression of cell-cycle proteins (cyclin A, cyclin E, p53, and p21), signaling-related proteins (ErbB1, ErbB2, and Raf-1), activity of extracellular signal-regulated kinase 1 and 2 (ERK1/2), binding of mutant p53 and Raf-1 to heat shock protein (Hsp)90, and acetylation of Hsp90. Results: FK228 treatment inhibited growth and induced apoptosis in NSCLC cells expressing wild-type or mutant p53. FK228 treatment led to altered expression of cyclin A, cyclin E, and p21, and to reduced expression of mutant, but not wild-type, p53. FK228-treated cells also were depleted of ErbB1, ErbB2, and Raf-1 proteins, and exhibited lower ERK1/2 activity. FK228 treatment also inhibited the binding of mutant p53 and Raf-1 to Hsp90; this inhibition was associated with acetylation of Hsp90. Conclusions: FK228 depletes the levels of several oncoproteins that are normally stabilized by binding to Hsp90 in cancer cells. The resulting ability of FK228 to diminish signal transduction via pathways involving Raf-1 and ERK may contribute to the potency and specificity of this novel antitumor agent. C1 NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NCI, Tumor Cell Biol Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schrump, DS (reprint author), NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res,NIH, Bldg 10,Rm 2B-07,10 Ctr Dr, Bethesda, MD 20892 USA. NR 52 TC 295 Z9 320 U1 0 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD APR 3 PY 2002 VL 94 IS 7 BP 504 EP 513 PG 10 WC Oncology SC Oncology GA 584EP UT WOS:000177454500010 PM 11929951 ER PT J AU Bao, RD Connolly, DC Murphy, M Green, J Weinstein, JK Pisarcik, DA Hamilton, TC AF Bao, RD Connolly, DC Murphy, M Green, J Weinstein, JK Pisarcik, DA Hamilton, TC TI Activation of cancer-specific gene expression by the survivin promoter SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ANTI-APOPTOSIS GENE; OVARIAN-CANCER; CELL-PROLIFERATION; MOUSE MODEL; CARCINOMAS; PROSTATE; PROTEIN AB Background: Survivin, a member of the IAP (inhibitor of apoptosis) gene family, appears to be overexpressed in common cancers but not in corresponding normal adult tissues. To investigate whether the survivin promoter controls cancer cell-specific gene expression, we determined whether the survivin gene promoter could regulate reporter gene expression in cancer cell lines and xenografts. Methods: Survivin protein levels were determined in human and murine cancer cell lines and in normal tissues of adult C57BL/6 mice by Western blot analysis. A reporter construct in which a portion of the survivin gene promoter was used to drive transcription of a human secreted alkaline phosphatase (SEAP) gene was transiently transfected into cancer cells, and promoter activity was extrapolated from SEAP activity. A2780 human ovarian cancer cells were transfected with this construct, and stable transfectants were injected into the intrabursal ovarian space of immunodeficient mice. Tumor growth was monitored, and plasma SEAP levels were used as a measure of survivin promoter activity in vivo. Results: Survivin protein was detected in all cancer cell lines examined but not in most normal adult mouse tissues. After transfection, the survivin promoter was more active in all cancer cell lines than in normal ovarian surface epithelial cells or mouse 3T3 cells. After 0.8 x 10(6) stable transfectant cells were injected into the intrabursal cavity of mouse ovaries, plasma SEAP activity was detected within 24 hours, and the activity increased with time and tumor growth. Conclusion: Transfection experiments indicate that survivin protein expression in cancer tissue appears to be regulated, at least in part, transcriptionally. Thus, the survivin promoter may be useful in controlling gene expression in cancer cells. C1 Fox Chase Canc Ctr, Ovarian Canc Program, Philadelphia, PA 19111 USA. Fox Chase Canc Ctr, Dept Pharmacol, Philadelphia, PA 19111 USA. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Hamilton, TC (reprint author), Fox Chase Canc Ctr, Ovarian Canc Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA. FU NCI NIH HHS [CA83638, CA06927, CA51228, CA56916, CA84242] NR 19 TC 92 Z9 114 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD APR 3 PY 2002 VL 94 IS 7 BP 522 EP 528 PG 7 WC Oncology SC Oncology GA 584EP UT WOS:000177454500012 PM 11929953 ER PT J AU Young, NS AF Young, NS TI Acquired aplastic anemia SO ANNALS OF INTERNAL MEDICINE LA English DT Review ID BONE-MARROW TRANSPLANTATION; COLONY-STIMULATING FACTOR; PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; HIGH-DOSE CYCLOPHOSPHAMIDE; ANTITHYMOCYTE GLOBULIN; NON-A; IMMUNOSUPPRESSIVE THERAPY; ANTILYMPHOCYTE GLOBULIN; FAILURE SYNDROMES; MALIGNANT-TUMORS AB In aplastic anemia, hematopoiesis fails: Blood cell counts are extremely low, and the bone marrow appears empty. The pathophysiology of aplastic anemia is now believed to be immune-mediated, with active destruction of blood-forming cells by lymphocytes. The aberrant immune response may be triggered by environmental exposures, such as to chemicals and drugs or viral infections and, perhaps, endogenous antigens generated by genetically altered bone marrow cells. In patients with post-hepatitis aplastic anemia, antibodies to the known hepatitis viruses are absent; the unknown infectious agent may be more common in developing countries, where aplastic anemia occurs more frequently than it does in the West. The syndrome paroxysmal nocturnal hemoglobinuria (PNH) is intimately related to aplastic anemia because many patients with bone marrow failure have an increased population of abnormal cells. In PNH, an entire class of proteins is not displayed on the cell surface because of an acquired X-chromosome gene mutation. The PNH cells may have a selective advantage in resisting immune attack. In contrast, the disease myelodysplasia can be confused with aplasia and can also evolve from aplastic anemia. The occurrence of cytogenetic abnormalities in patients years after presentation implies that genomic instability is a feature of this immune-mediated disease. Aplastic anemia can be effectively treated by stem-cell transplantation or immunosuppressive therapy, Transplantation is curative but is best used for younger patients who have histocompatible sibling donors. Antithymocyte globulin and cyclosporine restore hematopoiesis in approximately two thirds of patients. However, recovery of blood cell count is often incomplete, recurrent pancytopenia. requires retreatment, and some patients develop late complications (especially myelodysplasia). C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Young, NS (reprint author), NHLBI, NIH, Bldg 10,Room 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 62 TC 158 Z9 176 U1 1 U2 10 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 APR 2 PY 2002 VL 136 IS 7 BP 534 EP 546 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 536CA UT WOS:000174682100006 PM 11926789 ER PT J AU Ventura, ON Kieninger, M Denis, PA Cachau, RE AF Ventura, ON Kieninger, M Denis, PA Cachau, RE TI Density functional computational thermochemistry: solving the discrepancy between MO and DFT calculations on the enthalpy of formation of sulfine, CH2=S=O SO CHEMICAL PHYSICS LETTERS LA English DT Article ID CHEMISTRY; RADICALS; HEAT; BOND; MOLECULES; EXCHANGE; OXIDES AB The enthalpy of formation of sulfine is computed at the density functional (DFT) level to solve the discrepancy between previously recommended theoretical values. In agreement with the most recent CBS-QB3 calculations. which predict a value of -30 +/- 6 kJ/mol. DFT calculations on isodesmic reactions predict a value of -38 +/- 10 kJ/mol. Previous estimations of -9 +/- 14 kJ/mol (at the MO level) and -52 +/- 10 kJ/mol (at the DFT level) are discussed and shown to be artifacts of the methods of calculation employed. (C) 2002 Published by Elsevier Science B.V. C1 Univ Republica, Fac Quim, DEQUIFIM, CCPG, Montevideo, Uruguay. NCI, SAIC, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Ventura, ON (reprint author), Univ Republica, Fac Quim, DEQUIFIM, CCPG, CC 1157, Montevideo, Uruguay. OI Denis, Pablo/0000-0003-3739-5061 NR 30 TC 17 Z9 17 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-2614 J9 CHEM PHYS LETT JI Chem. Phys. Lett. PD APR 2 PY 2002 VL 355 IS 3-4 BP 207 EP 213 AR PII S0009-2614(02)00104-5 DI 10.1016/S0009-2614(02)00104-5 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 545FE UT WOS:000175205600001 ER PT J AU Koh, KK Schenke, WH Waclawiw, MA Csako, G Cannon, RO AF Koh, KK Schenke, WH Waclawiw, MA Csako, G Cannon, RO TI Statin attenuates increase in C-reactive protein during estrogen replacement therapy in postmenopausal women SO CIRCULATION LA English DT Article DE hormones; women; inflammation; endothelium; hypercholesterolemia ID CARDIOVASCULAR-DISEASE; RISK AB Background-HMG-CoA reductase inhibitor (statin) therapy reduces cardiovascular risk, mechanisms of which may include diminished arterial inflammation, as suggested by reduction in levels of C-reactive protein (CRP). Because oral estrogens increase CRP in postmenopausal women, with potential inflammatory and thrombotic consequences that could compromise any benefit to cardiovascular risk, we determined whether the coadministration of a statin might modify the estrogenic effect on CRP. Methods and Results-In a double-blind, 3-period crossover study, 28 postmenopausal women (average LDL cholesterol 163+/-36 mg/dL) were randomly assigned to daily conjugated equine estrogens (CEEs) 0.625 mg, simvastatin 10 mg, or their combination for 6 weeks, with each treatment period separated by 6 weeks. CEEB increased median CRP levels from 0.27 to 0.46 mg/dL, simvastatin decreased CRP from 0.29 to 0.28 mg/dL, and the therapies combined increased CRP from 0.28 to 0.36 mg/dL (all Pless than or equal to0.02 versus respective baseline values). Post hoc testing showed that the 29% increase in CRP on the combination of CEEB with simvastatin was significantly less than the 70% increase in CRP on CEEB alone (P<0.05). The effect of combination therapy on CRP levels did not correlate with baseline CRP or with baseline or treatment-induced changes in levels of interleukin-6, lipoproteins, or flow-mediated dilation of the brachial artery as a measure of nitric oxide bioactivity. Conclusions-The combination of statin with estrogen may attenuate the potential harmful effects of estrogen therapy in postmenopausal women and maximize any benefit to cardiovascular risk. C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. RP Cannon, RO (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 10,Room 7B15,10 Ctr Dr MSC 1650, Bethesda, MD 20892 USA. NR 25 TC 59 Z9 61 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD APR 2 PY 2002 VL 105 IS 13 BP 1531 EP 1533 DI 10.1161/01.CIR.0000013837.81710.DA PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 538VM UT WOS:000174835800008 PM 11927515 ER PT J AU Loftus, SK Larson, DM Baxter, LL Antonellis, A Chen, YD Wu, XF Jiang, Y Bittner, M Hammer, JA Pavan, WJ AF Loftus, SK Larson, DM Baxter, LL Antonellis, A Chen, YD Wu, XF Jiang, Y Bittner, M Hammer, JA Pavan, WJ TI Mutation of melanosome protein RAB38 in chocolate mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GENE-EXPRESSION; WAARDENBURG-SYNDROME; STRUCTURAL BASIS; MOUSE; PAX3; MELANOCYTES; MICROARRAY; PATTERNS; GTPASES; MITF AB Mutations of genes needed for melanocyte function can result in oculocutaneous albinism. Examination of similarities in human gene expression patterns by using microarray analysis reveals that RAB38, a small GTP binding protein, demonstrates a similar expression profile to melanocytic genes. Comparative genomic analysis localizes human RAB38 to the mouse chocolate (cht) locus. A G146T mutation occurs in the conserved GTP binding domain of RAB38 in cht mice. Rab38(cht)/Rab38(cht) mice exhibit a brown coat similar in color to mice with a mutation in tyrosinase-related protein 1 (Tyrp7), a mouse model for oculocutaneous albinism. The targeting of TYRP1 protein to the melanosome is impaired in Rab38(cht);/Rab38(cht) melanocytes. These observations, and the fact that green fluorescent protein-tagged RAB38 colocalizes with end-stage melanosomes in wild-type melanocytes, suggest that RAB38 plays a role in the sorting of TYRP1. This study demonstrates the utility of expression profile analysis to identify mammalian disease genes. C1 NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. George Washington Univ, Grad Program Genet, Washington, DC 20052 USA. RP Pavan, WJ (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 42 TC 107 Z9 112 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 APR 2 PY 2002 VL 99 IS 7 BP 4471 EP 4476 DI 10.1073/pnas.072087599 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 539DY UT WOS:000174856000062 PM 11917121 ER PT J AU Steingrimsson, E Tessarollo, L Pathak, B Hou, L Arnheiter, H Copeland, NG Jenkins, NA AF Steingrimsson, E Tessarollo, L Pathak, B Hou, L Arnheiter, H Copeland, NG Jenkins, NA TI Mitf and Tfe3, two members of the Mitf-Tfe family of bHLH-Zip transcription factors, have important but functionally redundant roles in osteoclast development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HELIX-LOOP-HELIX; WAARDENBURG-SYNDROME; MICROPHTHALMIC MICE; SPLEEN-CELLS; DNA-BINDING; GENE; OSTEOPETROSIS; MUTATION; PROTEIN; MOUSE AB The Mitf-Tfe family of basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factors encodes four family members: Mitf, Tfe3, Tfeb, and Tfec. In vitro, each protein in the family can bind DNA as a homo- or heterodimer with other family members. Mutational studies in mice have shown that Mitf is essential for melanocyte and eye development, whereas Tfeb is required for placental vascularization. Here, we uncover a role for Tfe3 in osteoclast development, a role that is functionally redundant with Mitf. Although osteoclasts seem normal in Mitf or Tfe3 null mice, the combined loss of the two genes results in severe osteopetrosis. We also show that Tfec mutant mice are phenotypically normal, and that the Tfec mutation does not alter the phenotype of Mitf, Tfeb, or Tfe3 mutant mice. Surprisingly, our studies failed to identify any phenotypic overlap between the different Mitf-Tfe mutations. These results suggest that heterodimeric interactions are not essential for Mitf-Tfe function in contrast to other bHLH-Zip families like Myc/Max/Mad, where heterodimeric interactions seem to be essential. C1 Univ Iceland, Dept Biochem & Mol Biol, Fac Med, IS-101 Reykjavik, Iceland. NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. NCI, Neural Dev Grp, Frederick, MD 21702 USA. NINCDS, Lab Dev Neurogenet, NIH, Bethesda, MD 20892 USA. RP Steingrimsson, E (reprint author), Univ Iceland, Dept Biochem & Mol Biol, Fac Med, IS-101 Reykjavik, Iceland. OI Hou, Ling/0000-0003-0705-8099 NR 42 TC 112 Z9 115 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 2 PY 2002 VL 99 IS 7 BP 4477 EP 4482 DI 10.1073/pnas.072071099 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 539DY UT WOS:000174856000063 PM 11930005 ER PT J AU Masse, E Gottesman, S AF Masse, E Gottesman, S TI A small RNA regulates the expression of genes involved in iron metabolism in Escherichia coli SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SUPEROXIDE-DISMUTASE; BACTERIOFERRITIN GENE; MESSENGER-RNA; FUR; PROTEIN; GROWTH; TRANSCRIPTION; DSRA; RPOS; HFQ AB A small RNA, RyhB, was found as part of a genomewide search for novel small RNAs in Escherichia coli. The RyhB 90-nt RNA down-regulates a set of iron-storage and iron-using proteins when iron is limiting; it is itself negatively regulated by the ferric uptake repressor protein, Fur (Ferric uptake regulator). RyhB RNA levels are inversely correlated with mRNA levels for the sdhCDAB operon, encoding succinate dehydrogenase, as well as five other genes previously shown to be positively regulated by Fur by an unknown mechanism. These include two other genes encoding enzymes in the tricarboxylic acid cycle, acnA and fumA, two ferritin genes, ftnA and bfr, and a gene for superoxide dismutase, soda. Fur positive regulation of all these genes is fully reversed in an ryhB mutant. Our results explain the previously observed inability of fur mutants to grow on succinate. RyhB requires the RNA-binding protein, Hfq, for activity. Sequences within RyhB are complementary to regions within each of the target genes, suggesting that RyhB acts as an antisense RNA. In sdhCDAB, the complementary region is at the end of the first gene of the sdhCDAB operon; full-length sdhCDAB message disappears and a truncated message, equivalent in size to the region upstream of the complementarity, is detected when RyhB is expressed. RyhB provides a mechanism for the cell to down-regulate iron-storage proteins and nonessential iron-containing proteins when iron is limiting, thus modulating intracellular iron usage to supplement mechanisms for iron uptake directly regulated by Fur. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Room 5132, Bethesda, MD 20892 USA. NR 40 TC 652 Z9 673 U1 6 U2 42 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 APR 2 PY 2002 VL 99 IS 7 BP 4620 EP 4625 DI 10.1073/pnas.032066599 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 539DY UT WOS:000174856000087 PM 11917098 ER PT J AU Slesarev, AI Mezhevaya, KV Makarova, KS Polushin, NN Shcherbinina, OV Shakhova, VV Belova, GI Aravind, L Natale, DA Rogozin, IB Tatusov, RL Wolf, YI Stetter, KO Malykh, AG Koonin, EV Kozyavkin, SA AF Slesarev, AI Mezhevaya, KV Makarova, KS Polushin, NN Shcherbinina, OV Shakhova, VV Belova, GI Aravind, L Natale, DA Rogozin, IB Tatusov, RL Wolf, YI Stetter, KO Malykh, AG Koonin, EV Kozyavkin, SA TI The complete genome of hyperthermophile Methanopyrus kandleri AV19 and monophyly of archaeal methanogens SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID EUKARYOTIC TOPOISOMERASE-I; TRANSFER-RNA SYNTHETASE; DNA TOPOISOMERASE; REVERSE GYRASE; GENE ORDER; PROTEIN; PREDICTION; PHYLOGENY; BACTERIAL; EVOLUTION AB We have determined the complete 1,694,969-nt sequence of the GC-rich genome of Methanopyrus kandleri by using a whole direct genome sequencing approach. This approach is based on unlinking of genomic DNA with the ThermoFidelase version of M. kandleri topoisomerase V and cycle sequencing directed by 2'-modified oligonucleotides (Fimers). Sequencing redundancy (3.3x) was sufficient to assemble the genome with less than one error per 40 kb. Using a combination of sequence database searches and coding potential prediction, 1,692 protein-coding genes and 39 genes for structural RNAs were identified. M. kandleri proteins show an unusually high content of negatively charged amino acids, which might be an adaptation to the high intracellular salinity. Previous phylogenetic analysis of 16S RNA suggested that M. kandleri belonged to a very deep branch, close to the root of the archaeal tree. However, genome comparisons indicate that, in both trees constructed using concatenated alignments of ribosomal proteins and trees based on gene content, M. kandleri consistently groups with other archaeal methanogens. M. kandleri shares the set of genes implicated in methanogenesis and, in part, its operon organization with Methanococcus jannaschii and Methanother-mobacter thermoautotrophicum. These findings indicate that archaeal methanogens are monophyletic. A distinctive feature of M. kandleri is the paucity of proteins involved in signaling and regulation of gene expression. Also, M. kandleri appears to have fewer genes acquired via lateral transfer than other archaea. These features might reflect the extreme habitat of this organism. C1 Fidel Syst, Gaithersburg, MD 20879 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Russian Acad Sci, MM Shemyakin & Yu A Ovchinnikov Inst Bioorgan Che, Moscow 117871, Russia. Univ Regensburg, Dept Microbiol, D-93053 Regensburg, Germany. RP Slesarev, AI (reprint author), Fidel Syst, Gaithersburg, MD 20879 USA. EM alex@fidelitysystems.com FU NHGRI NIH HHS [R43HG02186]; NIGMS NIH HHS [R44GM55485] NR 55 TC 203 Z9 613 U1 1 U2 17 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 2 PY 2002 VL 99 IS 7 BP 4644 EP 4649 DI 10.1073/pnas.032671499 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 539DY UT WOS:000174856000091 PM 11930014 ER PT J AU Smoot, JC Barbian, KD Van Gompel, JJ Smoot, LM Chaussee, MS Sylva, GL Sturdevant, DE Ricklefs, SM Porcella, SF Parkins, LD Beres, SB Campbell, DS Smith, TM Zhang, Q Kapur, V Daly, JA Veasy, LG Musser, JM AF Smoot, JC Barbian, KD Van Gompel, JJ Smoot, LM Chaussee, MS Sylva, GL Sturdevant, DE Ricklefs, SM Porcella, SF Parkins, LD Beres, SB Campbell, DS Smith, TM Zhang, Q Kapur, V Daly, JA Veasy, LG Musser, JM TI Genome sequence and comparative microarray analysis of serotype M18 group A Streptococcus strains associated with acute rheumatic fever outbreaks SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE streptococcus pyogenes; GAS; complete genome sequence; DNA microarray; genomic diversity ID GROUP-A STREPTOCOCCUS; MOLECULAR CHARACTERIZATION; HYALURONIDASE GENE; PYOGENES; EXPRESSION; DIVERSITY; PROTEIN; IDENTIFICATION; INFECTIONS; COMPLEMENT AB Acute rheumatic fever (ARF), a sequelae of group A Streptococcus (GAS) infection, is the most common cause of preventable childhood heart disease worldwide. The molecular basis of ARF and the subsequent rheumatic heart disease are poorly understood. Serotype M18 GAS strains have been associated for decades with ARF outbreaks in the U.S. As a first step toward gaining new insight into ARF pathogenesis, we sequenced the genome of strain MGAS8232, a serotype M18 organism isolated from a patient with ARF. The genome is a circular chromosome of 1,895,017 bp, and it shares 1.7 Mb of closely related genetic material with strain SF370 (a sequenced serotype M1 strain). Strain MGAS8232 has 178 ORFs absent in SF370. Phages, phage-like elements, and insertion sequences are the major sources of variation between the genomes. The genomes of strain MGAS8232 and SF370 encode many of the same proven or putative virulence factors. Importantly, strain MGAS8232 has genes encoding many additional secreted proteins involved in human-GAS interactions, including streptococcal pyrogenic exotoxin A (scarlet fever toxin) and two uncharacterized pyrogenic exotoxin homologues, all phage-associated. DNA microarray analysis of 36 serotype M18 strains from diverse localities showed that most regions of variation were phages or phage-like elements. Two epidemics of ARF occurring 12 years apart in Salt Lake City, UT, were caused by serotype M18 strains that were genetically identical, or nearly so. Our analysis provides a critical foundation for accelerated research into ARF pathogenesis and a molecular framework to study the plasticity of GAS genomes. C1 NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. Geospiza Inc, Seattle, WA 98107 USA. Univ Minnesota, Ctr Biomed Genom, St Paul, MN 55108 USA. Primary Childrens Med Ctr, Salt Lake City, UT 84123 USA. RP Musser, JM (reprint author), NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, 903 S 4th St, Hamilton, MT 59840 USA. RI Kapur, Vivek/F-7610-2013; OI Kapur, Vivek/0000-0002-9648-0138 NR 41 TC 299 Z9 730 U1 2 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 2 PY 2002 VL 99 IS 7 BP 4668 EP 4673 DI 10.1073/pnas.062526099 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 539DY UT WOS:000174856000095 PM 11917108 ER PT J AU Li, KCP AF Li, KCP TI The first John L. Doppman lecture SO ACADEMIC RADIOLOGY LA English DT Editorial Material C1 NIH, Dept Radiol, Bethesda, MD 20892 USA. RP Li, KCP (reprint author), NIH, Dept Radiol, 10 Ctr Dr,MSC 1182,Bldg 10,1C660, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD APR PY 2002 VL 9 IS 4 BP 455 EP 455 DI 10.1016/S1076-6332(03)80192-7 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 533ZW UT WOS:000174561000011 ER PT J AU Tsilou, ET Rubin, BI Caruso, RC Reed, GF Pikus, A Hejtmancik, JF Iwata, F Redman, JB Kaiser-Kupfer, MI AF Tsilou, ET Rubin, BI Caruso, RC Reed, GF Pikus, A Hejtmancik, JF Iwata, F Redman, JB Kaiser-Kupfer, MI TI Usher syndrome clinical types I and II: Could ocular symptoms and signs differentiate between the two types? SO ACTA OPHTHALMOLOGICA SCANDINAVICA LA English DT Article DE Usher syndrome; clinical study; retinal degeneration; retinitis pigmentosa; night blindness; hearing deficit; vestibular problems ID RETINITIS-PIGMENTOSA; GENETIC-HETEROGENEITY; VISUAL-ACUITY; HEARING-LOSS; LOCALIZATION; PREVALENCE; MAPS; CHROMOSOME-11; MUTATION; PROTEIN AB Put-pose: Usher syndrome types I and II are clinical syndromes with substantial genetic and clinical heterogeneity. We undertook the current study in order to identify ocular symptoms and signs that could differentiate between the two types. Methods: Sixty-seven patients with Usher syndrome were evaluated. Based on audiologic and vestibular findings, patients were classified as either Usher type I or II. The severity of the ocular signs and symptoms present in each type were compared. Results: Visual acuity, visual field area, electroretinographic amplitude, incidence of cataract and macular lesions were not significantly different between Usher types I and II. However, the ages when night blindness was perceived and retinitis pigmentosa was diagnosed differed significantly between the two types. Conclusions: There seems to be some overlap between types I and II of Usher syndrome in regard to the ophthalmologic findings. However, night blindness appears earlier in Usher type I (although the difference in age of appearance appears to be less dramatic than previously assumed). Molecular elucidation of Usher syndrome may serve as a key to understanding these differences and, perhaps, provide a better tool for use in clinical diagnosis, prognosis and genetic counseling. C1 NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Hearing Sect, Neurootol Branch, NIH, Bethesda, MD USA. RP Tsilou, ET (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, 10 Ctr Dr,MSC-1860,Bldg 10,Rm 10N226, Bethesda, MD 20892 USA. NR 41 TC 35 Z9 37 U1 0 U2 2 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1395-3907 J9 ACTA OPHTHALMOL SCAN JI Acta Ophthalmol. Scand. PD APR PY 2002 VL 80 IS 2 BP 196 EP 201 DI 10.1034/j.1600-0420.2002.800215.x PG 6 WC Ophthalmology SC Ophthalmology GA 543GJ UT WOS:000175092800015 PM 11952489 ER PT J AU Praetorius, J Friis, UG Ainsworth, MA De Muckadell, OBS Johansen, T AF Praetorius, J Friis, UG Ainsworth, MA De Muckadell, OBS Johansen, T TI The cystic fibrosis transmembrane conductance regulator is not a base transporter in isolated duodenal epithelial cells SO ACTA PHYSIOLOGICA SCANDINAVICA LA English DT Article DE bicarbonate transport; CFTR; duodenum; forskolin; intracellular pH ID INTRACELLULAR PH; HCO3 SECRETION; COTRANSPORT AB Duodenal epithelial bicarbonate secretion has previously been shown to be greatly impaired in mice deficient of the cystic fibrosis transmembrane conductance regulator (CFTR). It has been proposed that transmembranal bicarbonate transport occurs through the CFTR channel itself. In the present study, the transport of acid/base equivalents across the plasma membrane of proximal duodenal epithelial cells from CFTR deficient mice was compared with that of cells from normal littermates. Mixed epithelial cells from both vili and crypts were isolated from proximal duodenum and intracellular pH was assessed by cuvette-based fluorescence spectrometry using the pH sensitive dye 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein. The steady state intracellular pH, the acid extrusion rate and the alkaline extrusion rate were unaffected by CFTR deficiency in the presence of CO2/HCO3-. Forskolin had no effect on acid extrusion or alkaline extrusion rates. In control experiments without CO2/HCO3-, the intrinsic buffering capacities, the steady state intracellular pH and the acid extrusion rates were equivalent in the cells from CFTR deficient mice and normal littermates. The results are consistent with a model where acid/base transport is almost exclusively mediated by the previously described transporters in the murine duodenum (i.e. Na+/H+ exchange, Cl-/HCO3- exchange and Na+ : HCO3- cotransport. There were no evidence for significant CFTR dependent HCO3- transport in proximal duodenal epithelial cells of mixed villus and crypt origin. C1 Univ So Denmark, Odense Univ, Inst Med Biol, Dept Physiol & Pharmacol, Odense C, Denmark. Odense Univ Hosp, Dept Gastroenterol, DK-5000 Odense, Denmark. RP Praetorius, J (reprint author), NHLBI, LKEM, NIH, 10 Ctr Dr,Bldg 10,Room 6 N323, Bethesda, MD 20892 USA. NR 17 TC 5 Z9 5 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0001-6772 J9 ACTA PHYSIOL SCAND JI Acta Physiol. Scand. PD APR PY 2002 VL 174 IS 4 BP 327 EP 336 DI 10.1046/j.1365-201x.2002.00957.x PG 10 WC Physiology SC Physiology GA 539CJ UT WOS:000174851900004 PM 11942920 ER PT J AU Hill, EM Newlin, DB AF Hill, EM Newlin, DB TI Evolutionary approaches to addiction: introduction SO ADDICTION LA English DT Editorial Material ID PERSPECTIVE C1 Univ Detroit Mercy, Detroit, MI 48219 USA. NIDA, Baltimore, MD USA. RP Hill, EM (reprint author), Univ Detroit Mercy, 8200 W Outer Dr, Detroit, MI 48219 USA. NR 43 TC 10 Z9 10 U1 0 U2 6 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD APR PY 2002 VL 97 IS 4 BP 375 EP 379 DI 10.1046/j.1360-0443.2002.t01-1-00057.x PG 5 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 539BY UT WOS:000174850900002 PM 11964054 ER PT J AU Gerald, MS Higley, JD AF Gerald, MS Higley, JD TI Evolutionary underpinnings of excessive alcohol consumption SO ADDICTION LA English DT Article DE 5-HIAA; alcoholism; Darwinian medicine; evolution; primate behavior ID NONHUMAN PRIMATE MODEL; 5-HYDROXYINDOLEACETIC ACID CONCENTRATIONS; DIMINISHED SOCIAL COMPETENCE; SEROTONIN RECEPTOR SUBTYPES; SANTIAGO RHESUS MACAQUES; FEMALE MATE CHOICE; CEREBROSPINAL-FLUID; HEALTHY-VOLUNTEERS; AMINE METABOLITES; VIOLENT OFFENDERS AB Given our close phylogenctic relatedness, non-human primates, in principle, could serve as an ideal model for alcoholism. Indeed, many studies in both humans and rhesus macaques show relationships between excessive alcohol consumption, aggression and serotonergic function, as measured by concentrations of the principal metabolite of serotonin, 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF). An important behavioral predictor of excessive alcohol consumption in both humans and rhesus monkeys is the propensity toward impulsivity. Integrating behavioral and neuroendocrine data from captive and semi-free-ranging rhesus macaques, we posit that benefits derived from impulsive and aggressive behaviors in some contexts might contribute indirectly to the maintenance of traits involved in alcoholism and excessive alcohol intake. C1 NIAAA, Intramural Res Program, NIH, Anim Ctr, Poolesville, MD USA. RP Gerald, MS (reprint author), Cayo Santiago Caribbean Primate Res Ctr, POB 906, Punta Santiago, PR 00741 USA. NR 64 TC 34 Z9 35 U1 2 U2 20 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD APR PY 2002 VL 97 IS 4 BP 415 EP 425 DI 10.1046/j.1360-0443.2002.00023.x PG 11 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 539BY UT WOS:000174850900006 PM 11964058 ER PT J AU Newlin, DB AF Newlin, DB TI The self-perceived survival ability and reproductive fitness (SPFit) theory of substance use disorders SO ADDICTION LA English DT Article DE alcoholism; drug abuse; evolutionary biology; autoshaping; mesolimbic dopamine; modularity; motivation ID NUCLEUS-ACCUMBENS DOPAMINE; INTRAVENOUS COCAINE; DRUG-ADDICTION; MESOLIMBIC DOPAMINE; APPROACH MOTIVATION; SEEKING BEHAVIOR; FOOTSHOCK STRESS; SOCIAL DRINKING; AFFECTIVE STYLE; ALCOHOL-USE AB A now theory of substance use disorders is proposed-the SPFit theory-that is based on evolutionary biology and adaptive systems. Self-perceived survival ability and reproductive fitness (SPFit) is proposed as a human psychobiological construct that prioritizes and organizes (i.e. motivates) behavior, but is highly vulnerable to temporary, artificial activation by drugs of abuse, Autoshaping/ sign-tracking/feature positive phenomena are proposed to underlie the development of craving and expectations about drugs as the individual learns that abused drugs will easily and reliably inflate SPFit. The cortico-mesolimbic dopamine system and its modulating interconnections are viewed as the biological substrate of SPFit; it is proposed to be a survival and reproductive motivation system rather than a reward center or reward pathway. Finally, the concept of modularity of mind is applied to the SPFit construct. Although considerable empirical data are consistent with the theory, new research is needed to test specific hypotheses derived from SPFit theory. C1 NIDA, Intramural Res Program, Mol Neurobiol Branch, Baltimore, MD 21224 USA. RP Newlin, DB (reprint author), NIDA, Intramural Res Program, Mol Neurobiol Branch, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Reis, Aline/G-9573-2012 NR 93 TC 22 Z9 23 U1 3 U2 10 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD APR PY 2002 VL 97 IS 4 BP 427 EP 445 DI 10.1046/j.1360-0443.2002.00021.x PG 19 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 539BY UT WOS:000174850900007 PM 11964059 ER PT J AU Panksepp, J Knutson, B Burgdorf, J AF Panksepp, J Knutson, B Burgdorf, J TI The role of brain emotional systems in addictions: a neuro-evolutionary perspective and new 'self-report' animal model SO ADDICTION LA English DT Article DE addiction; appetitive motivation; emotion; evolution; seeking; social behavior; ultrasonic vocalizations ID FREQUENCY ULTRASONIC VOCALIZATIONS; NUCLEUS-ACCUMBENS DOPAMINE; SOCIAL-ISOLATION; SEXUAL-BEHAVIOR; REWARD PATHWAYS; JUVENILE RATS; D-AMPHETAMINE; DRUG; MORPHINE; COCAINE AB The evolutionary significance of neurochemical events in the brain has received minimal attention in the field of addiction research. Likewise, the general failure of neuroscientists to postulate how basic brain circuits might mediate emotional urges has retarded the development of scientific perspectives that could inform new inquiries into the underlying dynamics and treatment of addictions. In this paper, we revisit the argument that prototypically abused substances activate or alter specific emotional brain systems that were evolutionarily designed to signal potential increments or decrements in fitness, We then discuss two distinct emotional systems (reward seeking and separation distress) which may track different types of potential changes in fitness, Based on this evolutionarily inspired approach, we illustrate how a mammalian model of emotion (i.e. rodent ultrasonic vocalizations) may enable scientists to predict drug-related phenomena such as abuse potential, anatomical location of mediating neural substrates, and the psychological impact of withdrawal. We conclude by discussing some therapeutic and social implications of examining drug addiction processes with multiple emotional brain systems in mind. C1 Bowling Green State Univ, Dept Psychol, JP Scott Ctr Neurosci Mind & Behav, Bowling Green, OH 43403 USA. NIAAA, Intramural Res Program, Clin Studies Lab, Sect Brain Imaging, Bethesda, MD USA. NIAAA, Intramural Res Program, Clin Studies Lab, Electrophysiol Lab, Bethesda, MD USA. RP Panksepp, J (reprint author), Bowling Green State Univ, Dept Psychol, JP Scott Ctr Neurosci Mind & Behav, Bowling Green, OH 43403 USA. OI Knutson, Brian/0000-0002-7669-426X NR 90 TC 123 Z9 126 U1 9 U2 26 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD APR PY 2002 VL 97 IS 4 BP 459 EP 469 DI 10.1046/j.1360-0443.2002.00025.x PG 11 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 539BY UT WOS:000174850900009 PM 11964061 ER PT J AU Mattson, MP Duan, WZ Maswood, N AF Mattson, MP Duan, WZ Maswood, N TI How does the brain control lifespan? SO AGEING RESEARCH REVIEWS LA English DT Article DE akt; antioxidant; BDNF; glucose; insulin; stress ID GROWTH-FACTOR-I; CORTICOTROPIN-RELEASING HORMONE; GLUCAGON-LIKE PEPTIDE-1; DIETARY RESTRICTION; NEUROTROPHIC FACTOR; CAENORHABDITIS-ELEGANS; NERVOUS-SYSTEM; GLUCOSE-METABOLISM; NEURODEGENERATIVE DISORDERS; SIGNAL-TRANSDUCTION AB There is generally a positive correlation between brain/body size ratio and lifespan, particularly among mammals, suggesting a role for the brain in determining lifiespan. Recent studies in diverse organisms including nematodes, flies and rodents have provided; evidence that, indeed the brain may control lifiespan. Signaling pathways involved in both central nervous system and peripheral stress responses and regulation of energy metabolism may play important roles in lifiespan determination. Indeed, genetic and environmental manipulations of these systems can greatly affect lifespan by changing levels of hormones that modulate energy metabolism, stress resistance and regenerative capacity of cells throughout the body. A signal transduction pathway in neurons involving receptors coupled to phosphatidylinositol-3-kinase, Akt and glycogen synthase kinase-3beta appear's to play a ( key role in regulation of longevity by the brain. Mutations in genes that encode proteins in the insulin signaling pathway can increase lifespan in C. elegans and Drosophila, this signaling pathway in neurons in the brain may be particularly important in limiting lifespan; Dietary. restriction results in the upregulation of brain-derived neurotrophic factor (BDNF) in the,brain, which may increase the resistance of neurons to aging. Interestingly; BDNF signaling in the brain can increase peripheral insulin sensitivity, suggesting a mechanism whereby the brain can control lifiespan. We speculate that during evolution the brain took on the task (if monitoring and controlling peripheral energy metabolism, and thereby regulating lifespan in the context of food availability. Roles for other evolutionarily conserved brain signaling pathways in lifespan determination are likely to be discovered in the near future. Published by Elsevier Science Ireland Ltd. C1 NIA, Gerontol Res Ctr, Lab Neurosci 4F02, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Gerontol Res Ctr, Lab Neurosci 4F02, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 74 TC 35 Z9 37 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1568-1637 EI 1872-9649 J9 AGEING RES REV JI Ageing Res. Rev. PD APR PY 2002 VL 1 IS 2 BP 155 EP 165 AR PII S1568-1637(01)00003-4 DI 10.1016/S1568-1637(01)00003-4 PG 11 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 603AN UT WOS:000178536800001 PM 12039436 ER PT J AU Arking, R Buck, S Novoseltev, VN Hwangbo, DS Lane, M AF Arking, R Buck, S Novoseltev, VN Hwangbo, DS Lane, M TI Genomic plasticity, energy allocations, and the extended longevity phenotypes of Drosophila SO AGEING RESEARCH REVIEWS LA English DT Review DE aging; longevity; life span; selection; metabolism; energy allocations; Drosophila ID FATTY-ACID UNSATURATION; FREE-RADICAL PRODUCTION; LIFE-SPAN; STRESS RESISTANCE; CAENORHABDITIS-ELEGANS; OXIDATIVE DAMAGE; SUPEROXIDE-DISMUTASE; HEART-MITOCHONDRIA; GENE-EXPRESSION; AGING RATE AB The antagonistic pleiotropy theory of the evolution of aging is shown to be too simple to fully apply to the situation in which Drosophila are selected directly for delayed female fecundity and indirectly for extended longevity. We re-evaluated our own previously reported selection experiments using previously unreported data, as well as new data from the literature. The facts that led to this re-evaluation were: (1) the recognition that there are at least three different extended longevity phenotypes; (2) the existence of metabolic and mitochondrial differences between normal- and long-lived organisms; and most importantly; (3) the observation that animals selected for extended longevity are both more fecund and longer-lived than their progenitor control animals. This latter observation appears to contradict the theory. A revised interpretation of the events underlying the selection process indicates that there is a two-step change in energy allocations leading to a complex phenotype. Initial selection first allows the up-regulation of the antioxidant defense system genes and a shift to the use of the pentose shunt. This is later followed by alterations in mitochondrial fatty acid composition and other changes necessary to reduce the leakage of H2O2 from the mitochondria into the cytosol. The recaptured energy available from the latter step is diverted from somatic maintenance back into reproduction, resulting in animals that are both long-lived and fecund. Literature review suggests the involvement of mitochondrial and antioxidant changes are likely universal in the Type 1 extended longevity phenotype. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Wayne State Univ, Dept Biol Sci, Coll Sci, Detroit, MI 48202 USA. Inst Control Sci, Moscow, Russia. Max Planck Inst Demog Res, D-18057 Rostock, Germany. NIA, Nutr & Mol Physiol Unit, Neurosci Lab, Baltimore, MD 21224 USA. RP Arking, R (reprint author), Wayne State Univ, Dept Biol Sci, Coll Sci, Biol Sci Bldg, Detroit, MI 48202 USA. NR 59 TC 30 Z9 30 U1 1 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1568-1637 J9 AGEING RES REV JI Ageing Res. Rev. PD APR PY 2002 VL 1 IS 2 BP 209 EP 228 AR PII S1568-1637(01)00010-1 DI 10.1016/S1568-1637(01)00010-1 PG 20 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 603AN UT WOS:000178536800004 PM 12039439 ER PT J AU Hungund, BL Basavarajappa, BS Vadasz, C Kunos, G de Fonseca, FR Colombo, G Serra, S Parsons, L Koob, GF AF Hungund, BL Basavarajappa, BS Vadasz, C Kunos, G de Fonseca, FR Colombo, G Serra, S Parsons, L Koob, GF TI Ethanol, endocannabinoids, and the cannabinoidergic signaling system SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE ethanol; endocannabinoid; anandamide; 2-arachidonyl glycerol; CB1 receptor ID DOPAMINE-RECEPTOR AGONISTS; SYNAPTIC PLASMA-MEMBRANE; ALCOHOL-PREFERRING RATS; GAMMA-S BINDING; ANIMAL-MODEL; DBA/2 MICE; BRAIN; ANTAGONIST; SR-141716; STIMULATION AB This article represents the proceedings of a symposium at the 2001 annual meeting of the Research Society on Alcoholism in Montreal, Canada. The chairpersons were Appa Hungund and George Koob. The presentations were (1) Role of endocannabinoids in ethanol tolerance, by Appa Hungund; (2) Modulation of cannabinoid receptor and its signal transduction in chronic alcoholism, by B. S. Basavarajappa; 3) Endocannabinoid involvement in the control of appetitive behavior, by George Kunos; (4) Regulation of voluntary ethanol intake by cannabinoid receptor agonists and antagonists in alcohol-preferring sP rats, by Giancarlo Colombo; (5) Role of endogenous cannabinoid system in alcoholism, by Fernado Rodriguez de Fonseca; and (6) Endocannabinoids and dopamine interactions in vivo, by Loren Parsons and George Koob. C1 New York State Psychiat Inst & Hosp, Orangeburg, NY 10962 USA. Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. Columbia Univ, Coll Phys & Surg, New York, NY USA. NIAAA, Bethesda, MD USA. Univ Cagliari, Dept Neurosci, CNR, Ctr Neuropharmacol, Cagliari, Italy. Fdn Hosp Carlos Haya, Malaga, Spain. Scripps Res Inst, La Jolla, CA USA. RP Hungund, BL (reprint author), New York State Psychiat Inst & Hosp, Orangeburg, NY 10962 USA. RI RODRIGUEZ DE FONSECA, FERNANDO/E-9767-2012; koob, george/P-8791-2016 NR 36 TC 62 Z9 63 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD APR PY 2002 VL 26 IS 4 BP 565 EP 574 DI 10.1111/j.1530-0277.2002.tb02575.x PG 10 WC Substance Abuse SC Substance Abuse GA 544RX UT WOS:000175175300018 PM 11981134 ER PT J AU Abbey, A Zawacki, T Buck, PO Testa, M Parks, K Norris, J Martin, SE Livingston, JA McAuslan, P Clinton, AM Kennedy, CL George, WH Davis, KC Martell, J AF Abbey, A Zawacki, T Buck, PO Testa, M Parks, K Norris, J Martin, SE Livingston, JA McAuslan, P Clinton, AM Kennedy, CL George, WH Davis, KC Martell, J TI How does alcohol contribute to sexual assault? Explanations from laboratory and survey data SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE alcohol consumption; sexual assault; alcohol problems; prevention ID NATIONAL SAMPLE; DATING SITUATIONS; COLLEGE-WOMEN; RISK-FACTORS; VICTIMIZATION; AGGRESSION; EXPERIENCES; RAPE; EXPECTANCIES; CONSUMPTION AB This article summarizes the proceedings of a symposium of the 2001 RSA Meeting in Montreal, Canada. The chair was Antonia Abbey and the organizers were Tina Zawacki and Philip O. Buck. There were four presentations and a discussant. The first presentation was made by Maria Testa whose interviews with sexual assault victims suggest that there may be differences in the characteristics of sexual assaults in which both the victim and perpetrator were using substances as compared to when only the perpetrator was using substances. The second presentation was made by Tina Zawacki whose research found that perpetrators of sexual assaults that involved alcohol were in most ways similar to perpetrators of sexual assaults that did not involve alcohol, although they differed on impulsivity and several alcohol measures. The third presentation was made by Kathleen Parks who described how alcohol consumption affected women's responses to a male confederate's behavior in a simulated bar setting. The fourth presentation was made by Jeanette Norris who found that alcohol and expectancies affected men's self-reported likelihood of acting like a hypothetical sexually aggressive man. Susan E. Martin discussed the implications of these studies and made suggestions for future research. C1 Wayne State Univ, Dept Community Med, Detroit, MI 48201 USA. SUNY Coll Buffalo, Res Inst Addict, Buffalo, NY 14222 USA. Univ Washington, Seattle, WA 98195 USA. NIAAA, Bethesda, MD USA. Univ Michigan, Dearborn, MI 48128 USA. RP Abbey, A (reprint author), Wayne State Univ, Dept Community Med, 4201 St Antoine, Detroit, MI 48201 USA. OI McAuslan, Pam/0000-0001-7360-5981 FU NIAAA NIH HHS [R01 AA011996, AA00233, AA07271, AA11996, K01 AA000233, K02 AA000284, N01AA12013, Z01 AA000284] NR 22 TC 30 Z9 30 U1 2 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD APR PY 2002 VL 26 IS 4 BP 575 EP 581 DI 10.1111/j.1530-0277.2002.tb02576.x PG 7 WC Substance Abuse SC Substance Abuse GA 544RX UT WOS:000175175300019 PM 11981135 ER PT J AU Hahm, KB Lee, KM Kim, YB Hong, WS Lee, WH Han, SU Kim, MW Ahn, BO Oh, TY Lee, MH Green, J Kim, SJ AF Hahm, KB Lee, KM Kim, YB Hong, WS Lee, WH Han, SU Kim, MW Ahn, BO Oh, TY Lee, MH Green, J Kim, SJ TI Conditional loss of TGF-beta signalling leads to increased susceptibility to gastrointestinal carcinogenesis in mice SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article; Proceedings Paper CT 9th Taisho International Symposium on Gastroenterology CY APR 26-27, 2001 CL SHIMODA, JAPAN ID HELICOBACTER-PYLORI INFECTION; GROWTH-FACTOR-BETA; HUMAN GASTRIC-CANCER; II RECEPTOR GENE; NITRIC-OXIDE SYNTHASE; METHYL-N-NITROSOUREA; ABERRANT CRYPT FOCI; MONGOLIAN GERBILS; MICROSATELLITE INSTABILITY; STOMACH CARCINOGENESIS AB Background: Downregulation of TGF-beta receptors is implicated in colon cancer development. Inactivation of either of the two transmembrane serine/threonine kinases, TGF-beta1 types I/II receptors, is now implicated in carcinogenesis, especially gastrointestinal carcinogenesis. Methods: We generated transgenic mice, called pS2-dnRII or ITF-dnRII, of which the dominant negative mutant of the TGF-beta type II receptor was expressed under the control of tissue-specific promoters, the pS2 promoter for stomach and ITF for intestine. They were either infected with H. pylori (ATCC 43504 strain, CagA(+) and VacA(+) ) or administered with azoxymethane to determine the significance of loss of TGF-beta signalling in gastrointestinal carcinogenesis. Results: Gastric adenocarcinoma developed in pS2-dnRII mice, whereas only chronic active gastritis was noted in wild-type littermates after 36 weeks of H. pylori infection. Mice lacking in TGF-beta signalling specifically in the stomach showed a significantly higher proliferation cell nuclear antigen-labelling index when infected with H. pylori than wild-type littermates (P < 0.01). Development of colonic aberrant crypt foci was provoked in mice by intraperitoneal injections of azoxymethane, and ITF-dnRII mice showed significantly higher incidences of ACF and colon cancers than wild-type littermates. Conclusions: Maintaining normal TGF-beta signalling in the gastrointestinal tract seems to be important either for preventing abnormal mucosal proliferation, or for suppressing or retarding carcinogenesis. C1 Ajou Univ, Sch Med, Ajou Helicobacter Res Grp, Suwon 442749, South Korea. Univ Ulsan, Asan Med Ctr, Sch Med, Seoul, South Korea. Dong A Pharmaceut Res Inst, Yongin, South Korea. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD USA. RP Hahm, KB (reprint author), Ajou Univ, Sch Med, Dept Gastroenterol, San 5, Suwon 442749, South Korea. NR 46 TC 50 Z9 58 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0269-2813 J9 ALIMENT PHARM THERAP JI Aliment. Pharmacol. Ther. PD APR PY 2002 VL 16 SU 2 BP 115 EP 127 DI 10.1046/j.1365-2036.16.s2.3.x PG 13 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 542PY UT WOS:000175054500017 PM 11966532 ER PT J AU Enoch, MA AF Enoch, MA TI How can I help my patient stop drinking.? SO AMERICAN FAMILY PHYSICIAN LA English DT Editorial Material ID ALCOHOLISM C1 NIAAA, Bethesda, MD USA. RP Enoch, MA (reprint author), NIAAA, Bethesda, MD USA. NR 3 TC 0 Z9 0 U1 1 U2 2 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD APR 1 PY 2002 VL 65 IS 7 BP 1475 EP 1476 PG 2 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 541PU UT WOS:000174993600020 PM 11996430 ER PT J AU Shirani, J Alaeddini, J Pick, R Dilsizian, V AF Shirani, J Alaeddini, J Pick, R Dilsizian, V TI Variations in collagen content of asynergic left ventricular segments in explanted hearts of men with ischemic cardiomyopathy SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY DISEASE; HIBERNATING MYOCARDIUM; IRREVERSIBLE DEFECTS; VIABILITY; REVASCULARIZATION; DEGENERATION; REINJECTION; THALLIUM; RECOVERY; HUMANS AB Transmural left ventricular (LV) biopsies obtained at the time of coronary artery surgery have been used to evaluate the histomorphologic features of viable myocardium in patients with ischemic cardiomyopathy. (1-16) Usually, 1 or 2 biopsies are obtained from the center of the LV region supplied by the left anterior descending coronary artery. The biopsy specimens (1.2 to 1.5 mm in diameter) are subsequently used for quantification of collagen using grids with visual point counting.(1-16) The degree of myocardial fibrosis in these biopsy samples has been correlated with the results of various noninvasive tests used for assessment of preoperative regional myocardial viability. However, it is unclear whether the data obtained from these transmural biopsy samples would uniformly reflect the overall histomorphologic features of the entire LV region as evaluated by noninvasive imaging techniques. In this study, we determined the extent of variation in volume fraction of collagen of 2-mm-wide (biopsy-equivalent) consecutive transmural sections of mid-LV anterior wall from explanted hearts of men with chronic ischemic heart disease. Moreover, we examined the variability of fibrosis in normal. ischemic, and scarred myocardium as assessed by thallium. C1 Albert Einstein Coll Med, Jack D Weiler Hosp, Div Cardiol, Dept Med, Bronx, NY 10461 USA. Albert Einstein Coll Med, Jack D Weiler Hosp, Dept Pathol, Bronx, NY 10461 USA. Michael Reese Hosp & Med Ctr, Div Cardiol, Chicago, IL 60616 USA. NHLBI, Bethesda, MD USA. RP Shirani, J (reprint author), Albert Einstein Coll Med, Jack D Weiler Hosp, Div Cardiol, Dept Med, 1825 Eastchester Rd,Rm W1-70K, Bronx, NY 10461 USA. NR 20 TC 0 Z9 0 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD APR 1 PY 2002 VL 89 IS 7 BP 865 EP + AR PII S0002-9149(02)02204-X DI 10.1016/S0002-9149(02)02204-X PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 533YV UT WOS:000174558600019 PM 11909578 ER PT J AU Bieri, JG AF Bieri, JG TI Comments on the new dietary reference intake for vitamin E SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Letter C1 NIDDK, NIH, Silver Spring, MD 20906 USA. RP Bieri, JG (reprint author), NIDDK, NIH, 3612 Pimlico Pl, Silver Spring, MD 20906 USA. NR 5 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD APR PY 2002 VL 75 IS 4 BP 781 EP 781 PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 532RE UT WOS:000174488200025 PM 11916770 ER PT J AU Colevas, AD Norris, CM Tishler, RB Lamb, CC Fried, MP Goguen, LA Gopal, HV Costello, R Read, R Adak, S Posner, MR AF Colevas, AD Norris, CM Tishler, RB Lamb, CC Fried, MP Goguen, LA Gopal, HV Costello, R Read, R Adak, S Posner, MR TI Phase I/II trial of outpatient docetaxel, cisplatin, 5-fluorouracil, leucovorin (opTPFL) as induction for squamous cell carcinoma of the head and neck (SCCHN) SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE cisplatin; docetaxel; 5-FU; head and neck; induction chemotherapy; squamous cell carcinoma ID HIGH-DOSE LEUCOVORIN; LOCALLY ADVANCED HEAD; STAGE-IV HEAD; RANDOMIZED TRIAL; CONCOMITANT CHEMOTHERAPY; ADJUVANT CHEMOTHERAPY; III TRIAL; CANCER; FLUOROURACIL; RADIOTHERAPY AB The purpose of this study was to establish the maximum tolerated dose (MTD) of docetaxel in an outpatient docetaxel (T), cisplatin (P), 5-fluorouracil (5-FU) (F), and leucovorin (L) (opTPFL) regimen and to obtain preliminary assessment of opTPFL efficacy. Thirty-four patients with stage III or IV squamous cell carcinoma of the head and neck were treated with opTPFL. Docetaxel was escalated from 60 to 95 mg/m(2) in combination with 100 mg/m(2) cisplatin intravenous bolus, and 2,800 mg/m(2) 5-FU continuous infusion and 2,000 mg/m(2) leucovorin continuous infusion with prophylactic growth factors and antibiotics. Patients who achieved a complete (CR) or partial (PR) response to three cycles received definitive twice-daily radiation therapy. A total of 97 cycles were administered to 34 patients. The major acute toxicities were neutropenia and mucositis. The MTD of docetaxel was 90 mg/m(2), Seventy-seven of 97 cycles of were administered on an outpatient basis. The overall clinical response rate to opTPFL was 94%, with 44% CRs and 50% PRs. The MTD of opTPFL is 90 mg/m(2) docetaxel. Outpatient administration of opTPFL is tolerable, feasible, and does not alter the ability to administer definitive radiation therapy on schedule. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Head & Neck Oncol Program,Dana Farber Canc Inst, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Surg, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02138 USA. Albert Einstein Coll Med, Montefiore Med Ctr, Dept Otolaryngol, New York, NY USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA USA. Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. RP Colevas, AD (reprint author), NCI, Invest Drug Branch, Canc Therapy Evaluat Program, DCTD, Execut Pl N,Room 7000,6130 Execut Blvd, Rockville, MD 20852 USA. NR 31 TC 31 Z9 32 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD APR PY 2002 VL 25 IS 2 BP 153 EP 159 DI 10.1097/00000421-200204000-00010 PG 7 WC Oncology SC Oncology GA 540AR UT WOS:000174906300010 PM 11943893 ER PT J AU Cohn, BA Overstreet, JW Fogel, RJ Brazil, CK Baird, DD Cirillo, PM AF Cohn, BA Overstreet, JW Fogel, RJ Brazil, CK Baird, DD Cirillo, PM TI Epidemiologic studies of human semen quality: Considerations for study design SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE bias (epidemiology); environmental exposure; epidemiologic methods; longitudinal studies; semen ID POPULATION; FERTILITY; MEN AB Few empirical data exist on the characteristics of subjects who provide semen specimens in epidemiologic studies. The objective of this investigation was to determine participation rates and potential biases in a contemporary study of human semen quality. Subjects (n = 268) are a subset of the Child Health and Development Studies. Their mothers enrolled between 1960 and 1963 during pregnancy. Archived prenatal serum samples, prenatal and birth records, placental examinations, and follow-up for growth and development through adulthood are available. Sons were aged 36-39 years at the time of this study. Respondents to the initial mailing and nonrespondents, who were subsequently traced and recruited, differed in semen parameters, including sperm concentration (78.3 x 10(6)/ml for respondents vs. 37.2; p = 0.003) and the percentage of normal morphology according to the 1987 criteria of the World Health Organization (58.7% for respondents vs. 53.3%; p = 0.04). The authors conclude that researchers designing population-based studies of semen parameters should expect nonrepresentative samples. Adaptation of the design to anticipate and mitigate bias and to maximize efficiency can yield scientifically sound information. Recommendations for study designs are discussed. C1 Inst Publ Hlth, Ctr Res Womens & Childrens Hlth Child Hlth & Dev, Berkeley, CA 94709 USA. Univ Calif Davis, Inst Toxicol & Environm Hlth, Davis, CA 95616 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Cohn, BA (reprint author), Inst Publ Hlth, Ctr Res Womens & Childrens Hlth Child Hlth & Dev, 1683 Shattuck Ave,Suite B, Berkeley, CA 94709 USA. OI Baird, Donna/0000-0002-5544-2653 FU NICHD NIH HHS [N01-HD-6-3258]; NIEHS NIH HHS [R03 ES08612, R01 ES08345] NR 12 TC 39 Z9 40 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 1 PY 2002 VL 155 IS 7 BP 664 EP 671 DI 10.1093/aje/155.7.664 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 535KL UT WOS:000174643600011 PM 11914194 ER PT J AU Eggers, PW Frankenfield, DL Greer, JW McClellan, W Owen, WF Rocco, MV AF Eggers, PW Frankenfield, DL Greer, JW McClellan, W Owen, WF Rocco, MV TI Comparison of mortality and intermediate outcomes between medicare dialysis patients in HMO and fee for service SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE hemodialysis (HD); health maintenance organization (HMO); mortality; Medicare; transplantation ID UREA REDUCTION RATIO; HEMODIALYSIS-PATIENTS; BREAST-CANCER; MANAGED CARE; BENEFICIARIES; DISENROLLMENT; DIAGNOSIS; ENROLLEES; STAGE AB End-stage renal disease (ESRD) is the only disease entitlement for Medicare; therefore, most patients with ESRD have Medicare coverage. Patients with ESRD are prohibited by law from enrolling in health maintenance organizations (HMOs), the only group prohibited within Medicare. However, they may remain in an HMO if they enrolled in such a plan before their kidneys failed. Thus, it Is possible to compare patients with ESRD In HMOs with those In fee-for-service (FFS) plans. To determine whether mortality, transplantation rates, and intermediate outcomes differed between Medicare ESRD beneficiaries enrolled in HMO versus FFS providers, a retrospective cohort analysis was performed of patients with ESRD from three Health Care Financing Administration data sets containing administrative and outcome information for Medicare ESRD beneficiaries from 1990 to 1998. On December 31, 1998, a total of 278,510 prevalent patients with ESRD were In FFS plans, and 18,332 patients were In HMOs. HMO patients were older and more likely to be white and male and have diabetes mellitus and comorbid cardiovascular conditions than FFS patients. Unadjusted 2-year survival rates were 48.4% and 49.3% for FFS and HMO patients, respectively. In a multivariate model, HMO status had no significant effect on mortality, which was greater with older age, male sex, and white race. In 1998, unadjusted renal transplantation rates were 23.5% and 15.5% for FFS and HMO patients, respectively; age adjustment abrogated the apparent difference. For FFS and HMO patients, adequate hemodialysis was delivered to 72% and 82%, and 56% and 62% had hematocrits greater than the benchmark, respectively. There was no statistical difference in these outcomes in multivariate comparison. In conclusion, care by HMO for patients with an expensive chronic illness can achieve outcomes similar to those for FFS patients. Claims of poorer care and worse outcomes for patients with ESRD enrolled onto an HMO, an argument used to justify continued prohibition against widespread participation by patients with ESRD, are not supported. (C) 2002 by the National Kidney Foundation, Inc. C1 NIDDKD, Bethesda, MD 20892 USA. Ctr Medicare & Medicaid Serv, Baltimore, MD USA. Duke Univ, Med Ctr, Duke Inst Renal Outcomes Res & Hlth Policy, Durham, NC USA. W Georgia Med Ctr, La Grange, GA USA. Wake Forest Univ, Bowman Gray Sch Med, Nephrol Sect, Winston Salem, NC USA. RP Eggers, PW (reprint author), NIDDKD, Rm 615,6707 Democracy Blvd, Bethesda, MD 20892 USA. NR 31 TC 8 Z9 8 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 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD APR PY 2002 VL 39 IS 4 BP 796 EP 804 DI 10.1053/ajkd.2002.32000 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 538VD UT WOS:000174835000016 PM 11920346 ER PT J AU Eknoyan, G Agodoa, L AF Eknoyan, G Agodoa, L TI On improving outcomes and quality of dialysis care, and more SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material C1 Baylor Coll Med, Dept Med, Renal Sect, Houston, TX 77030 USA. NIDDK, ESRD Program, NIH, Bethesda, MD USA. RP Eknoyan, G (reprint author), Baylor Coll Med, Dept Med, Renal Sect, Houston, TX 77030 USA. NR 1 TC 4 Z9 4 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD APR PY 2002 VL 39 IS 4 BP 889 EP 891 DI 10.1053/ajkd.2002.32720 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 538VD UT WOS:000174835000028 PM 11920358 ER PT J AU Green, GB Kim, J Winkler, CA Kopp, JB Shaw, AS AF Green, GB Kim, J Winkler, CA Kopp, JB Shaw, AS TI Genetic polymorphisms within CD2AP in patients with focal segmental glomerulosclerosis SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Meeting Abstract C1 NIDDK, Bethesda, MD USA. NCI, Frederick, MD 21701 USA. Washington Univ, Sch Med, Dept Pathol, St Louis, MO USA. Washington Univ, Sch Med, Dept Internal Med, Div Renal, St Louis, MO 63110 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD APR PY 2002 VL 39 IS 4 MA 26 BP A17 EP A17 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 538VD UT WOS:000174835000059 ER PT J AU Shankaran, S Fanaroff, AA Wright, LL Stevenson, DK Donovan, EF Ehrenkranz, RA Langer, JC Korones, SB Stoll, BJ Tyson, JE Bauer, CR Lemons, JA Oh, W Papile, LA AF Shankaran, S Fanaroff, AA Wright, LL Stevenson, DK Donovan, EF Ehrenkranz, RA Langer, JC Korones, SB Stoll, BJ Tyson, JE Bauer, CR Lemons, JA Oh, W Papile, LA TI Risk factors for early death among extremely low-birth-weight infants SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE early death; extremely low-birth-weight infants; risk factors ID WEEKS GESTATION; NEONATAL-MORTALITY; PREMATURE-INFANTS; SURVIVAL; RESUSCITATION; EXPERIENCE; VIABILITY; DELIVERY; NEWBORNS AB OBJECTIVE: The purposes of this study were to compare the clinical characteristics of extremely low-birth-weight infants (501-1000 g birth weight) who die early (<12 hours of age) with those of infants who die >12 hours after birth and infants who survive to neonatal intensive care unit discharge and to develop a model of risk for early death. STUDY DESIGN: Perinatal data were prospectively collected on 5986 infants in the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network from March 1993 through December 1997. Maternal and neonatal characteristics of infants who died early were compared with infants who survived and infants who died beyond 12 hours of age, A model for risk for early death was developed by logistic regression analysis, with results expressed as odds ratio with 95% Cl. RESULTS: Mothers of infants who died early were more likely to be delivered in an inborn setting and experience labor and were less likely to have hypertension or preeclampsia, to receive antenatal corticosteroids, or to be delivered by cesarean birth than mothers of infants who died >12 hours after birth or infants who survived. Infants who died early were more likely to have lower Apgar scores and lower gestational age/birth weight and were less likely to be intubated at birth and to receive mechanical ventilation and surfactant therapy than infants who died >12 hours after birth or infants who survived, Greater risk for early death versus survival to neonatal intensive care unit discharge was associated with the lack of surfactant administration (odds ratio, 8.6; 95% Cl, 6.3-11.9), lack of delivery room intubation (odds ratio, 5.3; 95% Cl, 3.5-8.1), lack of antenatal corticosteroid use (odds ratio, 2.3; 95% Cl, 1.6-3.2), lower 1-minute Apgar score (odds ratio, 2.0; 95% Cl, 1.8-2.2), male sex (odds ratio, 1.7; 95% Cl, 1.3-2.3), multiple gestation (odds ratio, 1.7; 95% Cl, 1.2-2.5), no tocolytics (odds ratio, 1.7; 95% Cl, 1.2-2.3), lower gestational age per week (odds ratio, 1.4; 95% Cl, 1.3-1.6), and lower birth weight per 50 g (95% Cl, 1.2-1.4). CONCLUSION: Early death (<12 hours of age) among extremely low-birth-weight infants may reflect an assessment of nonviability by obstetricians and neonatologists. C1 Wayne State Univ, Detroit, MI 48202 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. NICHHD, Bethesda, MD 20892 USA. Stanford Univ, Stanford, CA 94305 USA. Univ Cincinnati, Cincinnati, OH 45221 USA. Yale Univ, New Haven, CT 06520 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Univ Tennessee, Memphis, TN USA. Emory Univ, Atlanta, GA 30322 USA. Univ Texas, SW Med Ctr, Houston, TX USA. Univ Miami, Coral Gables, FL 33124 USA. Indiana Univ, Indianapolis, IN 46204 USA. Brown Univ, Women & Infants Hosp, Providence, RI USA. Univ New Mexico, Albuquerque, NM 87131 USA. RP Shankaran, S (reprint author), Childrens Hosp Michigan, 3901 Beaubien, Detroit, MI 48201 USA. FU NICHD NIH HHS [U10 HD27856, U01 HD36790, U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD21415, U10 HD27851, U10 HD27853, U10 HD27871, U10 HD27880, U10 HD27881, U10 HD27904] NR 26 TC 61 Z9 68 U1 0 U2 1 PU MOSBY, 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 APR PY 2002 VL 186 IS 4 BP 796 EP 802 DI 10.1067/mob.2002.121651 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 551DY UT WOS:000175545300033 PM 11967510 ER PT J AU Stanyon, R Koehler, U Consigliere, S AF Stanyon, R Koehler, U Consigliere, S TI Chromosome painting reveals that galagos have highly derived karyotypes SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Article DE in situ hybridization; genome evolution; phylogeny; primates; prosimians ID CRASSICAUDATUS; PROSIMIANS; EVOLUTION; PRIMATES; HUMANS; MONKEY AB The differences in chromosome number between Otolemur crassicaudatus (2n = 62) and Galago moholi (2n = 38) are dramatic. However, the total number of signals given by hybridizing human chromosome paints to galago metaphases is similar: 42 in O. crassicaudatus and 38 G. moholi. Many human chromosome homologs are found fragmented in each species, and numerous translocations have resulted in chromosomal syntenies or hybridization associations which differ from those found in humans. Only 7 human autosomes showed conserved synteny in O. crassicaudatus, and 9 in G. moholi. Both galago species have numerous associations or syntenies not found in humans: O. crassicaudatus has 11, and G. moholi has 21. The phylogenetic line leading to the last common ancestor of the two galago species accumulated 6 synapomorphic fissions and 5 synapomorphic fusions. Since the divergence of the two galago species, 10 Robertsonian translocations have further transformed the G. moholi karyotype, and 2 fissions have been incorporated into the O. crassicaudatus karyotype. Comparison with other primates, tree shrews, and other mammals shows that both galagos have karyotypes which are a mixture of derived and conserved chromosomes, and neither has a karyotype close to that of the proposed ancestor of all primates. Published 2002 Wiley-Liss Inc.(dagger) C1 NCI, Genet Branch, Comparat Mol Cytogenet Sect, Canc Res Ctr, Frederick, MD 21702 USA. Ctr Med Genet, MGZ, D-80335 Munich, Germany. Univ Genoa, Dept Anthropol Sci, I-16126 Genoa, Italy. RP Stanyon, R (reprint author), NCI, Genet Branch, Comparat Mol Cytogenet Sect, Canc Res Ctr, Bldg 560,Room 11-74A, Frederick, MD 21702 USA. OI Stanyon, Roscoe/0000-0002-7229-1092 NR 43 TC 29 Z9 29 U1 2 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0002-9483 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PD APR PY 2002 VL 117 IS 4 BP 319 EP 326 DI 10.1002/ajpa.10047 PG 8 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 533ZN UT WOS:000174560300005 PM 11920367 ER PT J AU Kurihara, K Nakanishi, N Moore-Hoon, ML Turner, RJ AF Kurihara, K Nakanishi, N Moore-Hoon, ML Turner, RJ TI Phosphorylation of the salivary Na+-K+-2Cl(-) cotransporter SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE exocrine glands; fluid secretion; stimulus-secretion coupling; cation-chloride cotransporter ID K-CL COTRANSPORT; PAROTID ACINAR-CELLS; SHARK RECTAL GLAND; UP-REGULATION; ANCHORING PROTEINS; EPITHELIAL-CELLS; ACTIVATION; MEMBRANE AB We studied the phosphorylation of the secretory Na+-K+-2Cl(-) cotransporter (NKCC1) in rat parotid acinar cells. We have previously shown that NKCC1 activity in these cells is dramatically upregulated in response to beta-adrenergic stimulation and that this upregulation correlates with NKCC1 phosphorylation, possibly due to protein kinase A (PKA). We show here that when ATP is added to purified acinar basolateral membranes (BLM), NKCC1 is phosphorylated as a result of membrane-associated protein kinase activity. Additional NKCC1 phosphorylation is seen when PKA is added to BLMs, but our data indicate that this is due to an effect of PKA on endogenous membrane kinase or phosphatase activities, rather than its direct phosphorylation of NKCC1. Also, phosphopeptide mapping demonstrates that these phosphorylations do not take place at the site associated with the upregulation of NKCC1 by beta-adrenergic stimulation. However, this upregulatory phosphorylation can be mimicked by the addition of cAMP to permeabilized acini, and this effect can be blocked by a specific PKA inhibitor. These latter results provide good evidence that PKA is indeed involved in the upregulatory phosphorylation of NKCC1 and suggest that an additional factor present in the acinar cell but absent from isolated membranes is required to bring about the phosphorylation. C1 Natl Inst Dent & Craniofacial Res, Membrane Biol Sect, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. Meikai Univ, Sch Dent, Dept Oral Physiol, Sakada, Saitama 3500283, Japan. Meikai Univ, Sch Dent, Dept Biochem, Sakada, Saitama 3500283, Japan. RP Turner, RJ (reprint author), Natl Inst Dent & Craniofacial Res, Membrane Biol Sect, Gene Therapy & Therapeut Branch, NIH, Bldg 10,Rm 1A06,10 Ctr Dr MSC 1190, Bethesda, MD 20892 USA. NR 19 TC 22 Z9 25 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD APR PY 2002 VL 282 IS 4 BP C817 EP C823 DI 10.1152/ajpcell.00352.2001 PG 7 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 528EK UT WOS:000174231300018 PM 11880270 ER PT J AU Han, C Demetris, AJ Michalopoulos, G Shelhamer, JH Wu, T AF Han, C Demetris, AJ Michalopoulos, G Shelhamer, JH Wu, T TI 85-kDa cPLA(2) plays a critical role in PPAR-mediated gene transcription in human hepatoma cells SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE HepG2 cell; liver; arachidonic acid; prostaglandin; peroxisome proliferator response element ID CYTOSOLIC PHOSPHOLIPASE A(2); PROLIFERATOR-ACTIVATED RECEPTOR; BRONCHIAL EPITHELIAL-CELLS; BASOPHILIC LEUKEMIA-CELLS; TUMOR-NECROSIS-FACTOR; ALPHA-NULL MOUSE; ARACHIDONIC-ACID; NUCLEAR-ENVELOPE; SIGNAL-TRANSDUCTION; LIVER-REGENERATION AB In an effort to understand the role of key eicosanoid-forming enzymes in the activation of peroxisome proliferator-activated receptor (PPAR), this study was designed to evaluate the possible contributions of cytosolic phospholipase A(2) (cPLA(2)) and group IIA secretory phospholipase A(2) (sPLA(2)) in the regulation of PPAR-mediated gene transcription in a human hepatoma cell line (HepG2). The HepG2 cells express both PPAR-alpha and -gamma but not PPAR-beta. Overexpression of cPLA(2), but not group IIA sPLA2 in the HepG2 cells, caused a significantly increased PPAR-alpha/gamma-mediated reporter activity. Antisense inhibition of cPLA(2) resulted in a significantly decreased PPAR-alpha/gamma activity. The PPAR-alpha/gamma-induced gene transcription in the HepG2 cells was inhibited by the cPLA(2) inhibitors methyl arachidonyl fluorophosphonate and arachidonyltrifluoromethyl ketone, but not by the sPLA(2) inhibitor LY311727. The expression of PPAR-alpha-mediated endogenous gene apolipoprotein A-II was increased in cells with overexpression of cPLA(2), decreased in cells with antisense inhibition of cPLA(2), but unaltered in cells with overexpression of group IIA sPLA(2). The above results demonstrated an important role of cPLA(2), but not group IIA sPLA(2) in the control of PPAR activation. The cPLA(2)-mediated PPAR activation was likely mediated by arachidonic acid and prostaglandin E-2. This study reveals a novel intracellular function of cPLA(2) in PPAR activation in HepG2 cells. The cPLA(2) thus may represent a potential therapeutic target for the control of PPAR-related liver and metabolic disorders such as obesity, lipid metabolic disorders, diabetes mellitus, and atherosclerosis. C1 Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15213 USA. NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Wu, T (reprint author), Univ Pittsburgh, Sch Med, Dept Pathol, Presbyterian Univ Hosp C902, 200 Lothrop St, Pittsburgh, PA 15213 USA. NR 60 TC 39 Z9 45 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 APR PY 2002 VL 282 IS 4 BP G586 EP G597 DI 10.1152/ajpgi.00305.2001 PG 12 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 531FJ UT WOS:000174405100002 PM 11897617 ER PT J AU Itani, OA Auerbach, SD Husted, RF Volk, KA Ageloff, S Knepper, MA Stokes, JB Thomas, CP AF Itani, OA Auerbach, SD Husted, RF Volk, KA Ageloff, S Knepper, MA Stokes, JB Thomas, CP TI Alveolar epithelial ion and fluid transport - Glucocorticoid-stimulated lung epithelial Na+ transport is associated with regulated ENaC and sgk1 expression SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article; Proceedings Paper CT 96th International Conference of the American-Thoracic-Society CY MAY 05-10, 2000 CL TORONTO, CANADA SP Amer Thorac Soc DE epithelial sodium channel; amiloride; short-circuit current; patch clamp; adenosine 3 ',5 '-cyclic monophosphate; corticosteroids; airway epithelia; alveolar type II cells ID CHANNEL ALPHA-SUBUNIT; THREONINE PROTEIN-KINASE; SODIUM-CHANNEL; BIOPHYSICAL PROPERTIES; LIQUID CLEARANCE; GENE-EXPRESSION; PSEUDOHYPOALDOSTERONISM TYPE-1; MOLECULAR CHARACTERIZATION; TRANSCRIPTIONAL REGULATION; GENOMIC ORGANIZATION AB H441 cells, a bronchiolar epithelial cell line, develop a glucocorticoid-regulated amiloride-sensitive Na+ transport pathway on permeable supports (R. Sayegh, S. D. Auerbach, X. Li, R. Loftus, R. Husted, J. B. Stokes, and C. P. Thomas. J Biol Chem 274: 12431- 12437, 1999). To understand its molecular basis, we examined the effect of glucocorticoids (GC) on epithelial Na+ channel (ENaC)-alpha, -beta, and -gamma and sgk1 expression and determined the biophysical properties of Na+ channels in these cells. GC stimulated the expression of ENac-alpha,-beta, and -gamma and sgk1 mRNA, with the first effect seen by 1 h. These effects were abolished by actinomycin D, but not by cycloheximide, indicating a direct stimulatory effect on ENaC and sgk1 mRNA synthesis. The GC effect on transcription of ENaC-alpha mRNA was accompanied by a significant increase in ENaC-alpha protein levels. GC also stimulated ENaC-alpha,-beta, and -gamma and sgk1 mRNA expression in A549 cells, an alveolar type II cell line. To determine the biophysical properties of the Na+ channel, single-channel currents were recorded from cell-attached H441 membranes. An Na+-selective channel with slow kinetics and a slope conductance of 10.8 pS was noted, properties similar to ENaC-alpha,-beta, and -gamma expressed in Xenopus laevis oocytes. These experiments indicate that amiloride-sensitive Na+ transport is mediated through classic ENaC channels in human lung epithelia and that GC-regulated Na+ transport is accompanied by increased transcription of each of the component subunits and sgk1. C1 Univ Iowa, Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. Vet Affairs Med Ctr, Iowa City, IA 52246 USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Thomas, CP (reprint author), Univ Iowa, Coll Med, Dept Internal Med, E300 GH,200 Hawkins Dr, Iowa City, IA 52242 USA. FU NIDDK NIH HHS [DK-54348, R01 DK054348, DK 52617] NR 66 TC 82 Z9 82 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 APR PY 2002 VL 282 IS 4 BP L631 EP L641 DI 10.1152/ajplung.00085.2001 PG 11 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 528EM UT WOS:000174231500005 PM 11880287 ER PT J AU Wang, XY Beutler, K Nielsen, J Nielsen, S Knepper, MA Masilamani, S AF Wang, XY Beutler, K Nielsen, J Nielsen, S Knepper, MA Masilamani, S TI Decreased abundance of collecting duct urea transporters UT-A1 and UT-A3 with ECF volume expansion SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE aldosterone; aquaporin; angiotensin; extracellular fluid ID RAT-KIDNEY; WATER CHANNEL; VASOPRESSIN; EXPRESSION; CLONING; COTRANSPORTER; PERMEABILITY; PROTEIN; LIMB AB Clinical disorders of extracellular fluid (ECF) volume regulation are often associated with changes in plasma urea concentration. To investigate possible renal causes, we measured the relative abundance of the urea transporters UT-A1, UT-A2, and UT-A3 in renal medulla of rats with aldosterone-induced NaCl retention. ECF volume-expanded rats received aldosterone by osmotic minipump plus a diet containing a high level of NaCl. Control rats received the same infusion of aldosterone plus a virtually NaCl-free diet, which prevented ECF volume expansion. Preliminary measurements demonstrated transient positive Na and water balance, decreased serum urea concentration, and increased urea clearance, but no change in creatinine clearance. Immunoblotting of homogenates from inner medulla showed a marked decrease in the abundance of the collecting duct urea transporters UT-A1 and UT-A3. There were no differences in the abundance of UT-A2, aquaporin (AQP)-2, AQP-3, or AQP-4 in ECF volume-expanded rats vs. controls. Time course experiments demonstrated that changes in UT-A1 abundance paralleled the fall in serum urea concentration after the switch from a low-NaCl to a high-NaCl diet, whereas the fall in UT-A3 abundance was delayed. Candesartan administration markedly decreased the abundance of UT-A1 and UT-A3 in the renal inner medulla, which is consistent with a role for the angiotensin II type 1 receptor in urea transport regulation. The results support the view that ECF-related changes in serum urea concentration are mediated, at least in part, through altered urea transporter abundance. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Aarhus Univ, Water & Salt Res Inst, DK-8000 Aarhus C, Denmark. RP Knepper, MA (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Rm 6N260,Bldg 10,10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. EM knep@helix.nih.gov FU Intramural NIH HHS [Z99 HL999999, Z01 HL001285-21]; NHLBI NIH HHS [K22-HL66994, Z01-HL-01282-KE] NR 34 TC 22 Z9 22 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD APR PY 2002 VL 282 IS 4 BP F577 EP F584 DI 10.1152/ajprenal.00250.2001 PG 8 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 528EN UT WOS:000174231600002 PM 11880317 ER PT J AU Newman, TK Fairbanks, LA Pollack, D Rogers, J AF Newman, TK Fairbanks, LA Pollack, D Rogers, J TI Effectiveness of human microsatellite loci for assessing paternity in a captive colony of vervets (Chlorocebus aethiops sabaeus) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Article DE paternity analysis; vervets; microsatellites ID MACAQUES MACACA-MULATTA; POLYMORPHISMS; POPULATION; MONKEYS; DNA AB Microsatellite polymorphisms are playing an increasingly vital role in primatological research, and are particularly useful for paternity exclusion in both wild and captive populations. Although vervet monkeys (Chlorocebus aethiops) are commonly studied in both settings, few previous studies have utilized microsatellite markers for assessing genetic variation in this species. In a pilot project to assess paternity in the UCLA-VA Vervet Monkey Research Colony (VMRC), we screened 55 commercially available human microsatellite markers chosen from a panel of 370 that have been shown to be polymorphic in baboons (Papio hamadryas). Using a standard PCR protocol, 43 (78%) loci produced amplifiable product. Of these, 14 were polymorphic and 11 were genotyped in 51 individuals, including 19 offspring and 14 potential sires. The average heterozygosity across the 11 loci was .719. In all 19 paternity cases all but one male was excluded as the true sire at two or more loci. This includes successfully distinguishing between two maternal half-sib brothers who were potential sires in most of the paternity cases. Given that the colony is descended from 54 wild-caught founders trapped between 1975 and 1987 from an introduced population on St. Kitts, West Indies, these values imply high microsatellite variability in natural vervet populations. Our results provide a panel of markers derived from the human genome that is suitable for assessing genetic variation and paternity in vervets. (C) 2002 Wiley-Liss, Inc. C1 SW Fdn Biomed Res, Dept Genet, San Antonio, TX USA. Univ Calif Los Angeles, Inst Neuropsychiat, Los Angeles, CA 90024 USA. SW Reg Primate Res Ctr, San Antonio, TX USA. RP Newman, TK (reprint author), NIAAA, NIH, Anim Ctr, Lab Clin Studies,Primate Sect, POB 529,Bldg 112, Poolesville, MD 20837 USA. FU NCRR NIH HHS [R01-RR08781] NR 13 TC 22 Z9 22 U1 0 U2 6 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD APR PY 2002 VL 56 IS 4 BP 237 EP 243 DI 10.1002/ajp.1078 PG 7 WC Zoology SC Zoology GA 533WA UT WOS:000174552200005 PM 11948640 ER PT J AU Wendler, D Martinez, RA Fairclough, D Sunderland, T Emanuel, E AF Wendler, D Martinez, RA Fairclough, D Sunderland, T Emanuel, E TI Views of potential subjects toward proposed regulations for clinical research with adults unable to consent SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID ADVANCE DIRECTIVES; GUIDELINES AB Objective. The authors' goal was to assess healthy individuals' attitudes toward five of the most prominent proposed safeguards regarding the consent process for research with adults unable to consent. Method: Telephone interviews were conducted with 246 individuals with a family history of Alzheimer's disease who had participated in clinical research. Results: The majority of respondents said that they were willing to participate in research if they lost the ability to consent. Few completed a research advance directive. Many had discussed their preferences with their families, and the majority would allow their families to make research decisions for them. Conclusions: Enrolling individuals who are unable to consent in research that offers no potential for medical benefit is consistent with the preferences of at least some individuals. This suggests that such research should not be prohibited, provided there is sufficient evidence that it is consistent with the preferences of individual subjects. Requiring that such evidence be provided in a formal research advance directive may be unnecessarily restrictive. more research is needed to assess whether the findings in this group of subjects generalize to other groups. C1 NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bethesda, MD 20892 USA. NIMH, Geriatr Psychiat Branch, Bethesda, MD 20892 USA. AMC Canc Res Ctr, Ctr Res Methodol & Biometr, Denver, CO USA. RP Wendler, D (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bldg 10,Rm 1C118, Bethesda, MD 20892 USA. NR 24 TC 44 Z9 44 U1 3 U2 3 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD APR PY 2002 VL 159 IS 4 BP 585 EP 591 DI 10.1176/appi.ajp.159.4.585 PG 7 WC Psychiatry SC Psychiatry GA 538DZ UT WOS:000174800000012 PM 11925296 ER PT J AU Malhotra, AK Kestler, LJ Mazzanti, C Bates, JA Goldberg, T Goldman, D AF Malhotra, AK Kestler, LJ Mazzanti, C Bates, JA Goldberg, T Goldman, D TI A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID DOPAMINE; SCHIZOPHRENIA; MODEL; RAT AB Objective: In the prefrontal cortex, the enzyme catechol O-methyltransferase (COMT) is critical in the metabolic degradation of dopamine, a neurotransmitter hypothesized to influence human cognitive function. The COMT gene contains a functional polymorphism, Val158Met, that exerts a fourfold effect on enzyme activity. The current study investigated whether prefrontal cognition varies with COMT genotype. Method: Val158Met was genotyped in 73 healthy volunteers. A task of prefrontal cognition, the Wisconsin Card Sorting Test, was also administered. Results: Subjects with only the low-activity met allele made Significantly fewer perseverative errors on the Wisconsin Card Sorting Test than did subjects with the val allele. Conclusions: These data are consistent with those of previous studies, suggesting that a functional genetic polymorphism may influence prefrontal cognition. C1 Hillside Hosp, Unit Mol Psychiat, Glen Oaks, NY 11004 USA. NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. RP Malhotra, AK (reprint author), Hillside Hosp, Unit Mol Psychiat, 75-59 263rd St, Glen Oaks, NY 11004 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU NIMH NIH HHS [MH-60575, MH-01760] NR 12 TC 401 Z9 410 U1 0 U2 11 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD APR PY 2002 VL 159 IS 4 BP 652 EP 654 DI 10.1176/appi.ajp.159.4.652 PG 3 WC Psychiatry SC Psychiatry GA 538DZ UT WOS:000174800000021 PM 11925305 ER PT J AU Fee, IE Brown, TM Lazarus, J Theerman, P AF Fee, IE Brown, TM Lazarus, J Theerman, P TI A dedicated public health nurse SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article C1 NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20892 USA. Univ Rochester, Dept Hist, Rochester, NY 14627 USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY 14627 USA. RP Fee, IE (reprint author), Bldg 38,Room 1E21,8600 Rockville Pike, Bethesda, MD 20894 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD APR PY 2002 VL 92 IS 4 BP 565 EP 565 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 533YX UT WOS:000174558800019 ER PT J AU Hewitt, M Devesa, S Breen, N AF Hewitt, M Devesa, S Breen, N TI Papanicolaou test use among reproductive-age women at high risk for cervical cancer: Analyses of the 1995 national survey of family growth SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID PAP SMEAR AB Objectives. This study assessed the relationship between risk factors for cervical cancer and Papanicolaou (Pap) test use within the past year among reproductive-age women. Methods. The 1995 National Survey of Family Growth, a demographic and reproductive health survey of 10847 women aged 15 to 44, was analyzed with multiple logistic regression, Results. Of the women, 62% reported having had a Pap test within the past year. Use was significantly higher among women with risk factors and among African American women. Use was significantly lower among uninsured, poor, and foreign-born women and among women with lower educational attainment and of "other" race/ethnicity. Conclusions. Strategies to improve Pap test use include (1) educational campaigns that inform women Of cervical cancer risk factors and encourage screening and (2) increased support for programs that expand access to Pap tests. C1 Natl Canc Policy Board, Inst Med, Washington, DC 20418 USA. Natl Canc Inst, Div Canc Epidemiol & Genet, Washington, DC 20418 USA. Natl Canc Inst, Div Canc Control & Populat Sci, Washington, DC 20418 USA. RP Hewitt, M (reprint author), Natl Canc Policy Board, Inst Med, 2101 Constitut Ave NW, Washington, DC 20418 USA. NR 23 TC 31 Z9 33 U1 0 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD APR PY 2002 VL 92 IS 4 BP 666 EP 669 DI 10.2105/AJPH.92.4.666 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 533YX UT WOS:000174558800036 PM 11919069 ER PT J AU Meduri, GU Tolley, EA Chrousos, GP Stentz, F AF Meduri, GU Tolley, EA Chrousos, GP Stentz, F TI Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome - Evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE acute respiratory distress syndrome; glucocorticoid receptors; I kappa B; methylprednisolone; nuclear factor-kappa B ID FACTOR-KAPPA-B; RECEPTOR-BINDING AFFINITY; SEPTIC SHOCK; MOLECULAR MECHANISMS; ASTHMA; ACTIVATION; SEPSIS; ARDS; IMMUNOSUPPRESSION; CORTICOTROPIN AB Nuclear factor-kappaB (NF-kappaB) and glucocorticoid receptor-alpha (GR-alpha) have diametrically opposed functions in regulating inflammation. We investigated whether unresolving acute respiratory distress syndrome (ARDS) is associated with systemic inflammation-induced glucocorticoid resistance and whether prolonged methylprednisolone administration accelerates the suppression of systemic inflammatory indices and normalizes the sensitivity of the immune system to glucocorticoids. Patients enrolled into a randomized trial evaluating prolonged methylprednisolone administration in unresolving ARDS had serial plasma samples collected before and after randomization. In the plasma, we measured the concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukins (IL) IL-1beta and IL-6, adrenocorticotropic hormone (ACTH), and cortisol. The ability of patient plasma to influence the NF-kappaB and GR-signal transduction systems of normal peripheral blood leukocytes (PBL) was examined. Patients treated with methylprednisolone had progressive and sustained reductions of TNF-alpha, IL-1beta, IL-6, ACTH, and cortisol concentrations over time. Normal PBL exposed to plasma samples collected during methylprednisolone exhibited significant progressive increases in all aspects of GR-mediated activity and significant reductions in NF-kappaB DNA-binding and transcription of TNF-alpha and IL-1beta. These findings provide support for the presence of endogenous glucocorticoid inadequacy in the control of inflammation and systemic inflammation-induced peripheral glucocorticoid resistance in ARDS. Prolonged methylprednisolone administration accelerated the resolution of both systemic inflammation and peripheral acquired glucocorticoid resistance in ARDS. C1 Univ Tennessee, Div Pulm, Memphis Lung Res Program, Dept Med, Memphis, TN 38163 USA. Univ Tennessee, Div Crit Care Med, Memphis Lung Res Program, Dept Med, Memphis, TN 38163 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN 38163 USA. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Meduri, GU (reprint author), Univ Tennessee, Ctr Hlth Sci, Div Pulm & Crit Care Med, 956 Court Ave,Room H316, Memphis, TN 38163 USA. NR 43 TC 140 Z9 158 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD APR 1 PY 2002 VL 165 IS 7 BP 983 EP 991 DI 10.1164/rccm.2106014 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 536ZA UT WOS:000174730700020 PM 11934726 ER PT J AU Birukov, KG Birukova, AA Dudek, SM Verin, AD Crow, MT Zhan, X DePaola, N Garcia, JGN AF Birukov, KG Birukova, AA Dudek, SM Verin, AD Crow, MT Zhan, X DePaola, N Garcia, JGN TI Shear stress-mediated cytoskeletal remodeling and cortactin translocation in pulmonary endothelial cells SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article ID LIGHT-CHAIN KINASE; FLOWS IN-VITRO; TYROSINE PHOSPHORYLATION; P21-ACTIVATED KINASE; BARRIER DYSFUNCTION; PROTEIN-KINASES; MAP KINASE; RHO-KINASE; C-FOS; MYOSIN AB Hemodynamic forces in the form of shear stress (SS) and mechanical strain imposed by circulating blood are recognized factors involved in the control of systemic endothelial cell (EC) cytoskeletal structure and function. However, the effects of acute SS on pulmonary endothelium have not been precisely characterized, nor the mechanism of rapid SS-induced EC cytoskeletal rearrangement understood. We exposed bovine and human pulmonary EC monolayers to laminar SS (10 dynns/ cm(2)) in a parallel plate flow chamber and observed increased actin stress fiber formation 15 min after application of flow. Acute SS-induced pronounced cortical cytoskeletal rearrangement characterized by myosin light chain kinase (MLCK)- and Rho-associated kinase (RhoK)-dependent accumulation of diphosphorylated regulatory myosin light chains (MLC) in the cortical actin ring, functional protein tyrosine phosphorylation, and transient peripheral translocation of cortactin, an actin-binding protein involved in the regulation of actin polymerization. SS-induced cortactin translocation was independent of Erk-1,2,2 MAP kinase, p60s", MLCK, or RhoK activities, and unaffected by overexpression of a cortactin mutant lacking four major p60(Src) phosphorylation sites. However, both SS-induced transient cortactin translocation and cytoskeletal reorientation in response to sustained (24 h) SS was abolished in cells overexpressing either dominant negative Rac 1 or a dominant negative construct of its downstream target, p21-activated kinase (PAK)-1. Our results suggest a potential role for cortactin in the SS-induced EC cortical cytoskeletal remodeling and demonstrate a novel mechanism of Rac GTPase-dependent regulation of the pulmonary endothelial cytoskeleton by SS. C1 Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD 21224 USA. NIH, NIA, Gerontol Res Ctr, Vasc Biol Unit,Lab Cardiovasc Sci, Baltimore, MD USA. Amer Red Cross, Holland Lab, Dept Expt Pathol, Rockville, MD USA. Rensselaer Polytech Inst, Dept Biomed Engn, Troy, NY 12180 USA. RP Birukov, KG (reprint author), Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, JHAAC 5A-42,5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. RI Garcia, Joe/E-8862-2010 FU NHLBI NIH HHS [HL50533, HL58064] NR 56 TC 133 Z9 138 U1 0 U2 5 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD APR PY 2002 VL 26 IS 4 BP 453 EP 464 PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 537ZQ UT WOS:000174789900012 PM 11919082 ER PT J AU Montgomery, SP Mog, SR Xu, H Tadaki, DK Hirschberg, B Berning, JD Leconte, J Harlan, DM Hale, D Kirk, AD AF Montgomery, SP Mog, SR Xu, H Tadaki, DK Hirschberg, B Berning, JD Leconte, J Harlan, DM Hale, D Kirk, AD TI Efficacy and toxicity of a protocol using sirolimus, tacrolimus and daclizumab in a nonhuman primate renal allotransplant model SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE allograft; daclizumab; kidney transplantation; primate; sirolimus; tacrolimus ID RAPAMYCIN; TRANSPLANTATION; COMBINATION; PROGRESSION; ALLOGRAFTS; SURVIVAL; REGIMEN; FK506 AB A regimen combining sirolimus, tacrolimus, and daclizumab has recently been shown to provide adequate immunosuppression for allogeneic islet transplantation in humans, but remains unproven for primarily vascularized allografts. We evaluated this regimen for renal allograft transplantation in mismatched nonhuman primates. Dosages of sirolimus and tacrolimus were adjusted for trough levels of 10-15 ng/mL and 4-6 ng/mL, respectively. Treated monkeys (n = 5) had significantly prolonged allograft survival, with a mean survival of 36 days vs. 7 days in untreated controls (n = 6, p = 0.008). Four of five treated animals, but none of the controls, developed fibrinoid vascular necrosis of the small intestine. A review of gut histology from animals on other immunosuppressive protocols performed by our laboratory suggested that these lesions were a result of sirolimus exposure. In summary this regimen prolongs the survival of vascularized renal allografts, but is limited by profound GI toxicity in rhesus macaques. C1 NIDDK, Navy Transplant & Autoimmun Branch, Bethesda, MD 20892 USA. Naval Med Res Ctr, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Dept Gen Surg, Washington, DC 20307 USA. USN, Med Res Ctr, Dept Pathol, Bethesda, MD 20892 USA. RP Kirk, AD (reprint author), NIDDK, Navy Transplant & Autoimmun Branch, Room 11S-219,Bldg 10,Ctr Dr, Bethesda, MD 20892 USA. RI Kirk, Allan/B-6905-2012 FU NIAID NIH HHS [AI43900-01] NR 15 TC 21 Z9 21 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD APR PY 2002 VL 2 IS 4 BP 381 EP 385 DI 10.1034/j.1600-6143.2002.20415.x PG 5 WC Surgery; Transplantation SC Surgery; Transplantation GA 551AB UT WOS:000175536300015 PM 12118862 ER PT J AU Krishnamurti, C Peat, RA Cutting, MA Rothwell, SW AF Krishnamurti, C Peat, RA Cutting, MA Rothwell, SW TI Platelet adhesion to dengue-2 virus-infected endothelial cells SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID PROSTACYCLIN PGI2; ACTIVATING-FACTOR; VASCULAR CELLS; ADHERENCE; THROMBIN; IDENTIFICATION; AUTOCRINE; MOLECULE; ASPIRIN; RABBIT AB Platelets in circulation normally do not adhere to resting endothelial cells. However, in response to vascular injury they adhere to stimulated endothelium and thereby play an essential role in hemostasis and thrombosis. Infection with dengue-2 virus can cause illness accompanied by thrombocytopenia and hemorrhage. Increased adherence of platelets to stimulated endothelial cells could contribute to the thrombocytopenia. In this study, adherence of radioisotopically labeled platelets to 1) unstimulated, 2) lipopolysaccharide (LPS)-stimulated, and 3) dengue-2 virus-infected human umbilical vein endothelial cells (HUVEC) was measured in an in vitro assay. Primary HUVEC were cultured in 96-well tissue culture plates in the presence or absence of LPS or dengue-2 virus. These cells were coincubated with H-3-adenine-labeled fresh platelets for 30 min after which the cells were assayed for adherent platelets. Within 30 min there was maximum adherence of platelets to confluent LPS-stimulated HUVEC (36 +/- 4% over controls: P = 0.005). In comparison, there was a significant increase in adherence to dengue-2 infected HUVEC (78 +/- 7%; P less than or equal to 0.001). Additionally, platelet adherence was visualized using fluorescent microscopy. Dengue-2 infection stimulated the HUVEC as monitored by expression of E-selectin. Platelets that adhered to dengue-2 or LPS-stimulated HUVEC were activated as visualized by dual fluorescent probes. These data demonstrate that human platelets adhere to dengue-2 virus-stimulated HUVEC and this interaction could contribute to the thrombocytopenia observed during infection. C1 Walter Reed Army Inst Res, Dept Blood Res, Silver Spring, MD 20910 USA. RP Krishnamurti, C (reprint author), NHLBI, NIH, Dept Extramural Affairs, Review Branch, 6701 Rockledge Dr,Room 7206, Bethesda, MD 20892 USA. NR 33 TC 35 Z9 37 U1 0 U2 2 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD APR PY 2002 VL 66 IS 4 BP 435 EP 441 PG 7 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 577LM UT WOS:000177062400018 PM 12164302 ER PT J AU Patenaude, AF Guttmacher, AE Collins, FS AF Patenaude, AF Guttmacher, AE Collins, FS TI Genetic testing and psychology - New roles, new responsibilities SO AMERICAN PSYCHOLOGIST LA English DT Article; Proceedings Paper CT 108th Annual Convention of the American-Psychological-Association CY AUG 04-08, 2000 CL WASHINGTON, DC SP Amer Psychol Assoc ID BREAST-OVARIAN CANCER; HUMAN-GENOME-PROJECT; FOLLOW-UP CARE; PROPHYLACTIC MASTECTOMY; INHERITED PREDISPOSITION; FAMILIAL BREAST; BRCA1; RISK; SUSCEPTIBILITY; DISEASE AB Advances in genetics and genetic testing promise to catalyze a fundamental change in the practice of medicine. Psychologists have much to offer as psychotherapists, researchers, educators, and policymakers to a society heavily influenced by the genetic revolution. To make the most of new opportunities available to mental health professionals in genetics, psychologists must know basic genetic principles and learn what is new about 21st-century genetics. The core competencies for all health professionals developed by the National Coalition for Health Professional Education in Genetics are related in this article to the significant roles psychologists can play in helping individuals with genetic concerns to cope with vulnerability, optimize family interaction, and improve health behaviors. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Natl Human Genome Res Inst, Bethesda, MD USA. RP Patenaude, AF (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM andrea_patenaude@dfci.harvard.edu NR 55 TC 30 Z9 30 U1 0 U2 5 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0003-066X J9 AM PSYCHOL JI Am. Psychol. PD APR PY 2002 VL 57 IS 4 BP 271 EP 282 DI 10.1037//0003-066X.57.4.271 PG 12 WC Psychology, Multidisciplinary SC Psychology GA 541QW UT WOS:000174996100002 PM 11975377 ER PT J AU Pingpank, JF Hoffman, JP Sigurdson, ER Ross, E Sasson, AR Eisenberg, BL AF Pingpank, JF Hoffman, JP Sigurdson, ER Ross, E Sasson, AR Eisenberg, BL TI Pancreatic resection for locally advanced primary and metastatic nonpancreatic neoplasms SO AMERICAN SURGEON LA English DT Article; Proceedings Paper CT 44th Annual Meeting of the Midwest-Surgical-Association CY AUG 12-15, 2001 CL LAKE GENEVA, WISCONSIN SP Midwest Surg Assoc ID PRIMARY TUMORS; CARCINOMA; COLON; PANCREATICODUODENECTOMY AB We conducted a retrospective review of our single-institution experience with pancreas resection for locally advanced primary malignancy or metastases from other organs. From January 1989 through April 200135 patients underwent pancreatic resection for locally advanced primary (17) and recurrent nonpancreatic (18) tumors. Patient records were examined for recurrence and survival. Seventeen patients with locally advanced primary tumors presented with pancreatic extension either into the head/body (six) or tail (11). Pancreatic resections were completed as en bloc procedures with the primary disease of stomach (five), colon (four), sarcoma (five), adrenal gland (one), or spleen (one). Procedures performed included pancreaticoduodenectomy for proximal lesions and distal pancreatectomy for disease limited to the pancreatic tail. Median overall survival was 56 months. Fourteen of 17 patients remain alive: three with disease and 11 without evidence of recurrence. Eighteen patients presented with recurrent tumor from a previously resected right upper quadrant tumor (nine) or metastases from an intra-abdominal source (nine). The primary source was colon (eight), biliary (three), sarcoma (three), melanoma (two), ovary (one), and unknown primary (one). Patients underwent pancreaticoduodenectomy, distal pancreatectomy, or resection of residual pancreas. Overall median survival was 46 months. In this group of 18 patients there was no increased survival in those patients with a time to recurrence from their primary tumor resection greater than 2 years. We conclude that pancreatic resection for locally advanced nonpancreatic or recurrent intra-abdominal malignancies is possible in properly selected patients. The ability to obtain disease-free margins through en bloc resection is a key component of therapy. C1 Fox Chase Canc Ctr, Dept Surg Oncol, Philadelphia, PA 19111 USA. Fox Chase Canc Ctr, Dept Biostat, Philadelphia, PA 19111 USA. RP Pingpank, JF (reprint author), NCI, Surg Metab Sect,Surg Branch, NIH, Bldg 10,Room 3C426,10 Ctr Dr, Bethesda, MD 20892 USA. NR 17 TC 15 Z9 15 U1 0 U2 0 PU SOUTHEASTERN SURGICAL CONGRESS PI ATLANTA PA 141 WEST WIEUCA RD, STE B100, ATLANTA, GA 30342 USA SN 0003-1348 J9 AM SURGEON JI Am. Surg. PD APR PY 2002 VL 68 IS 4 BP 337 EP 340 PG 4 WC Surgery SC Surgery GA 536DE UT WOS:000174684800009 PM 11952243 ER PT J AU Pandeya, SN Smitha, S Stables, JP AF Pandeya, SN Smitha, S Stables, JP TI Anticonvulsant and sedative-hypnotic activities of N-substituted isatin semicarbazones SO ARCHIV DER PHARMAZIE LA English DT Article DE epilepsy; anticonvulsants; sedative-hypnotic activity; isatin semicarbazones AB A series of N-methyl/acetyl, 5-(un)-substituted isatin-3-semicarbazones were screened for anticonvulsant and sedative-hypnotic activities. The results revealed that protection was obtained in all the screens i.e., MES, scPTZ, and scSTY. Compounds 2, 4, 6, 10 but not 1 and 3 showed low neurotoxicity when compared to clinically used drugs. Compounds 5, 7, 8 and 9 were completely non-toxic. Compound 6 showed good activity in the rat oral MES screen. Among all the compounds, 3 and 6 emerged as the most active compounds as indicated by the protection they exhibit in MES, scSTY, and scPTZ screens. All the compounds showed significant sedative-hypnotic activity. C1 Banaras Hindu Univ, Inst Technol, Dept Pharmaceut, Varanasi 221005, Uttar Pradesh, India. Epilepsy Branch, Preclin Pharmacol Sect, NIH, Bethesda, MD USA. RP Pandeya, SN (reprint author), Banaras Hindu Univ, Inst Technol, Dept Pharmaceut, Varanasi 221005, Uttar Pradesh, India. NR 21 TC 6 Z9 7 U1 0 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0365-6233 J9 ARCH PHARM JI Arch. Pharm. PD APR PY 2002 VL 335 IS 4 BP 129 EP 134 DI 10.1002/1521-4184(200204)335:4<129::AID-ARDP129>3.0.CO;2-W PG 6 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 571KV UT WOS:000176717300002 PM 12112032 ER PT J AU Charmandari, E Brook, CGD Hindmarsh, PC AF Charmandari, E Brook, CGD Hindmarsh, PC TI Why is management of patients with classical congenital adrenal hyperplasia more difficult at puberty? SO ARCHIVES OF DISEASE IN CHILDHOOD LA English DT Review ID GROWTH-HORMONE-SECRETION; APPARENT MINERALOCORTICOID EXCESS; CORTICOSTEROID-BINDING GLOBULIN; HUMAN ADRENOCORTICAL-CELLS; POLYCYSTIC-OVARY-SYNDROME; I IGF-I; 11-BETA-HYDROXYSTEROID DEHYDROGENASE; 21-HYDROXYLASE DEFICIENCY; CYSTIC-FIBROSIS; INSULIN-RESISTANCE AB Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive condition in which deletions or mutations of the cytochrome P450 21-hydroxylase gene cause glucocorticoid and often mineralocorticoid deficiency. Despite optimal substitution therapy, control of classical CAH is often inadequate at puberty, and the problems encountered relate to hypocortisolism and/or hyperandrogenism. A number of physiological alterations in the endocrine milieu at puberty, which include alterations in the growth hormone/insulin-like growth factor axis, insulin sensitivity, as well as the activity of enzymes participating in cortisol metabolism and adrenal steroidogenesis, may account for the documented hypocortisolism and elevated androgen production, and may explain the difficulty in maintaining adequate adrenocortical suppression in pubertal patients with classical 21-hydroxylase deficiency. C1 UCL, London Ctr Paediat Endocrinol, London, England. RP Charmandari, E (reprint author), Natl Inst Child Hlth & Human Dev, Pediat & Reprod Endocrinol Branch, NIH, 10 Ctr Dr Bldg 10 Suite 9D42, Bethesda, MD 20892 USA. EM charmane@mail.nih.gov RI Hindmarsh, Peter/C-4964-2008; Charmandari, Evangelia/B-6701-2011 NR 48 TC 16 Z9 17 U1 1 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-9888 EI 1468-2044 J9 ARCH DIS CHILD JI Arch. Dis. Child. PD APR PY 2002 VL 86 IS 4 BP 266 EP 269 DI 10.1136/adc.86.4.266 PG 4 WC Pediatrics SC Pediatrics GA 540QW UT WOS:000174940500010 PM 11919101 ER PT J AU Heussler, HS Suri, M Young, ID Muenke, M AF Heussler, HS Suri, M Young, ID Muenke, M TI Extreme variability of expression of a Sonic Hedgehog mutation: attention difficulties and holoprosencephaly SO ARCHIVES OF DISEASE IN CHILDHOOD LA English DT Article ID GENE; PERSPECTIVES; EPIDEMIOLOGY; RECEPTOR; ENCODES AB Holoprosencephaly (HPE) is a clinically variable and genetically heterogeneous central nervous system (CNS) malformation. Alobar HPE, which is its most severe form, is associated with a poor prognosis. At the milder end of the HPE spectrum microcephaly, hypotelorism, and single central maxillary incisor may be recognised. Currently, four genes have been identified for this condition. These include Sonic Hedgehog (SHH) on chromosome 7q36, which is thought to be responsible for a significant proportion of autosomal dominant HPE. We report an index case with alobar holoprosencephaly caused by an SHH mutation and six members of his family over two generations with this mutation, with a broad range of clinical presentation, including attention deficit hyperactivity disorder (ADHD). The combination of microcephaly, hypotelorism, subtle midline facial anomalies, and ADHD within a sibship should alert the physician to the possible diagnosis of HPE. C1 Univ Nottingham, Acad Div Child Hlth, Nottingham NG7 2UH, England. City Hosp, Nottingham NG5 1PB, England. Leicester Royal Infirm, Leicester LE1 5WW, Leics, England. Natl Human Genome Res Inst, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Heussler, HS (reprint author), Univ Nottingham, Acad Div Child Hlth, Nottingham NG7 2UH, England. RI Heussler, Helen /F-4286-2010 NR 22 TC 37 Z9 39 U1 0 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-9888 J9 ARCH DIS CHILD JI Arch. Dis. Child. PD APR PY 2002 VL 86 IS 4 BP 293 EP 296 DI 10.1136/adc.86.4.293 PG 4 WC Pediatrics SC Pediatrics GA 540QW UT WOS:000174940500017 PM 11919111 ER PT J AU Fenton, WS Hoch, JS Herrell, JM Mosher, L Dixon, L AF Fenton, WS Hoch, JS Herrell, JM Mosher, L Dixon, L TI Cost and cost-effectiveness of hospital vs residential crisis care for patients who have serious mental illness SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID ECONOMIC EVALUATIONS; RANDOMIZED TRIAL; RESPITE-CARE; DEINSTITUTIONALIZATION; INTERVENTIONS; HOMELESS; SERVICES; ADULTS; ILL AB Background: This study evaluates the cost and cost-effectiveness of a residential crisis program compared with treatment received in a general hospital psychiatric unit for patients who have serious mental illness in need of hospital-level care and who are willing to accept voluntary treatment. Methods: Patients in the Montgomery County, Maryland, public mental health system (N = 119) willing to accept voluntary acute care were randomized to the psychiatric ward of a general hospital or a residential crisis program. Unit costs and service utilization data were used to estimate episode and 6-month treatment costs from the perspective of government payors. Episodic symptom reduction and days residing in the community over the 6 months after the episode were chosen to represent effectiveness. Results: Mean (SD) acute treatment episode costs was $3046 ($2124) in the residential crisis program, 44% lower than the $5549 ($3668) episode cost for the general hospital. Total 6-month treatment costs for patients assigned to the 2 programs were $19941 ($19282) and $25737 ($21835), respectively. Treatment groups did not differ significantly in symptom improvement or community days achieved. Incremental cost-effectiveness ratios indicate that in most cases, the residential crisis program provides near-equivalent effectiveness for significantly less cost. Conclusions: Residential crisis programs maybe a cost-effective approach to providing acute care to patients who have serious mental illness and who are willing to accept voluntary treatment. Where resources are scarce, access to needed acute care might be extended using a mix of hospital, community-based residential crisis, and community support services. C1 NIMH, Bethesda, MD 20892 USA. Univ Western Ontario, Sch Med & Dent, Dept Epidemiol & Biostat, London, ON, Canada. Univ Western Ontario, Sch Med & Dent, Dept Family Med, London, ON, Canada. Subst Abuse & Mental Hlth Serv Adm, Ctr Subst Abuse Treatment, Div Practice & Syst Dev, Rockville, MD USA. Soteria Associates, San Diego, CA USA. Univ Maryland, Baltimore, MD 21201 USA. RP Fenton, WS (reprint author), NIMH, 6001 Execut Blvd,Room 8029,MSC 9669, Bethesda, MD 20892 USA. OI Hoch, Jeffrey/0000-0002-4880-4281 NR 45 TC 27 Z9 27 U1 1 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD APR PY 2002 VL 59 IS 4 BP 357 EP 364 DI 10.1001/archpsyc.59.4.357 PG 8 WC Psychiatry SC Psychiatry GA 538EF UT WOS:000174800800006 PM 11926936 ER PT J AU Elghetany, MT Alter, BP AF Elghetany, MT Alter, BP TI p53 protein overexpression in bone marrow biopsies of patients with Shwachman-Diamond syndrome has a prevalence similar to that of patients with refractory anemia SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID MYELODYSPLASTIC SYNDROMES; APLASTIC-ANEMIA; FANCONI-ANEMIA; MUTATION; EXPRESSION; P53-GENE AB Context.-Shwachman-Diamond syndrome (SDS) is a rare inherited disorder characterized by pancreatic insufficiency, neutropenia, and in some patients, metaphyseal dysostosis. Patients with SDS are at a high risk for development of bone marrow failure, myelodysplastic syndrome, and acute leukemia. The p53 gene plays a major role in cell-cycle regulation, particularly in the presence of a genetic alteration in DNA, a critical step for the initiation of leukemogenesis. p53 gene up-regulation and p53 protein overexpression may occur as a cellular reaction to significant DNA damage. Shwachman-Diamond syndrome and refractory anemia patients have close similarities in the prevalence of acute leukemia and in cell-cycle changes in bone marrow cells. This similarity was further investigated for p53 protein overexpression using archived tissue from patients with hematologic diseases having various leukemic propensities, including SDS and refractory anemia. Methods.-Immunohistochemical staining for 1753 protein overexpression was performed on bone marrow biopsies from 9 patients with SDS. These specimens were compared with biopsies from 71 patients with acquired hematologic disorders with variable risk levels for leukemia, including acquired aplastic anemia (n = 14), refractory anemia (n = 46), and various acquired cytopenias (n = 11), as well as 37 control subjects. Results.-p53 protein overexpression was identified only in patients with SDS and in patients with refractory anemia; these groups exhibited comparable prevalences of 78% and 72%, respectively. None of the patients with acquired aplastic anemia, acquired cytopenias, or in the control group showed overexpression of p53 protein. Conclusion.-The prevalence of p53 protein overexpression in SDS is significantly different from that in acquired aplastic anemia and acquired cytopenias, but it is similar to the prevalence in refractory anemia. We speculate that p53 protein overexpression in this bone marrow failure syndrome may represent an early indicator of significant DNA genetic alteration, which is a crucial step in the process of leukemogenesis. C1 Univ Texas, Med Branch, Dept Pathol, Galveston, TX 77555 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Elghetany, MT (reprint author), Univ Texas, Med Branch, Dept Pathol, 301 Univ Blvd, Galveston, TX 77555 USA. NR 25 TC 27 Z9 27 U1 0 U2 1 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD APR PY 2002 VL 126 IS 4 BP 452 EP 455 PG 4 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 539EJ UT WOS:000174857100011 PM 11900571 ER PT J AU Celentano, DD DiIorio, C Hartwell, T Kelly, J Magana, R Maibach, E O'Leary, A Pequegnat, W Rotheram-Borus, MJ AF Celentano, DD DiIorio, C Hartwell, T Kelly, J Magana, R Maibach, E O'Leary, A Pequegnat, W Rotheram-Borus, MJ CA Natl I Mental Hlth Multisite HIV P TI Predictors of sexual behavior patterns over one year among persons at high risk for HIV SO ARCHIVES OF SEXUAL BEHAVIOR LA English DT Article DE HIV; STD; intervention; prevention; risk ID INJECTION-DRUG USERS; CONDOM USE; GENDER-DIFFERENCES; SUBSTANCE USE; COCAINE USE; GAY MEN; HOUSING DEVELOPMENTS; NATIONAL-SURVEY; ALCOHOL MYOPIA; SELF-EFFICACY AB This study examined the sexual risk act patterns of individuals who participated in the NIMH National Multisite HIV Prevention Trial. Patterns of sexual risk were examined over I year among 3,104 participants from 37 clinics in 7 regional sites, within both intervention and control conditions. Four patterns were assessed: 100% protected sex or abstinence at follow-up points; improved condom use or abstinence, but not completely protected behavior; relapse to unsafe sex; and unchanged protection. Participants in the intervention condition who responded to the intervention with consistently protected behavior were significantly more likely to be older or young adults, recent immigrants to the United States, and to not barter sex or have alcohol-related problems. The consistently protected participants in the control condition were also significantly more likely to be older. The intervention is likely to be particularly effective with clients in STD clinics with large immigrant populations. Specialized HIV prevention interventions may be needed for commercial sex workers, young persons, and those with alcohol-related problems. C1 Univ Calif Los Angeles, Los Angeles, CA 90024 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. Emory Univ, Atlanta, GA 30322 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. Univ Calif Irvine, Irvine, CA 92717 USA. Rutgers State Univ, New Brunswick, NJ 08903 USA. NIMH, Rockville, MD 20857 USA. RP Rotheram-Borus, MJ (reprint author), Univ Calif Los Angeles, 10920 Wilshire Blvd,Suite 350, Los Angeles, CA 90024 USA. EM rotheram@ucla.edu OI Maibach, Edward/0000-0003-3409-9187 NR 67 TC 9 Z9 9 U1 4 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0004-0002 J9 ARCH SEX BEHAV JI Arch. Sex. Behav. PD APR PY 2002 VL 31 IS 2 BP 165 EP 176 PG 12 WC Psychology, Clinical; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA 538JN UT WOS:000174812500005 ER PT J AU Demissie, S Cupples, LA Myers, R Aliabadi, P Levy, D Felson, DT AF Demissie, S Cupples, LA Myers, R Aliabadi, P Levy, D Felson, DT TI Genome scan for quantity of hand osteoarthritis - The Framingham study SO ARTHRITIS AND RHEUMATISM LA English DT Article ID RADIOGRAPHIC OSTEOARTHRITIS; LINKAGE; ASSOCIATION; TRAITS; LOCUS; CELLS; GENE; KNEE; DNA AB Objective. To search for markers linked to quantity of radiographic hand osteoarthritis (OA) in the Framingham Heart Study. Methods. The sample included 684 original cohort members and 793 offspring in 296 pedigrees. Radiographic OA features evaluated included the Kellgren/Lawrence (K/L) score, osteophytes, and joint space narrowing (0-3 scale). Four quantitative phenotypes were computed from these measurements: sum of K/L scores across hand joints, sum of osteophyte scores, sum of joint space narrowing scores, and proportion of affected joints. Prior to linkage analysis, these phenotypes were adjusted for age using a linear regression analysis from which standardized residuals were computed. The regression analysis was performed separately for each sex and each generation. The variance component model (SOLAR) was then applied to the normalized scores of the residuals. Results. The average age was 62 years for the original cohort and 54 years for the offspring. Fifty percent of the original cohort and 30% of their offspring had at least 1 affected joint (K/L score greater than or equal to2). Heritability ranged from 28% (proportion of joints affected with OA) to 34% (sum of K/L scores). Eight chromosomal regions indicated suggestive linkage (multipoint logarithm of odds [LOD] score >1.5) for at least 1 phenotype; LOD scores were highest for joint space narrowing, with a multipoint LOD score = 2.96 on chromosome 1p at D1S1665. Chromosomes 7,9,13, and 19 indicated consistent LOD score elevation for multiple OA phenotypes. Conclusion. There are several chromosomes that may harbor OA susceptibility genes. Further investigation of these regions using larger studies and finer maps will be important to confirm linkage. C1 Boston Univ, Sch Med, Clin Epidemiol Res & Training Unit, Boston, MA 02118 USA. Boston Univ, Sch Med, Ctr Arthritis, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. RP Felson, DT (reprint author), Boston Univ, Sch Med, Clin Epidemiol Res & Training Unit, 715 Albany St,A203, Boston, MA 02118 USA. FU NHLBI NIH HHS [N01-HC-38038]; NIAMS NIH HHS [AR-20613] NR 19 TC 64 Z9 70 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 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD APR PY 2002 VL 46 IS 4 BP 946 EP 952 DI 10.1002/art.10149 PG 7 WC Rheumatology SC Rheumatology GA 540TX UT WOS:000174946500014 PM 11953971 ER PT J AU Illei, GG Takada, K Parkin, D Austin, HA Crane, M Yarboro, CH Vaughan, EM Kuroiwa, T Danning, CL Pando, J Steinberg, AD Gourley, MF Klippel, JH Balow, JE Boumpas, DT AF Illei, GG Takada, K Parkin, D Austin, HA Crane, M Yarboro, CH Vaughan, EM Kuroiwa, T Danning, CL Pando, J Steinberg, AD Gourley, MF Klippel, JH Balow, JE Boumpas, DT TI Renal flares are common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive therapy - Long-term followup of a cohort of 145 patients participating in randomized controlled studies SO ARTHRITIS AND RHEUMATISM LA English DT Article ID AFRICAN-AMERICANS; CONTROLLED TRIAL; CYCLOPHOSPHAMIDE TREATMENT; BLACK-AMERICANS; ERYTHEMATOSUS; DISEASE; METHYLPREDNISOLONE; NEPHROPATHY; PREDNISONE; DEFICIENCY AB Objective. Immunosuppressive agents have become the standard of therapy for proliferative lupus nephritis, but some patients may relapse after discontinuing treatment. We reviewed the cases of renal flares in a cohort of patients who participated in 2 randomized controlled clinical trials at the National Institutes of Health and explored the prevalence, outcome, and predictive factors of renal flares. Methods. Data were obtained on 145 patients treated with pulse cyclophosphamide, pulse methylprednisolone, or the combination of both. Patients had not received immunosuppressive therapy for at least 6 months and had experienced complete or partial response according to defined criteria. Renal flares were classified as either proteinuric or nephritic based on changes in urinary protein and sediment. Most patients who experienced a flare received additional immunosuppressive therapy. Results. Seventy-three patients had a complete response, and 19 had partial response/stabilization. Forty-one of these patients (45%) experienced renal flares (nephritic in 33, proteinuric in 8) after a mean followup of 117 months; 31 of them received additional immunosuppressive therapy. The median time to renal flare was 36 months in the complete responders and 18 months in the partial responders. Eleven of the 41 patients (27%) progressed to end-stage renal disease (ESRD); 9 had nephritic flares (all severe except for 1) and 2 had proteinuric flares (1 in each responder group). Compared with patients who had a complete response, those with a partial response were more likely to experience a flare, to have a severe nephritic flare, or to progress to ESRD. Low C4 at the time of response and African American ethnicity were significant independent risk factors for renal flare, by multivariate Cox proportional hazards analysis. Conclusion. Nephritic flares are common in patients with proliferative lupus nephritis, even in those with a complete response to therapy, but they do not necessarily result in loss of renal function if treated with additional immunosuppressive agents. Renal flares are an important feature of the natural history of lupus nephritis and provide an opportunity for additional preventive strategies, as well as measures of efficacy in future therapeutic trials. C1 NIAMSD, Arthritis & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Kidney Dis Sect, NIH, Bethesda, MD USA. Washington Hosp Ctr, Washington, DC 20010 USA. Mitretek Syst, Mclean, VA USA. Univ Crete, Iraklion, Greece. RP Illei, GG (reprint author), NIAMSD, Arthritis & Rheumatism Branch, NIH, 10 Ctr Dr,Bldg 10 Room 9S205, Bethesda, MD 20892 USA. NR 30 TC 168 Z9 178 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 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD APR PY 2002 VL 46 IS 4 BP 995 EP 1002 DI 10.1002/art.10142 PG 8 WC Rheumatology SC Rheumatology GA 540TX UT WOS:000174946500020 PM 11953977 ER PT J AU Joe, B Cannon, GW Griffiths, MM Dobbins, DE Gulko, PS Wilder, RL Remmers, EF AF Joe, B Cannon, GW Griffiths, MM Dobbins, DE Gulko, PS Wilder, RL Remmers, EF TI Evaluation of quantitative trait loci regulating severity of mycobacterial adjuvant-induced arthritis in monocongenic and polycongenic rats - Identification of a new regulatory locus on rat chromosome 10 and evidence of overlap with rheumatoid arthritis susceptibility loci SO ARTHRITIS AND RHEUMATISM LA English DT Article ID COLLAGEN-INDUCED ARTHRITIS; AUTOANTIBODY PRODUCTION; AUTOIMMUNE-DISEASES; GENOME SCAN; MODEL AB Objective. To evaluate the regulatory potential of genetic loci controlling Mycobacterium butyricum adjuvant-induced arthritis (Mbt-AIA) using mono- and polycongenic rats. Methods. Of 4 quantitative trait loci (QTLs) that regulate Mbt-AIA, F344 alleles at 3 of these loci, Aia1, Aia2, and Aia3, are associated with lower arthritis severity, whereas F344 alleles at Aia4 are associated with greater arthritis severity. In this study, we constructed congenic lines by transferring 1 or more of the F344 genomic segments containing Aia1, Aia2, and Aia3 onto the DA genome. We comparatively evaluated their responses to Mbt-A-IA with the responses of parental DA and F344 rats. Results. Aia1, encompassing the rat major histocompatibility complex, reduced arthritis severity in monocongenic rats of both sexes. The arthritis-lowering effects of Aia2 and Aia3 were sex-influenced and were therefore observed in only males and only females, respectively. Polycongenic rats containing F344 genomic regions at Aia1, Aia2, and Aia3 developed Mbt-AIA of relatively greater severity than did F344 rats, implying that in DA and F344 rats, there could be other Mbt-A-IA loci in addition to Aia1, Aia2, Aia3, and Aia4. To test the possibility that some of these Mbt-AIA-regulatory loci may colocalize with other arthritis QTLs, we evaluated Mbt-AIA in DA.F344 monocongenic rats containing collagen-induced arthritis QTLs. Cia5 (the QTL region on chromosome 10), but not Cia5a, Cia4, or Cia6, also regulated Mbt-AIA, and was named Aia5. Conclusion. F344 genomic regions at Aia1, Aia2, and Aia3 and the newly identified Aia5 contain genes that reduce Mbt-AIA severity in DA rats. These Mbt-AIA-regulatory loci overlap rheumatoid arthritis-susceptibility loci in humans. C1 NIAMSD, Inflammatory Joint Dis Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Vet Affairs Salt Lake City Hlth Care Syst, Salt Lake City, UT USA. Univ Utah, Salt Lake City, UT USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Remmers, EF (reprint author), NIAMSD, Inflammatory Joint Dis Sect, Arthrit & Rheumatism Branch, NIH, 10 Ctr Dr,MSC 1820,Bldg 10,Room 9N228, Bethesda, MD 20892 USA. FU NIAMS NIH HHS [R01-AR46213, R01-AR47423-01] NR 31 TC 30 Z9 30 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD APR PY 2002 VL 46 IS 4 BP 1075 EP 1085 DI 10.1002/art.10164 PG 11 WC Rheumatology SC Rheumatology GA 540TX UT WOS:000174946500030 PM 11953987 ER PT J AU Senior, C AF Senior, C TI Principles, safety and utility of transcranial magnetic stimulation in cognitive neuropsychology SO AUSTRALIAN JOURNAL OF PSYCHOLOGY LA English DT Article ID HUMAN MOTOR CORTEX; POSITRON EMISSION TOMOGRAPHY; TRAUMATIC BRAIN INJURY; INTERHEMISPHERIC INHIBITION; CORTICAL STIMULATION; VISUAL-PERCEPTION; IMPLICIT-MOTION; VIRTUAL LESIONS; TERM-MEMORY; COIL DESIGN AB Transcranial magnetic stimulation (TMS) can safely disrupt cortical activity thus allowing investigation of the timing of cognitive functions and the connectivity between the neural substrates mediating these functions. Here, the principles behind TMS as well as contemporary safety guidelines necessary for its use are reviewed in addition to recent studies that highlight the types of approaches that may be useful for psychological investigation. The literature provides support for the general safety of the technique. Magnetic stimulation has great utility in creating models of neuropsychological disorders in the intact brain, as well as addressing the validity of existing cognitive models. C1 NIH, Bethesda, MD USA. RP Senior, C (reprint author), NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. NR 98 TC 0 Z9 0 U1 0 U2 1 PU AUSTRALIAN PSYCHOLOGICAL SOC PI CARLTON PA 1 GRATTAN STREET, CARLTON, VICTORIA 3053, AUSTRALIA SN 0004-9530 J9 AUST J PSYCHOL JI Aust. J. Psychol. PD APR PY 2002 VL 54 IS 1 BP 40 EP 46 DI 10.1080/00049530210001706503 PG 7 WC Psychology, Multidisciplinary SC Psychology GA 556GY UT WOS:000175842100006 ER PT J AU Stringa, E White, D Tuan, RS Knauper, V Gavrilovic, J AF Stringa, E White, D Tuan, RS Knauper, V Gavrilovic, J TI Role of newly synthesized fibronectin in vascular smooth muscle cell migration on matrix-metalloproteinase-degraded collagen SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT Colloquium on Proteases and Anti-proteases - Molecular Mechanisms and Novel Therapeutic Targets CY DEC 17-19, 2001 CL UNIV YORK, YORK, ENGLAND HO UNIV YORK DE cell migration; 3/4 collagen fragment; exon IIIA; exon IIIB ID GROWTH-FACTORS; EXPRESSION; PLAQUES AB The migration of vascular smooth muscle cells (VS-MC) is known to be a key process in the development of a number of vascular lesions, although the precise mechanisms involved have still to be elucidated. In the present study, the production of endogenous fibronectins by VSMC migrating across intact and matrix-metalloproteinase-degraded collagen type I has been explored. Cellular fibronectin seems to play a role in the enhanced migration seen when VSMC are exposed to degraded collagen and platelet-derived growth factor-BB. VSMC were found to synthesize both exon IIIA-containing fibronectin (which predominated) and exon IIIB-containing fibronectin. When these cells were exposed to substrates consisting of recombinant exon IIIA-or exon IIIB-containing fibronectin, rates of migration were not elevated above those seen with undegraded collagen. Endogenous fibronectin production may thus be necessary, but not sufficient, for VSMC migration over degraded collagenous substrates. C1 Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England. Thomas Jefferson Univ, Dept Orthopaed Surg, Philadelphia, PA 19107 USA. NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. Univ York, Dept Biol, York YO10 5YW, N Yorkshire, England. RP Gavrilovic, J (reprint author), Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England. RI Gavrilovic, Jelena/J-7754-2013; OI Knauper, Vera/0000-0002-3965-9924 NR 19 TC 3 Z9 5 U1 0 U2 1 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD APR PY 2002 VL 30 BP 102 EP 107 PN 2 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 550JM UT WOS:000175499900020 PM 12023834 ER PT J AU Banks, RS Thomas, W Mandel, JS Kaune, WT Wacholder, S Throne, RE Linet, MS AF Banks, RS Thomas, W Mandel, JS Kaune, WT Wacholder, S Throne, RE Linet, MS TI Temporal trends and misclassification in residential 60 Hz magnetic field measurements SO BIOELECTROMAGNETICS LA English DT Article DE EMF; exposure assessment; children; methods; 24 h measurement; 2 week measurement ID EXPOSURE; CHILDREN; LEUKEMIA AB This research addressed the question of how well measurement data collected during a single visit, made at an arbitrary hour of day, day of week, and season, estimate longer term residential 60 Hz magnetic field levels. We made repeat spot and 24 h measurements in 51 children's home, located in the Detroit, MI, and the Minneapolis-St. Paul, MN metropolitan areas, on a regular bimonthly schedule over a I year period, as well as a single 2 week measurement, for total of eight visits, producing 21 days of data for each residence. We defined the long term estimate (LTE) as the geometric mean of all available 24 h geometric means from the first six bimonthly visits. The LTE served as the reference level for assessing seasonal, day of week, and diurnal effects, as well as the potential for misclassification. We found a small, but statistically significant (P < .05), seasonal effect, with levels approximately 3% lower than the LTE in the spring and about 4% greater during the summer. No effect was found for day of week. However, we did find a systematic and appreciable diurnal effect, suggesting that, for example, an evening spot measurement may overestimate the LTE by 20% or more. We also assessed how well the 24 h measurement from the last visit, which was not used in calculation of the LTE, estimated the LTE. We found a high degree of correlation (r = .92) and fair to good agreement using four exposure categories (kappa = .53). Thus, the 24 h measurement appears to be a satisfactory LTE estimator. However, this finding must be interpreted with caution since considerable unexplained variability was present among the repeat 24 h measurements in about one-third of the homes. While the 2 week measurement does somewhat decrease exposure misclassification, its added intrusiveness and cost are likely to outweigh the improved precision. (C) 2002 Wiley-Liss, Inc. C1 Univ Minnesota, Sch Publ Hlth, Div Environm & Occupat Hlth, Minneapolis, MN USA. Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. EM Factors, Richland, WA USA. NCI, Biostat Branch, NIH, Bethesda, MD 20892 USA. NCI, Radiat Epidemiol Branch, NIH, Bethesda, MD 20892 USA. RP Banks, RS (reprint author), Robert S Banks Assoc Inc, 1573 Fulham St, St Paul, MN 55108 USA. FU NCI NIH HHS [N01-CP-05626] NR 18 TC 6 Z9 6 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 0197-8462 J9 BIOELECTROMAGNETICS JI Bioelectromagnetics PD APR PY 2002 VL 23 IS 3 BP 196 EP 205 DI 10.1002/bem.10002 PG 10 WC Biology; Biophysics SC Life Sciences & Biomedicine - Other Topics; Biophysics GA 531UJ UT WOS:000174435400003 PM 11891749 ER PT J AU Donze, D Kamakaka, RT AF Donze, D Kamakaka, RT TI Braking the silence: how heterochromatic gene repression is stopped in its tracks SO BIOESSAYS LA English DT Review ID BETA-GLOBIN LOCUS; SACCHAROMYCES-CEREVISIAE; TELOMERIC HETEROCHROMATIN; CHROMOSOMAL DOMAINS; BOUNDARY-ELEMENT; YEAST; CHROMATIN; EXPRESSION; DROSOPHILA; INSULATOR AB Eukaryotic DNA is assembled into nucleosomes, which are further packaged into higher order chromatin structures containing many non-histone chromosomal proteins. The details of this packaging have profound effects on gene expression and other cellular processes involving the genetic material. Heterochromatic domains of the genome are usually transcriptionally repressed, while euchromatic regions are transcriptionally competent. Current models of gene activation postulate the existence of boundary elements that either prevent inappropriate activation of genes by distal enhancers (enhancer blockers), or sequences that block the propagation of heterochromatin into euchromatic regions (barriers). While numerous boundary sequences have been identified, little is known with regard to the molecular mechanisms used to punctuate the genome. This review will focus on recent data that provide insight into the mode of action of barrier elements. (C) 2002 Wiley Periodicals, Inc. C1 NICHHD, Unit Chromatin & Transcript, Bethesda, MD 20892 USA. Louisiana State Univ, Dept Biol Sci, Baton Rouge, LA 70803 USA. RP Kamakaka, RT (reprint author), NICHHD, Unit Chromatin & Transcript, Bldg 18T,Room 106,18 Lib Dr, Bethesda, MD 20892 USA. OI Donze, David/0000-0002-7473-5902 NR 50 TC 59 Z9 59 U1 0 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0265-9247 J9 BIOESSAYS JI Bioessays PD APR PY 2002 VL 24 IS 4 BP 344 EP 349 DI 10.1002/bies.10072 PG 6 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 538AN UT WOS:000174792000008 PM 11948620 ER PT J AU Pine, DS Cohen, JA AF Pine, DS Cohen, JA TI Trauma in children and adolescents: Risk and treatment of psychiatric sequelae SO BIOLOGICAL PSYCHIATRY LA English DT Review DE trauma; children; therapeutics; anxiety; depression ID POSTTRAUMATIC-STRESS-DISORDER; COGNITIVE-BEHAVIORAL-THERAPY; ABUSED PRESCHOOL-CHILDREN; CHILDHOOD SEXUAL ABUSE; FOLLOW-UP; YOUNG ADULTHOOD; PHYSICAL ABUSE; NATURAL DISASTER; HURRICANE-ANDREW; SYMPTOMS AB The recent wave of terrorism affecting the United States and other countries raises concerns about the welfare of children and adolescents. This review is designed to address such concerns by summarizing data from two scientific areas. First, a series of recent studies examine psychiatric outcomes over time in children exposed to various forms of trauma. This review summarizes data on the various psychiatric consequences of childhood exposure to trauma, with specific emphasis on identifying factors that predict psychiatric outcome. Prior studies suggest that level of exposure, evidence of psychopathology before trauma exposure, and disruption in social support networks consistently, emerge as strong predictors of psychopathology following exposure to trauma. Hence, clinicians might monitor children exposed to trauma most closely when they present with these risk factors. Second, a series of randomized controlled trials documents the beneficial effects of cognitive behavioral therapy (CBT) in children exposed to sexual abuse. When combined with other data from open studies and controlled trials in nontraumatized children, these studies suggest that CBT represents a logical therapeutic option for children developing anxiety symptoms following the recent wave of terrorism. In terms of psychopharmacological treatments, data from randomized controlled trials in traumatized children have not been generated, but recent studies in other groups of children exhibiting symptoms of anxiety or depression suggest the utility, of selective serotonin reuptake inhibitors. (C) 2002 Society of Biological Psychiatry. C1 NIMH, Mood & Anxiety Program, Bethesda, MD 20892 USA. Med Coll Penn & Hahnemann Univ, Sch Med, Pittsburgh, PA USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. RP Pine, DS (reprint author), NIMH, Intramural Res Program, 15K North Dr,Room 110 MSC 2670, Bethesda, MD 20892 USA. FU CMHS SAMHSA HHS [SM 54319]; NIMH NIH HHS [K02 MH 01938, R10 MH 55963] NR 76 TC 152 Z9 158 U1 3 U2 23 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 1 PY 2002 VL 51 IS 7 BP 519 EP 531 AR PII S0006-3223(01)01352-X DI 10.1016/S0006-3223(01)01352-X PG 13 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 540YU UT WOS:000174959100001 PM 11950454 ER PT J AU El-Mestrah, M Castle, PE Borossa, G Kan, FWK AF El-Mestrah, M Castle, PE Borossa, G Kan, FWK TI Subcellular distribution of ZP1, ZP2, and ZP3 glycoproteins during folliculogenesis and demonstration of their topographical disposition within the zona matrix of mouse ovarian oocytes SO BIOLOGY OF REPRODUCTION LA English DT Article DE female reproductive tract; fertilization; follicle; oocyte development; ovary ID MAMMALIAN FERTILIZATION; MONOCLONAL-ANTIBODIES; PELLUCIDA PROTEIN; SPERM RECEPTOR; EXPRESSION; OOGENESIS; INVITRO; MICE; BIOSYNTHESIS; FOLLICLES AB The zona pellucida (ZP) is an extracellular coat synthesized and secreted by the oocyte during follicular development and surrounding the plasma membrane of mammalian eggs. To date, the mechanism of synthesis and secretion, mode of assembly, and intracellular trafficking of the ZP glycoproteins have not been fully elucidated. Using antibodies against mouse ZP1, ZP2, and ZP3 in conjunction with the protein A-gold technique, we have shown an association of immunolabeling with the Golgi apparatus, secretory granules, and a complex structure called vesicular aggregate, respectively, in mouse ovarian follicles. In contrast, the neighboring granulosa cells were not reactive to any of the three antibodies used. Immunolabeling of ZP1, ZP2, and ZP3 was detected throughout the entire thickness of the ZP, irrespective of the developmental stage of ovarian follicles. Double and triple immunolocalization studies, using antibodies tagged directly to different sizes of gold particles, revealed an asymmetric spatial distribution of the three ZP glycoproteins in the zona matrix at various stages of follicular development. All three glycoproteins were specifically localized over small patches of darkly stained flocculent substance dispersed throughout the zona matrix. Very often, ZP1, ZP2, and ZP3 were found in close association. These results confirm findings from previous studies demonstrating that ovarian oocytes and not granulosa cells are the only source for mouse ZP glycoproteins. In addition, results from our morphological and immunocytochemical experiments suggest that the vesicular aggregates in the ooplasm are likely to serve as an intermediary in the synthesis and secretion of ZP glycoproteins. The stoichiometric disposition of ZP1, ZP2, and ZP3 in the zona matrix as revealed by double and triple immunolocalization studies provide further insight into some of the unanswered questions pertinent to the current model of mouse ZP structure proposed by the Wassarman group. C1 Queens Univ, Fac Hlth Sci, Dept Anat & Cell Biol, Kingston, ON K7L 3N6, Canada. NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kan, FWK (reprint author), Queens Univ, Fac Hlth Sci, Dept Anat & Cell Biol, Kingston, ON K7L 3N6, Canada. NR 42 TC 22 Z9 26 U1 0 U2 4 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD APR PY 2002 VL 66 IS 4 BP 866 EP 876 DI 10.1095/biolreprod66.4.866 PG 11 WC Reproductive Biology SC Reproductive Biology GA 534LR UT WOS:000174588300002 PM 11906903 ER PT J AU Tomic, D Brodie, SG Deng, C Hickey, RJ Babus, JK Malkas, LH Flaws, JA AF Tomic, D Brodie, SG Deng, C Hickey, RJ Babus, JK Malkas, LH Flaws, JA TI Smad 3 may regulate follicular growth in the mouse ovary SO BIOLOGY OF REPRODUCTION LA English DT Article DE apoptosis; follicle; follicular development; growth factors; ovary ID TGF-BETA; TUMOR-SUPPRESSOR; ACTIVIN-A; MICE; GENE; FOLLICULOGENESIS; SMAD4/DPC4; FOLLICLES; PROTEINS; IMMATURE AB Although Smad 3 is known to serve as a signaling intermediate for the transforming growth factor beta (TGFbeta) family in nonreproductive tissues, its role in the ovary is unknown. Thus, we used a recently generated Smad 3-deficient (Smad 3-/-) mouse model to test the hypothesis that Smad 3 alters female fertility and regulates the growth of ovarian follicles from the primordial stage to the antral stage. In addition, we tested whether Smad 3 affects the levels of proteins that control apoptosis, survival, and proliferation in the ovarian follicle. To test this hypothesis, breeding studies were conducted using Smad 3-/- and wild-type mice. in addition, ovaries were collected from Smad 3-/- and wild-type mice on Postnatal Days 2-90. One ovary from each animal was used to estimate the total number of primordial, primary, and antral follicles. The other ovary was used for immunohistochemical analysis of selected members of the B-cell lymphoma/leukemia-2 family of protooncogenes (Bax, Bcl-2, Bcl-x), proliferating cell nuclear antigen (PCNA), and cyclin-dependent kinase 2 (Cdk-2). The results indicate that Smad 3-/- mice have reduced fertility compared with wild type mice. The results also indicate that Smad 3 may not affect the size of the primordial follicle pool at birth, but it may regulate growth of primordial follicles to the antral stage. Further, the results indicate that Smad 3 may regulate the expression of Bax and Bcl-2, but not Bcl-x, Cdk-2, and PCNA. Collectively, these data suggest that Smad 3 may play an important role in the regulation of ovarian follicle growth and female fertility. C1 Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Pharmacol & Expt Therapeut, Baltimore, MD 21201 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Flaws, JA (reprint author), Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, 660 W Redwood St, Baltimore, MD 21201 USA. RI deng, chuxia/N-6713-2016 NR 43 TC 56 Z9 61 U1 0 U2 4 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD APR PY 2002 VL 66 IS 4 BP 917 EP 923 DI 10.1095/biolreprod66.4.917 PG 7 WC Reproductive Biology SC Reproductive Biology GA 534LR UT WOS:000174588300008 PM 11906909 ER PT J AU Lee, J Lee, J Kang, MS Kim, KP Chung, SJ Blumberg, PM Yi, JB Park, YH AF Lee, J Lee, J Kang, MS Kim, KP Chung, SJ Blumberg, PM Yi, JB Park, YH TI Phenolic modification as an approach to improve the pharmacology of the 3-acyloxy-2-benzylpropyl homovanillic amides and thioureas, a promising class of vanilloid receptor agonists and analgesics SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID CAPSAICIN; RESINIFERATOXIN; ANALOGS; LIGANDS; BINDING AB In order to improve the analgesic activity and pharmacokinetics of thioureas 2 and 3, which we previously developed as potent vanilloid receptor (VR) agonists, we prepared and characterized phenolic modifications of them and of their amide surrogates (7, 8). The aminoethyl analogue of the amide template 13 was a potent analgesic with an EC(50) = 0.96 mug/kg in the AA-induced writhing test and with better in vivo stability than the parent phenol. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Seoul Natl Univ, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea. Seoul Natl Univ, Coll Pharm, Lab Pharmaceut, Seoul 151742, South Korea. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Pacific R&D Ctr, Yougin Si 449900, Kyounggi Do, South Korea. RP Lee, J (reprint author), Seoul Natl Univ, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr; jeewoo@snu.ac.kr OI Lee, Jiyoun/0000-0003-3819-5889 NR 20 TC 11 Z9 12 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD APR PY 2002 VL 10 IS 4 BP 1171 EP 1179 AR PII S0968-0896(01)00387-X DI 10.1016/S0968-0896(01)00387-X PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 526VZ UT WOS:000174151500040 PM 11836128 ER PT J AU Malev, VV Schagina, LV Gurnev, PA Takemoto, JY Nestorovich, EM Bezrukov, SM AF Malev, VV Schagina, LV Gurnev, PA Takemoto, JY Nestorovich, EM Bezrukov, SM TI Syringomycin E channel: A lipidic pore stabilized by lipopeptide? SO BIOPHYSICAL JOURNAL LA English DT Article ID ION CHANNELS; GRAMICIDIN CHANNELS; MEMBRANE-FUSION; SURFACE-CHARGE; BILAYERS; CONDUCTANCE; COLICIN-E1; SYRINGOTOXIN; SELECTIVITY; SYRINGAE AB Highly reproducible ion channels of the lipopeptide antibiotic syringomycin E demonstrate unprecedented involvement of the host bilayer lipids. We find that in addition to a pronounced influence of lipid species on the open-channel ionic conductance, the membrane lipids play a crucial role in channel gating. The effective gating charge, which characterizes sensitivity of the conformational equilibrium of the syringomycin E channels to the transmembrane voltage, is modified by the lipid charge and lipid dipolar moment. We show that the type of host lipid determines not only the absolute value but also the sign of the gating charge. With negatively charged bilayers, the gating charge sign inverts with increased salt concentration or decreased pH. We also demonstrate that the replacement of lamellar lipid by nonlamellar with the negative spontaneous curvature inhibits channel formation. These observations suggest that the asymmetric channel directly incorporates lipids. The charges and dipoles resulting from the structural inclusion of lipids are important determinants of the overall energetics that underlies channel gating. We conclude that the syringomycin E channel may serve as a biophysical model to link studies of ion channels with those of lipidic pores in membrane fusion. C1 NICHHD, NIH, Bethesda, MD 20892 USA. Russian Acad Sci, Inst Cytol, St Petersburg 194064, Russia. St Petersburg State Univ, St Petersburg, Russia. Utah State Univ, Logan, UT 84322 USA. St Petersburg Nucl Phys Inst, Gatchina 188350, Russia. RP Bezrukov, SM (reprint author), NICHHD, NIH, Bldg 9,Room 1E-122, Bethesda, MD 20892 USA. RI Takemoto, Jon/A-5309-2011 OI Takemoto, Jon/0000-0001-9919-9168 NR 56 TC 53 Z9 58 U1 0 U2 4 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD APR PY 2002 VL 82 IS 4 BP 1985 EP 1994 PG 10 WC Biophysics SC Biophysics GA 540MH UT WOS:000174932400027 PM 11916856 ER PT J AU Xu, S Gu, J Melvin, G Yu, LC AF Xu, S Gu, J Melvin, G Yu, LC TI Structural characterization of weakly attached cross-bridges in the A center dot M center dot ATP state in permeabilized rabbit psoas muscle SO BIOPHYSICAL JOURNAL LA English DT Article ID X-RAY-DIFFRACTION; LOW IONIC-STRENGTH; N-PHENYLMALEIMIDE REACTION; RELAXED FIBER STIFFNESS; MYOSIN SUBFRAGMENT-1; FORCE GENERATION; SKELETAL-MUSCLE; BINDING CROSSBRIDGES; CONFORMATIONAL-CHANGES; PARALLEL INHIBITION AB It is well established that in a skeletal muscle under relaxing conditions, cross-bridges exist in a mixture of four weak binding states in equilibrium (A.M.ATP, A.M.ADP.P-i, M.ATP, and M.ADP.P-i). It has been shown that these four weak binding states are in the pathway to force generation. In the past their structural, biochemical, and mechanical properties have been characterized as a group. However, it was shown that the myosin heads in the M.ATP state exhibited a disordered distribution along the thick filament, while in the M.ADP.P-i state they were well ordered. It follows that the structures of the weakly attached states of A.M.ATP and A-M-ADP-P, could well be different. Individual structures of the two attached states could not be assigned because protocol for isolating the two states has not been available until recently. In the present study, muscle fibers are reacted with N-phenylmaleimide such that ATP hydrolysis is inhibited, i.e., the cross-bridge population under relaxing conditions is distributed only between the two states of M.ATP and A.M.ATP. Two-dimensional x-ray diffraction was applied to determine the structural characteristics of the attached A.M.ATP state. Because the detached state of M.ATP is disordered and does not contribute to layer line intensities, changes as a result of increasing attachment in the A.M.ATP state are attributable to that state alone. The equilibrium toward the attached state was achieved by lowering the ionic strength. The results show that upon attachment, both the myosin and the first actin associated layer lines increased intensities, while the sixth actin layer line was not significantly affected. However, the intensities remain weak despite substantial attachment. The results, together with modeling (see J. Gu, S. Xu and L. C. Yu, 2002, Biophys. J. 82:2123-2133), suggest that there is a wide range of orientation of the attached A.M.ATP cross-bridges while the myosin heads maintain some degree of helical distribution on the thick filament, suggesting a high degree of flexibility in the actomyosin complex. Furthermore, the lack of sensitivity of the sixth actin layer line suggests that the binding site on actin differs from the putative site for rigor binding. The significance of the flexibility in the A.M.ATP complex in the process of force generation is discussed. C1 NIAMSD, NIH, Bethesda, MD 20892 USA. RP Xu, S (reprint author), NIAMS, NIH, Bldg 50,Rm 1349, Bethesda, MD 20892 USA. NR 60 TC 15 Z9 15 U1 0 U2 0 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD APR PY 2002 VL 82 IS 4 BP 2111 EP 2122 PG 12 WC Biophysics SC Biophysics GA 540MH UT WOS:000174932400038 PM 11916867 ER PT J AU Gu, J Xu, SG Yu, LC AF Gu, J Xu, SG Yu, LC TI A model of cross-bridge attachment to actin in the A center dot M center dot ATP state based on X-ray diffraction from permeabilized rabbit psoas muscle SO BIOPHYSICAL JOURNAL LA English DT Article ID MYOSIN MOTOR DOMAIN; RELAXED FIBER STIFFNESS; SKELETAL-MUSCLE; TROPONIN-TROPOMYOSIN; FILAMENT STRUCTURE; PARALLEL INHIBITION; ELECTRON-MICROSCOPY; FORCE GENERATION; ATOMIC-STRUCTURE; THICK FILAMENTS AB A model of cross-bridges binding to actin in the weak binding A.M.ATP state is presented. The modeling was based on the x-ray diffraction patterns from the relaxed skinned rabbit psoas muscle fibers where ATP hydrolysis was inhibited by N-phenylmaleimide treatment (S. Xu, J. Gu, G. Melvin, L. C. Yu. 2002. Biophys. J. 82:2111-2122). Calculations included both the myosin filaments and the actin filaments of the muscle cells, and the binding to actin was assumed to be single headed. To achieve a good fit, considerable flexibility in the orientation of the myosin head and the position of the S1-S2 junction is necessary, such that the myosin head can bind to a nearby actin whereas the tail end was kept in the proximity of the helical track of the myosin filament. Hence, the best-fit model shows that the head binds to actin in a wide range of orientations, and the tail end deviates substantially from its lattice position in the radial direction (similar to60 Angstrom). Surprisingly, the best fit model reveals that the detached head, whose location thus far has remained undetected, seems to be located close to the surface of the myosin filament. Another significant requirement of the best-fit model is that the binding site on actin is near the N terminus of the actin subunit, a position distinct from the putative rigor-binding site. The results support the idea that the essential role played by the weak binding states M.ATP <----> A.M.ATP for force generation lies in its flexibility, because the probability of attachment is greatly increased, compared with the weak binding M.ADP.P-i <----> A.M.ADP.Pi states. C1 NIAMSD, NIH, Bethesda, MD 20892 USA. RP Gu, J (reprint author), NIAMSD, NIH, Bldg 50,Room 1349, Bethesda, MD 20892 USA. NR 47 TC 27 Z9 28 U1 0 U2 0 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD APR PY 2002 VL 82 IS 4 BP 2123 EP 2133 PG 11 WC Biophysics SC Biophysics GA 540MH UT WOS:000174932400039 PM 11916868 ER PT J AU Steinbach, PJ Ionescu, R Matthews, CR AF Steinbach, PJ Ionescu, R Matthews, CR TI Analysis of kinetics using a hybrid maximum-entropy/nonlinear-least-squares method: Application to protein folding SO BIOPHYSICAL JOURNAL LA English DT Article ID DIHYDROFOLATE-REDUCTASE; INTEGRAL-EQUATIONS; ESCHERICHIA-COLI; LIGAND-BINDING; ENTROPY METHOD; HEME-PROTEINS; MYOGLOBIN; DYNAMICS; DISTRIBUTIONS; RELAXATION AB A hybrid analysis that combines the maximum entropy method (MEM) with nonlinear least squares (NLS) fitting has been developed to interpret a general time-dependent signal. Data that include processes of opposite sign and a slow baseline drift can be inverted to obtain both a continuous distribution of lifetimes and a sum of discrete exponentials. Fits by discrete exponentials are performed with initial parameters determined from the distribution of lifetimes obtained with the MEM. The regularization of the parameter space achieved by the MEM stabilizes the introduction of each successive exponential in the NLS fits. This hybrid approach is particularly useful when fitting by a large number of exponentials. Revision of the MEM "prior" based on features in the data can improve the lifetime distribution obtained. Standard errors in the mean are estimated automatically for raw data. The results presented for simulated data and for fluorescence measurements of protein folding illustrate the utility and accuracy of the hybrid algorithm. Analysis of the folding of dihydrofolate reductase reveals six kinetic processes, one more than previously reported. C1 NIH, Ctr Informat Technol, Ctr Mol Modelling, Bethesda, MD 20892 USA. Penn State Univ, Dept Chem, University Pk, PA 16802 USA. Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA 01655 USA. RP Steinbach, PJ (reprint author), 12 S Dr,MSC 5626,Bldg 12A,Rm 2051, Bethesda, MD 20892 USA. EM steinbac@helix.nih.gov NR 41 TC 112 Z9 113 U1 1 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD APR PY 2002 VL 82 IS 4 BP 2244 EP 2255 PG 12 WC Biophysics SC Biophysics GA 540MH UT WOS:000174932400050 PM 11916879 ER PT J AU Li, DW London, RE AF Li, DW London, RE TI Ligand discovery using the inter-ligand Overhauser effect: horse liver alcohol dehydrogenase SO BIOTECHNOLOGY LETTERS LA English DT Article DE alcohol dehydrogenase; inter-ligand Overhauser effect; methylbenzamide; NMR; sodium cyanoborohydride ID MAPPING STRUCTURAL RELATIONSHIPS; MACROMOLECULAR LIGANDS; NMR; CONFORMATION; BINDING; INHIBITION; FORMAMIDES; SUBSTRATE; EXCHANGE; COMPLEX AB Two dimensional nuclear Overhauser effect spectroscopy (NOESY) studies on horse liver alcohol dehydrogenase (LADH) in the presence of several ligands revealed unanticipated cross peaks arising from inter-ligand Overhasuer effects (ILOEs) connecting resonances of an inhibitor, m-methylbenzamide, and the reducing agent, cyanoborohydride, initially present to maintain NADH in the reduced state. The presence of NADH was not required to observe of these inter-ligand Overhauser effects. A model for the ternary complex was developed in which the methylbenzamide inhibitors bind to the hydrophobic pocket of the active site involved in benzyl alcohol binding, while the cyanoborohydride coordinates directly with Zn2+ at the active site. The observation of these effects supports the use of inter-ligand Overhauser effects for the identification of unanticipated ternary complexes that are of potential utility for the development of novel enzyme inhibitors. C1 NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP London, RE (reprint author), NIEHS, Struct Biol Lab, POB 12233,MR-01, Res Triangle Pk, NC 27709 USA. NR 26 TC 5 Z9 5 U1 1 U2 5 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-5492 J9 BIOTECHNOL LETT JI Biotechnol. Lett. PD APR PY 2002 VL 24 IS 8 BP 623 EP 629 DI 10.1023/A:1015095308654 PG 7 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 539YL UT WOS:000174900600007 ER PT J AU Manji, HK Young, LT AF Manji, HK Young, LT TI Structural plasticity and neuronal resilience: are these targets for mood stabilizers and antidepressants in the treatment of bipolar disorder? SO BIPOLAR DISORDERS LA English DT Editorial Material C1 NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. RP Manji, HK (reprint author), NIMH, Mol Pathophysiol Lab, 10 Ctr Dr,10-4 N-222 MSC 1381, Bethesda, MD 20892 USA. NR 13 TC 1 Z9 1 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD APR PY 2002 VL 4 IS 2 BP 77 EP 79 PG 3 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 545BF UT WOS:000175195800001 ER PT J AU Chuang, DM Chen, RW Chalecka-Franaszek, E Ren, M Hashimoto, R Senatorov, V Kanai, H Hough, C Hiroi, T Leeds, P AF Chuang, DM Chen, RW Chalecka-Franaszek, E Ren, M Hashimoto, R Senatorov, V Kanai, H Hough, C Hiroi, T Leeds, P TI Neuroprotective effects of lithium in cultured cells and animal models of diseases SO BIPOLAR DISORDERS LA English DT Review DE excitotoxicity; Huntington's disease; lithium; neuroprotection; stroke ID GLYCOGEN-SYNTHASE KINASE-3-BETA; SUBGENUAL PREFRONTAL CORTEX; CEREBELLAR GRANULE NEURONS; DNA-BINDING ACTIVITY; RAT STRIATUM; MITOCHONDRIAL RELEASE; HUNTINGTONS-DISEASE; SIGNAL-TRANSDUCTION; PROMOTES SURVIVAL; QUINOLINIC ACID AB Lithium, the major drug used to treat manic depressive illness robustly, protects cultured rat brain neurons from glutamate excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors. The lithium neuroprotection against glutamate excitotoxiciy is long-lasting, requires long-term pretreatment and occurs at therapeutic concentrations of this drug. The neuroprotective mechanisms involve inactivation of NMDA receptors, decreased expression of pro-apoptotic proteins, p53 and Bax, enhanced expression of the cytoprotective protein, Bcl-2, and activation of the cell survival kinase, Akt. In addition, lithium pretreatment suppresses glutamate-induced loss of the activities of Akt, cyclic AMP-response element binding protein (CREB), c-Jun - N-terminal kinase (JNK) and p38 kinase. Lithium also reduces brain damage in animal models of neurodegenerative diseases in which excitotoxicity has been implicated. In the rat model of stroke using middle cerebral artery occlusion, lithium markedly reduces neurologic deficits and decreases brain infarct volume even when administered after the onset of ischemia. In a rat Huntington's disease model, lithium significantly reduces brain lesions resulting from intrastriatal infusion of quinolinic acid, an excitotoxin. Our results suggest that lithium might have utility in the treatment of neurodegenerative disorders in addition to its common use for the treatment of bipolar depressive patients. C1 NIMH, Mol Neurobiol Sect, Mood & Anxiety Disorder Program, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, Mood & Anxiety Disorder Program, NIH, 10 Ctr Dr MSC 1363, Bethesda, MD 20892 USA. RI Hashimoto, Ryota/P-8572-2014 OI Hashimoto, Ryota/0000-0002-5941-4238 NR 65 TC 184 Z9 197 U1 1 U2 14 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD APR PY 2002 VL 4 IS 2 BP 129 EP 136 DI 10.1034/j.1399-5618.2002.01179.x PG 8 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 545BF UT WOS:000175195800006 PM 12071510 ER PT J AU Huang, JZ Sanger, WG Greiner, TC Staudt, LM Weisenburger, DD Pickering, DL Lynch, JC Armitage, JO Wamke, RA Alizadeh, AA Lossos, IS Levy, R Chan, WC AF Huang, JZ Sanger, WG Greiner, TC Staudt, LM Weisenburger, DD Pickering, DL Lynch, JC Armitage, JO Wamke, RA Alizadeh, AA Lossos, IS Levy, R Chan, WC TI The t(14;18) defines a unique subset of diffuse large B-cell lymphoma with a germinal center B-cell gene expression profile SO BLOOD LA English DT Article ID NON-HODGKINS-LYMPHOMA; CHROMOSOMAL TRANSLOCATION; PROTEIN EXPRESSION; REARRANGEMENTS; BCL-2; LINEAGE AB Recently we have identified subgroups of de novo primary diffuse large B-cell lymphoma (DLBCL) based on complementary DNA microarray-generated gene expression profiles. To correlate the gene expression profiles with cytogenetic abnormalities in these DLBCLs, we examined the occurrence of the t(14;18)(q32; q21) in the 2 distinctive subgroups of DLBCL: one with the germinal center B-cell gene expression signature and the other with the activated B cell-like gene expression signature. The t(14;18) was detected in 7 of 35 cases (20%). All 7 t(14;18)-positive, cases: had a germinal center B-cell gene expression profile, resenting 35% of the cases in this subgroup, and 6 of these 7 cases had very similar gene expression profiles. pression of bcl-2 and bcl-6 proteins was not significantly different between the t(14;18)-positive and negative cases, whereas CD10 was detected only in the group with the germinal center B-cell expression profile, and CD10 was most frequently expressed in the t(14,18)-positive cases. This study supports the validity of subdividing DLBCL into 2 major subgroups by gene expression profiling, with the t(1 4;18) being an important event in the pathogenesis of a subset of DLBCL arising from germinal center B cells. CD10 protein expression is useful in identifying cases of DLBCL with a germinal center B-cell gene expression profile and is often expressed in cases with the t(14;18). (C) 2002 by The American Society of Hematology. C1 Univ Nebraska, Med Ctr, Dept Pathol, Munroe Meyer Inst Genet & Rehabil Prevent & Socia, Omaha, NE USA. Univ Nebraska, Med Ctr, Dept Microbiol, Munroe Meyer Inst Genet & Rehabil Prevent & Socia, Omaha, NE USA. NCI, Metab Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. Stanford Univ, Med Ctr, Dept Pathol, Stanford, CA 94305 USA. Stanford Univ, Med Ctr, Dept Biochem, Stanford, CA 94305 USA. Stanford Univ, Med Ctr, Dept Med, Stanford, CA 94305 USA. RP Chan, WC (reprint author), Nebraska Med Ctr 983135, Dept Pathol & Microbiol, Omaha, NE 68198 USA. OI Alizadeh, Arash Ash/0000-0002-5153-5625 FU NCI NIH HHS [CA 34233, U01 CA 84967] NR 20 TC 192 Z9 207 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 1 PY 2002 VL 99 IS 7 BP 2285 EP 2290 DI 10.1182/blood.V99.7.2285 PG 6 WC Hematology SC Hematology GA 533ZC UT WOS:000174559300002 PM 11895757 ER PT J AU Pusic, I Pavletic, SZ Kessinger, A Tarantolo, SR Bishop, MR AF Pusic, I Pavletic, SZ Kessinger, A Tarantolo, SR Bishop, MR TI Pseudoautologous blood stem cell transplantation for refractory chronic graft-versus-host disease SO BONE MARROW TRANSPLANTATION LA English DT Article DE hematopoietic stem cell transplantation; chronic graft-versus-host disease; AML ID AUTOIMMUNE-DISEASE; MORTALITY AB A female patient with AML received an allogeneic BMT from her brother. She experienced two relapses managed with chemotherapy and donor leukocyte infusions. The patient subsequently developed extensive therapy-refractory chronic GVHD. Pseudoautologous blood stem cell transplantation was performed as a salvage treatment for chronic GVHD. Her blood stem cells were easily mobilized with cyclophosphamide and G-CSF. The conditioning regimen was well tolerated and consisted of 200 mg/kg cyclophosphamide and horse-derived antithymocyte globulin. A total of 4.03 X 10(6)/kg CD34(+) cells were infused and hematological recovery was rapid. Chronic GVHD improved with the ability to taper steroids. Nine months post transplantation the patient died from leukemia. C1 Univ Nebraska, Med Ctr, Dept Internal Med, Sect Oncol & Hematol, Omaha, NE 68198 USA. NCI, Dept Expt Transplantat & Immunol, NIH, Bethesda, MD 20892 USA. RP Pavletic, SZ (reprint author), Univ Nebraska, Med Ctr, Dept Internal Med, Sect Oncol & Hematol, 987680 Nebraska Med Ctr, Omaha, NE 68198 USA. NR 10 TC 7 Z9 7 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD APR PY 2002 VL 29 IS 8 BP 709 EP 710 DI 10.1038/sj/bmt/1703550 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 557FA UT WOS:000175896400013 PM 12180118 ER PT J AU Goldstein, JA AF Goldstein, JA TI CYP2C9 polymorphisms and CYP2C9*2 genotyping primers SO BRITISH JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Letter ID VARIANT C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Goldstein, JA (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. RI Goldstein, Joyce/A-6681-2012 NR 7 TC 6 Z9 6 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0306-5251 J9 BRIT J CLIN PHARMACO JI Br. J. Clin. Pharmacol. PD APR PY 2002 VL 53 IS 4 BP 409 EP 410 DI 10.1046/j.1365-2125.2002.01572_7.x PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 543RN UT WOS:000175115100019 PM 11966681 ER PT J AU Maciejewski, JP Ristiano, AM Sloand, EM Wisch, L Geller, N Barrett, JA Young, NS AF Maciejewski, JP Ristiano, AM Sloand, EM Wisch, L Geller, N Barrett, JA Young, NS TI A pilot study of the recombinant soluble human tumour necrosis factor receptor (p75)-Fc fusion protein in patients with myelodysplastic syndrome SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE MDS; TNF; Enbrel; bone marrow failure ID HEMATOPOIETIC PROGENITOR CELLS; COLONY-STIMULATING FACTOR; FACTOR-ALPHA; INTERFERON-GAMMA; RHEUMATOID-ARTHRITIS; APLASTIC-ANEMIA; MARROW-CELLS; SERUM LEVELS; TNF-ALPHA; FAS AB Laboratory observations suggest that, in some myelodysplastic syndromes (MDS), immune mechanisms may contribute to the impaired blood cell production. Tumor necrosis factor alpha (TNF-alpha), a potent inhibitor of haematopoiesis, has been hypothesized to mediate suppressive effects in MDS: TNF-alpha levels are elevated and correlated with marrow apoptosis and cytopenia. Inhibition of TNF-alpha production using the soluble TNF receptor (Enbrel) has been successful in rheumatoid arthritis, and we have now applied the same principle to MDS. We determined spontaneous TNF-alpha production by marrow cells in MDS; TNF-alpha production was elevated (> mean + 2 x SD of controls) in > 1/3 of patients, but did not correlate with clinical parameters. Sixteen patients participated in a 3-month pilot study of Enbrel. The drug was well tolerated and 15 patients were evaluable. Of these, one became temporarily (14 weeks) transfusion independent. In another patient, absolute neutrophil count (ANC) rose from 0.5 x 10(9)/l to 0.84 x 10(9)/l. Serious infections were seen in two out of six neutropenic patients. Progression to refractory anaemia with excess blasts in transformation (RAEBt) or leukaemia was observed in three patients. When the effects of Enbrel on haematopoietic colony formation were studied, no significant increase was seen in MDS and there was no correlation with TNF-alpha levels. Although anti-TNF therapy with Enbrel was well tolerated at the dosages used in MDS, its efficacy as a single agent appears low. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Maciejewski, JP (reprint author), Cleveland Clin Fdn, Taussig Canc Ctr, Hematopoiesis & Expt Hamatol Sect, 9500 Euclid Ave, Cleveland, OH 44195 USA. NR 51 TC 54 Z9 57 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD APR PY 2002 VL 117 IS 1 BP 119 EP 126 DI 10.1046/j.1365-2141.2002.03381.x PG 8 WC Hematology SC Hematology GA 549GK UT WOS:000175436000016 PM 11918541 ER PT J AU Prenner, JL Binenbaum, G Carpentieri, DF Goldstein, SM Douglas, RS Ruchelli, E Katowitz, JA Hertle, RW AF Prenner, JL Binenbaum, G Carpentieri, DF Goldstein, SM Douglas, RS Ruchelli, E Katowitz, JA Hertle, RW TI Treacher Collins syndrome with novel ophthalmic findings and visceral anomalies SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Letter ID MUTATIONS; REVEALS; TCOF1 C1 Univ Penn, Scheie Eye Inst, Dept Ophthalmol, Philadelphia, PA 19106 USA. Childrens Hosp Philadelphia, Dept Pediat Ophthalmol, Philadelphia, PA 19104 USA. Childrens Hosp Philadelphia, Dept Pathol, Philadelphia, PA 19104 USA. NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Prenner, JL (reprint author), Univ Penn, Scheie Eye Inst, Dept Ophthalmol, 51 N 39th St, Philadelphia, PA 19106 USA. NR 10 TC 2 Z9 2 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD APR PY 2002 VL 86 IS 4 BP 472 EP 473 DI 10.1136/bjo.86.4.472 PG 2 WC Ophthalmology SC Ophthalmology GA 540QX UT WOS:000174940600025 PM 11914220 ER PT J AU Boyer, JL Adams, M Ravi, RG Jacobson, KA Harden, TK AF Boyer, JL Adams, M Ravi, RG Jacobson, KA Harden, TK TI 2-chloro N-6-methyl-(N)-methanocarba-2 '-deoxyadenosine-3 ',5 '-bisphosphate is a selective high affinity P2Y(1) receptor antagonist SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE P2Y receptors; P2Y(1) receptor antagonist; 2-chloro N-6-methyl-(N)-methanocarba-2 '-deoxyadenosine-3',5'-bisphosphate; phosphotipase C; adenylyl cyclase; platelet aggregation ID INDUCED PLATELET ACTIVATION; GUANINE-NUCLEOTIDES; PHOSPHOLIPASE-C; DERIVATIVES; IDENTIFICATION; AGGREGATION; AGONISTS; ADENINE; RESISTANCE; METABOLISM AB 1 We reported previously that bisphosphate derivatives of adenosine are antagonists of the P2Y(1) receptor and that modification of the ribose in these analogues is tolerated in the P2Y(1) receptor binding pharmacophore. 2 Here we delineate the pharmacological activity of one such non-nucleotide molecule. 2-chloro N-6-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate (MRS2279). in which the ribose is replaced by a cyclopentane ring constrained in the (N)-conformation by a cyclopropane moiety. 3 MRS2279 antagonized 2MeSADP-stimulated inositol phosphate formation in turkey erythrocyte membranes kith competitive kinetics (pK(B)=7.75). High affinity competitive antagonism by MRS2279 was also observed at the human P2Y(1) receptor (Pk(B)=8.10) stably expressed in 1321N1 human astrocytoma cells. Antagonism was specific for the P2Y(1) receptor since MRS2279 had no effect on activation of the human P2Y(2), P2Y(4), P2Y(6), or P2Y(11) receptors by their cognate agonists. 4 MRS2279 also did not block the capacity of ADP to act through the Gi/adenylyl cyclase linked P2Y receptor of platelets to inhibit cyclic, MP accumulation. 5 In contrast, the P2Y(1) receptor is known to be obligatory in the process of ADP-induced platelet aggregation. and MRS2279 competitively inhibited ADP-promoted platelet aggregation with an apparent affnity (pK(B)=8.05) similar to that observed at the human P2Y(1) receptor heterologously expressed in 1321N1 cells. 6 Taken together these results illustrate selective high affinity antagonism of the P2Y, receptor by a non-nucleotide Molecule that Should prove useful for pharmacological delineation of this receptor in various tissues. C1 Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Harden, TK (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol, CB 7635, Chapel Hill, NC 27599 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NHLBI NIH HHS [HL54889, R01 HL054889, R29 HL054889]; NIGMS NIH HHS [GM38213, R01 GM038213] NR 31 TC 77 Z9 77 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD APR PY 2002 VL 135 IS 8 BP 2004 EP 2010 DI 10.1038/sj.bjp.0704673 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 545KB UT WOS:000175215200021 PM 11959804 ER PT J AU O'Brien, S Talpaz, M Cortes, J Shan, JQ Giles, FJ Faderl, S Thomas, D Garcia-Manero, G Mallard, S Rios, MB Koller, C Kornblau, S Andreeff, M Murgo, A Keating, M Kantarjian, HM AF O'Brien, S Talpaz, M Cortes, J Shan, JQ Giles, FJ Faderl, S Thomas, D Garcia-Manero, G Mallard, S Rios, MB Koller, C Kornblau, S Andreeff, M Murgo, A Keating, M Kantarjian, HM TI Simultaneous homoharringtonine and interferon-alpha in the treatment of patients with chronic-phase chronic myelogenous leukemia SO CANCER LA English DT Article DE chronic myeloid/myelogenous leukemia; homoharringtonine; interferon-alpha; chronic phase ID CHRONIC MYELOID-LEUKEMIA; LOW-DOSE CYTARABINE; CYTOGENETIC RESPONSE; THERAPY; SURVIVAL; INDUCTION AB BACKGROUND. Homoharringtonine (HHT) has antileukemic activity in patients with Philadelphia chromosome (Ph) positive chronic myelogenous leukemia (CML). Combinations of HHT, interferon-alpha (IFN-alpha), and cytarabine (ara-C) have been studied in various CML phases. The objectives of this study were to evaluate the efficacy and toxicity profiles of a combination regimen of simultaneous HHT and IFN-alpha therapy in patients with chronic-phase CML who were not exposed previously to either agent. METHODS. Forty-seven patients were treated: 37 patients with early chronic-phase CML (2 patients with clonal evolution) and 10 patients with late chronic-phase CML. Their median age was 62 years (range, 23-73 years). HHT was given at a dose of 2.5 mg/m(2) by continuous intravenous infusion over 24 hours daily for 5 days every month, and IFN-alpha was given daily at a target dose of 5 X 10(6) units/m(2) subcutaneously. Response, survival, and treatment toxicity were analyzed. RESULTS. Overall, the complete hematologic response (CHR) rate was 85%; the cytogenetic response rate was 66%, with. major cytogenetic responses (Ph positive in < 35% of metaphases) in 49% of patients and complete cytogenetic responses in 21% of patients. The CHR rate, cytogenetic response rate, and major cytogenetic response rate were 84%, 69%, and 52%, respectively, in patients with early chronic-phase CML. Among the 10 patients with late chronic-phase CML, the CHR rate, cytogenetic response rate, and major cytogenetic response rate were 80%, 50%, and 40%, respectively. Response rates in patients age > 60 years were 84%, 62%, and 49% for CHR, cytogenetic response, and major cytogenetic response. Myelosuppression was frequent but manageable: Anemia with hemoglobin < 8.0 g/dL occurred in 3676 of patients, requiring dose adjustments and erythropoietin therapy. Nonhematologic toxicities were mainly fatigue, aches, and gastrointestinal disturbances. Dose reductions with multiple courses were significant and were due to myelosuppression: After 6-24 courses, the median daily IFNI-α dose was I MU/m(2), and the median number of days on HHT per month was 2 days. With a median follow-up of 26 months, the estimated 2-year survival rate was 90% (95% confidence interval, 79-100%). CONCLUSIONS. The simultaneous combination of HHT and IFN-α is safe and effective, but the dose schedules that actually were delivered were significantly lower than the planned dose schedules. With the availability of signal-transduction inhibitor 571 (imatinib mesylate), studies of combination of HHT and IFN-α chemotherapy in patients with CML who have disease that fails to respond to imatinib mesylate and of combinations with imatinib mesylate need to be explored. C1 Univ Texas, MD Anderson Canc Ctr, Dept Leukemia & Bioimmunotherapy, Houston, TX 77030 USA. NCI, Bethesda, MD 20892 USA. RP Kantarjian, HM (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Leukemia, Box 428,1515 Holcombe Blvd, Houston, TX 77030 USA. NR 25 TC 51 Z9 51 U1 1 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD APR 1 PY 2002 VL 94 IS 7 BP 2024 EP 2032 DI 10.1002/cncr.10436 PG 9 WC Oncology SC Oncology GA 536TJ UT WOS:000174717700016 PM 11932905 ER PT J AU Kennel, SJ Brechbiel, MW Milenic, DE Schlom, J Mirzadeh, S AF Kennel, SJ Brechbiel, MW Milenic, DE Schlom, J Mirzadeh, S TI Actinium-225 conjugates of MAb CC49 and humanized Delta CH(2)CC49 SO CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS LA English DT Article DE MAb CC49; Ac-225; HEHA; micro-distribution; therapy; radiotoxicity ID SINGLE-CHAIN FV; MONOCLONAL-ANTIBODY; TUMOR-CELLS; RADIOIMMUNOTHERAPY; RADIOTOXICITY; BI-213; MICROMETASTASES; IMMUNOGLOBULIN; PROTEINS; THERAPY AB Radioisotopes With Moderate half-lives arc essential for conventional radioimmunotherapy using tumor selective MAbs which require days for localization. Actinium-225, with a half-life of 10 days and a yield of 4 alpha particles in its decal, Chain, may be all ideal choice for tumor-targeted radioimmunotheraphy. Release of daughter radioisotopes from the primary chelator after the first decay has been a complication With the use Of Ac-225. It has been reported that the domain-deleted product of MAb CC49, Hu-DeltaCH(2) CC49, is able to extravasate and penetrate more deeply into tumors than the parent IgG molecule. We reasoned that once the Ac-225-chelate-MAb had penetrated into the tumor, the daughter radioisotopes would remain trapped even if they had been released from the primary chelator. Actinium-225 HEHA MAb CC49 conjugates were tested for distribution, micro-distribution and therapy in immunocompromised mice which had LS174T tumors growing at subcutaneous Or intramuscular sites. Both I-125 and Ac-225 CC49 and Hu-DeltaCH(2) CC49 were efficient in delivery of the radioisotopes to tumor sites. Tissue micro-autoradiography for the two antibody forms did not demonstrate ally differences in micro-distribution of either I-125 or Ac-225 ill the tumor. Furthermore, there was no detectable difference for the two carriers ill the tumor retention of daughter radio isotopes from Ac-225. Therapy experiments with Ac-225 were complicated by radiotoxicity of the conjugates. The lethal dose was about 0.5 muCi ill two strains of mice regardless of the carrier. At injected closes of 0.5 and 0.25 muCi, CC49 was slightly active ill tumor stasis, whereas 170 consistent significant effect of Ac-225-Hu-DeltaCH(2) CC49 oil growth of tumors was observed. The potential of Ac-225 in radioimmunotherapy is limited by the radiotoxicity of its daughter radioisotopes. Its potential will only be realized if stable conjugates, capable of daughter radioisotope retention, call be devised. C1 Oak Ridge Natl Lab, Div Life Sci, Oak Ridge, TN 37831 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kennel, SJ (reprint author), Oak Ridge Natl Lab, Div Life Sci, Bldg 4500S,Rm F150, Oak Ridge, TN 37831 USA. NR 31 TC 12 Z9 12 U1 2 U2 4 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1084-9785 J9 CANCER BIOTHER RADIO JI Cancer Biother. Radiopharm. PD APR PY 2002 VL 17 IS 2 BP 219 EP 231 DI 10.1089/108497802753773847 PG 13 WC Oncology; Medicine, Research & Experimental; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Research & Experimental Medicine; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging GA 552ZW UT WOS:000175651300010 PM 12030116 ER PT J AU Maranchie, JK Vasselli, JR Riss, J Bonifacino, JS Linehan, WM Klausner, RD AF Maranchie, JK Vasselli, JR Riss, J Bonifacino, JS Linehan, WM Klausner, RD TI The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma SO CANCER CELL LA English DT Article ID LINDAU TUMOR-SUPPRESSOR; ENDOTHELIAL GROWTH-FACTOR; HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; PAS DOMAIN PROTEIN-1; TRANSCRIPTION FACTOR; PROLYL HYDROXYLATION; UBIQUITIN LIGASE; FACTOR 1-ALPHA; UP-REGULATION; GENE-PRODUCT AB Clear-cell renal carcinoma is associated with inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. VHL is the substrate recognition subunit of an E3 ligase, known to target the alpha subunits of the HIF heterodimeric transcription factor for ubiquitin-mediated degradation under normoxic conditions. We demonstrate that competitive inhibition of the VHL substrate recognition site with a peptide derived from the oxygen degradation domain of HIF1alpha recapitulates the tumorigenic phenotype of VHL-deficient tumor cells. These studies prove that VHL substrate recognition is essential to the tumor suppressor function of VHL. We further demonstrate that normoxic stabilization of HIF1alpha alone, while capable of mimicking some aspects of VHL loss, is not sufficient to reproduce tumorigenesis, indicating that it is not the critical oncogenic substrate of VHL. C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Biosyst & Canc, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. OI Maranchie, Jodi/0000-0002-8534-9468 NR 42 TC 316 Z9 321 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD APR PY 2002 VL 1 IS 3 BP 247 EP 255 DI 10.1016/S1535-6108(02)00044-2 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 599TU UT WOS:000178351900008 PM 12086861 ER PT J AU Weeraratna, AT Jiang, YA Hostetter, G Rosenblatt, K Duray, P Bittner, M Trent, JM AF Weeraratna, AT Jiang, YA Hostetter, G Rosenblatt, K Duray, P Bittner, M Trent, JM TI Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma SO CANCER CELL LA English DT Article ID MAMMARY EPITHELIAL-CELLS; CUTANEOUS MALIGNANT-MELANOMA; EXTRACELLULAR-MATRIX; GROWTH-FACTOR; EXPRESSION; GENE; PATHWAY; WNT-5A; TRANSFORMATION; MECHANISM AB Gene expression profiling identified human melanoma cells demonstrating increased cell motility and invasiveness. The gene WNT5A best determined in vitro invasive behavior. Melanoma cells were transfected with vectors constitutively overexpressing Wnt5a. Consistent changes included actin reorganization and increased cell adhesion. No increase in beta-catenin expression or nuclear translocation was observed. There was, however, a dramatic increase in activated PKC. In direct correlation with Wnt5a expression and PKC activation, there was an increase in melanoma cell invasion. Blocking this pathway using antibodies to Frizzled-5, the receptor for Wnt5a, inhibited PKC activity and cellular invasion. Furthermore, Wnt5a expression in human melanoma biopsies directly correlated to increasing tumor grade. These observations support a role for Wnt5a in human melanoma progression. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. NCI, Dept Pathol, NIH, Bethesda, MD 20892 USA. RP Trent, JM (reprint author), NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. NR 38 TC 573 Z9 601 U1 4 U2 18 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD APR PY 2002 VL 1 IS 3 BP 279 EP 288 DI 10.1016/S1535-6108(02)00045-4 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 599TU UT WOS:000178351900011 PM 12086864 ER PT J AU Hsing, AW Chokkalingam, AP Gao, YT Wu, G Wang, X Deng, J Cheng, JR Sesterhenn, IA Mostofi, FK Chiang, TY Chen, YL Stanczyk, FZ Chang, CS AF Hsing, AW Chokkalingam, AP Gao, YT Wu, G Wang, X Deng, J Cheng, JR Sesterhenn, IA Mostofi, FK Chiang, TY Chen, YL Stanczyk, FZ Chang, CS TI Polymorphic CAG/CAA repeat length in the AIB1/SRC-3 gene and prostate cancer risk: A population-based case-control study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ANDROGEN RECEPTOR GENE; NUCLEAR RECEPTOR; BREAST-CANCER; COACTIVATORS; CELLS; AIB1; SUSCEPTIBILITY; ESTROGEN AB In an earlier report, we showed that a shorter CAG repeat length in the androgen receptor (AR) gene is associated with an increased risk of prostate cancer in China, the population with the lowest reported prostate cancer incidence in the world. Because AR coactivators enhance transactivation of AR, in this report we evaluated the relationship of a CAG/CAA repeat length polymorphism in the AIB1/SRC-3 gene (amplified in breast cancer gene 1, a steroid receptor coactivator and an AR coactivator) with prostate cancer risk in a population-based case-control study in China. Genomic DNA from 189 prostate cancer patients and 301 healthy controls was used for the PCR-based assay. The AIB1/SRC-3 CAG/CAA repeat length ranged from 24 to 32, with the most common repeat length being 29. Homozygous 29/29 and heterozygous 28/29 were the most common genotypes, with 44 and 30% of the controls harboring these genotypes, respectively. Relative to subjects homozygous for 29 CAG/CAA repeats (29/29 genotype), individuals with the <29/29 genotype had a nonsignificant 31 % increased risk [odds ratio (OR), 1.31; 95% confidence interval (CI), 0.87-1.97], whereas those homozygous for the <29 allele had a significant 81% excess risk (OR, 1.81; 95% CI, 1.00-3.28). The combined effect of CAG repeat lengths in the AR and AIB1/SRC-3 genes was also evaluated. Relative to men with both the 29/29 genotype of the AIB1/SRC-3 gene and a long CAG repeat length (1,23) in the AR gene, those with both the <29/<29 AIB1/SRC-3 genotype and a short CAG repeat length in the AR gene (<23) had a 2.8-fold risk (OR, 2.78; 95% CI, 1.24-6.26). Together, our data indicate that the CAG/CAA repeat length in the AIB1/SRC-3 gene may be associated with prostate cancer risk in Chinese men and that the combination of CAG/CAA repeat lengths in both the AIBIISRC-3 and AR genes may provide a useful marker for clinically significant prostate cancer. Expanded studies in other populations are needed to confirm this association and the combined effect of AIBIISRC-3 and other hormone-related genes in prostate cancer etiology. C1 Div Canc Epidemiol & Genet, NCI, Rockville, MD 20852 USA. Shanghai Canc Inst, Shanghai 200032, Peoples R China. Univ Rochester, Rochester, NY 14642 USA. Armed Forces Inst Pathol, Washington, DC 20306 USA. Univ So Calif, Sch Med, Dept Obstet & Gynecol & Prevent Med, Los Angeles, CA 90033 USA. RP Hsing, AW (reprint author), Div Canc Epidemiol & Genet, NCI, EPS MSC 7234 Execut Blvd, Rockville, MD 20852 USA. NR 28 TC 34 Z9 35 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2002 VL 11 IS 4 BP 337 EP 341 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 540BJ UT WOS:000174908000002 PM 11927493 ER PT J AU Peck, JD Hulka, BS Poole, C Savitz, DA Baird, D Richardson, BE AF Peck, JD Hulka, BS Poole, C Savitz, DA Baird, D Richardson, BE TI Steroid hormone levels during pregnancy and incidence of maternal breast cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HUMAN PLACENTAL-LACTOGEN; MULTIPLE BIRTHS; SERUM CONCENTRATIONS; RISK; ESTRADIOL; PROGESTERONE; ESTRIOL; PLASMA; ESTROGENS; MOTHERS AB Previous studies evaluating pregnancy hormone levels and maternal breast cancer were limited to surrogate indicators of exposure. This study directly evaluates the association between measured serum steroid hormone levels during pregnancy and maternal risk of breast cancer. A nested case-control study was conducted to examine third-trimester serum levels of total unconjugated estradiol, estrone, estriol, and progesterone in women who were pregnant between 1959 and 1966. Cases (n = 194) were diagnosed with in situ or invasive breast cancer between 1969 and 1991. Controls (n = 374) were matched to cases by age at the time of index pregnancy, using randomized recruitment. Elevated progesterone levels were associated with a decreased incidence of breast cancer [odds ratio (OR) for progesterone greater than or equal to270 ng/ml, 0.49; 95% confidence interval (CI), 0.22-1.1] relative to those below the lowest decile. This association was stronger for cancers diagnosed at or before age 50 (OR for progesterone; greater than or equal to270 ng/ml, 0.3; 95% CI, 0.1-0.9). Increased estrone levels were associated with an increased incidence overall (OR for estrone greater than or equal to18.7 ng/ml, 2.5; 95% Cl, 1.0-6.2), whereas a positive association with estradiol was not observed. Too few cases occurred within 15 years of the index pregnancy to compare adequately the short- and long-term effects of pregnancy hormone exposure. When estrogen-to-progesterone ratios were evaluated, there was an indication of a modest increased incidence of breast cancer for those with high total estrogens and high estrone levels relative to progesterone. These findings suggest that pregnancy steroid hormone levels are risk factors for breast cancer. C1 Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27515 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Texas A&M Univ, Div Publ Hlth, Dept Vet Anatomy & Publ Hlth, College Stn, TX 77843 USA. Texas A&M Univ, Sch Rural Publ Hlth, Dept Epidemiol & Biostat, Bryan, TX 77802 USA. RP Peck, JD (reprint author), Texas A&M Univ, Sch Rural Publ Hlth, Dept Epidemiol & Biostat, 3000 Briarcrest Dr Suite 310, Bryan, TX 77802 USA. OI Baird, Donna/0000-0002-5544-2653 FU NCI NIH HHS [R03 CA75953]; NICHD NIH HHS [N01HD63258] NR 67 TC 54 Z9 55 U1 2 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2002 VL 11 IS 4 BP 361 EP 368 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 540BJ UT WOS:000174908000005 PM 11927496 ER PT J AU Zbar, B Alvord, WG Glenn, G Turner, M Pavlovich, CP Schmidt, L Walther, M Choyke, P Weirich, G Hewitt, SM Duray, P Gabril, F Greenberg, C Merino, MJ Toro, J Linehan, WM AF Zbar, B Alvord, WG Glenn, G Turner, M Pavlovich, CP Schmidt, L Walther, M Choyke, P Weirich, G Hewitt, SM Duray, P Gabril, F Greenberg, C Merino, MJ Toro, J Linehan, WM TI Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID INTESTINAL POLYPOSIS; CELL CARCINOMA; PERIFOLLICULAR FIBROMAS; HEREDITARY; FIBROFOLLICULOMAS; TRICHODISCOMAS; ACROCHORDONS; ONCOCYTOMA; PREVALENCE; PARENCHYMA AB The Birt-Hogg-Dube syndrome, a genodermatosis characterized by benign tumors of the hair follicle, has been associated with renal and colonic neoplasms and spontaneous pneumothorax, but the risk of developing these disorders is unknown. We identified risk factors for renal tumors and spontaneous pneumothorax in 98 patients affected with the Birt-Hogg-Dub6 syndrome, in 13 Birt-Hogg-Dub6 haplotype carriers, and in 112 unaffected family members. Development of renal tumors was strongly associated with the Birt-Hogg-Dub6 syndrome and age. The odds ratio for renal tumor in BHD-affected family members adjusted for age was 6.9 (95% confidence interval, 1.5-31.6) and -9.0 for the other risk factors considered. Chromophobe renal carcinoma, an uncommon type of renal cancer, was the predominant type of renal cancer found. Spontaneous pneumothorax was also strongly associated with the Birt-Hogg-Dube syndrome and age. The odds ratio for pneumothorax in BHD-affected individuals, adjusted for age, was 50.3 (95% confidence interval, 6.4-392), and about 32 times higher adjusting for the other risk variables. Colon cancer and colon polyps were not related to the Birt-Hogg-Dub6 syndrome. The Birt-Hogg-Dub6 syndrome confers an increased risk for the development of renal tumors and spontaneous pneumothorax. We found no increase in risk for the development of colon polyps or colon carcinomas. C1 Natl Canc Inst Frederick, Lab Immunol, Ft Detrick, MD 21702 USA. Natl Canc Inst Frederick, Lab Immunobiol, Ft Detrick, MD 21702 USA. Natl Canc Inst Frederick, Data Management Serv, Ft Detrick, MD 21702 USA. Natl Canc Inst Frederick, Intramural Res Support Program, Ft Detrick, MD 21702 USA. Natl Canc Inst Frederick, Sci Applicat Int Corp, Ft Detrick, MD 21702 USA. Natl Canc Inst, Dermatol Branch, Bethesda, MD 20894 USA. Natl Canc Inst, Lab Pathol, Bethesda, MD 20894 USA. Natl Canc Inst, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20894 USA. Natl Canc Inst, Ctr Canc Res, Bethesda, MD 20894 USA. NIH, Clin Ctr, Bethesda, MD 20894 USA. Natl Inst Diabet & Digest & Kidney Des, Digest Dis Branch, NIH, Bethesda, MD 20894 USA. Univ Manitoba, Dept Pediat & Child Hlth, Winnipeg, MB, Canada. Univ Manitoba, Dept Biochem & Med Genet, Winnipeg, MB, Canada. Tech Univ Munich, D-81675 Munich, Germany. RP Zbar, B (reprint author), Natl Canc Inst Frederick, Lab Immunol, Ft Detrick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 27 TC 235 Z9 241 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2002 VL 11 IS 4 BP 393 EP 400 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 540BJ UT WOS:000174908000009 PM 11927500 ER PT J AU Wang, SS Hildesheim, A Gao, XJ Schiffman, M Herrero, R Bratti, MC Sherman, ME Barnes, WA Greenberg, MD McGowan, L Mortel, R Schwartz, PE Zaino, RJ Glass, AG Burk, RD Karacki, P Carrington, M AF Wang, SS Hildesheim, A Gao, XJ Schiffman, M Herrero, R Bratti, MC Sherman, ME Barnes, WA Greenberg, MD McGowan, L Mortel, R Schwartz, PE Zaino, RJ Glass, AG Burk, RD Karacki, P Carrington, M TI Human leukocyte antigen class I alleles and cervical neoplasia: No heterozygote advantage SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HLA C1 NCI, Div Canc Epidemiol & Genet, Environm Epidemiol Branch, Interdisciplinary Studies Sect, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Lab Genet Divers, Frederick, MD 21701 USA. Georgetown Univ, Lombardi Canc Ctr, Washington, DC 20007 USA. Grad Hosp Philadelphia, Philadelphia, PA 19146 USA. George Washington Univ, Div Gynecol Oncol, Washington, DC 20052 USA. Penn State Univ, Milton S Hershey Med Ctr, Hershey, PA 17033 USA. Yale Univ, Sch Med, New Haven, CT 06510 USA. Kaiser Fdn Res Inst, Oakland, CA USA. Albert Einstein Coll Med, Bronx, NY 10461 USA. RP Wang, SS (reprint author), NCI, Div Canc Epidemiol & Genet, Environm Epidemiol Branch, Interdisciplinary Studies Sect, 6120 Execut Blvd EPS MSC 7234, Bethesda, MD 20892 USA. NR 7 TC 6 Z9 8 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2002 VL 11 IS 4 BP 419 EP 420 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 540BJ UT WOS:000174908000014 PM 11927505 ER PT J AU Guan, XY Zhang, HE Zhou, H Sham, JST Fung, JMW Trent, JM AF Guan, XY Zhang, HE Zhou, H Sham, JST Fung, JMW Trent, JM TI Characterization of a complex chromosome rearrangement involving 6q in a melanoma cell line by chromosome microdissection SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID PAINTING PROBES; IDENTIFICATION; DELETIONS; CANCER; GENE AB Deletion of 6q is one of the most frequent chromosomal alteration,; in human malignant melanoma. Recently, we used chromosome painting probes of 6p and 6q to study 21 melanoma cell lines. A reciprocal translocation between chromosomes 6q and 17p was detected in one cell line (UACC-930). Upon further characterization of the translocation market using the micro fluorescence in situ hybridization (FISH) technique, a complex rearrangement including an inversion of 6q and a translocation between the inverted 6q and 17p, [der(6)inv(6)(q16q27)t(6;17)(q26;p13)], was detected. A yeast artificial chromosome (YAC) clone spanning the breakpoint at 6q16 was isolated by the FISH screen. Loss of one or more copies of the YAC clone was also detected in 10 of 12 melanoma cell lines. This result implies that the YAC clone may contain a putative tumor suppressor gene related to the pathogenesis of malignant melanoma. Further characterizations of the breakpoint at 6q16 and molecular cloning breakpoints at 6q27 and 17p 13 are in progress. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Hong Kong, Dept Clin Oncol, Hong Kong, Hong Kong, Peoples R China. RP Guan, XY (reprint author), NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RI Guan, Xin-Yuan/A-3639-2009 OI Guan, Xin-Yuan/0000-0002-4485-6017 NR 16 TC 12 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD APR 1 PY 2002 VL 134 IS 1 BP 65 EP 70 AR PII S0165-4608(01)00608-2 DI 10.1016/S0165-4608(01)00608-2 PG 6 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 544ND UT WOS:000175165700013 PM 11996799 ER PT J AU Loud, JT Peters, JA Fraser, M Jenkins, J AF Loud, JT Peters, JA Fraser, M Jenkins, J TI Applications of advances in molecular biology and genomics to clinical cancer care SO CANCER NURSING LA English DT Article DE genetics; genetic counseling; oncology; cancer prevention; surveillance; diagnosis; prognosis; residual disease monitoring; treatment; gene therapy ID ACUTE PROMYELOCYTIC LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; ABL TYROSINE KINASE; SINGLE NUCLEOTIDE POLYMORPHISM; FAMILIAL ADENOMATOUS POLYPOSIS; SURGICAL ADJUVANT BREAST; BRCA2 MUTATION CARRIERS; ORAL-CONTRACEPTIVE USE; FOLLOW-UP CARE; OVARIAN-CANCER AB Genetics technologies, methods, and discoveries are being integrated rapidly into medical and nursing practices in a variety of ways. The purpose of this article is to familiarize nurses with how new genetic technologies and discoveries are being incorporated into various phases of clinical oncology practice. The scope of this article is broad to provide an overview of the of ways in which cancer prevention, surveillance, diagnosis, prognosis, monitoring, treatment, and gene therapy are evolving due to advances in the molecular biology of cancer. We use specific examples to demonstrate the use of genetic information to achieve these objectives and to illustrate principles and strategies that may be applied to a variety of cancers. C1 NCI, CGB, DCEG, NIH, Rockville, MD 20852 USA. NCI, Genet Epidemiol Branch, DCEG, NIH, Rockville, MD USA. NCI, Natl Naval Med Ctr, Bethesda, MD 20892 USA. RP Loud, JT (reprint author), NCI, CGB, DCEG, NIH, 6120 Execut Blvd,EPS 7019, Rockville, MD 20852 USA. EM loudj@mail.nih.gov NR 91 TC 4 Z9 5 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0162-220X J9 CANCER NURS JI Cancer Nurs. PD APR PY 2002 VL 25 IS 2 BP 110 EP 122 DI 10.1097/00002820-200204000-00007 PG 13 WC Oncology; Nursing SC Oncology; Nursing GA 536TG UT WOS:000174717500005 PM 11984099 ER PT J AU Conway, K Edmiston, SN Cui, L Drouin, SS Pang, JZ He, M Tse, CK Geradts, J Dressler, L Liu, ET Millikan, R Newman, B AF Conway, K Edmiston, SN Cui, L Drouin, SS Pang, JZ He, M Tse, CK Geradts, J Dressler, L Liu, ET Millikan, R Newman, B TI Prevalence and spectrum of p53 mutations associated with smoking in breast cancer SO CANCER RESEARCH LA English DT Article ID FEMALE LUNG-CANCER; CIGARETTE-SMOKING; ESTROGEN-RECEPTOR; ALCOHOL-CONSUMPTION; YOUNG-WOMEN; PROGNOSTIC-SIGNIFICANCE; TOBACCO-SMOKE; MOLECULAR EPIDEMIOLOGY; SYSTEMIC THERAPY; PASSIVE SMOKING AB To explore the role of smoking in breast cancer, we undertook a population-based study to evaluate the prevalence and spectrum of p53 mutations in the breast tumors of smokers and nonsmokers. We evaluated 456 archival invasive breast tumors for mutations in exons 4-8 of the p53 gene, using single-strand conformational polymorphism analysis and manual sequencing. Statistical analyses were performed to determine the association of p53 mutations with clinical and smoking characteristics. Of 108 mutations identified, 77 (71%) were point mutations and 31 (29%) were deletions or insertions. A higher prevalence of p,53 mutations was found in the breast tumors of current smokers (36.5%; P = 0.02) compared with never smokers (23.6%), whereas fewer mutations were found in former smokers (16.2%; P = 0.09). After adjustment for age, race, menopausal status, clinical stage, tumor size, and family history of breast cancer, current smokers were significantly more likely to harbor any p53 mutation [odds ratio (OR), 2.11; 95% confidence interval (CI), 1.17-3.78], p53 transversions (OR, 3.37; 95% CI, 1.03-11.06), and G:C-->T:A transversions (OR, 10.53; 95% CI, 1.77-62.55) compared with never smokers. Stage at diagnosis did not account for the increase in p53 mutation-positive breast cancer among current smokers. Former smokers vi ere also more likely than never smokers to harbor G:C-->T:A transversions (OR, 2.43; 95% CI, 0.37-15.73), although this association was not statistically significant. Among former smokers, the prevalence of p53 mutations varied with time since quitting: former smokers who quit smoking for longer than I year had a lower prevalence of p53 mutations (10.5% for 1-5 years and 12.9% for >5 years) than those who had stopped smoking within the year of their cancer diagnosis (26.3%). Our results indicate that cigarette smoking appears to modify the prevalence and spectrum of p53 mutations in breast tumors. Moreover, the difference in mutational spectra observed between smokers and nonsmokers is suggestive of the genotoxic effects of smoking in breast tissue. C1 Univ N Carolina, Dept Epidemiol, Sch Publ Hlth, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Epidemiol, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USA. Natl Canc Inst, Comparat Mol Pathol Unit, Gaithersburg, MD 20877 USA. Roswell Pk Canc Inst, Dept Pathol & Lab Med, Buffalo, NY 14263 USA. Natl Univ Singapore, Genome Inst Singapore, Singapore 117640, Singapore. Queensland Univ Technol, Sch Publ Hlth, Brisbane, Qld 4059, Australia. RP Conway, K (reprint author), Univ N Carolina, Dept Epidemiol, Sch Publ Hlth, Campus Box 7435 Mc Gavran Greenberg Hall, Chapel Hill, NC 27599 USA. RI Liu, Edison/C-4141-2008 FU NCI NIH HHS [CA58223] NR 99 TC 64 Z9 66 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD APR 1 PY 2002 VL 62 IS 7 BP 1987 EP 1995 PG 9 WC Oncology SC Oncology GA 539TT UT WOS:000174887700012 PM 11929815 ER PT J AU Rubio-Godoy, V Pinilla, C Dutoit, V Borras, E Simon, R Zhao, YD Cerottini, JC Romero, P Houghten, R Valmori, D AF Rubio-Godoy, V Pinilla, C Dutoit, V Borras, E Simon, R Zhao, YD Cerottini, JC Romero, P Houghten, R Valmori, D TI Toward synthetic combinatorial peptide libraries in positional scanning format (PS-SCL)-based identification of CD8(+) tumor-reactive T-cell ligands: A comparative analysis of PS-SCL recognition by a single tumor-reactive CD8(+) cytolytic T-lymphocyte clone SO CANCER RESEARCH LA English DT Article ID MELAN-A/MART-1 ANTIGENIC PEPTIDE; HLA-A2 MELANOMAS; CTL; EXPRESSION; EPITOPES; PROTEINS; POTENCY; GENES AB The use of synthetic combinatorial peptide libraries in positional scanning format (PS-SCL) has emerged recently as an alternative approach for the identification of peptides recognized by T lymphocytes. The choice of both the PS-SCL used for screening experiments and the method used for data analysis are crucial for implementing this approach. With this aim, we tested the recognition of different PS-SCL by a tyrosinase 368-376-specific CTL clone and analyzed the data obtained with a recently developed biometric data analysis based on a model of independent and additive contribution of individual amino acids to peptide antigen recognition. Mixtures defined with amino acids present at the corresponding positions in the native sequence were among the most active for an of the libraries. Somewhat surprisingly, a higher number of native amino acids were identifiable by using amidated COOH-terminal rather than free COOH-terminal PS-SCL. Also, our data clearly indicate that when using PS-SCL longer than optimal, frame shifts occur frequently and should be taken into account. Biometric analysis of the data obtained with the amidated COOH-terminal nonapeptide library allowed the identification of the native ligand as the sequence with the highest score in a public human protein database. However, the adequacy of the PS-SCL data for the identification for the peptide ligand varied depending on the PS-SCL used. Altogether these results provide insight into the potential of PS-SCL for the identification of CTL-defined tumor-derived antigenic sequences and may significantly implement our ability to interpret the results of these analyses. C1 CHU Vaudois, Div Clin Oncoimmunol, Ludwig Inst Canc Res, CH-1011 Lausanne, Switzerland. Torrey Pines Inst Mol Studies & Mixture Sci Inc, San Diego, CA 92121 USA. NCI, NIH, Biomet Res Branch, Mol Stat & Bioinformat Sect, Bethesda, MD 20892 USA. RP Valmori, D (reprint author), Hop Orthoped, Div Clin Oncoimmunol, Ave Pierre Decker 4, CH-1005 Lausanne, Switzerland. RI Valmori, Danila/K-2439-2015 NR 26 TC 20 Z9 20 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD APR 1 PY 2002 VL 62 IS 7 BP 2058 EP 2063 PG 6 WC Oncology SC Oncology GA 539TT UT WOS:000174887700022 PM 11929825 ER PT J AU O'Shea, JJ Gadina, M Schreiber, RD AF O'Shea, JJ Gadina, M Schreiber, RD TI Cytokine signaling in 2002: New surprises in the Jak/Stat pathway SO CELL LA English DT Review ID MICE LACKING SUPPRESSOR; IFN-GAMMA; IMMUNE-RESPONSE; TRANSCRIPTIONAL RESPONSES; PSEUDOKINASE DOMAIN; GENE-EXPRESSION; TYROSINE KINASE; CELL EXPANSION; EXPORT SIGNAL; JANUS KINASES AB The importance of Jak-Stat pathway signaling in regulating cytokine-dependent gene expression and cellular development/survival is well established. Nevertheless, advances continue to be made in defining Jak-Stat pathway effects on different cellular processes and in different organisms. This review focuses on recent advances in the field and highlights some of the most active areas of Jak-Stat pathway research. C1 NIAMSD, Mol Immunol & Inflammat Branch, NIH, Rockville, MD 20852 USA. Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63105 USA. RP O'Shea, JJ (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Rockville, MD 20852 USA. RI Schreiber, Robert/A-1276-2013 OI Schreiber, Robert/0000-0001-6311-0432 NR 105 TC 505 Z9 526 U1 4 U2 44 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD APR PY 2002 VL 109 SU S BP S121 EP S131 DI 10.1016/S0092-8674(02)00701-8 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 544UY UT WOS:000175181100011 PM 11983158 ER PT J AU Koonin, EV Aravind, L AF Koonin, EV Aravind, L TI Origin and evolution of eukaryotic apoptosis: the bacterial connection SO CELL DEATH AND DIFFERENTIATION LA English DT Review DE eukaryotic apoptosis; bacteria ID PROGRAMMED CELL-DEATH; SIGNAL-TRANSDUCTION; PROTEIN SEQUENCES; PSI-BLAST; GENES; GENOMES; FAMILY; MITOCHONDRIA; SMAC/DIABLO; CAULOBACTER AB The availability of numerous complete genome sequences of prokaryotes and several eukaryotic genome sequences provides for new insights into the origin of unique functional systems of the eukaryotes. Several key enzymes of the apoptotic machinery, including the paracaspase and metacaspase families of the caspase-like protease superfamily, apoptotic ATPases and NACHT family NTPases,and mitochondrial HtrA-like proteases, have diverse homologs in bacteria, but not in archaea. Phylogenetic analysis strongly suggests a mitochondrial origin for metacaspases and the HtrA-like proteases, whereas acquisition from Actinomycetes appears to be the most likely scenario for AP-ATPases. The homologs of apoptotic proteins are particularly abundant and diverse in bacteria that undergo complex development, such as Actinomycetes, Cyanobacteria and alpha-proteobacteria, the latter being progenitors of the mitochondria. In these bacteria,the apoptosis-related domains typically form multidomain proteins, which are known or inferred to participate in signal transduction and regulation of gene expression. Some of these bacterial multidomain proteins contain fusions between apoptosis-related domains, such as AP-ATPase fused with a metacaspase or a TIR domain. Thus, bacterial homologs of eukaryotic apoptotic machinery components might functionally and physically interact with each other as parts of signaling pathways that remain to be investigated. An emerging scenario of the origin of the eukaryotic apoptotic system involves acquisition of several central apoptotic effectors as a consequence of mitochondrial endosymbiosis and probably also as a result of subsequent, additional horizontal gene transfer events, which was followed by recruitment of newly emerging eukaryotic domains as adaptors. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bldg 38A,Rm 5N503,5th Floor,8600 Rockville Pike, Bethesda, MD 20894 USA. NR 82 TC 221 Z9 239 U1 12 U2 45 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD APR PY 2002 VL 9 IS 4 BP 394 EP 404 DI 10.1038/sj/cdd/4400991 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 534AK UT WOS:000174562300008 PM 11965492 ER PT J AU Bonini, MG Mason, RP Augusto, O AF Bonini, MG Mason, RP Augusto, O TI The mechanism by which 4-hydroxy-2,2,6,6-tetramethylpiperidene-1-oxyl (tempol) diverts peroxynitrite decomposition from nitrating to nitrosating species SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID PERMEABLE RADICAL SCAVENGER; PULSE-RADIOLYSIS; CARBON-DIOXIDE; TYROSINE NITRATION; SOD MIMICS; ACID; INTERMEDIATE; NITROXIDES; SUPEROXIDE; OXIDATION AB Tempol is a stable nitroxide radical that has been shown to protect laboratory animals from the injury associated with conditions of oxidative and nitrosoactive stress. Tempol's protective mechanisms against reactive oxygen species have been extensively studied, but its interactions with reactive nitrogen species remain little explored. Recently, it has been shown that tempol is a potent inhibitor of peroxynitrite-mediated phenol nitration while it increases phenol nitrosation by a complex mechanism [Carrol et al. (2000) Chem. Res. Toxicol. 13, 294]. To obtain further mechanistic insights, we reexamined the interaction of peroxynitrite with tempol in the absence and presence of carbon dioxide. Stopped-flow kinetic studies confirmed that tempol does not react directly with peroxynitrite but levels off the amount of oxygen (monitored with an oxygen electrode) and nitrite (monitored by chemiluminescence) produced from peroxynitrite in the presence and absence of carbon dioxide to about 30% and 70% of the initial oxidant concentration at pH 5.4, 6.4, and 7.4. Tempol inhibited phenol nitration while increasing the amounts of 4-nitrosophenol, that attained yields close to 30% of the peroxynitrite in the presence of carbon dioxide at pH 7.4. Fast-flow EPR experiments showed detectable changes in the instantaneous tempol concentration (maximum of 15%) only in the presence of carbon dioxide. Under these conditions, the instantaneous concentration of the carbonate radical anion was reduced by tempol in a concentration-dependent manner. The results indicate that tempol is oxidized by peroxynitrite-derived radicals (.OH and CO3.-, in the absence and presence of carbon dioxide, respectively) to the oxoammonium cation which, in turn, is reduced back to tempol while oxidizing peroxynitrite to oxygen and nitric oxide. The latter reacts rapidly with peroxynitrite-derived nitrogen dioxide to produce the nitrosating species, dinitrogen trioxide. Overall, the results support a role for peroxynitrite and its derived radicals in the tissue pathology associated with inflammatory conditions. C1 Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508 Sao Paulo, Brazil. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Augusto, O (reprint author), Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508 Sao Paulo, Brazil. RI Augusto, Ohara/D-3839-2012 OI Augusto, Ohara/0000-0002-7220-4286 NR 36 TC 44 Z9 44 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD APR PY 2002 VL 15 IS 4 BP 506 EP 511 DI 10.1021/tx015571z PG 6 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 543DB UT WOS:000175085000006 PM 11952336 ER PT J AU Hrabie, JA Keefer, LK AF Hrabie, JA Keefer, LK TI Chemistry of the nitric oxide-releasing diazeniumdiolate ("nitrosohydroxylamine") functional group and its oxygen-substituted derivatives SO CHEMICAL REVIEWS LA English DT Review ID RAY CRYSTAL-STRUCTURE; ANGELIS SALT; N-NITROSOHYDROXYLAMINES; AQUEOUS-SOLUTION; SODIUM TRIOXODINITRATE(II); THERMAL-DECOMPOSITION; BIOLOGICAL-SYSTEMS; AZOXY COMPOUNDS; AMMONIUM-SALTS; NITROGEN-OXIDE C1 NCI, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Hrabie, JA (reprint author), NCI, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01-CO-12400] NR 304 TC 247 Z9 254 U1 2 U2 30 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 J9 CHEM REV JI Chem. Rev. PD APR PY 2002 VL 102 IS 4 BP 1135 EP 1154 DI 10.1021/cr000028t PG 20 WC Chemistry, Multidisciplinary SC Chemistry GA 542CK UT WOS:000175025800010 PM 11942789 ER PT J AU Ortega, HG Weissman, DN Carter, DL Banks, D AF Ortega, HG Weissman, DN Carter, DL Banks, D TI Use of specific inhalation challenge in the evaluation of workers at risk for occupational asthma - A survey of pulmonary, allergy, and occupational medicine residency training programs in the United States and Canada SO CHEST LA English DT Article DE occupational asthma; specific inhalation challenge; residency training program ID BRONCHIAL HYPERRESPONSIVENESS; TOLUENE DIISOCYANATE; FLOW-RATE; ISOCYANATE; DIAGNOSIS AB Study objectives: To document the current practice of occupational asthma (OA) diagnosis and use of specific inhalation challenge (SIC). Design, setting, and participants: A survey evaluating the current practice of SIC was mailed to 259 residency, training programs in adult pulmonary diseases, allergy, and immunology, and occupational medicine accredited in the United State and Canada during the year 2000. Results: Forty-six percent (123 of 259 programs) participated. Ninety-two programs reported that patients with OA were seen during the previous year, 15 programs reported that SIC had been performed, and 10 programs reported that patients had been referred to other sites for SIC. A total of 259 patients underwent SIC. No unexpected adverse reactions were reported. Forty-one programs reported that they had been willing to undertake SIC but were unable to do so. The most common barriers cited were lack of availability of SIC within the evaluating institution, inability to locate a site for referral, concerns about reimbursement, and lack of an appropriate diagnostic reagent for use in SIC. Seventy-four programs indicated that SIC was useful, and 34 programs included training in the use of SIC was part of the residency curriculum. Conclusion: Although SIC is considered the "gold standard" for objective documentation of OA, the test is performed in only a few institutions in the United States and Canada. Many institutions indicate that SIC is not available, even when desired for patient management. Only a minority of participating residency training programs include SIC as a formal part of the training curriculum. C1 W Virginia Univ, Sch Med, Dept Med, Pulm & Crit Care Med Sect, Morgantown, WV 26506 USA. NIOSH, Morgantown, WV USA. RP Ortega, HG (reprint author), NHLBI, Div Lung Dis, 2 Rockledge Ctr,6701 Rockledge Dr,Ste 10018, Bethesda, MD 20892 USA. NR 23 TC 32 Z9 33 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD APR PY 2002 VL 121 IS 4 BP 1323 EP 1328 DI 10.1378/chest.121.4.1323 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 545PM UT WOS:000175226400048 PM 11948069 ER PT J AU Miller, FG Shorr, AF AF Miller, FG Shorr, AF TI Ethical assessment of industry-sponsored clinical trials - A case analysis SO CHEST LA English DT Article DE ethics; industry-sponsored clinical trials; placebo controls ID DRY POWDER INHALER; MOMETASONE FUROATE; FLUTICASONE PROPIONATE; PERSISTENT ASTHMA; MODERATE ASTHMA; EFFICACY; BECLOMETHASONE; SAFETY AB The rapid growth of clinical trials sponsored by the pharmaceutical industry and conducted by community physicians raises concerns about the scientific quality of thin research and the adequacy of protections for research participants. In this article, we present an in-depth ethical analysis of a recent industry-sponsored placebo-controlled study for treatment of asthma. The ethical analysis uses a proposed ethical framework for evaluating clinical research focusing on seven ethical requirements: (1) scientific value, (2) scientific validity, (3) fair subject selection, (4) favorable risk/benefit ratio, (5) independent review, (6) informed consent, and (7) respect for enrolled subjects. C1 NIH, Dept Clin Bioeth, Ctr Clin, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. RP Miller, FG (reprint author), NIH, Dept Clin Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. NR 22 TC 25 Z9 25 U1 0 U2 2 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD APR PY 2002 VL 121 IS 4 BP 1337 EP 1342 DI 10.1378/chest.121.4.1337 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 545PM UT WOS:000175226400050 PM 11948071 ER PT J AU Morgan, CM Tanofsky-Kraff, M Wilfley, DE Yanovski, JA AF Morgan, CM Tanofsky-Kraff, M Wilfley, DE Yanovski, JA TI Childhood obesity SO CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Review ID BODY-MASS INDEX; FAMILY-BASED TREATMENT; CONGENITAL LEPTIN DEFICIENCY; BEHAVIORAL WEIGHT CONTROL; PEDIATRIC OBESITY; NATIONAL-HEALTH; YOUNG ADULTHOOD; MORBID-OBESITY; FOLLOW-UP; ANTIPSYCHOTIC-DRUGS AB This article reviews the epidemiology, differential diagnosis, predisposing factors, and therapeutic interventions for pediatric obesity. The prevalence of childhood obesity is increasing as a result of the interaction between a strong genetic predisposition that facilitates storage of fat, and environmental influences, including the easy access to calorically-dense foods and the low levels of physical activity that characterize modern societies. Mental health care professionals must frequently address pediatric obesity not only because of its rising prevalence in the general population, but also because a number of pharmacotherapies used to treat psychological disorders appear to increase body weight. Childhood obesity has pervasive psychosocial and medical consequences, both in the short and the long-term. C1 NICHHD, DEB, Unit Growth & Obes, NIH, Bethesda, MD 20892 USA. Univ Fed Sao Paulo, Dept Psychiat, BR-04024002 Sao Paulo, Brazil. Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. San Diego State Univ, San Diego Joint Doctoral Program Clin Psychol, Dept Psychol, San Diego, CA 92182 USA. Univ Calif San Diego, San Diego, CA 92103 USA. RP Yanovski, JA (reprint author), NICHD, DEB, Unit Growth & Obes, NIH, Ctr Dr,Bldg 10,Room 10N262 MSC 1862, Bethesda, MD 20892 USA. NR 130 TC 16 Z9 17 U1 0 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 1056-4993 J9 CHILD ADOL PSYCH CL JI Child Adolesc. Psychiatr. N. Am. PD APR PY 2002 VL 11 IS 2 BP 257 EP + AR PII S1056-4993(01)00007-4 DI 10.1016/S1056-4993(01)00007-4 PG 23 WC Psychiatry SC Psychiatry GA 567NC UT WOS:000176490000008 PM 12109321 ER PT J AU Ayala, AR Wartofsky, L AF Ayala, AR Wartofsky, L TI The case for more aggressive screening and treatment of mild thyroid failure SO CLEVELAND CLINIC JOURNAL OF MEDICINE LA English DT Review ID L-THYROXINE THERAPY; CORONARY HEART-DISEASE; SUBCLINICAL HYPOTHYROID PATIENTS; AUTOIMMUNE-THYROIDITIS; RISK FACTOR; FOLLOW-UP; DIABETES-MELLITUS; EARLY-PREGNANCY; ARTERY DISEASE; NATURAL COURSE AB "Subclinical" (mild) thyroid failure is not benign: it tends to progress to overt thyroid failure and it has adverse clinical effects. We believe it should be screened for more aggressively in the general population, and treated with levothyroxine. C1 NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Wartofsky, L (reprint author), Washington Hosp Ctr, Dept Med, 110 Irving St NW, Washington, DC 20010 USA. NR 86 TC 7 Z9 8 U1 0 U2 1 PU CLEVELAND CLINIC PI CLEVELAND PA 9500 EUCLID AVE, CLEVELAND, OH 44106 USA SN 0891-1150 J9 CLEV CLIN J MED JI Clevel. Clin. J. Med. PD APR PY 2002 VL 69 IS 4 BP 313 EP 320 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 540XY UT WOS:000174957200005 PM 11996201 ER PT J AU Gore, SD Weng, LJ Figg, WD Zhai, SP Donehower, RC Dover, G Grever, MR Griffin, C Grochow, LB Hawkins, A Burks, K Zabelena, Y Miller, CB AF Gore, SD Weng, LJ Figg, WD Zhai, SP Donehower, RC Dover, G Grever, MR Griffin, C Grochow, LB Hawkins, A Burks, K Zabelena, Y Miller, CB TI Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia SO CLINICAL CANCER RESEARCH LA English DT Article ID ACUTE PROMYELOCYTIC LEUKEMIA; HISTONE DEACETYLASE COMPLEX; TRANS-RETINOIC ACID; BONE-MARROW; CELLS; PHENYLACETATE; APOPTOSIS AB The aromatic fatty acid sodium phenylbutyrate (PB) promotes cytostasis and differentiation in a wide variety of tumor types; among several molecular activities, inhibition of histone deacetylase (HDAC) may account for many of its pharmacodynamic effects. A Phase I study demonstrated promising preliminary evidence of clinical activity in acute myeloid leukemia and myelodysplastic syndrome; however, plasma concentrations achieved at the maximum tolerated dose were less than those targeted based on in vitro studies. Because prolonged exposure to suboptimal concentrations of PB in vitro led to pharmacodynamic changes similar to a more brief exposure to higher concentrations, a study of the feasibility of prolonged administration of sodium PB was performed. Selected patients with acute myeloid leukemia and myelodysplastic syndrome were treated with sodium PB as a continuous i.v. infusion via ambulatory infusion pump. Sequential cohorts were treated for 7 consecutive days out of 14 or with 21 consecutive days out of 28. Prolonged infusions were well tolerated; dose-limiting central nervous system toxicity developed in 1 of 23 patients treated. End-of-infusion plasma concentrations were maintained within a range sufficient to inhibit HDAC. Two patients on the 21/28 schedule developed hematological improvement. Prolonged infu- sions of PB are well tolerated making this an attractive platform for the clinical investigation of HDAC inhibition. C1 Johns Hopkins Univ, Sch Med, Johns Hopkins Oncol Ctr, Baltimore, MD 21231 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21231 USA. NCI, Clin Pharmacokinet Sect, Bethesda, MD 20892 USA. RP Gore, SD (reprint author), Johns Hopkins Univ, Sch Med, Johns Hopkins Oncol Ctr, 1650 Orleans St,Room 288, Baltimore, MD 21231 USA. RI Figg Sr, William/M-2411-2016 FU NCI NIH HHS [CA 15396, R01 CA067803, R01 CA67803]; NCRR NIH HHS [M01 RR000052] NR 19 TC 124 Z9 137 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR PY 2002 VL 8 IS 4 BP 963 EP 970 PG 8 WC Oncology SC Oncology GA 540TU UT WOS:000174946200007 PM 11948101 ER PT J AU Salvatore, G Beers, R Margulies, I Kreitman, RJ Pastan, I AF Salvatore, G Beers, R Margulies, I Kreitman, RJ Pastan, I TI Improved cytotoxic activity toward cell lines and fresh leukemia cells of a mutant anti-CD22 immunotoxin obtained by antibody phage display SO CLINICAL CANCER RESEARCH LA English DT Article ID MIMICKING SOMATIC HYPERMUTATION; AFFINITY MATURATION; PHASE-I; HEMATOLOGIC MALIGNANCIES; RECOMBINANT IMMUNOTOXIN; PSEUDOMONAS EXOTOXIN; LYMPHOMA; THERAPY; RFB4(DSFV)-PE38; MUTAGENESIS AB Recombinant immunotoxins are fusion proteins composed of the Fv domains of antibodies fused to bacterial or plant toxins that are being developed for the targeted therapy of cancer. RFB4 (Fv)-Pseudomonas exotoxin 38 (PE38) is an immunotoxin that targets CD22 expressed on B cells and B-cell malignancies. A disulfide-stabilized form of RFB4 (Fv)-PE38 is being evaluated in a Phase I clinical trial. The aim of the present study was to improve the activity of RFB4 (Fv)-PE38 to more effectively treat patients with leukemias and lymphomas. To Increase the affinity of RFB4 (Fv), we used the techniques of phage display and hot spot mutagenesis. We identified mutational hot spot sequences in heavy chain complementary determining region 3 (V-H CDR3) and randomized these in a phage display library. Mutant phages were panned on CD22-positive Daudi cells. A variety of mutant Fvs were obtained, and the corresponding immunotoxins were prepared. Several mutant immunotoxins with increased binding affinity and cytotoxic activity were obtained. The most active immunotoxin contained amino acid residues Thr-His-Trp (THW) in place of Ser-Ser-Tyr (SSY) at positions 100, 100A, and 100B of the Fv and had an affinity improved from 85 nM to 6 nM. The THW mutant had a 5- to 10-fold increase in activity on various CD22-positive cell lines and was up to 50 times more cytotoxic to cells from patients with chronic lymphocytic leukemia and hairy-cell leukemia. C1 NCI, Mol Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Canc Res Ctr, NIH, Bldg 37,Room 5106,37 Convent Dr,MSC 4264, Bethesda, MD 20892 USA. NR 29 TC 101 Z9 103 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR PY 2002 VL 8 IS 4 BP 995 EP 1002 PG 8 WC Oncology SC Oncology GA 540TU UT WOS:000174946200011 PM 11948105 ER PT J AU Hu, N Li, G Li, WJ Wang, CY Goldstein, AM Tang, ZZ Roth, MJ Dawsey, SM Huang, J Wang, QH Ding, T Giffen, C Taylor, PR Emmert-Buck, MR AF Hu, N Li, G Li, WJ Wang, CY Goldstein, AM Tang, ZZ Roth, MJ Dawsey, SM Huang, J Wang, QH Ding, T Giffen, C Taylor, PR Emmert-Buck, MR TI Infrequent mutation in the BRCA2 gene in esophageal squamous cell carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID CANCER SUSCEPTIBILITY GENE; ALLELIC LOSS; BREAST-CANCER; CHROMOSOME 13Q12-13; IDENTIFICATION; CHINA; RAD51; P53 AB Purpose: Previous studies have shown a high rate of allelic loss in esophageal squamous cell carcinoma (ESCC) in the vicinity of the BRCA2 gene. We aimed to assess whether the tumor suppressor gene BRCA2 was the inactivation target for allelic loss observed on chromosome 13q in ESCC. Experimental Design: We examined the entire coding sequence of the BRCA2 gene for mutations using single-strand conformation polymorphism analysis and DNA sequencing in 56 ESCC patients from Shanxi, China. Results: Eight mutations were identified in 5 patients (9%), including 3 with germ-line mutations and 2 with only somatic mutations. However, all but 1 of the mutations were missense or silent changes and of unknown significance. Evidence for potential biallelic inactivation was seen in only 4 (7%) cases. Conclusions: BRCA2 mutations occur in ESCC but are infrequent and of unknown consequence. The putative target tumor suppressor gene corresponding to the high rate of chromosome 13q allelic loss remains unknown. C1 NCI, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. Shanxi Canc Hosp, Taiyuan 030013, Shanxi, Peoples R China. Chinese Acad Med Sci, Canc Inst & Hosp, Beijing 100021, Peoples R China. Informat Management Serv Inc, Silver Spring, MD 20904 USA. RP Emmert-Buck, MR (reprint author), NCI, Canc Prevent Studies Branch, 6116 Execut Plaza,Suite 705, Bethesda, MD 20892 USA. NR 22 TC 22 Z9 25 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR PY 2002 VL 8 IS 4 BP 1121 EP 1126 PG 6 WC Oncology SC Oncology GA 540TU UT WOS:000174946200029 PM 11948123 ER PT J AU McDoniels-Silvers, AL Nimri, CF Stoner, GD Lubet, RA You, M AF McDoniels-Silvers, AL Nimri, CF Stoner, GD Lubet, RA You, M TI Differential gene expression in human lung adenocarcinomas and squamous cell carcinomas SO CLINICAL CANCER RESEARCH LA English DT Article ID TISSUE GROWTH-FACTOR; PROTEIN-TYROSINE-PHOSPHATASE; FACTOR EGR-1 SUPPRESSES; FACTOR SCATTER-FACTOR; MESSENGER-RNA; IN-VIVO; CANCER-CELLS; FACTOR-BETA; C-KIT; MOLECULAR PATHOGENESIS AB Purpose: Differential cDNA library screening was performed on 7 human lung adenocarcinomas and 7 human lung squamous cell carcinomas and their corresponding adjacent normal tissues using a human lung cDNA library constructed from the normal bronchoalveolar cells of a 72-year-old male smoker. Experimental Design: Of the 2758 clones that were differentially expressed between normal and tumor tissues in the preliminary cDNA library screening analysis, 1163 clones were confirmed by dot blot, revealing a confirmation rate of >40%. DNA of confirmed clones was sequence an was subjected to GenBank Blast searches. RNA expression levels were then individually analyzed by semiquantitative reverse transcription-PCR. Results: Ninety-two genes/sequences were differentially expressed in adenocarcinomas and/or squamous cell carcinomas compared with their corresponding normal tissues. Several genes were underexpressed by at least 50% in both tumor types such as c-fos, decorin, alpha-2-macroglobulin, platelet endothelial cell adhesion molecule 1, EGR1, and fibronectin. Ribosomal protein S3 was underexpressed only in squamous cell carcinomas, whereas expression of hepatocyte growth factor activator inhibitor type 2, ubiquitin-conjugating enzyme UBC9, and clone 333E23 on chromosome Xq21.1 were altered only in adenocarcinomas. Several genes discovered recently of which the functions are unknown, such as KIAA0728 and KIAA0425, were also differentially expressed in both adenocarcinomas and squamous cell carcinomas of the lung. Conclusions: Many of these known and novel genes may be involved in human lung tumorigenesis; therefore, additional characterization is warranted and will be beneficial to the understanding of this deadly disease. C1 Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Columbus, OH 43210 USA. Med Coll Ohio, Dept Pathol, Toledo, OH 43614 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP You, M (reprint author), Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, 420 W 12th Ave, Columbus, OH 43210 USA. FU NCI NIH HHS [R01CA58554, CA16058, CN05113, R01CA78797] NR 81 TC 107 Z9 118 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR PY 2002 VL 8 IS 4 BP 1127 EP 1138 PG 12 WC Oncology SC Oncology GA 540TU UT WOS:000174946200030 PM 11948124 ER PT J AU Chang, TH Szabo, E AF Chang, TH Szabo, E TI Enhanced growth inhibition by combination differentiation therapy with ligands of peroxisome proliferator-activated receptor-gamma and inhibitors of histone deacetylase in adenocarcinoma of the lung SO CLINICAL CANCER RESEARCH LA English DT Article ID ACUTE PROMYELOCYTIC LEUKEMIA; PPAR-GAMMA; TERMINAL DIFFERENTIATION; CANCER; ACETYLTRANSFERASES; APOPTOSIS; P300; OVEREXPRESSION; LIPOSARCOMA; ACETYLATION AB Purpose: Histone deacetylase (HDAC) inhibitors and ligands of the peroxisome proliferator-activated receptor gamma (PPARgamma) have been shown previously to induce growth arrest and differentiation in a variety of cancer cell lines. The purpose of this study was to determine whether HDAC inhibitors function similarly in non-small cell lung cancer (NSCLC) and whether combination treatment with HDAC inhibitors and PPARgamma ligands is more efficacious than either agent alone. Experimental Design and Results: Nanomolar concentrations of trichostatin A induced growth arrest in rive of seven NSCLC cell lines, whereas sodium phenylbutyrate (PB) was markedly less potent. In adenocarcinomas, trichostatin A up-regulated general differentiation markers (gelsolin, Mad, and p21/WAF1) and down-regulated markers of the type II pneumocyte progenitor cell lineage (MUC1 and SP-A), indicative of a more mature phenotype. PB had a similar effect. Simultaneous treatment with a PPARgamma ligand and PB enhanced the growth inhibition in adenocarcinomas but not in nonadenocarcinomas. Growth arrest was accompanied by markedly decreased cyclin D1 expression but not enhanced differentiation. Conclusions: The present study demonstrates potent growth-inhibitory and differentiation-inducing activity of HDAC inhibitors in NSCLC and suggests that combination differentiation therapy should be explored further for the treatment of lung adenocarcinomas. C1 NCI, Div Canc Prevent, Lung & Upper Aerodigest Canc Res Grp, Bethesda, MD 20892 USA. NINCDS, Mol Physiol & Biophys Unit, Bethesda, MD 20892 USA. RP Szabo, E (reprint author), NCI, Div Canc Prevent, Lung & Upper Aerodigest Canc Res Grp, 6130 Execut Blvd,Room 2132, Bethesda, MD 20892 USA. NR 27 TC 67 Z9 72 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR PY 2002 VL 8 IS 4 BP 1206 EP 1212 PG 7 WC Oncology SC Oncology GA 540TU UT WOS:000174946200040 PM 11948134 ER PT J AU Beliveau, R Gingras, D Kruger, EA Lamy, S Sirois, P Tranqui, L Baffert, F Beaulieu, E Dimitriadou, V Pepin, MC Courjal, F Ricard, I Poyet, P Falardeau, P Figg, WD Dupont, E AF Beliveau, R Gingras, D Kruger, EA Lamy, S Sirois, P Tranqui, L Baffert, F Beaulieu, E Dimitriadou, V Pepin, MC Courjal, F Ricard, I Poyet, P Falardeau, P Figg, WD Dupont, E TI The antiangiogenic agent Neovastat (AE-941) inhibits vascular endothelial growth factor-mediated biological effects SO CLINICAL CANCER RESEARCH LA English DT Article ID FOCAL ADHESION KINASE; PLATELET-ACTIVATING-FACTOR; IN-VITRO ANGIOGENESIS; AMINO-ACID-SEQUENCE; PERMEABILITY FACTOR; SIGNAL-TRANSDUCTION; TYROSINE PHOSPHORYLATION; SHARK CARTILAGE; TUMOR-GROWTH; CELL PROLIFERATION AB Purpose: Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis, which exerts direct effects on vascular endothelial cells, including endothelial cell proliferation and survival, tubulogenesis, and vascular permeability. In this study, we examined whether Neovastat, a naturally occurring multifunctional antiangiogenic drug, could inhibit the endothelial cell response to VEGF stimulation. Results: We demonstrated that Neovastat was able to block the VEGF-dependent microvessel sprouting from Matrigel-embedded rat aortic rings, and it also blocked the VEGF-induced endothelial cell tubulogenesis in vitro. lit vivo studies showed that Neovastat was able to specifically inhibit VEGF-induced plasma extravasation in numerous tissues, including pancreas and skin. The mechanism of action of Neovastat on VEGF-mediated effects was also evaluated at the molecular level. Neovastat was shown to compete against the binding of VEGF to its receptor in endothelial cells and significantly inhibited the VEGF-dependent tyrosine phosphorylation of VEGF receptor-2, whereas it had no significant effect on VEGF receptor-1 activity. Moreover, the inhibition of receptor phosphorylation was correlated with a marked decrease in the ability of VEGF to induce pERK activation. Neovastat does not compete against the binding of basic fibroblast growth factor, indicating a preferential inhibitory effect on the VEGF receptor. Conclusions: Because Neovastat was shown previously to inhibit metalloproteinase activities, these results suggest that Neovastat is able to target multiple steps In tumor neovascularization, further emphasizing its use as a pleiotropic, multifunctional antiangiogenic drug. C1 Ste Justine UQAM, Lab Med Mol, Ctr Canc Charles Bruneau, Montreal, PQ H3T 1C5, Canada. NCI, Div Clin Sci, Med Branch, NIH, Bethesda, MD 20892 USA. Univ Sherbrooke, Fac Med, Dept Pharmacol, Sherbrooke, PQ J1H 5N4, Canada. Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada. CEA, EMI 105, BRCE, DBMS, F-38054 Grenoble 9, France. Eterna Labs Inc, Quebec City, PQ G1P 4P5, Canada. RP Beliveau, R (reprint author), Ste Justine UQAM, Lab Med Mol, Ctr Canc Charles Bruneau, 3175 Chemin, Montreal, PQ H3T 1C5, Canada. EM molmed@justine.umontreal.ca RI Figg Sr, William/M-2411-2016 NR 75 TC 55 Z9 60 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR PY 2002 VL 8 IS 4 BP 1242 EP 1250 PG 9 WC Oncology SC Oncology GA 540TU UT WOS:000174946200045 PM 11948139 ER PT J AU Arcos-Burgos, M Muenke, M AF Arcos-Burgos, M Muenke, M TI Genetics of population isolates SO CLINICAL GENETICS LA English DT Review DE population genetics; complex disorder; Columbia ID OLD ORDER AMISH; GIRDLE MUSCULAR-DYSTROPHY; HEREDITARY CEREBROVASCULAR-DISEASE; NEURONAL CEROID-LIPOFUSCINOSIS; ASTHMA-SUSCEPTIBILITY LOCI; BIPOLAR AFFECTIVE-DISORDER; ONSET ALZHEIMER-DISEASE; MAPPING COMPLEX TRAITS; VAN-CREVELD-SYNDROME; GENOME-WIDE SEARCH AB Genetic isolates, as shown empirically by the Finnish, Old Order Amish, Hutterites, Sardinian and Jewish communities among others, represent a most important and powerful tool in genetically mapping inherited disorders. The main features associated with that genetic power are the existence of multigenerational pedigrees which are mostly descended from a small number of founders a short number of generations ago, environmental and phenotypic homogeneity, restricted geographical distribution, the presence of exhaustive and detailed records correlating individuals in very well ascertained pedigrees, and inbreeding as a norm. On the other hand, the presence of a multifounder effect or admixture among divergent populations in the founder time (e.g. the Finnish and the Paisa community from Colombia) will theoretically result in increased linkage disequilibrium among adjacent loci. The present review evaluates the historical context and features of some genetic isolates with emphasis on the basic population genetic concepts of inbreeding and genetic drift, and also the state-of-the-art in mapping traits, both Mendelian and complex, on genetic isolates. C1 Natl Ctr Human Genome Res, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Antioquia, Mutacarcinogenesis & Genet Epidemiol Grp, Medellin, Colombia. RP Muenke, M (reprint author), Natl Ctr Human Genome Res, Med Genet Branch, NIH, 10 Ctr Drive,MSC 1852,Bldg 10,Room 10C103, Bethesda, MD 20892 USA. EM muenke@nih.gov NR 198 TC 148 Z9 153 U1 4 U2 21 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD APR PY 2002 VL 61 IS 4 BP 233 EP 247 DI 10.1034/j.1399-0004.2002.610401.x PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 560MQ UT WOS:000176086200001 PM 12030885 ER PT J AU Krogstad, P Lee, S Johnson, G Stanley, K McNamara, J Moye, J Jackson, JB Aguayo, R Dieudonne, A Khoury, M Mendez, H Nachman, S Wiznia, A AF Krogstad, P Lee, S Johnson, G Stanley, K McNamara, J Moye, J Jackson, JB Aguayo, R Dieudonne, A Khoury, M Mendez, H Nachman, S Wiznia, A CA Pediatric AIDS Clinical Trials Grp TI Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human immunodeficiency virus type 1 SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID RANDOMIZED CONTROLLED TRIAL; COMBINATION TREATMENT; HIV-1 INFECTION; VIRAL LOAD; THERAPY; ZIDOVUDINE; DIDANOSINE; INFANTS; RNA; QUANTITATION AB The relative potency and tolerability of multidrug regimens used to treat infants and children infected with human immunodeficiency virus type 1 (HIV-1) are largely unknown. In Pediatric AIDS Clinical Trials Group (PACTG) Protocol 377, 181 infants and children were assigned to receive stavudine (d4T) plus nevirapine (NVP) and ritonavir (RTV); d4T plus lamivudine (3TC) and nelfinavir (NFV); d4T plus NVP and NFV; or d4T plus 3TC, NVP, and NFV. Eleven additional children received d4T and NVP plus NFV given twice daily. All subjects had not previously received protease inhibitors or nonnucleoside reverse-transcriptase inhibitors and all had been immunologically stable while receiving reverse-transcriptase inhibitor therapy. After 48 weeks of therapy, 17 (41%) of 41 subjects receiving d4T-NVP-RTV, 13 (30%) of 44 receiving d4T-NVP-NFV, 21 (42%) of 50 receiving d4T-3TC and NFV (3 times daily), and 22 (52%) of 42 receiving d4T-3TC-NVP-NFV were still receiving their assigned therapy and had HIV-1 RNA suppression to less than or equal to400 copies/mL. These regimens were similar in their drug activity, but the 4-drug regimen offered slightly more durable suppression of viremia. C1 Univ Calif Los Angeles, Sch Med, Dept Pediat, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. Univ So Calif, Sch Med, Los Angeles, CA USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Med Univ S Carolina, Charleston, SC 29425 USA. NIAID, NIH, Bethesda, MD 20892 USA. NICHHD, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD USA. Ramon Ruiz Aranu Univ Hosp, Bayamon, PR USA. Univ Med & Dent New Jersey, Newark, NJ 07103 USA. SUNY Stony Brook, Hlth Sci Ctr, Stony Brook, NY 11794 USA. Lincoln Hosp, Bronx, NY USA. Jacobi Med Ctr, Pediat HIV Serv, Bronx, NY USA. RP Krogstad, P (reprint author), Univ Calif Los Angeles, Sch Med, Dept Pediat, 10833 Le Conte Ave,Rm 22-442 MDCC, Los Angeles, CA 90095 USA. OI moye, john/0000-0001-9976-8586 FU NIAID NIH HHS [AI-41110] NR 25 TC 46 Z9 47 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD APR 1 PY 2002 VL 34 IS 7 BP 991 EP 1001 DI 10.1086/338814 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 529WJ UT WOS:000174324000015 PM 11880966 ER PT J AU Simpson, JK Metcalfe, DD AF Simpson, JK Metcalfe, DD TI Mastocytosis and disorders of mast cell proliferation SO CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY LA English DT Review ID C-KIT MUTATION; BLOOD MONONUCLEAR-CELLS; SYSTEMIC MASTOCYTOSIS; PEDIATRIC MASTOCYTOSIS; CATALYTIC DOMAIN; DISEASE; LEUKEMIA; SARCOMA C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Metcalfe, DD (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 62 TC 7 Z9 7 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1080-0549 J9 CLIN REV ALLERG IMMU JI Clin. Rev. Allergy Immunol. PD APR PY 2002 VL 22 IS 2 BP 175 EP 188 DI 10.1385/CRIAI:22:2:175 PG 14 WC Allergy; Immunology SC Allergy; Immunology GA 535CN UT WOS:000174627800006 PM 11975422 ER PT J AU Iwata, H Yoshinari, K Negishi, M Stegeman, JJ AF Iwata, H Yoshinari, K Negishi, M Stegeman, JJ TI Species-specific responses of constitutively active receptor (CAR) - CYP2B coupling: lack of CYP2B inducer-responsive nuclear translocation of CAR in marine teleost, scup (Stenotomus chrysops) SO COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY LA English DT Article DE nuclear receptor; constitutively active receptor or constitutive androstane receptor; transcription factor; cytochrome P4502B; halogenated aromatic hydrocarbons; 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene; Stenotomus chrysops; alkoxyresorufin O-dealkylase activity; phenobarbital-type chemical ID PHENOBARBITAL-LIKE INDUCER; OKADAIC ACID PRODUCTION; MONO-OXYGENASE ACTIVITY; CORAL-REEF ECOSYSTEM; PREGNANE-X-RECEPTOR; ENHANCER MODULE; GENE; INDUCTION; 1,4-BIS<2-(3,5-DICHLOROPYRIDYLOXY)>BENZENE; CYTOCHROME-P-450 AB The mammalian constitutively active receptor (CAR) is a novel ligand-activated transcription factor that participates in controlling the expression of cytochrome P450 2B (CYP2B) genes in response to pharmaceutical agents (phenobarbital) and halogenated aromatic hydrocarbons (ortho-substituted PCBs). The occurrence and physiological function of this protein are as yet unknown in marine animals, where there has been a paradoxical lack of induction by PB-type chemicals. One approach to understanding CAR function is to study the evolutionary history of processes such as CAR-CYP2B coupling. In this study, CAR function was evaluated in a representative teleost fish (scup, Stenotomus chrysops). Treatment of scup with 1,4-bis [2- (3,5-dichloropyridyloxy)] benzene (TCPOBOP), which is one of the most potent CYP2B inducers in mouse, caused no increase in hepatic alkoxyresorufin O-dealkylase activity nor in immunodetectable CYP2B-like protein levels. Western blot analyses of scup livers using anti-human CAR antisera revealed the occurrence of a putative CAR homologue in nuclear and cytoplasmic fractions, but no nuclear accumulation of CAR following TCPOBOP treatment, which is a first step regulating the transcriptional activation of CYP2B genes in mouse. Immunohistochemical study also showed no translocation of CAR into nucleus in the hepatocytes of TCPOBOP-treated scup. These results suggest that there may be species-specific differences in CAR activation or CAR-CYP2B coupling signaling transduction in fish from those in mouse. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Ehime Univ, Ctr Marine Environm Studies, Matsuyama, Ehime 7908566, Japan. Woods Hole Oceanog Inst, Biol Dept, Woods Hole, MA 02543 USA. Ehime Univ, Ctr Marine Environm Studies, Matsuyama, Ehime 7908566, Japan. NIEHS, Lab Reprod & Dev Toxicol, Res Triangle Pk, NC 27709 USA. RP Iwata, H (reprint author), Ehime Univ, Ctr Marine Environm Studies, Tarumi 3-5-7, Matsuyama, Ehime 7908566, Japan. RI Iwata, Hisato/A-5478-2013 OI Iwata, Hisato/0000-0002-6867-0532 FU NIEHS NIH HHS [ES-07381] NR 35 TC 26 Z9 28 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1532-0456 J9 COMP BIOCHEM PHYS C JI Comp. Biochem. Physiol. C-Toxicol. Pharmacol. PD APR PY 2002 VL 131 IS 4 BP 501 EP 510 AR PII S1532-0456(02)00038-8 DI 10.1016/S1532-0456(02)00038-8 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Toxicology; Zoology SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Toxicology; Zoology GA 549DY UT WOS:000175430300011 PM 11976065 ER PT J AU Unda, FJ Iehara, N De Vega, S De la Fuente, M Vilaxa, A Cobourne, M Sharpe, PT Yamada, Y AF Unda, FJ Iehara, N De Vega, S De la Fuente, M Vilaxa, A Cobourne, M Sharpe, PT Yamada, Y TI Analysis of cDNAs from a mouse embryo tooth library: Identification of novel genes during tooth development SO CONNECTIVE TISSUE RESEARCH LA English DT Article; Proceedings Paper CT International Conference on Tooth Morphogenesis and Differentiation CY 2001 CL LYON, FRANCE DE cDNA library; odontogenesis; genes ID ODONTOBLAST DIFFERENTIATION; IN-VITRO; MORPHOGENESIS; AMELOBLASTIN; TGF-BETA-1 AB Signaling molecules, their receptors, and target genes from pathways and networks regulate the development of the tooth from initiation through cell differentiation. In order to identify genes involved in odontoblast and ameloblast differentiation, we constructed a cDNA library from E19.5 mouse molars. In this work, we report the partial cDNA sequences of 10 noncharacterized genes and we show cell expression of the transcripts on mouse embryo molars by in situ hybridization. C1 Univ Basque Country, Fac Med & Dent, Dept Cell Biol, Leioa 48940, Vizcaya, Spain. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. Univ Tarapaca, Dept Biol & Salud, Arica, Chile. Guys Hosp, UMDS, Dept Craniofacial Dev, London SE1 9RT, England. RP Unda, FJ (reprint author), Univ Basque Country, Fac Med & Dent, Dept Cell Biol, Leioa 48940, Vizcaya, Spain. NR 17 TC 1 Z9 1 U1 2 U2 19 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0300-8207 J9 CONNECT TISSUE RES JI Connect. Tissue Res. PD APR PY 2002 VL 43 IS 2-3 BP 176 EP 179 DI 10.1080/03008200290000844 PG 4 WC Cell Biology; Orthopedics SC Cell Biology; Orthopedics GA 573QB UT WOS:000176841400019 PM 12489155 ER PT J AU Chen, S Gu, TT Sreenath, T Kulkarni, AB Karsenty, G MacDougall, M AF Chen, S Gu, TT Sreenath, T Kulkarni, AB Karsenty, G MacDougall, M TI Spatial expression of Cbfa1/Runx2 isoforms in teeth and characterization of binding sites in the DSPP gene SO CONNECTIVE TISSUE RESEARCH LA English DT Article; Proceedings Paper CT International Conference on Tooth Morphogenesis and Differentiation CY 2001 CL LYON, FRANCE DE Cbfa1; Runx2 isoforms; dentin sialophosphoprotein; odontogenesis; in situ hybridization; gene regulation ID TRANSCRIPTION FACTOR OSF2/CBFA1; OSTEOCALCIN GENE; OSTEOBLAST DIFFERENTIATION; DENTIN PHOSPHOPROTEIN; TOOTH DEVELOPMENT; CBFA1; SIALOPROTEIN; MOUSE; PATTERNS; PRODUCTS AB Cbfa1/Runx2 is an essential transcription factor for osteoblast and odontoblast differentiation. Heterogeneous mutations of Cbfa1 gene result in cleidocranial dysplasia, an autosomal dominant syndrome, characterized by abnormal skeletal genesis and dental disorders. Recently three Cbfa1/Runx isoforms (Pebp2alphaA/type I, til-1/type II, and Osf2/type III) have been identified that differ in their amino-terminal sequences. The precise roles of Cbfa1/Runx2 isoforms in odontoblast development are not known. The purpose of this study was to determine and compare expression patterns of the three Cbfa1/Runx2 isoforms in newborn tooth organs. Toward this aim, we developed three probes: type I and type II, which specifically hybridize with Pebp2alphaA and til-1, respectively, and type II/III, which hybridizes with osf2 and partially with til-1. In addition, Cbfa1/Runx2 binding sites were identified in the regulatory elements of mouse dentin sialophosphoprotein (mDSPP) gene, which encodes a matrix protein expressed during odontogenesis. In situ hybridization performed with the specific Cbfa1/Runx2 isoform probes demonstrated that all isoforms are expressed in teeth and bone. The type I isoform was expressed at higher levels than isoforms type II and type II/III in developing newborn mouse incisors. Genomic mDSPP clones were isolated and characterized containing similar to2.6 kb of the promoter region. Computer analysis of the promoter segment and intron 1 revealed a number of potential transcriptional factor binding sites including five Cbfa1/Runx2 binding sites, three in the promoter region and two within intron 1. DNA-protein assay and antibody supershift experiments showed that these binding sites interact with nuclear extracts isolated from the mouse odontoblast cell line MO6-G3. Further characterization of the functional role of Cbfa1/Runx2 in the regulation of the mDSPP gene expression is being investigated. C1 Univ Texas, Hlth Sci Ctr, Sch Dent, Dept Pediat Dent, San Antonio, TX 78229 USA. Natl Inst Dent & Craniofacial Res, Funct Genom Unit, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Gene Targeting Facil, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Houston, TX 77030 USA. RP Chen, S (reprint author), Univ Texas, Hlth Sci Ctr, Sch Dent, Dept Pediat Dent, 7703 Floyd Curl Dr MC 7888, San Antonio, TX 78229 USA. FU NIDCR NIH HHS [Z0DE00694-010, DE113221] NR 27 TC 19 Z9 19 U1 0 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0300-8207 J9 CONNECT TISSUE RES JI Connect. Tissue Res. PD APR PY 2002 VL 43 IS 2-3 BP 338 EP 344 DI 10.1080/03008200290000691 PG 7 WC Cell Biology; Orthopedics SC Cell Biology; Orthopedics GA 573QB UT WOS:000176841400042 PM 12489178 ER PT J AU Putt, ME Ravina, B AF Putt, ME Ravina, B TI Randomized, placebo-controlled, parallel group versus crossover study designs for the study of dementia in Parkinson's disease SO CONTROLLED CLINICAL TRIALS LA English DT Article DE crossover design; study design; Parkinson's disease; Alzheimer's disease; bias ID CLINICAL-TRIALS; ALZHEIMERS-DISEASE; CARRY-OVER; 2-TREATMENT; STATISTICS; TACRINE; ROBUST AB In studies of dementia, crossover designs are controversial, reflecting concerns about temporal stability of disease, confounding of treatment effects with period by treatment interactions and/or carryover effects. Carryover effects are differences in the lingering effect of treatments (placebo) into subsequent periods. In the context of a trial to study the effect of donepezil on dementia in patients with Parkinson's disease, we examine two-sequence crossover studies with two or four periods, and a four-sequence design with two periods. We quantify bias in estimated treatment effects due to carryover effects and explore the use of biased estimators in hypothesis testing. For hypothesis testing, type I error rates are valid if (1) repeated administration of treatment alters the outcome only for effective treatments and (2) carryover effects due to placebo following treatment periods are nonzero only for effective treatments. For crossover and parallel group designs, sample sizes are adjusted for reduced statistical power due to carryover effects and temporal changes in variance. For the proposed clinical study, we estimate that a single-period parallel group design with baselines would require 104 patients and take about 23 months to complete. A two-sequence, four-period parallel group design with baselines would require about 80 patients and about 20 months to complete. We conservatively assume a carryover effect of 50% of the treatment effect for a two-sequence four-period crossover design. The estimated treatment effect for this model may underestimate the true treatment effect by up to 13%. The sample size/study length requirements are 28 patients or 12.4 months, respectively, a substantial saving over either parallel group design. The cost of allowing for carryover in the sample size calculation is about 1.2 months of study time. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Dept Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. NINCDS, Clin Trials Cluster, NIH, Rockville, MD USA. RP Putt, ME (reprint author), Univ Penn, Dept Biostat & Epidemiol, 621 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. FU NICHD NIH HHS [P30-HD 26979-11] NR 36 TC 18 Z9 18 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD APR PY 2002 VL 23 IS 2 BP 111 EP 126 AR PII S0197-2456(01)00207-0 DI 10.1016/S0197-2456(01)00207-0 PG 16 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 539EU UT WOS:000174858200002 PM 11943439 ER PT J AU Emery, S Abrams, DI Cooper, DA Darbyshire, JH Lane, HC Lundgren, JD Neaton, JD AF Emery, S Abrams, DI Cooper, DA Darbyshire, JH Lane, HC Lundgren, JD Neaton, JD CA ESPRIT Study Grp TI The Evaluation of Subcutaneous Proleukin (R) (interleukin-2) in a Randomized International Trial: rationale, design, and methods of ESPRIT SO CONTROLLED CLINICAL TRIALS LA English DT Article DE interleukin-2; HIV; clinical endpoint study ID HUMAN-IMMUNODEFICIENCY-VIRUS; PNEUMOCYSTIS-CARINII PNEUMONIA; ACTIVE ANTIRETROVIRAL THERAPY; NUCLEOSIDE ANALOG THERAPY; AIDS CLINICAL-TRIALS; CD4 CELL COUNTS; HIV-INFECTION; CUBIC MILLIMETER; INTRAVENOUS INTERLEUKIN-2; SECONDARY PROPHYLAXIS AB The Evaluation of Subcutaneous Proleukin(R) in a Randomized International Trial (ESPRIT) is a large ongoing randomized trial of subcutaneous interleukin-2 (IL-2) plus antiretroviral therapy versus antiretroviral therapy alone in patients with HIV (human immunodeficiency virus) disease and CD4 cell counts of at least 300 cells/mm(3). The primary objective is to determine whether the addition of IL-2 to combination antiretroviral therapy improves morbidity and mortality. The aim is to recruit 4000 participants and follow them for an average of 5 years. Eligible subjects will be recruited at 275 investigational sites in 23 countries around the world. Coupled with broad eligibility criteria this will ensure widely applicable results. A range of secondary objectives will also be addressed in this setting that will include the conduct of observational studies and nested substudies with a public health focus. This article describes the rationale supporting the trial in addition to reviewing the study design, coordination, and governance. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Univ New South Wales, Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW 2010, Australia. Univ Calif San Francisco, San Francisco, CA USA. UCL, Med Sch, MRC Clin Trials Unit, London, England. Natl Inst Allergy & Infect Dis, NIH, Bethesda, MD USA. Univ Copenhagen, Hvidovre Hosp, Dept Infect Dis, Copenhagen, Denmark. Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN USA. RP Emery, S (reprint author), Univ New South Wales, Natl Ctr HIV Epidemiol & Clin Res, Level 2 376 Victoria St, Sydney, NSW 2010, Australia. EM semery@nchecr.unsw.edu.au RI Emery, Sean/H-4920-2013; OI Emery, Sean/0000-0001-6072-8309; Lundgren, Jens/0000-0001-8901-7850 FU NIAID NIH HHS [1U01 AI 46957] NR 50 TC 68 Z9 69 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD APR PY 2002 VL 23 IS 2 BP 198 EP 220 AR PII S0197-2456(01)00179-9 DI 10.1016/S0197-2456(01)00179-9 PG 23 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 539EU UT WOS:000174858200011 PM 11943448 ER PT J AU Zalla, T Phipps, M Grafman, J AF Zalla, T Phipps, M Grafman, J TI Story processing in patients with damage to the prefrontal cortex SO CORTEX LA English DT Article DE prefrontal cortex; narrative comprehension; story-grammar knowledge; scripts; complex-event categorization; amnesia ID FRONTAL-LOBE DAMAGE; DISCOURSE COMPREHENSION; TEXT COMPREHENSION; RIGHT-HEMISPHERE; HEAD-INJURY; IMPAIRMENTS; MEMORY; RECALL; INFERENCES; KNOWLEDGE AB The prefrontal cortex is known to be involved in performing complex cognitive tasks requiring reasoning, planning and decision-making. Neuropsychological evidence also supports the idea that the prefrontal cortex is generally involved in encoding and retrieving complex events, such as action and narrative knowledge. Patients with frontal lobe damage are reported to have difficulty in processing different aspects of narrative representations, such as the figurative moral meaning, syntactic features, and inference generation. In the present study, we examined story processing in 17 patients with frontal lobe lesions and compared their performance to 7 amnesic patients and 17 normal controls. Two stories were presented by using two slightly different processing demands in order to assess the subject's ability to draw inferences on-line during the course of comprehension or later retrieval. Although all patients had impaired story memory, patients with frontal lobe lesions showed a pattern of deficit at an early stage of story comprehension that specifically involved the ability to reconstruct the sequential links among events and to extract inferential knowledge from the text during encoding. Amnesic patients were severely impaired in recalling story semantic units, including single events and larger narrative constituents, as well as in the event recognition task. Consequently, they were unable to establish inferential relations among the events and, thus, the global sequential structure of the stories during retrieval. In contrast, they had no difficulty in extracting inferential knowledge during story comprehension on the basis of readily available information. This study shows that damage to different cortical regions may induce impairments at various levels of story processing. C1 NINCDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Zalla, T (reprint author), Inst Cognit Sci, 67 Blvd Pinel, F-69675 Bron, France. OI Phipps, Michael/0000-0001-8398-5404; Grafman, Jordan H./0000-0001-8645-4457 NR 47 TC 16 Z9 16 U1 3 U2 3 PU MASSON DIVISIONE PERIODICI PI MILAN PA VIA FRATELLI BRESSAN 2, 20126 MILAN, ITALY SN 0010-9452 J9 CORTEX JI Cortex PD APR PY 2002 VL 38 IS 2 BP 215 EP 231 DI 10.1016/S0010-9452(08)70651-8 PG 17 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 559RH UT WOS:000176038800009 PM 12056690 ER PT J AU Cui, XH Quezado, AMN Eichacker, PQ AF Cui, XH Quezado, AMN Eichacker, PQ TI Inhaled nitric oxide: Is systemic host defense at risk? SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE nitric oxide; inhalation; respiratory distress syndrome; sepsis; host defense; leukocyte ID RESPIRATORY-DISTRESS-SYNDROME; LUNG INJURY; INHALATION; HEMOGLOBIN; RATS; NO C1 NIH, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIH, Dept Anesthesiol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Cui, XH (reprint author), NIH, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RI Quezado, Zenaide/O-4860-2016 OI Quezado, Zenaide/0000-0001-9793-4368 NR 20 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD APR PY 2002 VL 30 IS 4 BP 945 EP 946 DI 10.1097/00003246-200204000-00048 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 540YB UT WOS:000174957500048 PM 11940783 ER PT J AU Ma, PL Danner, RL AF Ma, PL Danner, RL TI The many faces of sepsis-induced vascular failure SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE septic shock; hypotension; norepinephrine; nitric oxide; superoxide; peroxynitrite ID NITRIC-OXIDE SYNTHASE; HUMAN SEPTIC SHOCK; ENDOTOXIC-SHOCK; ENDOTHELIAL DYSFUNCTION; THORACIC AORTA; IN-VIVO; SUPEROXIDE; INHIBITION; CATECHOLAMINES; PEROXYNITRITE C1 NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Danner, RL (reprint author), NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. NR 36 TC 7 Z9 12 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD APR PY 2002 VL 30 IS 4 BP 947 EP 949 DI 10.1097/00003246-200204000-00049 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA 540YB UT WOS:000174957500049 PM 11940784 ER PT J AU Hager, GL Elbi, C Becker, M AF Hager, GL Elbi, C Becker, M TI Protein dynamics in the nuclear compartment SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Article ID LIVING HUMAN-CELLS; GLUCOCORTICOID RECEPTOR; RAPID EXCHANGE; CHROMATIN; VISUALIZATION; GENE; TRANSCRIPTION; ORGANIZATION; SEQUENCES; MOBILITY AB The classic view of a transcriptional initiation complex is that of an assembly of factors with many protein-protein contacts, leading to a multi-component complex whose existence is a result of the stabilizing influence of the many intermolecular interactions. Recent findings from protein mobility experiments in living cells indicate that many kinds of nuclear factors move rapidly and exchange quickly with multiple targets. Two countervailing views of factor/regulatory site interactions emerge from the current literature. C1 NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, NIH, Bldg 41,B602,41 Lib Dr, Bethesda, MD 20892 USA. NR 36 TC 62 Z9 64 U1 1 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD APR PY 2002 VL 12 IS 2 BP 137 EP 141 DI 10.1016/S0959-437X(02)00278-2 PG 5 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 530KL UT WOS:000174356800003 PM 11893485 ER PT J AU Redon, C Pilch, D Rogakou, E Sedelnikova, O Newrock, K Bonner, W AF Redon, C Pilch, D Rogakou, E Sedelnikova, O Newrock, K Bonner, W TI Histone H2A variants H2AX and H2AZ SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Article ID TETRAHYMENA-THERMOPHILA; SACCHAROMYCES-CEREVISIAE; DROSOPHILA-MELANOGASTER; SEQUENCE; PHOSPHORYLATION; PROTEIN; ISOPROTEIN; SERINE-139; COMPLEXES; CHROMATIN AB Two of the nucleosomal histone families, H3 and H2A, have highly conserved variants with specialized functions. Recent studies have begun to elucidate the roles of two of the H2A variants, H2AX and H2AZ. H2AX is phosphorylated on a serine four residues from the carboxyl terminus in response to the introduction of DNA double-strand breaks, whether these breaks are a result of environmental insult, metabolic mistake, or programmed process. H2AZ appears to alter nucleosome stability, is partially redundant with nucleosome remodeling complexes, and is involved in transcriptional control. C1 NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Erasmus Univ, Ctr Biomed Genet, MGC Dept Cell Biol & Genet, NL-3000 DR Rotterdam, Netherlands. RP Redon, C (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 45 TC 489 Z9 517 U1 10 U2 39 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD APR PY 2002 VL 12 IS 2 BP 162 EP 169 DI 10.1016/S0959-437X(02)00282-4 PG 8 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 530KL UT WOS:000174356800007 PM 11893489 ER PT J AU Dhillon, N Kamakaka, RT AF Dhillon, N Kamakaka, RT TI Breaking through to the other side: silencers and barriers SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Article ID ORIGIN RECOGNITION COMPLEX; SACCHAROMYCES-CEREVISIAE; EPIGENETIC INHERITANCE; DNA-REPLICATION; FISSION YEAST; PROTEIN; HETEROCHROMATIN; SIR1; DOMAINS; LOCI AB The establishment and restriction of transcriptionally inactive regions in the nucleus is mediated by silencer and barrier elements. Silencer-bound proteins recruit additional factors to establish the silenced domain during the S-phase of the cell cycle but, contrary to previous models, DNA replication is not a pre-requisite for the establishment. Characteristically, silenced domains contain hypoacetylated histones and recent data have identified residue-specific methylation of histone H3 as an additional signature that distinguishes active regions from inactive ones. Peaks of acetylated histones demarcate the boundaries between these regions and recruitment of HAT activities provides a mechanism to restrict the spread of heterochromatin. C1 NICHD, Unit Chromatin & Transcript, NIH, Bethesda, MD 20892 USA. RP Dhillon, N (reprint author), NICHD, Unit Chromatin & Transcript, NIH, Bldg 18T,Rm 106,18 Lib Dr, Bethesda, MD 20892 USA. NR 44 TC 28 Z9 30 U1 2 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD APR PY 2002 VL 12 IS 2 BP 188 EP 192 DI 10.1016/S0959-437X(02)00285-X PG 5 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 530KL UT WOS:000174356800010 PM 11893492 ER PT J AU Singer, A AF Singer, A TI New perspectives on a developmental dilemma: the kinetic signalling model and the importance of signal duration for the CD4/CD8 lineage decision SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID T-CELL RECEPTOR; CD8 LINEAGE; ANTIGEN RECEPTOR; POSITIVE SELECTION; TYROSINE KINASE; SP THYMOCYTES; COMMITMENT; DIFFERENTIATION; NOTCH1; INSTRUCTION AB Double-positive thymocytes are short-lived bipotential cells whose developmental fate is determined by the specificity of their TCRs. A relatively small number of double-positive thymocytes undergo positive selection in the thymus and these are signaled to differentiate either into CD4(+) or CD8(+) mature T cells. The mechanism by which double-positive thymocytes determine their appropriate CD4/CD8 fate has been the subject of intense theoretical debate and rigorous experimental analysis. In the last year, 'signal duration' has been offered as a replacement for 'signal strength' as a major determinant of the CD4/CD8 decision, a deceptively minor refinement that requires a major change in our understanding of how signaled double-positive thymocytes differentiate into mature T cells. Indeed, the kinetic signaling model provides a radically new perspective on the mechanism by which the CD4/CD8 lineage decision is made. C1 NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, Bldg 10,Room 4B36, Bethesda, MD 20892 USA. NR 43 TC 112 Z9 113 U1 0 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD APR PY 2002 VL 14 IS 2 BP 207 EP 215 DI 10.1016/S0952-7915(02)00323-0 PG 9 WC Immunology SC Immunology GA 524RK UT WOS:000174026500009 PM 11869894 ER PT J AU Hikosaka, O Nakamura, K Sakai, K Nakahara, H AF Hikosaka, O Nakamura, K Sakai, K Nakahara, H TI Central mechanisms of motor skill learning SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Review ID MEDIAL FRONTAL-CORTEX; BASAL GANGLIA; SEQUENTIAL-PROCEDURES; SENSORIMOTOR SEQUENCES; VISUOMOTOR SEQUENCE; NEURONAL-ACTIVITY; TIME-COURSE; CEREBELLAR; MONKEY; REPRESENTATIONS AB Recent studies have shown that frontoparietal cortices and interconnecting regions in the basal ganglia and the cerebellum are related to motor skill learning. We propose that motor skill learning occurs independently and in different coordinates in two sets of loop circuits: cortex-basal ganglia and cortex-cerebellum. This architecture accounts for the seemingly diverse features of motor learning. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. Ctr Neural Basis Cognit, Pittsburgh, PA 15213 USA. Inst Neurol, Wellcome Dept Cognit Neurol, London WC1N 3BG, England. RIKEN Brain Sci Inst, Lab Math Neurosci, Wako, Saitama 3510198, Japan. RP Hikosaka, O (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50, Bethesda, MD 20892 USA. RI Nakahara, Hiroyuki/N-5411-2015 OI Nakahara, Hiroyuki/0000-0001-6891-1175 NR 66 TC 413 Z9 420 U1 3 U2 65 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD APR PY 2002 VL 12 IS 2 BP 217 EP 222 DI 10.1016/S0959-4388(02)00307-0 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 540ZZ UT WOS:000174961900014 PM 12015240 ER PT J AU Theodore, WH AF Theodore, WH TI When is positron emission tomography really necessary in epilepsy diagnosis? SO CURRENT OPINION IN NEUROLOGY LA English DT Article ID TEMPORAL-LOBE EPILEPSY; BENZODIAZEPINE RECEPTOR-BINDING; FLUORODEOXYGLUCOSE-PET; PARTIAL SEIZURES; FLUMAZENIL-PET; METABOLISM; LANGUAGE; MRI AB Positron emission tomography can be used for localization of epileptic foci, and preoperative functional mapping. Rapid improvements in magnetic resonance imaging, however, have restricted the need for positron emission tomography to a minority of patients who have unrevealing magnetic resonance imaging scans. Positron emission tomography will continue to be of value in investigations of the pathophysiology of seizure disorders. C1 NIH, Clin Epilepsy Sect, Bethesda, MD 20892 USA. RP Theodore, WH (reprint author), NIH, Clin Epilepsy Sect, 9000 Rockville Pike,Bldg 10,Room 5N-250, Bethesda, MD 20892 USA. NR 52 TC 9 Z9 9 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1350-7540 J9 CURR OPIN NEUROL JI Curr. Opin. Neurol. PD APR PY 2002 VL 15 IS 2 BP 191 EP 195 DI 10.1097/00019052-200204000-00011 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 539AJ UT WOS:000174847000011 PM 11923634 ER PT J AU Clore, GM Schwieters, CD AF Clore, GM Schwieters, CD TI Theoretical and computational advances in biomolecular NMR spectroscopy SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID RESIDUAL DIPOLAR COUPLINGS; PHOSPHORYL TRANSFER COMPLEX; GLOBAL FOLD DETERMINATION; LIQUID-CRYSTALLINE PHASE; RIGID-BODY MINIMIZATION; TORSION ANGLE DYNAMICS; SITE-DIRECTED SPIN; STRUCTURE REFINEMENT; ORIENTED MACROMOLECULES; ALIGNMENT TENSOR AB Recent developments in experimental and computational aspects of NMR spectroscopy have had a significant impact on the accuracy and speed of macromolecular structure determination in solution, particularly with regard to systems of high complexity (such as protein complexes). These include experiments designed to provide long-range orientational and translational restraints, improvements in internal coordinate dynamics used for simulated annealing, and the development of database potentials of mean force to improve the description of the non-bonded contacts. C1 NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. NIH, Computat Biosci & Engn Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Phys Chem Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 67 TC 34 Z9 34 U1 2 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD APR PY 2002 VL 12 IS 2 BP 146 EP 153 DI 10.1016/S0959-440X(02)00302-0 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 542KQ UT WOS:000175043000002 PM 11959490 ER PT J AU Li, P Roller, PP Xu, JC AF Li, P Roller, PP Xu, JC TI Current synthetic approaches to peptide and peptidomimetic cyclization SO CURRENT ORGANIC CHEMISTRY LA English DT Review ID SOLID-PHASE SYNTHESIS; RING-CLOSING METATHESIS; HIGHLY EFFICIENT SYNTHESIS; TAIL CYCLIC-PEPTIDES; SAFETY-CATCH LINKER; INTRAMOLECULAR DISULFIDE BONDS; HOST-SELECTIVE PHYTOTOXICITY; RECEPTOR-BINDING AFFINITIES; ASYMMETRIC TOTAL SYNTHESIS; RATIONAL MOLECULAR DESIGN AB An increasingly large number of bioactive cyclic peptides have been found in nature. The enhanced biological specificity, activity, and metabolic stability of cyclopeptides, by virtue of their conformationally constrained structural feature, have attracted much attention and made these compounds extensively studied. Cyclic peptidomimetic scaffolds and templates have been widely used to assemble various spatially defined functional groups for molecular recognition and drug discovery. These efforts are complemented optimally by NMR and X-ray based structure information, and assisted by molecular modeling based structure predictive methods. Peptide cyclization also becomes an effective and commonly employed strategy for peptide modifications. During the past several decades, great effort has been made to develop more efficient methods for the synthesis of cyclic peptides and peptidomimetics, as potential drug leads and/or as models for conformational analysis. This review is aimed at highlighting novel recently developed peptide cyclization approaches, and illustrating the profitable applications. C1 NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. Chinese Acad Sci, Shanghai Inst Organ Chem, Shanghai 200032, Peoples R China. RP Li, P (reprint author), NCI, Med Chem Lab, NIH, 376 Boyles St, Frederick, MD 21702 USA. NR 244 TC 83 Z9 83 U1 2 U2 27 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1385-2728 J9 CURR ORG CHEM JI Curr. Org. Chem. PD APR PY 2002 VL 6 IS 5 BP 411 EP 440 DI 10.2174/1385272024604970 PG 30 WC Chemistry, Organic SC Chemistry GA 591FA UT WOS:000177868000001 ER PT J AU Li, WEI Waldo, K Linask, KL Chen, T Wessels, A Parmacek, MS Kirby, ML Lo, CW AF Li, WEI Waldo, K Linask, KL Chen, T Wessels, A Parmacek, MS Kirby, ML Lo, CW TI An essential role for connexin43 gap junctions in mouse coronary artery development SO DEVELOPMENT LA English DT Article DE connexin43; gap junctions; coronary artery; cell proliferation; cell migration; proepicardial cell ID NEURAL CREST CELLS; SMOOTH-MUSCLE CELLS; INTERCELLULAR COMMUNICATION; HEART MALFORMATIONS; GENE; ORIGIN; MICE; MUTATIONS; DIFFERENTIATION; EXPRESSION AB Connexin43 knockout mice die neonatally from conotruncal heart malformation and outflow obstruction. Previous studies have indicated the involvement of neural crest perturbations in these cardiac anomalies. We provide evidence for the involvement of another extracardiac cell population, the proepicardial cells. These cells give rise to the vascular smooth muscle cells of the coronary arteries and cardiac fibroblasts in the heart. We have observed the abnormal presence of fibroblast and vascular smooth muscle cells in the infundibular pouches of the connexin43 knockout mouse heart. In addition, the connexin43 knockout mice exhibit a variety of coronary artery patterning defects previously described for neural crest-ablated chick embryos, such as anomalous origin of the coronary arteries, absent left or right coronary artery, and accessory coronary arteries. However, we show that proepicardial cells also express connexin43 gap junctions abundantly. The proepicardial cells are functionally well coupled, and this coupling is significantly reduced with the loss of connexin43 function. Further analysis revealed an elevation in the speed of cell locomotion and cell proliferation rate in the connexin43-deficient proepicardial cells. A parallel analysis of proepicardial cells in transgenic mice with dominant negative inhibition of connexin43 targeted only to neural crest cells showed none of these coupling, proliferation or migration changes. These mice exhibit outflow obstruction, but no infundibular pouches. Together these findings indicate an important role for connexin43 in coronary artery patterning, a role that probably involves the proepicardial and cardiac neural crest cells. We discuss the potential involvement of connexin43 in human cardiovascular anomalies involving the coronary arteries. C1 Univ Penn, Dept Biol, Goddard Labs, Philadelphia, PA 19104 USA. Duke Univ, Dept Pediat, Div Neonatol, Durham, NC 27706 USA. NHLBI, Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Med Univ S Carolina, Dept Cell Biol & Anat, Charleston, SC 29425 USA. Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. RP Lo, CW (reprint author), Univ Penn, Dept Biol, Goddard Labs, Philadelphia, PA 19104 USA. FU NHLBI NIH HHS [HL36059]; NICHD NIH HHS [HD36457, HD39946] NR 51 TC 95 Z9 101 U1 0 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD APR PY 2002 VL 129 IS 8 BP 2031 EP 2042 PG 12 WC Developmental Biology SC Developmental Biology GA 549YA UT WOS:000175473800022 PM 11934868 ER PT J AU Couldrey, C Moitra, J Vinson, C Anver, M Nagashima, K Green, J AF Couldrey, C Moitra, J Vinson, C Anver, M Nagashima, K Green, J TI Adipose tissue: A vital in vivo role in mammary gland development but not differentiation SO DEVELOPMENTAL DYNAMICS LA English DT Article DE adipocytes; mammary gland; development; transgenic; mice ID EPIDERMAL GROWTH-FACTOR; DUCTAL MORPHOGENESIS; RECEPTOR; MOUSE; HORMONE; INHIBITION; EXPRESSION; FAT AB Development and differentiation of the mammary gland occurs by means of critical stromal-epithelial interactions. Although many studies have attempted to understand these complex interactions, it has been difficult to demonstrate the essential role of adipose tissue in the development and function of the mammary gland. By using the A-ZIP/F-1 transgenic mice lacking in white adipose tissue (WAT), we have studied the role of adipocytes in mammary gland development and differentiation. In the absence of WAT, rudimentary mammary anlagen form but are unable to grow and branch normally, resulting in a few, short, severely distended ducts. However, during pregnancy, a tremendous amount of epithelial cell division and alveolar cell formation occurs even in the absence of adipocytes, illustrating that adipose tissue is not required for mammary gland differentiation. Mammary gland transplantation revealed that epithelial cells from these transgenic mice possess the potential for normal growth and differentiation when placed into a normal stromal environment. These experiments clearly demonstrate that the absence of adipocytes in the mammary gland results in disruption of stromal-epithelial interactions that prevent normal mammary gland development. The rudimentary epithelial anlage, however, contain mammary stem cells, which are fully capable of alveolar differentiation. Published 2002 Wiley-Liss, Inc.dagger C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD USA. NCI, Lab Metab, Bethesda, MD USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD USA. NCI, SAIC, Frederick, MD 21701 USA. RP Green, J (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bldg 41,Room C629,41 Lib Dr, Bethesda, MD USA. FU NCI NIH HHS [N01-CO-56000] NR 26 TC 40 Z9 40 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 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD APR PY 2002 VL 223 IS 4 BP 459 EP 468 DI 10.1002/dvdy.10065 PG 10 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 537QG UT WOS:000174769900002 PM 11921335 ER PT J AU Amano, T Leu, K Yoshizato, K Shi, YB AF Amano, T Leu, K Yoshizato, K Shi, YB TI Thyroid hormone regulation of a transcriptional coactivator in Xenopus laevis: Implication for a role in postembryonic tissue remodeling SO DEVELOPMENTAL DYNAMICS LA English DT Article DE HMG protein; metamorphosis; thyroid hormone receptor; chromatin; Xenopus laevis ID RETINOID-X RECEPTORS; CHROMOSOMAL-PROTEINS; AMPHIBIAN METAMORPHOSIS; CELL; BETA; ACTIVATION; GENE; EMBRYOGENESIS; SUPERFAMILY; REPRESSION AB Thyroid hormone (TH) affects biological processes by regulating gene transcription through TH receptors (TRs). In the presence of TH, TR activates target gene transcription by recruiting one or more transcription coactivators belonging to diverse groups. Here, we demonstrate that during TH-dependent anuran metamorphosis, one such coactivator gene, the Xenopus laevis homolog of human Trip7, is up-regulated by TH. Kinetic studies suggest that Xenopus Trip7 is most likely induced indirectly by TH in a tissue-dependent manner. In the intestine, which undergoes extensive remodeling as the animal changes from being herbivorous to carnivorous, Trip7 is expressed at high levels during but not before or after metamorphosis. It is also up-regulated in other growing or remodeling tissues such as the brain and limb but not in degenerating tadpole tail skin. By using frog oocyte as a model, we show that Trip7 influences basal transcription in a chromatin structure-dependent manner but enhances the function of liganded TR regardless of the chromatin structure of the target promoter. In vitro studies indicate that Trip7 interacts directly with TR. These results suggest that during Xenopus metamorphosis, TH up-regulates, albeit indirectly, Trip7 to enhance TR function during larval-to-adult tissue transformation. Published 2002 Wiley-Liss, Inc.dagger C1 NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. Hiroshima Univ, Grad Sch Sci, Yoshizato Morphomatrix Project, Hiroshima, Japan. Hiroshima Univ, Grad Sch Sci, Dev Biol Lab, Dept Biol Sci,Fac Sci, Hiroshima, Japan. RP Shi, YB (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bldg 18T,Room 106, Bethesda, MD 20892 USA. NR 35 TC 26 Z9 27 U1 0 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD APR PY 2002 VL 223 IS 4 BP 526 EP 535 DI 10.1002/dvdy.10075 PG 10 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 537QG UT WOS:000174769900007 PM 11921340 ER PT J AU Gao, GQ Li, Y Fant, J Crosson, CE Becerra, SP Ma, JX AF Gao, GQ Li, Y Fant, J Crosson, CE Becerra, SP Ma, JX TI Difference in ischemic regulation of vascular endothelial growth factor and pigment epithelium-derived factor in Brown Norway and Sprague Dawley rats contributing to different susceptibilities to retinal neovascularization SO DIABETES LA English DT Article ID OXYGEN-INDUCED RETINOPATHY; PROLIFERATIVE DIABETIC-RETINOPATHY; EXTRARETINAL NEOVASCULARIZATION; NEONATAL RAT; NEWBORN RAT; MODEL; ANGIOGENESIS; EXPRESSION; MOUSE; EYES AB The present study compared susceptibilities of Sprague Dawley (SD) and Brown Norway (BN) rats with ischemia-induced retinal neovascularization. An exposure to constant hyperoxia followed by normoxia induced significant retinal neovascularization in BN rats but not in SD rats, as demonstrated by fluorescein retinal angiography, measurement of avascular area, and count of preretinal vascular cells. These results indicate a rat strain difference in susceptibility to retinal neovascularization. To understand the molecular basis responsible for the strain difference, we have measured the levels of pigment epithelium-derived factor (PEDF), an angiogenic inhibitor, and vascular endothelial growth factor (VEGF), a major angiogenic stimulator in the retina. The hyperoxia-treated BN rats showed a significant reduction in retinal PEDF, but they showed a substantial increase of VEGF at both the protein and RNA levels, resulting in an increased VEGF-to-PEDF ratio. Hyperoxia-treated SD rats showed changes in PEDF and VEGF levels that were less in magnitude and of shorter duration than in BN rats. In age-matched normal BN and SD rats, however, there was no detectable difference in the basal VEGF-to-PEDF ratio between the strains. These observations support the idea that different regulation of angiogenic inhibitors and stimulators under ischemia are responsible for the differences in susceptibility to ischemia-induced retinal neovascularization in SD and BN rats. C1 Med Univ S Carolina, Dept Ophthalmol, Charleston, SC 29403 USA. NEI, Retinal Cell & Mol Biol Lab, Bethesda, MD 20892 USA. RP Ma, JX (reprint author), Med Univ S Carolina, Dept Ophthalmol, 167 Ashley Ave, Charleston, SC 29403 USA. FU NEI NIH HHS [EY12600, EY09741, EY12231] NR 32 TC 74 Z9 81 U1 2 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD APR PY 2002 VL 51 IS 4 BP 1218 EP 1225 DI 10.2337/diabetes.51.4.1218 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 537BR UT WOS:000174737500045 PM 11916948 ER PT J AU Peila, R Rodriguez, BL Launer, LJ AF Peila, R Rodriguez, BL Launer, LJ TI Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies - The Honolulu-Asia Aging Study SO DIABETES LA English DT Article ID CORONARY HEART-DISEASE; JAPANESE-AMERICAN MEN; ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; CLINICAL-DIAGNOSIS; GLUCOSE-TOLERANCE; BLOOD-PRESSURE; END-PRODUCTS; ASSOCIATION; MELLITUS AB Type 2 diabetes may be a risk factor for dementia, but the associated pathological mechanisms remains unclear. We evaluated the association of diabetes alone or combined with the apolipoprotein E (APOE) gene with incident dementia and neuropathological outcomes in a population-based cohort of 2,574 Japanese-American men enrolled in the Honolalu-Asia Aging Study, including 216 subjects who underwent autopsy. Type 2 diabetes was ascertained by interview and direct glucose testing. Dementia was assessed in 1991 and 1994 by clinical examination and magnetic resonance imaging and was diagnosed according to international guidelines. Logistic regression was used to assess the RR of developing dementia, and log-linear regression was used to estimate the incident rate ratio (IRR) of neuropathological outcomes. Diabetes was associated with total dementia (RR 1.5 [95% CI 1.01-2.2]), Alzheimer's disease (AD; 1.8 [1.1-2.9]), and vascular dementia (VsD; 2.3 [1.1-5.0]). Individuals with both type 2 diabetes and the APOE epsilon4 allele had an RR of 5.5 (CI 2.2-13.7) for AD compared with those with neither risk factor. Participants with type 2 diabetes and the epsilon4 allele had a higher number of hippocampal neuritic plaques (IRR 3.0 [CI 1.2-7.3]) and neurofibrillary tangles in the cortex (IRR 3.5 [1.6-7.5]) and hippocampus (IRR 2.5 [1.5-3.7]), and they had a higher risk of cerebral amyloid angiopathy (RR 6.6, 1.5-29.6). Type 2 diabetes is a risk factor for AD and VsD. The association between diabetes and AD is particularly strong among carriers of the APOE epsilon4 allele. The neuropathological data are consistent with the clinical results. C1 NIA, Lab Epidemiol, Demog & Biometry Program, NIH, Bethesda, MD 20892 USA. Univ Hawaii Manoa, Dept Med, Clin Epidemiol & Geriatr Div, Honolulu, HI 96822 USA. RP Peila, R (reprint author), NIA, Lab Epidemiol, Demog & Biometry Program, NIH, Room 3C-309 Gateway Bldg,7201 Wisconsin Ave, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [N01-HC-O5102]; NIA NIH HHS [N01-AG-4-2149] NR 50 TC 610 Z9 638 U1 7 U2 30 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD APR PY 2002 VL 51 IS 4 BP 1256 EP 1262 DI 10.2337/diabetes.51.4.1256 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 537BR UT WOS:000174737500050 PM 11916953 ER PT J AU Hanley, AJG D'Agostino, R Wagenknecht, LE Saad, MF Savage, PJ Bergman, R Haffner, SM AF Hanley, AJG D'Agostino, R Wagenknecht, LE Saad, MF Savage, PJ Bergman, R Haffner, SM TI Increased proinsulin levels and decreased acute insulin response independently predict the incidence of type 2 diabetes in the Insulin Resistance Atherosclerosis Study SO DIABETES LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; BETA-CELL FUNCTION; NONESTERIFIED FATTY-ACIDS; MINIMAL MODEL; SECRETORY DYSFUNCTION; FASTING PROINSULIN; SENSITIVITY; MELLITUS; NIDDM; PATHOGENESIS AB Previous studies have indicated that beta-cell dysfunction predicts the development of diabetes, although it is unknown whether the use of combinations of insulin secretory measures further improves prediction. The Insulin Resistance Atherosclerosis Study is a prospective, multicenter, epidemiological study of the relationship between insulin sensitivity and the risk of diabetes and cardiovascular disease. At baseline, fasting concentrations of insulin, intact proinsulin (PI), and split PI were measured, and acute insulin response (AIR) was determined during a frequently sampled intravenous glucose tolerance test (FSIGTT). Subjects who were nondiabetic at baseline (n = 903) were reexamined after 5 years of follow-up; 148 had developed diabetes. In separate logistic regression models adjusted for age, sex, clinic, and ethnicity, 1 SD differences in measures of P-cell dysfunction were associated with diabetes incidence (AIR: odds ratio [OR] 0.37, 95% CI 0.27-0.52; intact PI: OR 1.90, 95% CI 1.57-2.30; split PI: OR 1.94, 95% CI 1.63-2.31). After additional adjustment for BMI, impaired glucose tolerance, and insulin sensitivity, these measures continued to be significantly associated with risk of diabetes (all P < 0.0001). Furthermore, in models that included both PI and AIR, each was an independent predictor, and individuals who had combined low AIR and high PI experienced the highest diabetes risk. In conclusion, both low AIR and high PI independently predicted diabetes in a well-characterized multiethnic population. Although fasting PI is simpler to assess, determining AIR from an FSIGTT may further improve prediction. If pharmacological agents to prevent diabetes are proved to be efficacious in ongoing clinical trials, then it may be beneficial to perform FSIGTTs to identify better (for intensive intervention) prediabetic subjects who would ultimately require lifelong pharmacological therapy. C1 Univ Texas, Hlth Sci Ctr, Div Clin Epidemiol, San Antonio, TX 78229 USA. Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Div Epidemiol & Biostat, Toronto, ON M5G 1X5, Canada. Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC USA. Univ So Calif, Sch Med, Dept Med, Los Angeles, CA 90033 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ So Calif, Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. RP Haffner, SM (reprint author), Univ Texas, Hlth Sci Ctr, Div Clin Epidemiol, Mail Code 7873,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. RI Dagostino Jr, Ralph/C-4060-2017 OI Dagostino Jr, Ralph/0000-0002-3550-8395 FU NIDDK NIH HHS [R01 DK029867] NR 57 TC 62 Z9 65 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD APR PY 2002 VL 51 IS 4 BP 1263 EP 1270 DI 10.2337/diabetes.51.4.1263 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 537BR UT WOS:000174737500051 PM 11916954 ER PT J AU Volpato, S Blaum, C Resnick, H Ferrucci, L Fried, LP Guralnik, JM AF Volpato, S Blaum, C Resnick, H Ferrucci, L Fried, LP Guralnik, JM TI Comorbidities and impairments explaining the association between diabetes and lower extremity disability - The Women's Health and Aging Study SO DIABETES CARE LA English DT Article ID PERIPHERAL ARTERIAL-DISEASE; NONDISABLED OLDER PERSONS; ADULTS; DEPRESSION; COMMUNITY; PREDICTOR; AGE; US AB OBJECTIVE - To elucidate the role of diabetes-related impairments and comorbidities in the association between diabetes and physical disability, this study examined the association between diabetes and lower extremity function in a sample of disabled older women. RESEARCH DESIGN AND METHODS - Cross-sectional analysis of 1,002 women (aged 2:65 years) enrolled in the Women's Health and Aging Study (one-third most disabled of the total community-dwelling population). Diabetes and other medical conditions were ascertained by standard criteria that used Multiple sources of information. Functional status was assessed using self-reported and objective performance measures, RESULTS - Women with diabetes were significantly more likely to have cardiovascular diseases, peripheral nerve dysfunction, visual impairment, obesity, and depression, After adjustment for age, women with diabetes had a greater prevalence of mobility disability (odds ratio [OR] 1.85, 95% Cl 1.12-3.06), activities of daily living disability (1.61, 1.06-2.43), and severe walking limitation (2.34, 1.56-3.50), and their summary mobility performance score (0-12 scale based on balance, gait speed, chair stands) was 1.4 points lower than in nondiabetic women (P < 0.001). Peripheral artery disease, peripheral nerve dysfunction, and depression were the main individual contributing factors; however, none of these conditions alone fully explained the association between diabetes and disability. Conversely, only after adjusting for all potential mediators,vas the relationship between, diabetes and disability reduced to a large degree, CONCLUSIONS - Even among physically impaired older women, diabetes is associated with a major burden of disability A wide range of impairments and comorbidities explains the diabetes-disability relationship, suggesting that the mechanism for such an association is multifactorial. C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Univ Ferrara, Dept Clin & Expt Med, I-44100 Ferrara, Italy. Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Epidemiol, Baltimore, MD 21205 USA. MedStar Res Inst, Washington, DC USA. INRCA, Geriatr Dept I Fraticini, Florence, Italy. RP Volpato, S (reprint author), NIA, Lab Epidemiol Demog & Biometry, 7201 Wisconsin Ave,Gateway Bldg,Suite 3C-309, Bethesda, MD 20892 USA. RI VOLPATO, STEFANO/H-2977-2014 OI VOLPATO, STEFANO/0000-0003-4335-6034 FU NIA NIH HHS [N01-AG-1-2112] NR 29 TC 129 Z9 133 U1 1 U2 6 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD APR PY 2002 VL 25 IS 4 BP 678 EP 683 DI 10.2337/diacare.25.4.678 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 535FV UT WOS:000174635300006 PM 11919124 ER PT J AU Sherwin, RS Anderson, RM Buse, JB Chin, MH Eddy, D Fradkin, J Ganiats, TG Ginsberg, HN Kahn, R Nwankwo, R Rewers, M Schlessinger, L Stern, M Vinicor, F Zinman, B AF Sherwin, RS Anderson, RM Buse, JB Chin, MH Eddy, D Fradkin, J Ganiats, TG Ginsberg, HN Kahn, R Nwankwo, R Rewers, M Schlessinger, L Stern, M Vinicor, F Zinman, B CA Amer Diabet Assoc Natl Inst Diabet Digestive & Kidne TI The prevention or delay of type 2 diabetes SO DIABETES CARE LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; MICROVASCULAR COMPLICATIONS; CARDIOVASCULAR EVENTS; INSULIN RESISTANCE; NONDIABETIC MEN; BLOOD-GLUCOSE; RISK-FACTORS; FOLLOW-UP; MELLITUS; NIDDM C1 Amer Diabet Assoc, Alexandria, VA 22311 USA. NIDDK, NIH, Bethesda, MD 20892 USA. RP Sherwin, RS (reprint author), Amer Diabet Assoc, Alexandria, VA 22311 USA. NR 60 TC 171 Z9 177 U1 1 U2 6 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD APR PY 2002 VL 25 IS 4 BP 742 EP 749 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 535FV UT WOS:000174635300017 PM 11919135 ER PT J AU Delle Fave, G Marignani, M Corleto, VD Angeletti, D D'Ambra, G Ferraro, G D'Adda, T Azzoni, C Jensen, RT Annibale, B Bordi, C AF Delle Fave, G Marignani, M Corleto, VD Angeletti, D D'Ambra, G Ferraro, G D'Adda, T Azzoni, C Jensen, RT Annibale, B Bordi, C TI Progression of gastric enterochromaffin-like cells growth in Zollinger-Ellison syndrome and atrophic body gastritis patients SO DIGESTIVE AND LIVER DISEASE LA English DT Article DE atrophic body gastritis; enterochromaffin-like cell proliferation; hypergastrinaemia; Zollinger-Ellison syndrome ID MULTIPLE ENDOCRINE NEOPLASIA; CARCINOID-TUMORS; OXYNTIC MUCOSA; PERNICIOUS-ANEMIA; DUODENAL-ULCER; ACID-SECRETION; OMEPRAZOLE THERAPY; HYPERPLASIA; HYPERGASTRINEMIA; CLASSIFICATION AB Background. Enterochromaffin-like cell hyperplasia of the gastric body mucosa occurs in hypergastrinaemic conditions such as atrophic body gastritis and Zollinger-Ellison syndrome, However the time course of change or factors involved are not known. Aims. To compare the rate of change of enterochromaffin-like cell proliferation in patients with atrophic body gastritis and Zollinger-Ellison syndrome. Patients. From a consecutive series of atrophic body gastritis and Zollinger-Ellison syndrome patients, studied at the time of first diagnosis, 10 atrophic body gastritis (4 with pernicious anaemia) and 14 Zollinger-Ellison syndrome (4 with multiple endocrine neoplasia type 1) patients were followed-up for a median time of 48 months. Methods. At entry and during follow-up patients underwent: plasma gastrin determination, endoscopic sampling of body mucosa for qualitative assessment of enterochromaffin-like cell hyperplasia pattern and degree of glandular atrophy qualitative and morphometric analyses of body mucosa endocrine cells. Results. At time of diagnosis, enterochromaffin-like cell lesions were more severe in atrophic body gastritis than in Zollinger-Ellison syndrome. During follow-up, no significant variations were observed in gastrin values, enterochromaffin-like cell patterns and grade of body mucosa atrophy in atrophic body gastritis. In contrast, gastrin levels were significantly increased [median 1200 (235-2625) vs 1947 (2255200) pg/ml; p<0.001)] as was total volume density of enterochromaffin-like cells [median 1.60 (0,53-4.06) vs 3.18 (1.35-21. 13)% of mucosal epithelial component; (p<0.005)] in Zollinger-Ellison syndrome, Micronodular hyperplasia of enterochromaffin-like cells, present in only one patient at diagnosis, was observed in B Zollinger-Ellison syndrome patients at follow-up. Conclusions. These data suggest that the progression of enterochromaffin-like cell growth in human gastric mucosa requires an increase of and/or a prolonged exposure to severe hypergastrinaemia. C1 Univ Roma La Sapienza, Sch Med 2, Div Digest & Liver Dis, Rome, Italy. NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. Univ Parma, Dept Pathol & Lab Med, Sect Anat Pathol, I-43100 Parma, Italy. RP Delle Fave, G (reprint author), Policlin Umberto 1, Dipartimento Sci Clin, Viale Policlin 155, I-00161 Rome, Italy. EM gianfranco.dellefave@uniroma1.it NR 52 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1590-8658 EI 1878-3562 J9 DIGEST LIVER DIS JI Dig. Liver Dis. PD APR PY 2002 VL 34 IS 4 BP 270 EP 278 DI 10.1016/S1590-8658(02)80147-5 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 548GQ UT WOS:000175380600007 PM 12038811 ER PT J AU Kurata, JH Nogawa, AN Everhart, JE AF Kurata, JH Nogawa, AN Everhart, JE TI A prospective study of dyspepsia in primary care SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE dyspepsia; prospective study; primary care ID NON-ULCER DYSPEPSIA; FUNCTIONAL DYSPEPSIA; ENDOSCOPY; TECHNOLOGY; PROGNOSIS; SUBGROUPS; SYMPTOMS AB Dyspepsia is a common complaint, but its course and associated resource utilization have not been well described. In this study, 288 adult, primary care patients with dyspepsia treated at ambulatory clinics were followed prospectively for one year. Medical chart, utilization, and baseline and one-year follow-up survey data were collected. These patients had 13.3 medical visits (sex- and age-standardized) during the follow-up period, 55% above standardized mean visits for a comparison group of nondyspepsia patients. Standardized mean charges of $3542 for dyspeptics was 126% above nondyspepsia patient charges. Over half had gastrointestinal-related follow-up visits; 61% used gastrointestinal drugs; and 43% had gastrointestinal procedures. NSAID users had higher gastrointestinal-related utilization than did nonusers, recording an additional gastrointestinal visit (P < 0.001) and $678 more in charges (P = 0.03). Eighty-six percent of the 189 follow-up survey respondents experienced gastrointestinal symptoms at some time during the follow-up year. This study showed that most primary care dyspepsia patients remained symptomatic after one year and were intensive users of medical care. C1 Dept Hlth Serv, Chron Dis Epidemiol & Control Sect, Sacramento, CA USA. Arrowhead Reg Med Ctr, Dept Family Med, Colton, CA USA. Univ Calif Irvine, Dept Family Med, Irvine, CA USA. NIDDKD, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. RP Kurata, JH (reprint author), Dept Hlth Serv, Chron Dis Epidemiol Sect, 601 N 7th St,MS-725,POB 942732, Sacramento, CA 94234 USA. FU AHRQ HHS [R03 HS07257] NR 29 TC 7 Z9 7 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD APR PY 2002 VL 47 IS 4 BP 797 EP 803 AR UNSP 0163-2116/02/0400-0797/0 DI 10.1023/A:1014748202229 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 545QC UT WOS:000175227900021 PM 11991613 ER PT J AU Radko, SP Chen, HT Zakharov, SF Bezrukov, L Yergey, AL Vieira, NE Chrambach, A AF Radko, SP Chen, HT Zakharov, SF Bezrukov, L Yergey, AL Vieira, NE Chrambach, A TI Electroelution without gel sectioning of proteins from sodium dodecyl sulfate-polyacrylamide gel electrophoresis: Fluorescent detection, recovery, isoelectric focusing and matrix assisted laser desorption/ionization-time of flight of the electroeluate SO ELECTROPHORESIS LA English DT Article DE electroelution; fluorescent detection; isoelectric focusing ID MASS-SPECTROMETRY; SEPARATED PROTEINS; IDENTIFICATION; BANDS; STEP; PROTEOMICS AB A method of direct electroelution of intact proteins, without gel sectioning and orthogonal to the orientation of electrophoretic migration, was developed in application to Novex gels, using a simple home-made experimental setup. Six model proteins covering the molecular mass range of 14-120 kDa were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), stained with an aqueous solution of the fluorescent dye, SYPRO-red, and electroeluted from the intact gel. The sensitivity of visual detection was 0.1-0.2 mug upon illumination by a green laser and 0.5-1 mug of protein on side-ways UV-illumination. Duration (for each protein) and field strength were optimized to render protein electroelution from the gel near-quantitative (above 80%) and relatively fast (1-12 min at 1 kV). At a given field strength, the optimal duration was found to be inversely proportional to the mobility of proteins in SDS-PAGE. Sequential ultrafiltration was evaluated as a simple approach to concentrate electroeluted proteins and deplete SDS to a level compatible with mass spectrometry of proteins: protein yields in the electroeluate were 25-33% (depending on the protein used) after three steps of ultrafiltration with water. The analysis of the electroeluate by isoelectric focusing in an immobilized pH gradient, to reveal protein heterogeneity under a single SDS-PAGE band (prior, e.g., to mass spectrometric analysis), was demonstrated. C1 Natl Taiwan Univ, Macromol Anal Sect, Taipei 10764, Taiwan. Natl Taiwan Univ, Dept Chem, Taipei 10764, Taiwan. NICHHD, Sect Membrane & Cellular Biophys, NIH, Bethesda, MD 20892 USA. NICHHD, Sect Mass Spectrometry & Metab, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Chrambach, A (reprint author), NIH, Bldg 10,Rm 9D50, Bethesda, MD 20892 USA. NR 23 TC 14 Z9 14 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD APR PY 2002 VL 23 IS 7-8 BP 985 EP 992 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 549GM UT WOS:000175436200002 PM 11981843 ER PT J AU Lefebvre, B Ozato, K Lefebvre, P AF Lefebvre, B Ozato, K Lefebvre, P TI Phosphorylation of histone H3 is functionally linked to retinoic acid receptor beta promoter activation SO EMBO REPORTS LA English DT Article ID NUCLEAR RECEPTORS; IN-VIVO; ESTROGEN-RECEPTOR; GENE ACTIVATION; HYPERACETYLATION; TRANSCRIPTION; CHROMATIN; KINASE; ALPHA; RESPONSIVENESS AB Ligand-dependent transcriptional activation of retinoic acid receptors (RARs) is a multistep process culminating in the formation of a multimeric co-activator complex on regulated promoters. Several co-activator complexes harbor an acetyl transferase activity, which is required for retinoid-induced transcription of reporter genes. Using murine P19 embryonal carcinoma cells, we examined the relationship between histone post-translational modifications and activation of the endogenous RARP2 promoter, which is under the control of a canonical retinoic acid response element and rapidly induced upon retinoid treatment. While histones H3 and H4 were constitutively acetylated at this promoter, retinoid agonists induced a rapid phosphorylation at Ser10 of histone H3. A retinoid antagonist, whose activity was independent of co-repressor binding to PAR, could oppose this agonist-induced H3 phosphorylation. Since such post-translational modifications were not observed at several other promoters, we conclude that histone H3 phosphorylation may be a molecular signature of the activated, retinoid-controlled mRARP2 gene promoter. C1 INSERM, U459, F-59045 Lille, France. Fac Med Henri Warembourg, Ligue Natl Canc, F-59045 Lille, France. NICHHD, Lab Mol Growth, NIH, Bethesda, MD 20892 USA. RP Lefebvre, B (reprint author), INSERM, U459, 1 Pl Verdun, F-59045 Lille, France. RI Lefebvre, Philippe/F-2685-2010 OI Lefebvre, Philippe/0000-0002-9366-5129 NR 31 TC 28 Z9 28 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD APR PY 2002 VL 3 IS 4 BP 335 EP 340 DI 10.1093/embo-reports/kvf066 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 546KR UT WOS:000175273700013 PM 11897660 ER PT J AU Shepard, PM Northridge, ME Prakash, S Stover, G AF Shepard, PM Northridge, ME Prakash, S Stover, G TI Preface: Advancing environmental justice through community-based participatory research SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 WE ACT, New York, NY 10027 USA. Mailman Sch Publ Hlth, Dept Environm Hlth Sci, Community Outreach & Educ Program, NIEHS,Ctr Environm Hlth No Manhattan, New York, NY USA. Columbia Univ, Mailman Sch Publ Hlth, Dept Sociomed Sci, Harlem Hlth Promot Ctr, New York, NY USA. RP Shepard, PM (reprint author), WE ACT, 271 W 125th St,Ste 308, New York, NY 10027 USA. NR 9 TC 55 Z9 55 U1 3 U2 11 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2002 VL 110 SU 2 BP 139 EP 140 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 542WE UT WOS:000175066600002 ER PT J AU Sharp, RR Foster, MW AF Sharp, RR Foster, MW TI Community involvement in the ethical review of genetic research: Lessons from American Indian and Alaska native populations SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material DE ethics; indigenous populations; informed consent; participatory research; research oversight ID PROTECTING COMMUNITIES; INFORMED CONSENT; GUIDELINES; RISKS; IDENTITY; ISSUES; HEALTH AB The National Bioethics Advisory Commission has proposed that regulatory oversight for research with human subjects be extended beyond the protection of individual research participants to include the protection of social groups. To accomplish this, the commission recommends that investigators and ethics review boards a) work directly with community representatives to develop study methods that minimize potential group harms, b) discuss group implications as part of the informed consent process, and c) consider group harms in reporting research results. We examine the utility of these recommendations in the context of research with American Indian and Alaska Native communities. Because much attention has been given to the question of how best to consult with members of these communities in the design and conduct of research, we believe it behooves investigators to consider the lessons to be learned from research involving American Indians and Alaska Natives. After describing several difficulties surrounding the application of the commission's approach to these research contexts, we propose a research agenda to develop best practices for working with local communities in the ethical assessment of epidemiologic and environmental health research. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Duke Univ, Ctr Study Med Eth & Humanities, Durham, NC USA. Univ Oklahoma, Dept Anthropol, Norman, OK 73019 USA. RP Sharp, RR (reprint author), NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. FU NHGRI NIH HHS [HG010302] NR 38 TC 45 Z9 45 U1 3 U2 8 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2002 VL 110 SU 2 BP 145 EP 148 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 542WE UT WOS:000175066600004 PM 11929722 ER PT J AU O'Fallon, LR Dearry, A AF O'Fallon, LR Dearry, A TI Community-based participatory research as a tool to advance environmental health sciences SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material DE community-based participatory research; translational research; environmental health sciences; environmental justice; community outreach; health disparities; children's health ID NORTH-CAROLINA; PUBLIC-HEALTH; PROMOTION; HARLEM AB The past two decades have witnessed a rapid proliferation of community-based participatory research (CBPR) projects. CBPR methodology presents an alternative to traditional population-based biomedical research practices by encouraging active and equal partnerships between community members and academic investigators. The National Institute of Environmental Health Sciences (NIEHS), the premier biomedical research facility for environmental health, is a leader in promoting the use of CBPR in instances where community-university partnerships serve to advance our understanding of environmentally related disease. In this article, the authors highlight six key principles of CBPR and describe how these principles are met within specific NIEHS-supported research investigations. These projects demonstrate that community-based participatory research can be an effective tool, to enhance our knowledge of the causes and mechanisms of disorders having an environmental etiology, reduce adverse health outcomes through innovative intervention strategies and policy change, and address the environmental health concerns of community residents. C1 NIEHS, Chem Exposures & Mol Biol Branch, Off Program Dev, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. RP O'Fallon, LR (reprint author), NIEHS, Chem Exposures & Mol Biol Branch, Off Program Dev, Div Extramural Res & Training, POB 12233,111 TW Alexander Dr,EC-21, Res Triangle Pk, NC 27709 USA. NR 34 TC 183 Z9 186 U1 5 U2 33 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2002 VL 110 SU 2 BP 155 EP 159 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 542WE UT WOS:000175066600006 PM 11929724 ER PT J AU Jemal, A Graubard, BI Devesa, SS Flegal, KM AF Jemal, A Graubard, BI Devesa, SS Flegal, KM TI The association of blood lead level and cancer mortality among whites in the United States SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE cancer; lead; mortality; NHANES II; United States ID EXPOSURE; HEALTH AB Lead is classified as a possible carcinogen in humans. We studied the relationship of blood lead level and all cancer mortality in the general population of the United States using data from the National Health and Nutrition Examination Survey 11 (NHANTES 11) Mortality Study, 1992, consisting of a total of 203 cancer deaths (117 men and 86 women) among 3,592 whites (1,702 men and 1,890 women) with average of 13.3 years of follow-up. We used Cox proportional hazard regression models to estimate the dose-response relationship between blood lead and all cancer mortality. Log-transformed blood lead was either categorized into quartiles or treated as a continuous variable in a cubic regression spline. Relative risks (RRs) were estimated for site-specific cancers by categorizing lead above and below the median. Among men and women combined, dose-response relationship between quartile of blood lead and all cancer mortality was not significant (p(trend) = 0.16), with RRs of 1.24 [95% percent confidence interval (CI), 0.66-2.33], 1.33 (95% CI, 0.57-3-09), and 1.50 (95% CI, 0.75-3.01) for the second, third, and fourth quartiles, respectively, compared with the first quartile. Spline analyses found no dose response (p = 0.29), and none of the site-specific cancer RRs were significant. Among men, no significant dose-response relationships were found for quartile or spline analyses (p(trend) = 0.57 and p = 0.38, respectively). Among women, no dose-response relationship was found for quartile analysis (p(trend) = 0.22). However, the spline dose-response results were significant (p = 0.001), showing a threshold effect at the 94th. percentile of blood lead or a lead concentration of 24 mug/dL, with an RR of 2.4 (95% CI, 1.1-5.2) compared with the risk at 12.5 percentile. Because the dose-response relationship found in women was not found in men, occurred at only the highest levels of lead, and has no clear biologic explanation, further replication of this relationship is needed before it can be considered believable. In conclusion, individuals with blood lead levels in the range of NHANES II do not appear to have increased risk of cancer mortality. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Jemal, A (reprint author), Amer Canc Soc, Dept Epidemiol & Surveillance Res, 1599 Clifton Rd NE, Atlanta, GA 30329 USA. RI Flegal, Katherine/A-4608-2013; OI Flegal, Katherine/0000-0002-0838-469X NR 31 TC 30 Z9 31 U1 1 U2 5 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2002 VL 110 IS 4 BP 325 EP 329 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 541GB UT WOS:000174975900018 PM 11940448 ER PT J AU Koo, JW Parham, F Kohn, MC Masten, SA Brock, JW Needham, LL Portier, CJ AF Koo, JW Parham, F Kohn, MC Masten, SA Brock, JW Needham, LL Portier, CJ TI The association between biomarker-based exposure estimates for phthalates and demographic factors in a human reference population SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE demographic factors; phthalates; risk assessment ID BUTYL BENZYL PHTHALATE; TESTICULAR ATROPHY; RAT-LIVER; METABOLISM; ESTERS; EXCRETION; IDENTIFICATION; DIBUTYL AB Population-based estimates of environmental exposures using biomarkers can be difficult to obtain for a variety of reasons, including problems with limits of detection, undersampling of key strata, time between exposure and sampling, variation across individuals, variation within individuals, and the ability to find and interpret a given biomarker. In this article, we apply statistical likelihoods, weighted sampling, and regression methods for censored data to the analysis of biomarker data. Urinary metabolites for seven phthalates, reported by Blount et al., are analyzed using these methods. In the case of the phthalates data, we assumed the underlying model to be a log-normal distribution with the mean of the distribution defined as a function of a number of demographic variables that might affect phthalate levels in individuals. Included as demographic variables were age, sex, ethnicity, residency, family income, and education level. We conducted two analyses: an unweighted analysis where phthalate distributions were estimated with changes in the means of these distributions as a function of demographic variables, and a weighted prediction for the general population in which weights were assigned for a subset of the population depending on the frequency of their demographic variables in the general U.S. population. We used statistical tests to determine whether any of the demographic variables affected mean phthalate levels. Individuals with only a high school education had higher levels of di-n-butyl phthalate than individuals with education beyond high school. Subjects who had family income less than $1,500 in the month before sampling and/or only high school education had higher levels of n-buryl. benzyl phthalate levels than other groupings. Di(2-ethylhexyl) phthalate was higher in males and/or in urban populations and/or in people who had family income less than $1,500 per month. Our findings suggest that there may be significant demographic variations in exposure and/or metabolism of phthalates and that health-risk assessments for phthalate exposure in humans should consider different potential risk groups. C1 Natl Inst Environm Hlth Sci, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. RP Portier, CJ (reprint author), Natl Inst Environm Hlth Sci, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RI Portier, Christopher/A-3160-2010; Needham, Larry/E-4930-2011; masten, scott/R-1403-2016 OI Portier, Christopher/0000-0002-0954-0279; masten, scott/0000-0002-7847-181X NR 48 TC 54 Z9 56 U1 4 U2 10 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2002 VL 110 IS 4 BP 405 EP 410 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 541GB UT WOS:000174975900029 PM 11940459 ER PT J AU Olden, K Goehl, TJ AF Olden, K Goehl, TJ TI Evolution of a journal: Environmental Health Perspectives SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Olden, K (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2002 VL 110 IS 4 BP A174 EP A174 DI 10.1289/ehp.110-a174 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 541GB UT WOS:000174975900001 ER PT J AU Winkler, D Willeit, M Praschak-Rieder, N Lucht, MJ Hilger, E Konstantinidis, A Stastny, J Thierry, N Pjrek, E Neumeister, A Moller, HJ Kasper, S AF Winkler, D Willeit, M Praschak-Rieder, N Lucht, MJ Hilger, E Konstantinidis, A Stastny, J Thierry, N Pjrek, E Neumeister, A Moller, HJ Kasper, S TI Changes of clinical pattern in seasonal affective disorder (SAD) over time in a German-speaking sample SO EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE LA English DT Article DE seasonal affective disorder; SAD; fall-winter depression; seasonality ID WINTER DEPRESSION; LIGHT TREATMENT; MOOD VARIATION; PREVALENCE; THERAPY; EPIDEMIOLOGY; BEHAVIOR; JAPAN; ANTIDEPRESSANT; AVAILABILITY AB Objective The goals of this study are to provide estimates of clinical and demographic variables of patients with seasonal affective disorder (SAD) in Germany and Austria, to compare our results with those of previously published SAD studies, and to find out whether the clinical pattern of SAD remained stable over several years. Method We investigated 610 SAD patients from the outpatient clinics in Bonn (n = 190) and Vienna (n = 420). Patients in Bonn were recruited in the fall-winter season of the years 1989-1992, those in Vienna in the years 1993-2001. Results We observed a change in the clinical pattern in our patients: patients from Bonn, who were diagnosed and treated about 5 years earlier, were more likely to suffer from melancholic depression, whereas Viennese patients rather suffered from atypical depression (chi(2) = 54.952, df = 2, p < 0.001). The symptoms of hypersomnia, daytime fatigue, increased eating and carbohydrate-craving were more frequent in the Viennese sample, anxiety and deterioration of patients' capacity to perform at work predominated in Bonn. In addition, patients from Vienna obtained a higher GSS (global seasonality score, measured by the SPAQ - Seasonal Pattern Assessment Questionnaire) than those from Bonn (15.7 +/- 3.3 and 14.6 +/- 4.1 respectively; t = 3.104, p = 0.002). Taken together, our results were in good accordance to other published SAD materials, but we were able to demonstrate that our patients reported "feeling worst" (measured by item 13H of the SPAQ) in November and December, whereas SAD patients in the USA clearly had their worst months in January and February. Conclusions We suggest that an increase in awareness of fall-winter depression in the last decade by both doctors, who referred patients, as well as patients or the entire population must have caused patients to sign up for light therapy at the Viennese SAD clinic because of having heard about the atypical symptom profile. This increased awareness of SAD can also be measured by a statistically significant reduction in the diagnostic latency (from the age of onset to the diagnosis of SAD) when comparing the two study locations. C1 Univ Vienna, Hosp Psychiat, Dept Gen Psychiat, A-1090 Vienna, Austria. Univ Greifswald, Hosp Psychiat & Psychotherapy, Greifswald, Germany. NIMH, Mood & Anxiety Disorders Res Program, Bethesda, MD 20892 USA. Univ Munich, Dept Psychiat, D-8000 Munich, Germany. RP Kasper, S (reprint author), Univ Vienna, Hosp Psychiat, Dept Gen Psychiat, Waehringer Guertel 18-20, A-1090 Vienna, Austria. NR 61 TC 17 Z9 17 U1 0 U2 0 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PO BOX 10 04 62, D-64204 DARMSTADT, GERMANY SN 0940-1334 J9 EUR ARCH PSY CLIN N JI Eur. Arch. Psych. Clin. Neurosci. PD APR PY 2002 VL 252 IS 2 BP 54 EP 62 DI 10.1007/s004060200012 PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 576CF UT WOS:000176984700002 PM 12111337 ER PT J AU Lopez-Carrillo, L Lopez-Cervantes, M Torres-Sanchez, L Blair, A Cebrian, ME Garcia, RM AF Lopez-Carrillo, L Lopez-Cervantes, M Torres-Sanchez, L Blair, A Cebrian, ME Garcia, RM TI Serum levels of beta-hexachlorocyclohexane, hexachloro benzene and polychlorinated biphenyls and breast cancer in Mexican women SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE beta-hexachlorocyclohexane; breast cancer; case-control; hexachlorobenzene; Mexico; organochlorine compounds; polychlorinated biphenyls; serum levels ID ENVIRONMENTAL ORGANOCHLORINE EXPOSURE; ADIPOSE-TISSUE CONCENTRATIONS; RISK; PESTICIDES AB Information on the association between exposure to beta-hexachlorocyclobexane (beta-HCH), hexachlorobenzene (HCB) or polychlorinated byphenyls (PCBs) and the incidence of breast cancer is inconclusive. However, exposure to such compounds is a public health concern in Mexico and is subject to recent regulation. Serum levels of beta-HCH, HCB and PCBs were analysed in 95 histologically confirmed breast cancer cases and 95 hospital controls, 20-79 years of age, from Mexico City, enrolled between March 1994 and April 1996. After adjusting for established risk factors, there was no evidence of a relationship between beta-HCH, HCB and PCBs and breast cancer risk (OR for beta-HCH tertile 3 versus tertile 1: 1.05 95% CI 0.46-2.40; OR for HCB tertile 3 versus tertile 1: 0.46 95% CI 0.20-1.07; OR for PCBs 1.3195% CI 0.33-5.21 for the high category of exposure). This study lends no support to the case for a role for beta-HCH, HCB or PCBs in breast cancer aetiology. (C) 2002 Lippincott Williams Wilkins. C1 Mexico Secretariat Hlth, Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico. Natl Inst Hlth, Mexico City, DF, Mexico. NCI, Rockville, MD USA. Natl Polytech Inst, Ctr Res & Adv Studies, Mexico City, DF, Mexico. RP Lopez-Carrillo, L (reprint author), Av Univ 655,Col Sta Maria Ahuacatitlan, Cuernavaca 62508, Morelos, Mexico. NR 39 TC 25 Z9 29 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-8278 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD APR PY 2002 VL 11 IS 2 BP 129 EP 135 DI 10.1097/00008469-200204000-00004 PG 7 WC Oncology SC Oncology GA 549GR UT WOS:000175436600004 PM 11984130 ER PT J AU Mathew, A Devesa, SS Fraumeni, JF Chow, WH AF Mathew, A Devesa, SS Fraumeni, JF Chow, WH TI Global increases in kidney cancer incidence, 1973-1992 SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE incidence; kidney neoplasm; renal parenchyma; renal pelvis; trends ID RENAL-CELL CANCER; UNITED-STATES; TRENDS; HYPERTENSION; PREVALENCE; RISK; POPULATION; OBESITY; CHINESE; WEIGHT AB Reports of increasing rates for kidney cancers in several countries prompted this analysis of global incidence trends for total kidney cancers and by subsite. International incidence data for 5-year periods 1973-1977, 1978-1982, 1983-1987 and 19881992 were obtained from volumes IV to VII of Cancer Incidence in Five Continents published by the International Agency for Research on Cancer. The USA data for the same 5-year periods were obtained from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Percentage changes in incidence rates were computed using the relative difference between the time periods 1973-1977 and 1988-1992, and annual percentage changes in incidence rates were computed using log linear regression. In 1988-1992, kidney cancer incidence rates (age-adjusted to the world-standard population) were highest in France (16.1/100 000 man-years and 7.3/100 000 woman-years) and lowest in India (2.0 and 0.9, respectively). Between 1973-1977 and 1988-1992, incidence rates rose among men and women in all regions and ethnic groups, with a few exceptions, mostly in Scandinavian countries. The largest percentage increase for men was in Japan (171%) and for women in Italy (107%). Rates for renal pelvis cancer were less than 1/100 000 person-years in almost all regions in both sexes, and the temporal trends were inconsistent. Incidence trends for renal parenchyma cancer tracked those for total kidney cancers, and appeared to result from increases in the prevalence of risk factors and in use of diagnostic imaging procedures. (C) 2002 Lippincott Williams Wilkins. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Coll Med, Reg Canc Ctr, Div Canc Epidemiol & Clin Res, Trivandrum 695011, Kerala, India. RP Chow, WH (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8100, Rockville, MD 20852 USA. NR 32 TC 195 Z9 205 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-8278 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD APR PY 2002 VL 11 IS 2 BP 171 EP 178 DI 10.1097/00008469-200204000-00010 PG 8 WC Oncology SC Oncology GA 549GR UT WOS:000175436600010 PM 11984136 ER PT J AU Mi, QS Rezanka, LJ Lustig, A Zhou, L Longo, DL Kenny, JJ AF Mi, QS Rezanka, LJ Lustig, A Zhou, L Longo, DL Kenny, JJ TI The M603 idiotype is lost in the response to phosphocholine in terminal deoxynucleotidyl transferase-deficient mice SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE phosphocholine; Proteus morganii; idiotype; terminal deoxynucleotidyl transferase; junctional diversity ID IMMUNE-RESPONSE; PROTEUS-MORGANII; B-CELL; ANTIPHOSPHORYLCHOLINE ANTIBODIES; JUNCTIONAL DIVERSITY; SOMATIC MUTATION; CHAIN GENE; ADULT MICE; N-REGIONS; PHOSPHORYLCHOLINE AB The majority of anti-phosphocholine (PC) antibodies induced by the PC epitope in Proteus morganii (PM) express the M603 idiotype (id), which is characterized by an invariant Asp to Asn substitution at the V-H:D-H junction. To elucidate the molecular basis by which M603-like B cells acquire the mutations resulting in this invariant substitution, we analyzed the immune response to PC-PM in terminal deoxynucleotidyl transferase (TdT) gene knockout (KO) mice. In the absence of TdT, T15-id antibodies comprised 80-100% of the primary response to PC-PM. Less than 10% of the response in wild-type mice is T15-id(+). In TdT KO mice, the secondary response to PC-KLH was higher than in wild-type mice and was dominated by the germ-line T15-id. About 10% of this response, in both TdT KO and wild-type mice, comprised M167-id(+) antibodies. Additionally, none of the functionally rearranged V1/DFL16.1/J(H)1 cDNA isolated from PC-PM-immunized TdT KO mice showed the Asp/Asn substitution characteristic of PC-binding, PC-PM-induced M603-like antibodies. These data indicate that production of M603-id antibody is TdT dependent, while generation of M167-id antibody is TdT independent, and that in the absence of competition from M603-like B cells, T15-id B cells can respond to PC-PM. C1 NIA, Immunol Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Taishan Med Coll, Clin Immunol Lab, Tai An, Peoples R China. Taishan Med Coll, Dept Dermatol, Tai An, Peoples R China. RP Rezanka, LJ (reprint author), NIA, Immunol Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 38 TC 4 Z9 4 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD APR PY 2002 VL 32 IS 4 BP 1139 EP 1146 DI 10.1002/1521-4141(200204)32:4<1139::AID-IMMU1139>3.3.CO;2-5 PG 8 WC Immunology SC Immunology GA 541CY UT WOS:000174968700026 PM 11932921 ER PT J AU Spitzer, JH Visintin, A Mazzoni, A Kennedy, MN Segal, DM AF Spitzer, JH Visintin, A Mazzoni, A Kennedy, MN Segal, DM TI Toll-like receptor 1 inhibits Toll-like receptor 4 signaling in endothelial cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE innate immunity; Toll-like receptor; lipopolysaccharide ID DIFFERENTIAL EXPRESSION; KAPPA-B; PROTEIN; FAMILY; ACTIVATION; LEUKOCYTES; PATHWAYS AB Toll-like receptor 4 (TLR4) is the signal-transducing component of the LPS recognition complex and is essential for LPS-induced septic shock. Here we demonstrate that TLR1 has the capacity to abrogate TLR4 signaling. Human microvascular endothelial cells express TLR4 but not TLR1 and respond to LPS through TLR4. The ability of these cells to respond to LIPS was lost, however, when they were transfected with TLR1. Inhibition was specific for TLR1 because TL5 failed to block TLR4 function. Moreover, TLR1 had no effect upon TNF-alpha signaling, indicating that TLR1 operated at a step upstream of the convergence between the two pathways. Inhibition of TLR4 signaling was mediated by the extracellular, but not cytoplasmic domain of TLR1. In addition, TLR1 physically associated with TLR4 in coprecipitation experiments. These findings suggest that TLR1 might restrain potentially dangerous innate response to LPS by binding to TLR4 and preventing the formation of active signaling complexes. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Segal, DM (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10 Room 4B36, Bethesda, MD 20892 USA. NR 23 TC 37 Z9 38 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD APR PY 2002 VL 32 IS 4 BP 1182 EP 1187 DI 10.1002/1521-4141(200204)32:4<1182::AID-IMMU1182>3.3.CO;2-0 PG 6 WC Immunology SC Immunology GA 541CY UT WOS:000174968700031 PM 11932926 ER PT J AU Praschak-Rieder, N Willeit, M Winkler, D Neumeister, A Hilger, E Zill, P Hornik, K Stastny, J Thierry, N Ackenheil, M Bondy, B Kaspera, S AF Praschak-Rieder, N Willeit, M Winkler, D Neumeister, A Hilger, E Zill, P Hornik, K Stastny, J Thierry, N Ackenheil, M Bondy, B Kaspera, S TI Role of family history and 5-HTTLPR polymorphism in female seasonal affective disorder patients with and without premenstrual dysphoric disorder SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Review DE seasonal affective disorder; premenstrual dysphoric disorder; 5-HTTLPR; family history; genetics ID HUMAN SEROTONIN TRANSPORTER; POPULATION-BASED TWIN; BRIGHT LIGHT THERAPY; TRYPTOPHAN DEPLETION; MENSTRUAL-CYCLE; M-CHLOROPHENYLPIPERAZINE; ENVIRONMENTAL-FACTORS; BEHAVIORAL-RESPONSES; MOOD; SYMPTOMS AB Seasonal affective disorder (SAD) and premenstrual dysphoric disorder (PMDD) share many clinical features. and have been associated with brain serotortin dysfunction. Females with SAD frequently fulfil the diagnostic criteria for PMDD. A polymorphism in the serotonin transporter promoter gene (5-HTTLPR) bus been associated with SAD. We investigated the role of family history and 5-HTTLPR in female SAD patients with and without PMDD, Forty-four SAD females with, and 43 SAD females without PMDD, were genotyped for 5-HTTLPR. Family history of affective disorders in first degree relatives was assessed, An association between the presence of PMDD and family history (P=0.0029) and 5-HTTLPR long/short allele-heterozygosity (P=0.033) was found in females with SAD. PMDD and SAD may share genetic vulnerability factors, one candidate gene being 5-HTTLPR. The elevated rate of affective disorders in relatives of patients with SAD and PMDD suggests higher genetic vulnerability in this subgroup when compared to patients with SAD alone. (C) 2002 Elsevier Science B.V/ECNP All rights reserved. C1 Univ Vienna, Dept Gen Psychiat, A-1090 Vienna, Austria. NIMH, Mood & Anxiety Disorders Res Program, Bethesda, MD 20892 USA. Univ Hosp Psychiat, Dept Neurochem, Munich, Germany. Univ Vienna, Dept Probabil Theory & Stat, Vienna, Austria. RP Praschak-Rieder, N (reprint author), Univ Vienna, Dept Gen Psychiat, Waehringer Guertel 18-20, A-1090 Vienna, Austria. NR 53 TC 20 Z9 20 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD APR PY 2002 VL 12 IS 2 BP 129 EP 134 AR PII S0924-977X(01)00146-8 DI 10.1016/S0924-977X(01)00146-8 PG 6 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 539LU UT WOS:000174872300006 PM 11872329 ER PT J AU Shibaki, A Katz, SI AF Shibaki, A Katz, SI TI Induction of skewed Th1/Th2 T-cell differentiation via subcutaneous immunization with Freund's adjuvant SO EXPERIMENTAL DERMATOLOGY LA English DT Article DE dendritic cells; Langerhans cells; T cells; cytokine ID HUMAN DENDRITIC CELLS; IN-VIVO; ATOPIC-DERMATITIS; OX40 LIGAND; ACTIVATION; EXPRESSION; PSORIASIS; TOLERANCE; DISTINCT; LYMPHOCYTES AB CD4(+) T cells differentiate into at least two distinct subsets, Th1 and Th2, that are characterized by their cytokine-producing profiles. In this study, we attempted to delineate whether and how CD4(+) T-cell responses could be skewed in one direction or another. BALB/c mice were immunized with chicken ovalbumin (OVA) emulsified with either incomplete or complete Freund's adjuvant (IFA or CFA). When lymph node cells were assessed on day 7, antigen specific proliferation was similarly observed both in the mice immunized with IFA and CFA. In contrast, on day 28 there was a less significant response in the mice primed with IRA than in those primed with CFA. ELISA analyses revealed more Th1 predominant cytokine production by T cells immunized with OVA+CFA rather than in IFA, which resulted in balanced IFN-gamma and IL-4 production. Flow cytometric analyses of intracellular cytokines confirmed that T cells from mice primed with CFA produced Th1 cytokines more predominantly. When lymph node dendritic cells (DC) were compared for their co-stimulatory molecule expression, priming with CFA and IFA similarly upregulated CD80 and CD86 expression by lymph node DC, and no significant differences were observed in CD40, 54, 80 and 86 expression between the DC harvested from IFA and CFA immunized mice. In addition, both priming with IFA and CFA similarly induced IL-12 production by DC. Thus, although the reason(s) for the preferential induction of a Th1/Th2 response remains unknown, these results indicate that a relatively Th1/Th2 skewed response is differentially induced by different types of adjuvants, and induction of a Th1 skewed response may be responsible for long lasting cellular immunity. C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Katz, SI (reprint author), NCI, Dermatol Branch, NIH, Bldg 10,Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. NR 35 TC 39 Z9 40 U1 1 U2 7 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0906-6705 J9 EXP DERMATOL JI Exp. Dermatol. PD APR PY 2002 VL 11 IS 2 BP 126 EP 134 DI 10.1034/j.1600-0625.2002.110204.x PG 9 WC Dermatology SC Dermatology GA 549GN UT WOS:000175436300004 PM 11994139 ER PT J AU Brosh, RM Bohr, VA AF Brosh, RM Bohr, VA TI Roles of the Werner syndrome protein in pathways required for maintenance of genome stability SO EXPERIMENTAL GERONTOLOGY LA English DT Review DE Werner syndrome; helicase; genome stability ID SYNDROME GENE-PRODUCT; SINGLE-STRANDED-DNA; LYMPHOBLASTOID CELL-LINES; SACCHAROMYCES-CEREVISIAE; FUNCTIONAL INTERACTION; POLYMERASE-DELTA; BINDING-PROTEIN; P53-MEDIATED APOPTOSIS; JAPANESE POPULATION; HELICASE ACTIVITY AB Werners syndrome is a disease of premature aging where the patients appear much older than their chronological age. The gene codes for a protein that is a helicase and an exonuclease, and recently we have learned about some of its protein interactions. These interactions are being discussed as they shed light on the molecular pathways in which Werner protein participates. Insight into these pathways brings insight into the aging process. Published by Elsevier Science Inc. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 102 TC 63 Z9 64 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD APR PY 2002 VL 37 IS 4 BP 491 EP 506 AR PII S0531-5565(01)00227-3 DI 10.1016/S0531-5565(01)00227-3 PG 16 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 534EL UT WOS:000174571600003 PM 11830352 ER PT J AU Geller, HM Fawcett, JW AF Geller, HM Fawcett, JW TI Building a bridge: Engineering spinal cord repair SO EXPERIMENTAL NEUROLOGY LA English DT Review DE regeneration; biomaterials; grafts; nervous system; injury; implants; polymers; growth factors; trophic factors; extracellular matrix; adhesion molecules ID CELL-ADHESION MOLECULES; PERIPHERAL-NERVE REGENERATION; RAT SCHWANN-CELLS; PROTEIN-KINASE-C; CHONDROITIN-SULFATE PROTEOGLYCAN; PROMOTE NEURITE OUTGROWTH; GROWTH CONE GUIDANCE; ADULT-RAT; AXONAL REGENERATION; TENASCIN-C AB Injuries to the spinal cord that result in disruption of axonal continuity have devastating consequences for injured patients. Current therapies that use biologically active agents to promote neuronal survival and/or growth have had modest success in allowing injured neurons to regrow through the area of the lesion. Strategies for successful regeneration will require an engineering approach. We propose the design of cell-free grafts of biocompatible materials to build a bridge across the injured area through which axons can regenerate. There are three critical regions of this bridge: the on-ramp, the surface of the bridge itself, and the off-ramp. Each of these regions has specific design requirements, which, if met, can promote regeneration of axons in the injured spinal cord. These requirements, and proposed solutions, are discussed. (C) 2002 Elsevier Science (USA). C1 NHLBI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pharmacol, Piscataway, NJ 08854 USA. Cambridge Ctr Brain Repair, Cambridge CB2 2PY, England. RP Geller, HM (reprint author), NHLBI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. OI Geller, Herbert/0000-0002-7048-6144; Fawcett, James/0000-0002-7990-4568 NR 156 TC 150 Z9 157 U1 2 U2 26 PU ACADEMIC PRESS INC ELSEVIER SCIENCE 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 APR PY 2002 VL 174 IS 2 BP 125 EP 136 DI 10.1006/exnr.2002.7865 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 541PM UT WOS:000174993000001 PM 11922655 ER PT J AU Dimitrakakis, C Zhou, J Bondy, CA AF Dimitrakakis, C Zhou, J Bondy, CA TI Androgens and mammary growth and neoplasia SO FERTILITY AND STERILITY LA English DT Article; Proceedings Paper CT Conference on Androgen Insufficiency in Women CY JUL 29, 2001 CL PRINCETON, NEW JERSEY DE breast cancer; estrogen; androgen receptor; testosterone; oral contraceptive; hormone replacement ID HUMAN-BREAST-CANCER; SEX-HORMONE LEVELS; CAG REPEAT LENGTH; POSTMENOPAUSAL WOMEN; CELL-PROLIFERATION; RECEPTOR GENE; 17-BETA-HYDROXYSTEROID DEHYDROGENASES; ADRENAL-HYPERPLASIA; PREMENOPAUSAL WOMEN; ORAL-CONTRACEPTIVES AB Objective: Evaluation of current clinical, experimental, genetic, and epidemiological data pertaining to the role of androgens in mammary growth and neoplasia. Design: Literature review. Setting: National Institutes of Health. Subject(s): Recent, basic, clinical, and epidemiological studies. Intervention(s): None. Main Outcome Measure(s): Effects of androgens on mammary epithelial proliferation and/or breast cancer incidence. Result(s): Experimental data derived from rodents and cell lines provide conflicting results that appear be strain- and cell line-dependent. Epidemiologic studies have significant methodological limitations and provide inconclusive results, The study, of molecular defects involving androgenic pathways in breast cancer is in its infancy. Clinical and nonhuman primate studies, however, suggest that androgens inhibit mammary epithelial proliferation and breast growth and that conventional estrogen treatment suppresses endogenous androgens. Conclusion(s). Abundant clinical evidence suggests that androgens normally inhibit mammary epithelial proliferation and breast growth. Suppression of androgens by conventional estrogen treatment may thus enhance estrogenic breast stimulation and possibly breast cancer risk. Clinical trials to evaluate the impact of combined estrogen and androgen hormone replacement regimens on mammary gland homeostasis are needed to address this issue. (Fertil Steril((R)) 2002;77(Suppl 4):S26-33. (C) 2002 by American Society for Reproductive Medicine.). C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD USA. RP Bondy, CA (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC 1862, Bethesda, MD USA. NR 96 TC 40 Z9 41 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD APR PY 2002 VL 77 IS 4 SU 4 BP S26 EP S33 AR PII S0015-0282(02)02979-5 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 544CW UT WOS:000175141500007 PM 12007899 ER PT J AU Pinn, VW Lobo, RA AF Pinn, VW Lobo, RA TI Androgen insufficiency in women: The Princeton Conference - Preface SO FERTILITY AND STERILITY LA English DT Editorial Material C1 NIH, Off Res Womens Hlth, Bethesda, MD 20892 USA. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. RP Pinn, VW (reprint author), NIH, Off Res Womens Hlth, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD APR PY 2002 VL 77 IS 4 SU 4 BP S1 EP S1 AR PII S0015-0282(02)02963-1 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 544CW UT WOS:000175141500001 ER PT J AU Felix, K Rockwood, LD Pretsch, W Nair, J Bartsch, H Bornkamm, GW Janz, S AF Felix, K Rockwood, LD Pretsch, W Nair, J Bartsch, H Bornkamm, GW Janz, S TI Moderate G6PD deficiency increases mutation rates in the brain of mice SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE glucose-6-phoshpate dehydrogenase; endogenous oxidative stress; in vivo mutagenicity reporter gene; lacZ; etheno DNA adducts; free radicals ID OXIDATIVE STRESS; TRANSGENIC MICE; NITRIC-OXIDE; GLUCOSE-6-PHOSPHATE-DEHYDROGENASE G6PD; ESCHERICHIA-COLI; SACCHAROMYCES-CEREVISIAE; POSITIVE SELECTION; HYDROGEN-PEROXIDE; DNA GLYCOSYLASES; MAMMALIAN-CELLS AB Mice that harbored the x-ray-induced low efficiency allele of the major X-linked isozyme of glucose-6-phospate dehydrogenase (G6PD), Gpdx(a-m2Neu), and, in addition, harbored the transgenic shuttle vector for the determination of mutagenesis in vivo, pUR288, were employed to further our understanding of the interdependence of general metabolism, oxidative stress control, and somatic mutagenesis. The Gpdx(a-m2Neu) mutation conferred moderate G6PD deficiency in hemizygous males (Gpdx(a-m2Neu/y)) displaying residual enzyme activities of 27% in red blood cells and 13% in brain (compared to wild-type controls, Gpdx(a/y) males). In spite of this mild phenotype, the brains of G6PD-deficient males exhibited a significant distortion of redox control (similar to3-fold decrease in the ratio of reduced glutathione to oxidized glutathione), a considerable accumulation of promutagenic etheno DNA adducts (similar to13-fold increase in ethenodeoxyadenosine and similar to5-fold increase in ethenodeoxycytidine), and a substantial elevation of somatic mutation rates (similar to3-fold increase in mutant frequencies in lacZ, the target and reporter gene of mutagenesis in the shuttle vector, pUR288). The mutation pattern in the brain was dominated by illegitimate genetic recombinations, a presumed hallmark of oxidative mutagenesis. These findings suggested a critical function for G6PD in limiting oxidative mutagenesis in the mouse brain. (C) 2002 Elsevier Science Inc. C1 NCI, Genet Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. German Canc Res Ctr, Div Toxicol & Canc Risk Factors, DKFZ, D-6900 Heidelberg, Germany. Inst Mol Biol & Tumor Genet, Munich, Germany. RP Janz, S (reprint author), NCI, Genet Lab, Canc Res Ctr, NIH, Bldg 37,Room 2B10, Bethesda, MD 20892 USA. NR 62 TC 15 Z9 15 U1 0 U2 0 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 APR 1 PY 2002 VL 32 IS 7 BP 663 EP 673 DI 10.1016/S0891-5849(02)00756-6 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 536GE UT WOS:000174691700011 PM 11909700 ER PT J AU Navas, P Fernandez-Ayala, DM Martin, SF Lopez-Lluch, G De Cabo, R Rodriguez-Aguilera, JC Villalba, JM AF Navas, P Fernandez-Ayala, DM Martin, SF Lopez-Lluch, G De Cabo, R Rodriguez-Aguilera, JC Villalba, JM TI Ceramide-dependent caspase 3 activation is prevented by coenzyme Q from plasma membrane in serum-deprived cells SO FREE RADICAL RESEARCH LA English DT Article; Proceedings Paper CT 2nd Conference of the International-Coenzyme-Q10-Association CY DEC 01-03, 2000 CL FRANKFURT, GERMANY SP Int Coenzyme Q10 Assoc DE coenzyme Q; caspase; plasma membrane; ceramide ID TUMOR-NECROSIS-FACTOR; INDUCED APOPTOSIS; FACTOR-ALPHA; DEATH; BCL-2; INHIBITION; INDUCTION; PHOSPHOLIPASE-A2; MITOCHONDRIA; GENERATION AB Coenzyme Q (CoQ) is the key factor for the activity of the eukaryotic plasma membrane electron transport chain. Consequently, CoQ is essential in the cellular response against redox changes affecting this membrane. Serum withdrawal induces a mild oxidative stress, which produces lipid peroxidation in membranes. In fact, apoptosis induced by serum withdrawal can be prevented by several antioxidants including CoQ. Also, CoQ can maintain cell growth in serum-limiting conditions, whereas plasma membrane redox system (PMRS) inhibitors such as capsaicin, which compete with CoQ, inhibit cell growth and induce apoptosis. To understand how plasma membrane CoQ prevents oxidative stress-induced apoptosis we have studied the induction of apoptosis by serum withdrawal in CEM cells and its modulation by CoQ. Serum-withdrawal activates neutral sphingomyelinase (N-SMase), ceramide release and caspase-3-related proteases. CoQ addition to serum-free cultures inhibited a 60% N-SMase activation, an 80% ceramide release, and a 50% caspase-3 activity induced by serum deprivation. Caspase activation dependent on ceramide release since C-ceramide was only able to mimic this effect in 10% foetal calf serum cultured cells but not in serum-free cultures. Also, in vitro experiments demonstrated that C-2-ceramide and ceramide-rich lipid extracts directly activated caspase-3. Taken together, our results indicate that CoQ protects plasma membrane components and controls stress-mediated lipid signals by its participation in the PMRS. C1 Univ Pablo de Olavide, Lab Andaluz Biol, Seville 41013, Spain. Univ Cordoba, Dept Biol Celular Fisiol & Inmunol, Cordoba 14071, Spain. NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. RP Navas, P (reprint author), Univ Pablo de Olavide, Lab Andaluz Biol, Carretera de Utrera,Km 1, Seville 41013, Spain. RI de Cabo, Rafael/E-7996-2010; Lopez-Lluch, Guillermo/N-4742-2014; de Cabo, Rafael/J-5230-2016; OI Lopez-Lluch, Guillermo/0000-0001-9830-8502; de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 NR 34 TC 45 Z9 47 U1 0 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK,, ABINGDON OX14 4RN, OXON, ENGLAND SN 1071-5762 J9 FREE RADICAL RES JI Free Radic. Res. PD APR PY 2002 VL 36 IS 4 BP 369 EP 374 DI 10.1080/10715760290021207 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 540GG UT WOS:000174920700003 PM 12069099 ER PT J AU Blackstone, C Sheng, M AF Blackstone, C Sheng, M TI Postsynaptic calcium signaling microdomains in neurons SO FRONTIERS IN BIOSCIENCE LA English DT Review DE postsynaptic density; PDZ domain; dendritic spine; review; calcium; neuron; review ID METABOTROPIC GLUTAMATE RECEPTORS; LONG-TERM POTENTIATION; D-ASPARTATE RECEPTOR; HIPPOCAMPAL PYRAMIDAL NEURONS; OPERATED HTRP3 CHANNELS; NITRIC-OXIDE SYNTHASE; DENDRITIC SPINES; NMDA RECEPTOR; TYROSINE PHOSPHORYLATION; ION CHANNELS AB Calcium ions are crucial messengers in the regulation of synaptic efficacy. In the postsynaptic neuron, this is exemplified by the tight temporal and spatial co-segregation of calcium ions with calcium-dependent signal transduction protein complexes in dendritic spines. Over the last several years optical imaging, physiological, structural, and biological studies have clarified the molecular mechanisms underlying differential calcium signaling within the spine. In this review, we discuss how calcium signaling "microdomains" are organized and regulated. We emphasize the structural and functional features of precisely regulated supramolecular complexes incorporating proteins involved in calcium influx, calcium efflux, and signal transduction. These complexes act in concert to orchestrate the sophisticated postsynaptic calcium signaling that underlies synaptic plasticity. C1 NINCDS, Cellular Neurol Unit, NIH, Bethesda, MD 20892 USA. MIT, RIKEN MIT Neurosci Res Ctr, Ctr Learning & Memory, Cambridge, MA 02139 USA. RP Blackstone, C (reprint author), NINCDS, Cellular Neurol Unit, NIH, Bldg 36,Room 5W21,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 110 TC 13 Z9 14 U1 0 U2 4 PU FRONTIERS IN BIOSCIENCE INC PI MANHASSET PA C/O NORTH SHORE UNIV HOSPITAL, BIOMEDICAL RESEARCH CENTER, 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1093-9946 J9 FRONT BIOSCI JI Front. Biosci. PD APR PY 2002 VL 7 BP D872 EP D885 DI 10.2741/blacksto PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 534RP UT WOS:000174600800015 PM 11897549 ER PT J AU Gukovskaya, AS Vaquero, E Zaninovic, V Gorelick, FS Lusis, AJ Brennan, ML Holland, S Pandol, SJ AF Gukovskaya, AS Vaquero, E Zaninovic, V Gorelick, FS Lusis, AJ Brennan, ML Holland, S Pandol, SJ TI Neutrophils and NADPH oxidase mediate intrapancreatic trypsin activation in murine experimental acute pancreatitis SO GASTROENTEROLOGY LA English DT Article ID OXIDATIVE STRESS; SUPEROXIDE-DISMUTASE; ACINAR-CELLS; OXYGEN RADICALS; RESPIRATORY BURST; CERULEIN; RATS; PATHOGENESIS; CHOLECYSTOKININ; CATALASE AB Background & Aims: Intrapancreatic activation of digestive enzymes is a key event in the parenchymal cell injury of pancreatitis. We hypothesized that neutrophils recruited to the pancreas during pancreatitis may contribute to such activation. Methods: To cause experimental pancreatitis, rats and mice were treated with high doses of cerulein. Activation of the digestive enzyme, trypsin, was measured in pancreatic homogenates using a fluorogenic assay and localized immunocytochemically with antibody to trypsin-activation peptide (TAP). Results: Compared with controls, rats depleted of neutrophils with antineutrophil serum exhibited a marked attenuation in intrapancreatic trypsin activation and acinar cell TAP labeling induced by high-dose cerulein. To examine the mechanism, mice deficient in either nicontinamide adenine dinucleotide phosphate (NADPH) oxidase, or myeloperoxidase (MPO) were studied for trypsin activation. Mice deficient in NADPH oxidase exhibited attenuation of the cerulein-induced trypsin activation, but those deficient in MPO did not. Using measurements of Western blot analysis, generation of reactive oxygen species, and immunocytochemistry, we demonstrated the NADPH oxidase activity is in neutrophils and not pancreatic acinar tissue. Conclusions: The results demonstrate a novel role for neutrophils infiltrating the pancreas in pathologic activation of digestive enzymes in acute pancreatitis and indicate that this effect is mediated by products of NADPH oxidase. C1 Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA 90073 USA. NIAID, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, New Haven, CT USA. Vet Affairs Connecticut Healthcare Syst, Dept Med, West Haven, CT USA. Univ Calif Los Angeles, Dept Med, Dept Human Genet, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90024 USA. RP Gukovskaya, AS (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, Blsg 258,Room 340,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM agukovsk@ucla.edu FU NHLBI NIH HHS [HL30568]; NIAAA NIH HHS [P50 AA11999] NR 57 TC 136 Z9 141 U1 1 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD APR PY 2002 VL 122 IS 4 BP 974 EP 984 DI 10.1053/gast.2002.32409 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 534ZA UT WOS:000174618600019 PM 11910350 ER PT J AU Radaeva, S Jaruga, B Hong, F Kim, WH Fan, SJ Cai, HB Strom, S Liu, YH El-Assal, O Gao, B AF Radaeva, S Jaruga, B Hong, F Kim, WH Fan, SJ Cai, HB Strom, S Liu, YH El-Assal, O Gao, B TI Interferon-alpha activates multiple STAT signals and downregulates c-Met in primary human hepatocytes SO GASTROENTEROLOGY LA English DT Article ID CHRONIC HEPATITIS-C; HEPATOCELLULAR-CARCINOMA; RECEPTOR GENE; TRANSCRIPTION FACTOR; TARGETED DISRUPTION; SYNTHETASE FAMILY; INDUCED PROTEINS; GROWTH-FACTOR; LIVER-CANCER; CELL-GROWTH AB Background & Aims: Interferon (IFN)-alpha therapy is currently the primary choice for viral hepatitis and a promising treatment for hepatocellular carcinoma (HCC). Primary mouse and rat hepatocytes respond poorly to IFN-alpha stimulation. Thus, it is very important to examine the IFN-a signal pathway in primary human hepatocytes. Methods: The IFN-alpha-activated signals and genes in primary human hepatocytes and hepatoma cells were examined by Western blotting and microarray analyses. Results: Primary human hepatocytes respond very well to IFN-alpha stimulation as shown by activation of multiple signal transducer and activator of transcription factor (STAT) :1, 2, 3, 5, and multiple genes. The differential response to IFN-alpha stimulation in primary human and mouse hepatocytes may be caused by expression of predominant functional IFN-alpha receptor 2c (IFNAR2c) in primary human hepatocytes vs. expression of predominant inhibitory IFNAR2a in mouse hepatocytes. Microarray analyses of primary human hepatocytes show that IFN-a up-regulates about 44 genes by over 2-fold and down-regulates about 9 genes by 50%. The up-regulated genes include a variety of antiviral and tumor suppressors/proapoptotic genes. The down-regulated genes include c-myc and c-Met, the hepatocyte growth factor (HGF) receptor. Down-regulation of c-Met is caused by IFN-alpha suppression of the c-Met promoter through downregulation of Sp1 binding and results in attenuation of HGF-induced signals and cell proliferation. Conclusions: IFN-a directly targets human hepatocytes, followed by activation of multiple STATs and regulation of a wide variety of genes, which may contribute to the antiviral and antitumor activities of IFN-alpha in human liver. C1 NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. Long Isl Jewish Med Ctr, Albert Einstein Coll Med, New Hyde Pk, NY 11042 USA. RP Gao, B (reprint author), NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Pk Bldg,Room 120,12420 Parklawn Dr,MSC 8115, Bethesda, MD 20892 USA. OI Strom, Stephen/0000-0002-2889-3387 NR 60 TC 98 Z9 102 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD APR PY 2002 VL 122 IS 4 BP 1020 EP 1034 DI 10.1053/gast.2002.32388 PG 15 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 534ZA UT WOS:000174618600023 PM 11910354 ER PT J AU Mautino, MR Morgan, RA AF Mautino, MR Morgan, RA TI Inhibition of HIV-1 replication by novel lentiviral vectors expressing transdominant Rev and HIV-1 env antisense SO GENE THERAPY LA English DT Article DE lentiviral vector; HIV/AIDS; transdominant Rev; envelope antisense ID IMMUNODEFICIENCY-VIRUS TYPE-1; CONSTITUTIVE TRANSPORT ELEMENT; MEDIATED GENE-TRANSFER; T-CELLS; RETROVIRAL VECTORS; ACCESSORY PROTEINS; PARTICLE FORMATION; HUMAN-LYMPHOCYTES; CD34(+) CELLS; THERAPY AB Retroviral vectors expressing transdominant negative mutants of Rev (TdRev) inhibit HIV-1 replication by preventing the nuclear export of unspliced viral transcripts, thus inhibiting the synthesis of Gag-Pol, Env and reducing the levels of genomic RNA available for packaging. Due to these effective mechanisms of inhibition, production of HIV-1-based lentiviral vectors expressing TdRev has been difficult, Here we describe HIV-based vectors in which expression of TdRev is negatively regulated by Rev expression. In these vectors, we maintained the wild-type HIV-1 Tat/Rev exons and intron configuration and its mode of splicing regulation. The second Rev exon was mutated to encode TdRev. Inhibition of TdRev expression by Rev during vector production yields high titer vector preparations. A second vector containing an additional anti-HIV gene (env-antisense) was constructed by flipping a 1.2-kb env fragment contained within the Tat/TdRev intron. SupT1 cells and primary CD4(+) lymphocytes transduced with these vectors inhibit HIV-1 replication and show a preferential advantage for survival. Although these vectors are poorly mobilized to secondary target cells by wild-type HIV-1, they reduce the infectivity of the wild-type virions escaping inhibition. C1 Natl Human Genome Res Inst, Clin Gene Therapy Branch, NIH, Bethesda, MD USA. RP Mautino, MR (reprint author), Newlink Genet, 2901 South Loop Dr Suite 9900, Ames, IA USA. NR 53 TC 16 Z9 18 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD APR PY 2002 VL 9 IS 7 BP 421 EP 431 DI 10.1038/sj/gt/3301674 PG 11 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 538NW UT WOS:000174822900001 PM 11938457 ER PT J AU Chaudru, V Laing, A Dunston, GM Adams-Campbell, LL Williams, R Lynch, JJ Leffall, LD DeWitty, RL Gause, BL Bonney, GE Demenais, F AF Chaudru, V Laing, A Dunston, GM Adams-Campbell, LL Williams, R Lynch, JJ Leffall, LD DeWitty, RL Gause, BL Bonney, GE Demenais, F TI Interactions between genetic and reproductive factors in breast cancer risk in a population-based sample of African-American families SO GENETIC EPIDEMIOLOGY LA English DT Article DE breast cancer; segregation analysis; regressive models; gene-environment interactions; risk factors ID REGRESSIVE LOGISTIC-MODELS; PEDIGREE DATA; BLACK-WOMEN; BRCA1; EPIDEMIOLOGY; DISEASES; HISTORY; CELLS AB Incidence of breast cancer (BC) varies among ethnic groups, with higher rates in white than in African-American women. Until now, most epidemiological and genetic studies have been carried out in white women. To investigate whether interactions between genetic and reproductive risk factors may explain part of the ethnic disparity in BC incidence, a genetic epidemiology study was conducted, between 1989 and 1994, at the Howard University Cancer Center (Washington, DC), which led to the recruitment of 245 African-American families. Segregation analysis of BC was performed by use of the class D regressive logistic model that allows for censored data to account for a variable age of onset of disease, as implemented in the REGRESS program. Segregation analysis of BC was consistent with a putative dominant gene effect (P < 0.000001) and residual sister-dependence (P < 0.0001). This putative gene was found to interact significantly with age at menarche (P = 0.048), and an interaction with a history of spontaneous abortions was suggested (P = 0.08). A late age at menarche increased BC risk in gene carriers but had a protective effect in non-gene carriers. A history of spontaneous abortions had a protective effect in gene carriers and increased BC risk in non-gene carriers. Our findings agree partially with a similar analysis of French families showing a significant gene x parity interaction and a suggestive gene x age at menarche interaction. Investigating gene X risk factor interactions in different populations may have important implications for further biological investigations and for BC risk assessment. (C) 2002 Wiley-Liss, Inc. C1 Univ Evry, INSERM, EMI 00 06, F-91034 Evry, France. Howard Univ, Ctr Canc, Washington, DC 20059 USA. Howard Univ, Natl Human Genome Ctr, Washington, DC 20059 USA. Washington Hosp Ctr, Washington Canc Inst, Washington, DC 20010 USA. Howard Univ Hosp, Dept Surg, Washington, DC USA. NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Demenais, F (reprint author), Univ Evry, INSERM, EMI 00 06, Tour Evry 2,523,Pl Terrasses Agora, F-91034 Evry, France. RI Demenais, Florence/G-3298-2013 OI Demenais, Florence/0000-0001-8361-0936 FU NCI NIH HHS [R01-CA55772] NR 29 TC 7 Z9 7 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 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD APR PY 2002 VL 22 IS 4 BP 285 EP 297 DI 10.1002/gepi.0171 PG 13 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 548WW UT WOS:000175413700002 PM 11984862 ER PT J AU Americo, J Whiteley, M Brown, JL Fujioka, M Jaynes, JB Kassis, JA AF Americo, J Whiteley, M Brown, JL Fujioka, M Jaynes, JB Kassis, JA TI A complex array of DNA-binding proteins required for pairing-sensitive silencing by a polycomb group response element from the drosophila engrailed gene SO GENETICS LA English DT Article ID TRITHORAX GROUP PROTEINS; HOMEOTIC GENE; BITHORAX COMPLEX; TRANSCRIPTION FACTOR; CHROMATIN INSULATOR; REGULATORY REGION; TARGET GENES; GAGA FACTOR; TRANS; TRANSVECTION AB Regulatory DNA from the Drosophila gene engrailed causes silencing of a linked reporter gene (mini-white) in transgenic Drosophila. This silencing is strengthened in flies homozygous for the transgene and has been called "pairing-sensitive silencing." The pairing-sensitive silencing activities of a large fragment (2.6 kb) and a small subfragment (181 bp) were explored. Since pairing-sensitive silencing is often associated with Polycomb group response elements (PREs), we tested the activities of each of these engrailed fragments fit a construct designed to detect PRE activity in embryos. Both fragments were found to behave as PREs in a bxd-Ubx-lacZ reporter construct, while the larger fragment showed additional silencing capabilities. Using the mini-white reporter gene, a 139-bp minimal pairing-sensitive element (PSE) was defined. DNA mobility-shift assays using Drosophila nuclear extracts suggested that there are eight protein-binding sites within this 139-bp element. Mutational analysis showed that at least five of these sites are important for pairing-sensitive silencing. One of the required sites is for the Polycomb group protein Pleiohomeotic and another is GAGAG, a sequence bound h the protein,, GAGA factor and Pipsqueak. The identity of the other proteins is unknown. These data suggest a surprising degree of complexity in the DNA-binding proteins required for PSE function. C1 NICHHD, LMG, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapeut, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Kimmel Canc Inst, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA. RP Kassis, JA (reprint author), NICHHD, LMG, NIH, 6 Ctr Dr,MSC 2785, Bethesda, MD 20892 USA. OI Kassis, Judith/0000-0001-9268-3213 FU NIGMS NIH HHS [R01 GM050231, R01 GM050231-05A2, GM50231] NR 54 TC 50 Z9 50 U1 1 U2 1 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD APR PY 2002 VL 160 IS 4 BP 1561 EP 1571 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 545VA UT WOS:000175237200026 PM 11973310 ER PT J AU Klar, AJS AF Klar, AJS TI The chromosome 1;11 translocation provides the best evidence supporting genetic etiology for schizophrenia and bipolar affective disorders SO GENETICS LA English DT Article ID ASYMMETRY; FAMILY AB Genetics is assumed to cause susceptibility to psychosis, but no major locus has been identified. These disorders cosegregate with a chromosome 1:11 translocation in a Scottish pedigree where 50% of the carriers are diseased. A genetic model originally proposed to explain the basis of these illnesses predicts such an outcome. C1 NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RP Klar, AJS (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, POB B,Ft Detrick,Bldg 539, Frederick, MD 21702 USA. NR 11 TC 15 Z9 16 U1 0 U2 1 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD APR PY 2002 VL 160 IS 4 BP 1745 EP 1747 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 545VA UT WOS:000175237200042 PM 11973326 ER PT J AU Deb-Rinker, P O'Reilly, RL Torrey, EF Singh, SM AF Deb-Rinker, P O'Reilly, RL Torrey, EF Singh, SM TI Molecular characterization of a 2.7-kb, 12q13-specific, retroviral-related sequence isolated by RDA from monozygotic twin pairs discordant for schizophrenia SO GENOME LA English DT Article DE ERV; methylation; retroviral integration; 12q13; neurodevelopment; schizophrenia ID PROTEIN-COUPLED RECEPTORS; ENDOGENOUS RETROVIRUSES; DNA-SEQUENCE; GENE; HYPOTHESIS; EXPRESSION; IDENTIFICATION; INTEGRATION; ELEMENTS; DISEASE AB This report deals with the molecular characterization of a representational difference analysis (RDA)-derived sequence (SZRV-2, GenBank accession No. AF135486; Genome Database accession Nos. 7692183 and 7501402) from three monozygotic twin pairs discordant for schizophrenia (MZD). The results suggest that it is a primate-specific, heavily methylated, and placentally expressed (similar to7-kb mRNA) endogenous retroviral-related (ERV) sequence of the human genome. We have mapped this sequence to 12q13 using two SZRV-2 positive BAC clones (4K11 (Genome Survey Sequence Database No. 1752076; GenBank accession No. AZ301773) and 501H16) by fluorescence in situ hybridization. End sequencing of the 4K11 BAC clone has allowed identification of nearby genes from the human genome database at NCBI that may be of interest in schizophrenia research. These include viral-related sequences (potential hot spots for insertions), developmental, channel, and signal transduction genes, as well as genes affecting expression of certain receptors in neurons. Furthermore, when used as a probe on Southern blots, SZRV-2 detected no difference between schizophrenia patients from southwestern Ontario and their matched controls. However, it identified aberrant methylation in one of the eight patients and none of the 21 unaffected controls. Although additional experiments will be required to establish the significance, if any, of SZRV-2 methylation in the complex etiology of schizophrenia, molecular results included offer a novel insight into the role of retroviral-related sequences in the origin, organization, and regulation of the human genome. C1 Univ Western Ontario, Dept Zool, Mol Genet Unit, London, ON N6A 5B7, Canada. Univ Western Ontario, Div Med Genet, London, ON N6A 5B7, Canada. Univ Western Ontario, Dept Psychiat, London, ON N6A 5A5, Canada. NIMH, Neurosci Ctr St Elizabeths, Stanley Fdn Res Programs, Washington, DC 20032 USA. London Hlth Sci Ctr, Child Hlth Res Inst, Mol Med Genet Program, London, ON N6A 2V5, Canada. RP Singh, SM (reprint author), Univ Western Ontario, Dept Zool, Mol Genet Unit, London, ON N6A 5B7, Canada. EM ssingh@uwo.ca NR 42 TC 11 Z9 11 U1 0 U2 0 PU CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS PI OTTAWA PA 1200 MONTREAL ROAD, BUILDING M-55, OTTAWA, ON K1A 0R6, CANADA SN 0831-2796 J9 GENOME JI Genome PD APR PY 2002 VL 45 IS 2 BP 381 EP 390 DI 10.1139/G01-152 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 530AM UT WOS:000174333500019 PM 11962635 ER PT J AU Wu, YY Mujtaba, T Han, SSW Fischer, I Rao, MS AF Wu, YY Mujtaba, T Han, SSW Fischer, I Rao, MS TI Isolation of a glial-restricted tripotential cell line from embryonic spinal cord cultures SO GLIA LA English DT Article DE GRP cells; self-renewal; neuroblast; glioblast; immortalization; v-myc; GRIP; oligodendrocyte; astrocyte ID NEUROEPITHELIAL STEM-CELLS; REGION-SPECIFIC DIFFERENTIATION; CENTRAL-NERVOUS-SYSTEM; NEURAL-TUBE; MONOCLONAL-ANTIBODIES; NEURONAL PRECURSORS; PROGENITOR CELLS; MOUSE CEREBELLUM; MAMMALIAN BRAIN; IMMORTALIZATION AB Neuroepithelial stem cells (NEPs), glial-restricted precursors (GRPs), and neuron-restricted precursors (NRPs) are present during early differentiation of the spinal cord and can be identified by cell surface markers. In this article, we describe the properties of GRP cells that have been immortalized using a regulatable v-myc retrovirus construct. Immortalized GRP cells can be maintained in an undifferentiated dividing state for long periods and can be induced to differentiate into two types of astrocytes and into oligodendrocytes in culture. A clonal cell line prepared from immortalized GRP cells, termed GRIP-1, was also shown to retain the properties of a glial-restricted tripotential precursor. Transplantation of green fluorescent protein (GFP)-labeled subclones of the immortalized cells into the adult CNS demonstrates that this cell line can also participate in the in vivo development of astrocytes and oligodendrocytes. Late passages of the immortalized cells undergo limited transdifferentiation into neurons as assessed by expression of multiple neuronal markers. The availability of a conditionally immortalized cell line obviates the difficulties of obtaining a large and homogeneous population of GRPs that can be used for studying(C)c 2002 Wiley-Liss, Inc. C1 NIA, Neurosci Lab, GRC, Baltimore, MD 21224 USA. Univ Utah, Sch Med, Dept Neurobiol & Anat, Salt Lake City, UT USA. Med Coll Penn & Hahnemann Univ, Sch Med, Dept Neurobiol & Anat, Philadelphia, PA 19102 USA. RP Rao, MS (reprint author), NIA, Neurosci Lab, GRC, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Fischer, Itzhak/D-1080-2012 OI Fischer, Itzhak/0000-0003-3187-8740 NR 52 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 0894-1491 J9 GLIA JI Glia PD APR 1 PY 2002 VL 38 IS 1 BP 65 EP 79 DI 10.1002/glia.10049 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 537TD UT WOS:000174774900006 PM 11921204 ER PT J AU Hartos, J Eitel, P Simons-Morton, B AF Hartos, J Eitel, P Simons-Morton, B TI Parenting practices and adolescent risky driving: A three-month prospective study SO HEALTH EDUCATION & BEHAVIOR LA English DT Article ID SUBSTANCE USE; LONGITUDINAL EXAMINATION; RECKLESS BEHAVIOR; YOUNG DRIVERS; DRINKING; ADJUSTMENT; SCHOOL; INVOLVEMENT; PERSONALITY; PERCEPTION AB This study examined relations between risky driving, parenting, and deviance, and the stability of risky driving over time. Two hundred and sixty-one licensed adolescents completed telephone interviews about risky driving, parenting practices, and orientations toward deviance at baseline and about risky driving at follow-up 3 months later. The results indicated that risky driving at follow-up was predicted by risky driving at baseline, parental restrictions on driving, and sensation seeking. In addition, risky driving was stable within 80% of teens. When compared with adolescents with low risky driving over time (n = 129), adolescents with high risky driving over time (n = 79) were 3 times more likely to report low parental monitoring, 2 times more likely to report low parental restrictions, and almost 5 times more likely to report high deviance acceptance. The results suggest that high levels of risky driving are related to parenting. C1 Ogilvy & Mather, New York, NY USA. NICHHD, Prevent Res Branch, Bethesda, MD 20892 USA. OI Simons-Morton, Bruce/0000-0003-1099-6617 NR 43 TC 65 Z9 66 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD APR PY 2002 VL 29 IS 2 BP 194 EP 206 DI 10.1177/109019810202900205 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 534YV UT WOS:000174618100004 PM 11942714 ER PT J AU McCoy, JP AF McCoy, JP TI Basic principles of flow cytometry SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article ID CELL COUNTS; STANDARDIZATION; LYMPHOCYTE; VALIDATION; CD4 AB This article reviews the basic design of flow cytometers, as well as many of the essential concepts for use of flow cytometry. The goal of this article is to provide the reader with a fundamental understanding of flow cytometry, which will permit appreciation of applications described elsewhere in this issue. A brief discussion of cytometry safety and quality control/standardization also is presented to introduce the reader to these concepts. C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP McCoy, JP (reprint author), NHLBI, NIH, Bldg 10,10 Ctr Dr,MSC 1357,Room 4A07, Bethesda, MD 20892 USA. NR 23 TC 11 Z9 14 U1 6 U2 20 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD APR PY 2002 VL 16 IS 2 BP 229 EP + AR PII S0889-8588(01)00015-6 DI 10.1016/S0889-8588(01)00015-6 PG 16 WC Oncology; Hematology SC Oncology; Hematology GA 564RB UT WOS:000176326400002 PM 12094472 ER PT J AU Mallet, VO Mitchell, C Mezey, E Fabre, M Guidotti, JE Renia, L Coulombel, L Kahn, A Gilgenkrantz, H AF Mallet, VO Mitchell, C Mezey, E Fabre, M Guidotti, JE Renia, L Coulombel, L Kahn, A Gilgenkrantz, H TI Bone marrow transplantation in mice leads to a minor population, of hepatocytes that can be selectively amplified in vivo SO HEPATOLOGY LA English DT Article ID STEM-CELLS; IN-VIVO; LIVER; REGENERATION; REPOPULATION; EXPRESSION; BRAIN AB Cell-based therapy may some day be a therapeutic alternative to liver transplantation. Recent observations indicating that hematopoietic stem cells can differentiate into hepatocytes have opened new therapeutic prospects. However, the clinical relevance of this phenomenon is unknown. We have previously developed a strategy based on the protective effect of Bcl-2 against Fas-mediated apoptosis to selectively amplify a small number of hepatocytes in vivo. We now show that this approach can be used to amplify a minor population of bone marrow-derived hepatocytes. Normal mice were transplanted with unfractionated bone marrow cells from transgenic animals expressing Bcl-2 under the control of a liver-specific promoter. Recipients were then submitted to weekly injections of the anti-Fas antibody, Jo2. Upon sacrifice, the liver of the recipients showed bone marrow- derived dusters of mature hepatocytes expressing Bcl-2, which showed that the hepatocyte progeny of a genetically modified bone marrow can be selectively expanded in vivo. In contrast, no Bcl-2 expression could be detected without the selective pressure of Jo2, suggesting that differentiation of bone marrow cells into mature hepatocytes is very inefficient under physiologic conditions. We conclude that a selection strategy will be required to achieve a therapeutic level of liver repopulation with bone marrow- derived hepatocytes. C1 Inst Cochin, Dept Genet Dev & Mol Pathol, F-75014 Paris, France. NINCDS, Basic Neurosci Program, NIH, Bethesda, MD 20892 USA. Hop Bicetre, Pathol Lab, Le Kremlin Bicetre, France. Cochin Inst, Dept Immunol, Paris, France. Univ Paris 12, Sch Med, INSERM U 421, Creteil, France. RP Gilgenkrantz, H (reprint author), Inst Cochin, Dept Genet Dev & Mol Pathol, 24 Rue Faubourg St Jacques, F-75014 Paris, France. RI Renia, Laurent/E-2117-2011; OI Renia, Laurent/0000-0003-0349-1557; Mallet, Vincent/0000-0003-2219-9201 NR 24 TC 105 Z9 120 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD APR PY 2002 VL 35 IS 4 BP 799 EP 804 DI 10.1053/jhep.2002.32530 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 534ZB UT WOS:000174618700008 PM 11915025 ER PT J AU Umemura, T Alter, HJ Tanaka, E Orii, K Yeo, AET Shih, JWK Matsumoto, A Yoshizawa, K Kiyosawa, K AF Umemura, T Alter, HJ Tanaka, E Orii, K Yeo, AET Shih, JWK Matsumoto, A Yoshizawa, K Kiyosawa, K TI SEN virus: Response to interferon alfa and influence on the severity and treatment response of coexistent hepatitis C SO HEPATOLOGY LA English DT Article ID NON-B-HEPATITIS; NON-A; THERAPY; TRANSFUSION; INFECTION; ANTIBODY; SYSTEM; RNA AB The SEN virus (SENV) is a recently identified single,stranded, circular DNA virus. A strong association between 2 SENV variants (SENV-D and SENV-H) and transfusion-associated non-A-to-E hepatitis has been reported. To clarify the effect of SENV infection on coexisting chronic hepatitis C and them effect of interferon alfa (IFN-alpha) therapy on SENV replication, SENV DNA was quantitated by polymerase chain reaction in serum samples from 186 patients with chronic hepatitis C. Thirty-nine of 186 (21%) patients with chronic hepatitis C were positive for SENV DNA. There were no differences in the clinical, virologic and histologic features between patients with and without SENV infection. Eighteen of 102 patients with chronic hepatitis C who received IFN-alpha were positive for SENV DNA. The sustained response rate for hepatitis C virus (HCV) clearance after IFN-alpha treatment did not differ significantly between patients with SENV (28%) and without SENV infection (39%). SENV DNA levels decreased during therapy in 15 of 16 patients, and 11 of the 16 patients (69%) had a sustained loss of SENV DNA in response to IFN-alpha. In coinfected patients, SENV responses to IFN-alpha were significantly better in those who failed to dear HCV RNA than in those who lost HCV RNA (P =.013). In conclusion, SENV infection was frequently found in patients with chronic hepatitis C. SENV infection had no apparent influence on the severity of HCV-related liver disease or the HCV response to IFN-alpha. SENV was sensitive to IFN-alpha therapy and the majority of patients had a sustained virologic response. C1 NIH, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. Shinshu Univ, Sch Med, Dept Internal Med 2, Matsumoto, Nagano 390, Japan. RP Umemura, T (reprint author), NIH, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bldg 10,Rm 1C-711, Bethesda, MD 20892 USA. NR 28 TC 33 Z9 36 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 APR PY 2002 VL 35 IS 4 BP 953 EP 959 DI 10.1053/jhep.2002.32536 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 534ZB UT WOS:000174618700027 PM 11915044 ER PT J AU Stratakis, CA Miller, WR Severin, E Chin, KV Bertherat, J Amieux, PS Eng, C Kammer, GM Dumont, JE Tortora, G Beaven, MA Puck, TT de Beur, SMJ Weistein, LS Cho-Chung, YS AF Stratakis, CA Miller, WR Severin, E Chin, KV Bertherat, J Amieux, PS Eng, C Kammer, GM Dumont, JE Tortora, G Beaven, MA Puck, TT de Beur, SMJ Weistein, LS Cho-Chung, YS TI Protein-kinase A and human disease: The core of cAMP-dependent signaling in health and disease SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE protein kinase A; regulatory subunits; endocrine tumors; chromosome 17; tumor suppressor gene; oncogene; G-proteins; multiple endocrine neoplasia; Carney complex ID CARNEY COMPLEX; CYCLIC-AMP; MUTATIONS; GROWTH; GENE AB This report summarizes several aspects of protein kinase A (PKA) signaling and its involvement in health and disease. It follows the discovery that PRKAR1A, the gene that codes for the relatively abundant regulatory subunit type 1A of protein kinase A, is the tumor suppressor gene responsible for the multiple endocrine neoplasia syndrome known as "Carney complex." Although cyclic AMP (cAMP)-dependent signaling has already been found to be involved in the pathogenesis of other genetic conditions predisposing to tumor development, this is the first time that PKA itself was directly involved in tumorigenesis and, perhaps, carcinogenesis in an inherited disease. C1 NICHHD, Unit Genet & Endocrinol, DEB, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHHD, Unit Genet & Endocrinol, DEB, NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC1862, Bethesda, MD 20892 USA. RI Chin, Khew-Voon/F-2670-2013; OI Eng, Charis/0000-0002-3693-5145 NR 6 TC 1 Z9 1 U1 0 U2 2 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD APR PY 2002 VL 34 IS 4 BP 169 EP 175 DI 10.1055/s-2002-26710 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 555VJ UT WOS:000175813700001 ER PT J AU Strickland, JA Guth, DJ AF Strickland, JA Guth, DJ TI Quantitative exposure-response assessment approaches to evaluate acute inhalation toxicity of phosgene SO HUMAN AND ECOLOGICAL RISK ASSESSMENT LA English DT Article DE carbon dichloride oxide; categorical regression; benchmark dose; acute toxicity; risk assessment; dose-response assessment ID HIGH-LEVEL EXPOSURE; RAT LUNGS; INHALED PHOSGENE; PULMONARY; REGRESSION; INJURY AB Phosgene has been a long-term subject of toxicological research due to its widespread use, high toxicity, and status as a model of chemically induced lung injury. To take advantage of the abundant data set for the acute inhalation toxicity of phosgene, methods for exposure-response analysis that use more data than the traditional no-observed-adverse-effect level approach were used to per-form an exposure-response assessment for phosgene. Categorical regression is particularly useful for acute exposures due to the ability to combine studies of various exposure durations, and thus provide estimates of effect severity for a range of both exposure concentrations and durations. Results from the categorical regression approach were compared to those from parametric curve fitting models (i.e., benchmark concentration models) that make use of information from an entire dose-response, but only for one exposure duration. While categorical regression analysis provided results that were comparable to benchmark concentration results, categorical regression provides an improvement over that technique by accounting for the effects of both exposure concentration and duration on response. The other major advantage afforded by categorical regression is the ability to combine studies, allowing the quantitative use of a larger data set, which increases confidence in the final result. C1 US EPA, Natl Ctr Environm Assessment, Res Triangle Pk, NC 27711 USA. NIEHS, Integrated Lab Syst Inc, Res Triangle Pk, NC 27709 USA. Boeing Co, Seattle, WA 98124 USA. RP Strickland, JA (reprint author), US EPA, Natl Ctr Environm Assessment, Res Triangle Pk, NC 27711 USA. NR 57 TC 0 Z9 1 U1 0 U2 3 PU CRC PRESS LLC PI BOCA RATON PA 2000 CORPORATE BLVD NW, JOURNALS CUSTOMER SERVICE, BOCA RATON, FL 33431 USA SN 1080-7039 J9 HUM ECOL RISK ASSESS JI Hum. Ecol. Risk Assess. PD APR PY 2002 VL 8 IS 3 BP 511 EP 536 PG 26 WC Biodiversity Conservation; Environmental Sciences SC Biodiversity & Conservation; Environmental Sciences & Ecology GA 549VM UT WOS:000175467500005 ER PT J AU Ming, JE Kaupas, ME Roessler, E Brunner, HG Golabi, M Tekin, M Stratton, RF Sujansky, E Bale, SJ Muenke, M AF Ming, JE Kaupas, ME Roessler, E Brunner, HG Golabi, M Tekin, M Stratton, RF Sujansky, E Bale, SJ Muenke, M TI Mutations in PATCHED-1, the receptor for SONICHEDGEHOG, are associated with holoprosencephaly SO HUMAN GENETICS LA English DT Article ID SONIC-HEDGEHOG GENE; BASAL-CELL CARCINOMAS; SIGNALING PATHWAY; HUMAN HOMOLOG; NEURAL-TUBE; MICE; INDUCTION; SKIN; FOREBRAIN; CYCLOPIA AB Holoprosencephaly (HPE) is the most commonly occurring congenital structural forebrain anomaly in humans. HPE is associated with mental retardation and craniofacial malformations. The genetic causes of HPE have recently begun to be identified, and we have previously shown that HPE can be caused by haploinsufficiency for SONIC HEDGEHOG (SHIP). We hypothesize that mutations in genes encoding other components of the SHH signaling pathway could also be associated with HPE. PATCHED-1 (PTCH), the receptor for SHH, normally acts to repress SHH signaling. This repression is relieved when SHH binds to PTCH. We analyzed PTCH as a candidate gene for HPE. Four different mutations in PTCH were detected in five unrelated affected individuals. We predict that by enhancing the repressive activity of PTCH on the SHH pathway, these mutations cause decreased SHH signaling, and HPE results. The mutations could affect the ability of PTCH to bind SHH or perturb the intracellular interactions of PTCH with other proteins involved in SHH signaling. These findings further demonstrate the genetic heterogeneity associated with HPE, as well as showing that mutations in different components of a single signaling pathway can result in the same clinical condition. C1 Natl Human Genome Res Inst, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Pediat,Div Human Genet, Philadelphia, PA 19104 USA. Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Genet,Div Human Genet, Philadelphia, PA 19104 USA. Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Pediat,Div Neurol, Philadelphia, PA 19104 USA. Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Genet,Div Neurol, Philadelphia, PA 19104 USA. Univ Nijmegen, Nijmegen, Netherlands. Univ Calif San Francisco, San Francisco, CA 94143 USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Childrens Hosp, Denver, CO 80218 USA. NIAMS, NIH, Bethesda, MD USA. RP Muenke, M (reprint author), Natl Human Genome Res Inst, Med Genet Branch, NIH, 10 Ctr Dr,MSC 1852,Bldg 10,10C103, Bethesda, MD 20892 USA. RI Brunner, Han/C-9928-2013 FU NICHD NIH HHS [HD01218, HD29862] NR 30 TC 128 Z9 132 U1 0 U2 5 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD APR PY 2002 VL 110 IS 4 BP 297 EP 301 DI 10.1007/s00439-002-0695-5 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 550AE UT WOS:000175479900001 PM 11941477 ER PT J AU Arcos-Burgos, M Parodi, E Salgar, M Bedoya, E Builes, JJ Jaramillo, D Ceballos, G Uribe, A Rivera, N Rivera, D Fonseca, I Camargo, M Palacio, LG AF Arcos-Burgos, M Parodi, E Salgar, M Bedoya, E Builes, JJ Jaramillo, D Ceballos, G Uribe, A Rivera, N Rivera, D Fonseca, I Camargo, M Palacio, LG TI Vitiligo: complex segregation and linkage disequilibrium analyses with respect to microsatellite loci spanning the HLA SO HUMAN GENETICS LA English DT Article ID HAPLOTYPE RELATIVE RISK; CLINICAL-FEATURES; COLOMBIA; POPULATION; MUTATION; ONSET; POLYMORPHISMS; ASSOCIATION; COMMUNITY; ALLELES AB Familial clustering and linkage disequilibrium studies suggest that genetic factors predispose to vitiligo, although a clear transmission pattern and cosegregation of vitiligo with specific mutations have not been demonstrated. We collected pedigree data on vitiligo from a set of 56 multigeneration families belonging to the Paisa community from Antioquia. Colombia, with the goal of applying the unified model of complex segregation and linkage disequilibrium analyses to test the hypotheses of the existence of a major gene predisposing to vitiligo and that allelic or haplotype polymorphisms of microsatellite loci at 6p21.3-21.4 spanning HLA (D6S276, D6S265, D6S273, and D6S291) are associated with this predisposition. Minimum sibship sample size to discriminate dominant and recessive inheritance models was largely accomplished. Between the 15 models of complex segregation used, the one that best fitted the data was that of a major dominant gene and the existence of strong environmental effects acting on the recessive genotype. The penetrance and risk estimations discriminated two sets of vitiligo patients: those with early onset of vitiligo cosegregating with a dominant mode of inheritance without environmental effects, and those with late onset of vitiligo cosegregating with the recessive genotype and being influenced by environmental effects. After establishing the normal distribution of allelic frequencies and performing multiple comparisons correction, the linkage disequilibrium analysis suggested that a major genetic factor could be located at 6p21.3-21.4, because we detected significant case-control differences for allele 122 at D6S265 (Pc=0.0264) and significant linkage disequilibrium between loci D6S276 and D6S273 in the cases but not in the controls. We cannot explain these results Lts a consequence of evolutionary forces or as genetic stratification acting differentially on cases and controls, because there was neither deviation from the Hardy-Weitlberg expectations nor genetic subdivision between cases and controls, as theta (non-biased F-ST) was not significantly different from 0. C1 Univ Antioquia, Inst Biol, Populat Genet Mutacarcinogenesis & Genet Epidemio, Medellin, Colombia. Univ Antioquia, Dept Internal Med, Dermatol Serv, Medellin, Colombia. RP Arcos-Burgos, M (reprint author), Natl Human Genome Res Inst, Med Genet Branch, NIH, 10 Ctr Dr,MSC 1852,Bldg 10,Room 10C107, Bethesda, MD 20892 USA. OI Builes Gomez, Juan Jose/0000-0001-8403-6809 NR 42 TC 52 Z9 60 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD APR PY 2002 VL 110 IS 4 BP 334 EP 342 DI 10.1007/s00439-002-0687-5 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 550AE UT WOS:000175479900006 PM 11941482 ER PT J AU Tong, ZB Bondy, CA Zhou, J Nelson, LM AF Tong, ZB Bondy, CA Zhou, J Nelson, LM TI A human homologue of mouse Mater, a maternal effect gene essential for early embryonic development SO HUMAN REPRODUCTION LA English DT Article DE embryo; infertility; MATER; oocyte; premature ovarian failure ID PREMATURE OVARIAN FAILURE; AUTOIMMUNE OOPHORITIS; THYMECTOMIZED MICE; MAMMALIAN EMBRYOS; PROTEINS; ACTIVATION; EXPRESSION; STAGE; CELL AB BACKGROUND: Mater is a maternal effect gene required for early embryonic development in mice, and its protein serves as an autoantigen in a mouse model of autoimmune premature ovarian failure. METHODS: Human MATER cDNA was cloned by PCR techniques. The mRNA and protein were determined using hybridization and immunodetection respectively. The cDNA and protein sequences were analysed using bioinformatics software. RESULTS: Human MATER gene spans a similar to63 kbp DNA at chromosome 19 and is composed of 15 exons and 14 introns. Expression of its mRNA (similar to4.2 kb) is restricted to the oocytes. Human MATER cDNA (3885 nt) shows an open reading frame (3600 nt) encoding a polypeptide chain composed of 1200 residues with a predicted molecular mass of 134 236 Da. MATER protein (similar to134 kDa) was detected in human oocytes. The human and mouse cDNA share 67% homology while their deduced polypeptide chains have 53% identity of amino acids. Also, their protein structures have a number of similar features. CONCLUSIONS: The human MATER and mouse Mater genes and proteins are conserved. Characterization of the human MATER and its protein provides a basis for investigating their clinical implications in autoimmune premature ovarian failure and infertility in women. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Tong, ZB (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr, Bethesda, MD 20892 USA. NR 41 TC 70 Z9 76 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD APR PY 2002 VL 17 IS 4 BP 903 EP 911 DI 10.1093/humrep/17.4.903 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 543UA UT WOS:000175118500010 PM 11925379 ER PT J AU Cho, SI Goldman, MB Ryan, LM Chen, C Damokosh, AI Christiani, DC Lasley, BL O'Connor, JF Wilcox, AJ Xu, X AF Cho, SI Goldman, MB Ryan, LM Chen, C Damokosh, AI Christiani, DC Lasley, BL O'Connor, JF Wilcox, AJ Xu, X TI Reliability of serial urine HCG as a biomarker to detect early pregnancy loss SO HUMAN REPRODUCTION LA English DT Article DE early pregnancy loss; human chorionic gonadotrophin; immunoradiometric assay; reliability ID HUMAN CHORIONIC-GONADOTROPIN; HEALTH; WOMEN AB Background: To examine the reliability of HCG as a biomarker for early pregnancy loss, five experienced researchers independently assessed data from 153 menstrual cycles, determining whether each cycle represented,no conception,' a 'continuing conception' or a 'conception lost.' Methods: Urine samples were analysed by immunoradiometric assay using a combination of capture antibodies for the intact heterodimer (B109) and for an epitope common to the beta subunit and the beta core fragment (B204). For each cycle, HCG data were presented as graphs of daily assay results. Summary statistics for HCG assays from 46 women who had undergone bilateral tubal ligation represented baseline values. Results: Pairwise agreement among the assessors for any of the three options ranged from 78-89%. At least three experts agreed for 147 cycles (96%), accounting for 28 conception losses and 19 continuing conceptions. The multi-rater kappa was 0.62 for the conception lost category and 0.68 for continuing conceptions, indicating substantial agreement. Conclusion: The main sources of disagreement involved deciding whether there was sufficient information for assessment, interpreting cycle parameters such as cycle length or bleeding event, and interpreting a distinct HCG rise pattern that does not exceed the baseline value obtained from the sterilized women. C1 Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Occupat Hlth Program, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Univ Calif Davis, Inst Toxicol & Environm Hlth, Davis, CA 95616 USA. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab, Boston, MA 02115 USA. RP Xu, X (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Occupat Hlth Program, 665 Huntington Ave, Boston, MA 02115 USA. RI Ryan, Louise/A-4562-2009; OI Ryan, Louise/0000-0001-5957-2490; Wilcox, Allen/0000-0002-3376-1311 FU NICHD NIH HHS [1R01 HD32505-01]; NIEHS NIH HHS [1R01 ES08337-01, 5P30 ES000002-38]; NIOSH CDC HHS [1R01 OH03027] NR 16 TC 6 Z9 7 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD APR PY 2002 VL 17 IS 4 BP 1060 EP 1066 DI 10.1093/humrep/17.4.1060 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 543UA UT WOS:000175118500037 PM 11925406 ER PT J AU Thurin, M Kieber-Emmons, T AF Thurin, M Kieber-Emmons, T TI SA-Le(a) and tumor metastasis: The old prediction and recent findings SO HYBRIDOMA AND HYBRIDOMICS LA English DT Article ID SIALYL-LEWIS-X; E-SELECTIN; MONOCLONAL-ANTIBODY; COLON-CARCINOMA; P-SELECTIN; VASCULAR ENDOTHELIUM; COLORECTAL-CARCINOMA; CELL-ADHESION; CANCER-CELLS; IN-VIVO AB Several in vivo studies demonstrated that tumor metastasis depend on the expression of carbohydrate Lewis structures. Lewis antigens and their derivatives such as Lewis b (Le(b)), Lewis X (LeX), sialyl Lewis X (SA-LeX), sialyl Lewis a (SA-Le(a)), and Lewis Y (LeY) were identified as tumor-associated structures approximately 20 years ago by Koprowski et al. using hybridoma technology and showed that upregulation and/or de novo expression of these determinants on the tumor cell surface is associated with a poor prognosis. LeX and SA-LeX are ligands for selectin adhesion molecules; E- and P-selectins are vascular receptors expressed on activated endothelial cells (ECs) and L-selectin is expressed on leukocytes. Leukocytes also express on their surface LeX and SA-LeX determinants, which are involved in the initial steps of extravasation, that is, rolling, which is a step mediated by interaction with E-selectin on ECs. We hypothesized that the tumor cells transmigration from the bloodstream to metastatic sites is similar to lymphocyte extravasation and that adhesion of cancer cells in analogy with the lymphocyte rolling is mediated by interaction of carbohydrate determinants on tumor cells with selectins on ECs. To assess the role of interaction of carbohydrate structures with E-selectin in metastatic process in vivo, we demonstrated that the peptides mimicking SA-Le(a) blocked colonization of tumor cells in experimental model of lung metastasis in vivo. Furthermore, the metastases formation was completely attenuated in E-selectin-knock out (KO) mice demonstrating the importance of selectin-mediated interaction in this process. We also showed that a peptide mimicking SA-Le(a) E-selectin ligand has an ability to significantly reduce neutrophil recruitment into peritoneal cavity in acute inflammatory conditions. These studies support the hypothesis that the interaction of tumor cells via the carbohydrate SA-Le(a) determinant and E-selectin constitutes the important step in the metastatic process in analogy with lymphocyte extravasation and that carbohydrate antigen mimics have a potential as anti-inflammatories and anti-adhesive tumor therapeutics. C1 NCI, Canc Diagnosis Program, NIH, Rockville, MD 20852 USA. Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Thurin, M (reprint author), NCI, Canc Diagnosis Program, NIH, 6130 Execut Blvd, Rockville, MD 20852 USA. NR 49 TC 23 Z9 24 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0272-457X J9 HYBRIDOMA HYBRIDOM JI Hybrid. Hybridomics PD APR PY 2002 VL 21 IS 2 BP 111 EP 116 DI 10.1089/153685902317401708 PG 6 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Immunology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Immunology GA 551FC UT WOS:000175548200005 PM 12031100 ER PT J AU Theilig, F Campean, V Paliege, A Breyer, M Briggs, JP Schnermann, J Bachmann, S AF Theilig, F Campean, V Paliege, A Breyer, M Briggs, JP Schnermann, J Bachmann, S TI Epithelial COX-2 expression is not regulated by nitric oxide in rodent renal cortex SO HYPERTENSION LA English DT Article DE nitric oxide synthase; macula densa; renin; juxtaglomerular apparatus; prostaglandins ID CORTICAL CYCLOOXYGENASE-2 EXPRESSION; MACULA DENSA; RAT-KIDNEY; MESSENGER-RNA; RENIN CONTENT; UP-REGULATION; INHIBITION; CHLORIDE; RELEASE; MOUSE AB In the adult rodent kidney cortex, cyclooxygenase-2 (COX-2), NO synthase (NOS 1), and renin synthesis change in parallel on alterations in distal tubular NaCl concentration, and their products in part may mutually determine synthesis and activity of these enzymes. Epithelial NO synthesis has been postulated to exert a stimulatory role on COX-2 expression. Changes in COX-2 and NOS1 may be assessed histochemically by determining changes in the number of positive cells. In rat, macula densa and adjacent cells may co-express COX-2 and NOS 1, whereas cell groups of the upstream thick ascending limb (cTAL) express COX-2 alone. We have tested whether the stimulation of COX-2 expression by short- and long-term unilateral renal artery stenosis, low salt, and furosemide treatment depends on co-expression of NOS L These conditions produced significant respective increases (40% to 351%, P < 0.05) in the number of COX-2 immunoreactive cells, regardless of whether NOS I was present or not, suggesting that co-expression of NOS I is not necessary to produce these changes. Under high-salt conditions, analogous though inverse changes were recorded (-62% to -73%, P < 0.05). In mice with genetic deletion of NOS 1, low- and high-salt diets caused similar changes of COX-2 immunoreactivity (106% and -52%, P < 0.05) than those seen in wild-type mice (43% and -78%, P < 0.05). We conclude that alterations of distal tubular NaCl concentration and presumably NaCl transport induce changes in epithelial COX-2 expression that does not depend on presence of co-expressed NOS1. It therefore seems unlikely that NO is part of a signal transduction chain between tubular chloride sensing and the modulating effects of prostaglandins in tubulo-vascular information transfer. C1 Humboldt Univ, Inst Anat, Berlin, Germany. Dept Nephrol, Nashville, TN USA. NIH, Bethesda, MD 20892 USA. RP Bachmann, S (reprint author), AG Atom Charite, Campus Virchow Klinikum,Augustenburger Platz 1, D-13353 Berlin, Germany. RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 NR 28 TC 22 Z9 22 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD APR PY 2002 VL 39 IS 4 BP 848 EP 853 DI 10.1161/01.HYP.0000013082.99285.35 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 544UG UT WOS:000175179600004 PM 11967238 ER PT J AU Wang, M Lakatta, EG AF Wang, M Lakatta, EG TI Altered regulation of matrix metalloproteinase-2 in aortic remodeling during aging SO HYPERTENSION LA English DT Article DE aging; aorta; extracellular matrix; gene expression; immunohistochemistry; metalloprotease ID SMOOTH-MUSCLE CELLS; EXTRACELLULAR-MATRIX; ENDOTHELIAL-CELLS; TISSUE INHIBITOR; TENASCIN-C; INCREASED EXPRESSION; PROGELATINASE-A; I COLLAGEN; ACTIVATION; SYSTEM AB To elucidate potential mechanisms of enhanced type 2 matrix metalloprotease levels and activity within the thickened aged rat aorta. the present study measured its mRNA and protein levels and those of its membrane bound activator, MTI-MMP, its endogenous tissue inhibitor, TIMP-2, tissue type, and urokinase plasminogen activators and their receptors, and an inhibitor of plasminogen activation in aortae from Fisher 344X Brown Norway rats, 2 to 30 months of age. Semiquantitative immunohistochemistry, in situ hybridization, and in situ zymography of aortae detected a marked age-associated increase in gelatinolytic activity of type 2 metalloprotease within the thickened intima, internal elastic lamina, and elastic fibers in the inner part of the thickened tunica media, whereas the intimal tissue inhibitor of metalloprotease-2 mRNA and protein levels were not age related. Both activators of plasminogen and their receptors increased approximately 2-fold within the intima between 2 to 30 months. Similar, but not identical, age-associated changes in factors that regulate protease activity within the aortic media were also observed. We conclude that discordant regulation of factors that determine the activation status of type 2 matrix metalloprotease, coupled with an increase in the expression of its zymogen, occur with aging, which lead to an increase in the amount of activated protease. These factors are candidate mechanisms for age-associated vascular remodeling, a potent risk factor for vascular diseases with advancing age. C1 NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Dr,3-B-03, Baltimore, MD 21224 USA. NR 37 TC 89 Z9 97 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD APR PY 2002 VL 39 IS 4 BP 865 EP 873 DI 10.1161/01.HYP.0000014506.13322.66 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 544UG UT WOS:000175179600007 PM 11967241 ER PT J AU Muntner, P He, J Roccella, EJ Whelton, PK AF Muntner, P He, J Roccella, EJ Whelton, PK TI The impact of JNC-VI guidelines on treatment recommendations in the US population SO HYPERTENSION LA English DT Article DE guidelines; treatment; drug therapy; lifestyle ID LEFT-VENTRICULAR HYPERTROPHY; BLOOD-PRESSURE; PREVALENCE; HYPERTENSION; HEALTH AB Using epidemiological and clinical trial evidence, the sixth report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure (JNC-VI) updated previous guidelines to suggest that in addition to blood pressure, decisions on initial treatment should emphasize absolute cardiovascular disease risk. We estimated the impact of using cardiovascular disease risk on treatment recommendations for the US population using data from 16 527 participants in the Third National Health and Nutrition Examination Survey. In the US population greater than or equal to20 years of age, 36% (62 million) had high-normal blood pressure or greater (systolic/diastolic blood pressure greater than or equal to130 mm Hg/greater than or equal to85 mm Hg) or were taking antihypertensive medication. Of this population, 5.1% (3.2 million) were stratified into risk group A (no cardiovascular disease risk factors or prevalent cardiovascular disease), 66.3% (41.4 million) into risk group B ( ! I major risk factor), and 28.6% (17.9 million) into risk group C (diabetes mellitus, clinical cardiovascular disease, target organ damage). Also, 26% of this group (16.2 million) had high-normal blood pressure and were in risk groups A or B, a context in which vigorous lifestyle modification is recommended in the JNC-VI guidelines. Additionally, 11% (7.0 million) had high-normal blood pressure (systolic/diastolic, 130 to 139 mm. Hg/85 to 89 mm Hg respectively) or stage-1 hypertension (140 to 159 min Hg/90 to 99 mm Hg), and at least I factor, placing them in risk group C, but they were not currently on antihypertensive medication. JNC-VI, but not previous JNC guidelines, specifically recommends drug therapy as initial treatment for these patients. We conclude that JNC-VI refines cardiovascular risk and enfranchises more Americans to undertake more aggressive risk reduction maneuvers. C1 Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70112 USA. Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. NHLBI, Bethesda, MD 20892 USA. RP Muntner, P (reprint author), Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, 1430 Tulane Ave,SL-18, New Orleans, LA 70112 USA. NR 16 TC 33 Z9 35 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD APR PY 2002 VL 39 IS 4 BP 897 EP 902 DI 10.1161/01.HYP.0000013862.13962.1D PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 544UG UT WOS:000175179600012 PM 11967246 ER PT J AU Feiveson, AH Metter, EJ Paloski, WH AF Feiveson, AH Metter, EJ Paloski, WH TI A statistical model for interpreting computerized dynamic posturography data SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE balance control; beta distribution; equilibrium score; latent response; maximum-likelihood; mixed distribution; nonresponse; posture test ID PATENT FORAMEN OVALE; ECHOCARDIOGRAPHY; TRANSESOPHAGEAL; CONTRAST AB Computerized dynamic posturography (CDP) is widely used for assessment of altered balance control. CDP trials are quantified using the equilibrium score (ES), which ranges from zero to 100, as a decreasing function of peak sway angle. The problem of how best to model and analyze ESs from a controlled study is considered. The ES often exhibits a skewed distribution in repeated trials, which can lead to incorrect inference when applying standard regression or analysis of variance models. Furthermore, CDP trials are terminated when a patient loses balance. In these situations, the ES is not observable, but is assigned the lowest possible score-zero. As a result, the response variable has a mixed discrete-continuous distribution, further compromising inference obtained by standard statistical methods. Here, we develop alternative methodology for analyzing ESs under a stochastic model extending the ES to a continuous latent random variable that always exists, but is unobserved in the event of a fall. Loss of balance occurs conditionally, with probability depending on the realized latent ES. After fitting the model by a form of quasi-maximum-likelihood, one may perform statistical inference to assess the effects of explanatory variables. An example is provided, using data from the NIH/NIA Baltimore Longitudinal Study on Aging. C1 NASA, Lyndon B Johnson Space Ctr, Houston, TX 77058 USA. NIA, Clin Invest Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Feiveson, AH (reprint author), NASA, Lyndon B Johnson Space Ctr, Mail Code SD3, Houston, TX 77058 USA. FU NIA NIH HHS [1Z01AG00014-41]; PHS HHS [00205] NR 25 TC 12 Z9 12 U1 0 U2 1 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD APR PY 2002 VL 49 IS 4 BP 300 EP 309 AR PII S0018-9294(02)02900-7 DI 10.1109/10.991157 PG 10 WC Engineering, Biomedical SC Engineering GA 533HX UT WOS:000174524700003 PM 11942721 ER PT J AU Ebert, DS Morris, CJ Rheingans, P Yoo, TS AF Ebert, DS Morris, CJ Rheingans, P Yoo, TS TI Designing effective transfer functions for volume rendering from photographic volumes SO IEEE TRANSACTIONS ON VISUALIZATION AND COMPUTER GRAPHICS LA English DT Article DE volume rendering; transfer functions; photographic data ID VISUALIZATION; IMAGES AB Photographic volumes present a unique, interesting challenge for volume rendering. In photographic volumes, voxel color is predetermined, making color selection through transfer functions unnecessary. However, photographic data does not contain a clear mapping from the multivalued color values to a scalar density or opacity, making projection and compositing much more difficult than with traditional volumes. Moreover, because of the nonlinear nature of color spaces, there is no meaningful norm for the multivalued voxels. Thus, the individual color channels of photographic data must be treated as incomparable data tuples rather than as vector values. Traditional differential geometric tools, such as intensity gradients, density, and Laplacians, are distorted by the nonlinear nonorthonormal color spaces that are the domain of the voxel values. We have developed different techniques for managing these issues while directly rendering volumes from photographic data. We present and justify the normalization of color values by mapping RGB values to the CIE L*u*v* color space. We explore and compare different opacity transfer functions that map three channel color values to opacity, We apply these many-to-one mappings to the original RGB values as well as to the voxels after conversion to L*u*v* space. Direct rendering using transfer functions allows us to explore photographic volumes without having to commit to an a priori segmentation that might mask fine variations of interest. We empirically compare the combined effects of each of the two color spaces with our opacity transfer functions using source data from the Visible Human Project. C1 Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA. IBM Corp, TJ Watson Res Ctr, Visual Technol Grp, Hawthorne, NY 10532 USA. Univ Maryland Baltimore Cty, Dept Comp Sci & Elect Engn, Baltimore, MD 21250 USA. Natl Lib Med, Off High Performance Comp & Commun, NIH, Bethesda, MD 20894 USA. RP Purdue Univ, Sch Elect & Comp Engn, 1285 EE Bldg, W Lafayette, IN 47907 USA. EM ebertd@pudrue.edu; cjmorris@us.ibm.com; rheingan@cs.umbc.edu; yoo@nlm.nih.gov OI Ebert, David/0000-0001-6177-1296 NR 32 TC 31 Z9 38 U1 0 U2 0 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 1077-2626 EI 1941-0506 J9 IEEE T VIS COMPUT GR JI IEEE Trans. Vis. Comput. Graph. PD APR-JUN PY 2002 VL 8 IS 2 BP 183 EP 197 DI 10.1109/2945.998670 PG 15 WC Computer Science, Software Engineering SC Computer Science GA 543BG UT WOS:000175080500007 ER PT J AU Salvador, JM Hollander, MC Nguyen, AT Kopp, JB Barisoni, L Moore, JK Ashwell, JD Fornace, AJ AF Salvador, JM Hollander, MC Nguyen, AT Kopp, JB Barisoni, L Moore, JK Ashwell, JD Fornace, AJ TI Mice lacking the p53-effector gene Gadd45a develop a Lupus-like syndrome SO IMMUNITY LA English DT Article ID P53-REGULATED PROTEIN GADD45; MURINE MODELS; P21; P53; EXPRESSION; ACTIVATION; INDUCTION; PATHWAY; MYD118; GROWTH AB This study addresses the biological function of the p53-effector genes Gadd45a and p21 in the immune system. We find that Gadd45a is a negative regulator of T cell proliferation because, compared to wild-type cells, Gadd45a(-/-) T cells have a lower threshold of activation and proliferate to a greater extent following primary T cell receptor stimulation. Gadd45a(-/-) mice develop an autoimmune disease, similar to human systemic lupus erythematosus (SLE), characterized by high titers of anti-dsDNA, anti-ssDNA, and anti-histone autoantibodies, severe hematological disorders, autoimmune glomerulonephritis, and premature death. Here we show that the lack of both Gadd45a and p21 dramatically accelerates the development of autoimmunity observed in each individual single-gene disruption mutant, demonstrating that these genes play nonredundant roles in the immune response. C1 Natl Canc Inst, Ctr Canc Res, Gene Response Sect, Bethesda, MD 20892 USA. Natl Inst Diabetes & Digest & Kidney Dis, Metab Dis Branch, Kidney Dis Sect, Bethesda, MD 20892 USA. Natl Canc Inst, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. RP Fornace, AJ (reprint author), Natl Canc Inst, Ctr Canc Res, Gene Response Sect, Bethesda, MD 20892 USA. RI Fornace, Albert/A-7407-2008; OI Fornace, Albert/0000-0001-9695-085X; Kopp, Jeffrey/0000-0001-9052-186X NR 27 TC 109 Z9 111 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD APR PY 2002 VL 16 IS 4 BP 499 EP 508 DI 10.1016/S1074-7613(02)00302-3 PG 10 WC Immunology SC Immunology GA 543PD UT WOS:000175109600002 PM 11970874 ER PT J AU Kumar, S Villinger, F Oakley, M Aguiar, JC Jones, TR Hedstrom, RC Gowda, K Chute, J Stowers, A Kaslow, DC Thomas, EK Tine, J Klinman, D Hoffman, SL Weiss, WW AF Kumar, S Villinger, F Oakley, M Aguiar, JC Jones, TR Hedstrom, RC Gowda, K Chute, J Stowers, A Kaslow, DC Thomas, EK Tine, J Klinman, D Hoffman, SL Weiss, WW TI A DNA vaccine encoding the 42 kDa C-terminus of merozoite surface protein 1 of Plasmodium falciparum induces antibody, interferon-gamma and cytotoxic T cell responses in rhesus monkeys: immuno-stimulatory effects of granulocyte macrophage-colony stimulating factor SO IMMUNOLOGY LETTERS LA English DT Article DE Plasmodium falciparum; rhesus monkey; merozoite surface protein 1 (MSP1); cytotoxic T cells (CTL); interferon-gamma (IFN-gamma); DNA vaccine ID AOTUS MONKEYS; PROTECTIVE IMMUNITY; PLASMID DNA; MALARIA; EXPRESSION; IMMUNOGENICITY; FRAGMENT; ANTIGEN; YOELII; MICE AB We have constructed a DNA plasmid vaccine encoding the C-terminal 42-kDa region of the merozoite surface protein1 (pMSP1(42)) from the 3D7 strain of Plasmodium falciparum (Pf3D7). This plasmid expressed recombinant MSP1(42) after in vitro transfection in mouse VM92 cells. Rhesus monkeys immunized with pMSP1(42) produced antibodies reactive with Pf3D7 infected erythrocytes by IFAT, and by ELISA against yeast produced MSP1(19) (yMSP1(19)). Immunization also induced antigen specific T cell responses Lis measured by interferon-gamma production. and by classical CTL chromium release assays, In addition. immunization with pMSP1(42) primed animals for an enhanced antibody response to a subsequent boost with the recombinant yMSP1(19). We also evaluated Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) as an adjuvant for pMSP1(42). We tested both rhesus GM-CSF expressed from a DNA plasmid and E. coli produced recombinant human GM-CSF, Plasmids encoding rhesus GM-CSF (prhGM-CSF) and human GM-CSF (phuGM-CSF) were constructed, these plasmids expressed bio-active recombinant GMCSF. Co-immunization with a mixture of prhGM-CSF and pMSP1(42) induced higher specific antibody responses after the first dose of plasmid. but after three doses of DNA monkeys immunized with or without prhGM-CSF had the same final antibody titers and T cell responses. In comparison, rhuGM-CSF protein did not lead to accelerated antibody production after the first DNA dose. However, antibody titers ere maintained at it slightly higher level in monkeys receiving GM-CSF protein, and they had a higher response to boosting with recombinant MSP1(19). The GM-CSF plasmid or protein appears to be less potent as an adjutant in rhesus monkeys than each is in mice, and more work is needed to determine if GM-CSF can be a useful adjuvant in DNA vaccination of primates. (C) 2002 Published by Elsevier Science B.V. C1 USN, Med Res Ctr, Malaria Program, Silver Spring, MD 20910 USA. Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. Emory Univ, Sch Med, Winship Canc Ctr, Dept Pathol & Lab Med, Atlanta, GA 30333 USA. NIDDK, Stem Cell Biol Sect, USN, Transplantat & Autoimmun Branch, Bethesda, MD 20889 USA. NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. Immunex Corp, Seattle, WA 98101 USA. Virogenet Corp, Troy, NY 12180 USA. US FDA, Ctr Biol Evaluat & Res, Sect Retroviral Immunol, Bethesda, MD 20892 USA. RP Kumar, S (reprint author), SUNY Albany, Merck Pharmaceut, W Point, PA 19486 USA. NR 37 TC 39 Z9 42 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD APR 1 PY 2002 VL 81 IS 1 BP 13 EP 24 AR PII S0165-2478(01)00316-9 DI 10.1016/S0165-2478(01)00316-9 PG 12 WC Immunology SC Immunology GA 529UR UT WOS:000174318800002 PM 11841841 ER PT J AU Botos, J Barhoumi, R Burghardt, R Kochevar, DT AF Botos, J Barhoumi, R Burghardt, R Kochevar, DT TI Rb localization and phosphorylation kinetics correlate with the cellular phenotype of cultured breast adenocarcinoma cells SO IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL LA English DT Article DE breast neoplasms; cell cycle proteins; nuclear proteins; phosphoproteins; retinoblastoma protein ID RETINOBLASTOMA SUSCEPTIBILITY GENE; CYCLIN-CDK COMPLEXES; MITOTIC HELA-CELLS; CANCER-CELLS; KINASE INHIBITORS; REDUNDANT CYCLIN; PROTEIN; EXPRESSION; CARCINOMA; IDENTIFICATION AB Retinoblastoma protein (Rb) expression has been correlated with state of differentiation, proliferation rate, and metastatic potential in breast adenocarcinomas and established cell lines. These observations, based on immunoreactivity of total Rb rather than hypophosphorylated protein, do not address the relationship between functional Rb and indicators of an aggressive transformed cellular phenotype. We hypothesized that the distribution of functional Rb and the kinetics of Rh phosphorylation would differ between cell lines representing immortalized mammary epithelium (MCF10A), differentiated nonmetastatic mammary, adenocarcinoma (MCF-7), and poorly differentiated, highly metastatic mammary adenocarcinoma (MDA-MB-231) and that these differences would be informative of the cellular phenotype. Direct immunofluorescence microscopy was used to compare qualitatively the subcellular localization of total and hypophosphorylated Rb protein in synchronized and asynchronous cells. This technique was also used to quantitatively assess the amounts of hypophosphorylated Rb throughout the cell cycle in these representative cell lines. Total Rb stained more prominently than hypophosphorylated Rb in the nucleus of all asynchronous cells. Rb phosphorylation was more rapid in MCF-7 cells than in MCF10A cells, whereas Rb dephosphorylation appeared deregulated in MDA-MB-231 cells. We conclude that assessment of hypophosphorylated Rb may be, more useful than assessment of total Rb for the evaluation of transformed breast adenocarcinoma phenotypes. C1 Texas A&M Univ, Dept Vet Physiol & Pharmacol, College Stn, TX 77843 USA. Texas A&M Univ, Dept Vet Anat & Publ Hlth, College Stn, TX 77843 USA. RP Botos, J (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, 41 Lib Dr,Room C310, Bethesda, MD 20892 USA. OI Burghardt, Robert/0000-0003-1021-8444 NR 67 TC 2 Z9 2 U1 0 U2 0 PU SOC IN VITRO BIOLOGY PI LARGO PA 9315 LARGO DR WEST, STE 25, LARGO, MD 20774 USA SN 1071-2690 J9 IN VITRO CELL DEV-AN JI In Vitro Cell. Dev. Biol.-Anim. PD APR PY 2002 VL 38 IS 4 BP 235 EP 241 PG 7 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 588QG UT WOS:000177711700011 PM 12197776 ER PT J AU Bos, MP Kao, D Hogan, DM Grant, CCR Belland, RJ AF Bos, MP Kao, D Hogan, DM Grant, CCR Belland, RJ TI Carcinoembryonic antigen family receptor recognition by gonococcal Opa proteins requires distinct combinations of hypervariable Opa protein domains SO INFECTION AND IMMUNITY LA English DT Article ID NEISSERIA-GONORRHOEAE; EPITHELIAL-CELLS; OPACITY PROTEINS; GENE FAMILY; PATHOGENIC NEISSERIAE; STRUCTURAL BASIS; CEA FAMILY; HOST-CELLS; CD66; BINDING AB Neisserial Opa proteins function as a family of adhesins that bind heparan sulfate proteoglycan (HSPG) or carcinoembryonic antigen family (CEACAM) receptors on human host cells. In order to define the CEACAM binding domain on Opa proteins, we tested the binding properties of a series of gonococcal (strain MS11) recombinants producing mutant and chimeric Opa proteins with alterations in one or more of the four surface-exposed loops. Mutagenesis demonstrated that the semivariable domain, present in the first loop, was completely dispensable for CEACAM binding. In contrast, the two hypervariable (HV) regions present in the second and third loops were essential for binding; deletion of either domain resulted in loss of receptor recognition. Deletion of the fourth loop resulted in a severe decrease in Opa expression at the cell surface and could therefore not be tested for CEACAM binding. Chimeric Opa variants, containing combinations of RV regions derived from different CEACAM binding Opa proteins, lost most of their receptor binding activity. Some chimeric variants gained HSPG binding activity. Together, our results indicate that full recognition of CEACAM receptors by Opa proteins requires a highly coordinate interplay between both HV regions. Furthermore, shuffling of HV regions may result in novel HSPG receptor binding activity. C1 NIAID, Rocky Mt Lab, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. RP Bos, MP (reprint author), Univ Utrecht, Dept Mol Microbiol, Padualaan 8, NL-3584 CH Utrecht, Netherlands. RI Kao, David/K-3288-2013 OI Kao, David/0000-0002-2832-9348 NR 43 TC 24 Z9 24 U1 0 U2 4 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 APR PY 2002 VL 70 IS 4 BP 1715 EP 1723 DI 10.1128/IAI.70.4.1715-1723.2002 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 534FE UT WOS:000174573200006 PM 11895933 ER PT J AU Elias, AF Stewart, PE Grimm, D Caimano, MJ Eggers, CH Tilly, K Bono, JL Akins, DR Radolf, JD Schwan, TG Rosa, P AF Elias, AF Stewart, PE Grimm, D Caimano, MJ Eggers, CH Tilly, K Bono, JL Akins, DR Radolf, JD Schwan, TG Rosa, P TI Clonal polymorphism of Borrelia burgdorferi strain B31 MI: Implications for mutagenesis in an infectious strain background SO INFECTION AND IMMUNITY LA English DT Article ID OUTER-SURFACE-PROTEIN; LYME-DISEASE SPIROCHETE; WHITE-FOOTED MICE; CIRCULAR PLASMID; GENE; OSPB; CULTIVATION; ANTIBODY; MUTANT; MARKER AB A major obstacle to studying the functions of particular gene products in the mouse-tick infectious cycle of Borrelia burgdorferi has been an inability to knock out genes in pathogenic strains. Here, we investigated conditions for site-directed mutagenesis in B31 MI, the low-passage-number, infectious B. burgdorferi strain whose genome was sequenced. We inactivated several plasmid and chromosomal genes in B31 MI and determined that clones carrying these mutations were not infectious for mice. However, we found extensive heterogeneity among clones and mutants derived from B31 MI based on colony phenotype, growth rate, plasmid content, protein profile, and transformability. Significantly, several B31 MI clones that were not subjected to mutagenesis but that lacked particular plasmids also exhibited defects at various stages in the infectious cycle. Therefore, the high degree of clonal polymorphism within B31 MI complicates the assessment of the contributions of individual genes to the observed phenotypes of the mutants. Our results indicate that B31 MI is not an appropriate strain background for genetic studies in infectious B. burgdorferi, and a well-defined isogenic clone is a prerequisite for targeted mutagenesis. To this end, we derived several wild-type clones from B31 MI that were infectious for mice, and gene inactivation was successful in one of these clones. Due to the instability of the genome with in vitro propagation, careful monitoring of plasmid content of derived mutants and complementation of inactivated genes will be crucial components of genetic studies with this pathogen. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Univ Connecticut, Ctr Hlth, Ctr Microbial Pathogenesis, Farmington, CT 06030 USA. Univ Connecticut, Ctr Hlth, Dept Pathol, Farmington, CT 06030 USA. Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT 06030 USA. Univ Connecticut, Ctr Hlth, Dept Genet & Dev Biol, Farmington, CT 06030 USA. Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. RP Elias, AF (reprint author), Charite Univ Klinikum, Inst Mikrobiol & Hyg, Campus Charite Mitte,Dorotheenstr 96, D-10117 Berlin, Germany. FU NCRR NIH HHS [P20 RR015564, RR-15564]; NIAID NIH HHS [AI-29735, R01 AI029735, R56 AI029735] NR 48 TC 202 Z9 205 U1 2 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 APR PY 2002 VL 70 IS 4 BP 2139 EP 2150 DI 10.1128/IAI.70.4.2139-2150.2002 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 534FE UT WOS:000174573200053 PM 11895980 ER PT J AU Evans, AG Wellems, TE AF Evans, AG Wellems, TE TI Coevolutionary genetics of Plasmodium malaria parasites and their human hosts SO INTEGRATIVE AND COMPARATIVE BIOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Integrative-and-Comparative-Biology CY JAN 03-07, 2001 CL CHICAGO, IL SP Soc Integrat & Comparat Biol ID SICKLE-CELL TRAIT; PAPUA-NEW-GUINEA; FALCIPARUM-INFECTED ERYTHROCYTES; SOUTHEAST-ASIAN OVALOCYTOSIS; ANTIGENIC VARIATION; CHLOROQUINE RESISTANCE; ALPHA-THALASSEMIA; CEREBRAL MALARIA; RECENT ORIGIN; P-FALCIPARUM AB Malaria has been invoked, perhaps more than any other infectious disease, as a force for the selection of human genetic polymorphisms. Evidence for genome-shaping interactions can be found in the geographic and ethnic distributions of the hemoglobins, blood group antigens, thalassemias, red cell membrane molecules, human lymphocyte antigen (HLA) classes, and cytokines. Human immune responses and genetic variations can correspondingly influence the structure and polymorphisms of Plasmodium populations, notably in genes that affect the success and virulence of infection. In Africa, where the burden from Plasmodium falciparum predominates, disease severity and manifestations vary in prevalence among human populations. The evolutionary history and spread of Plasmodium species inform our assessment of malaria as a selective force. Longstanding host-pathogen relationships, as well as recent changes in this dynamic, illustrate the selective pressures human and Plasmodium species place on one another. Investigations of malaria protection determinants and virulence factors that contribute to the complexity of the disease should advance our understanding of malaria pathogenesis. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Wellems, TE (reprint author), NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM tew@helix.nih.gov NR 98 TC 5 Z9 5 U1 1 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1540-7063 EI 1557-7023 J9 INTEGR COMP BIOL JI Integr. Comp. Biol. PD APR PY 2002 VL 42 IS 2 BP 401 EP 407 DI 10.1093/icb/42.2.401 PG 7 WC Zoology SC Zoology GA 597TX UT WOS:000178237800025 PM 21708733 ER PT J AU Prete, SP Cappelletti, D Baier, S Nasuti, P Guadagni, F De Vecchis, L Greiner, JW Bonmassar, E Graziani, G Aquino, A AF Prete, SP Cappelletti, D Baier, S Nasuti, P Guadagni, F De Vecchis, L Greiner, JW Bonmassar, E Graziani, G Aquino, A TI Pharmacological modulation of carcinoembryonic antigen in human cancer cells: studies with staurosporine SO INTERNATIONAL IMMUNOPHARMACOLOGY LA English DT Article DE staurosporine; CEA; antigen modulation; cancer; immunotherapy; molecular diagnosis ID PROTEIN-KINASE-C; POLYMERASE CHAIN-REACTION; MONOCLONAL-ANTIBODY; GAMMA-INTERFERON; PERIPHERAL-BLOOD; CARCINOMA-CELLS; IMMUNE-RESPONSES; POTENT INHIBITOR; VACCINIA VIRUS; TUMOR-CELLS AB Preliminary studies, performed in our laboratory, showed that staurosporine (ST), a protein-kinase (PK) inhibitor, increases the expression of the carcinoembryonic antigen (CEA) in a human colon cancer cell line. The present study explores the cellular and molecular effects of ST on the CEA expression in breast cancer MCF-7 line and in a number of colon cancer cell lines characterized by the different basal levels of the antigen, including two cloned sublines (i.e. C22.20 and C6.6, expressing low and high CEA levels, respectively). In all cases, increase of the CEA expression was observed at drug concentrations devoid of marked cytostatic effects (e.g. 5 nM) and was accompanied by the enhanced CEA shedding in the supernatant. Moreover, the increase of the CEA levels both occurred in the cell membranes and in the cytosolic compartments and appeared to be the result of the enhanced CEA gene transcription. Similar results have been previously obtained with interferon-gamma. However, ST treatment, different from interferon-gamma, did not up-regulate the level of the HLA class I molecules. A preliminary investigation also showed that other PKC inhibitors did not substantially modulate the CEA expression. Therefore, the biochemical mechanism underlying the effect of ST should not be correlated with that involved in the PKC inhibition. The present study suggests that ST and, presumably, its analogs used in the cancer treatment could enhance the CEA expression on neoplastic cells in patients affected by the CEA-positive malignancies. This appears to be of potential clinical interest for the development of new immunotherapeutic or diagnostic approaches based on the pharmacological modulation of this antigenic marker. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Roma Tor Vergata, Dept Neurosci, Sect Pharmacol & Med Oncol, I-00133 Rome, Italy. Regina Elena Inst Canc Res, Clin Pathol Lab, Rome, Italy. NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. CNR, Inst Expt Med, Rome, Italy. RP Bonmassar, E (reprint author), Univ Roma Tor Vergata, Dept Neurosci, Sect Pharmacol & Med Oncol, Via Tor Vergata 135, I-00133 Rome, Italy. RI Graziani, Grazia/G-5747-2012; Guadagni, Fiorella/J-4432-2013; OI Guadagni, Fiorella/0000-0003-3652-0457; GRAZIANI, GRAZIA/0000-0002-0221-768X NR 49 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-5769 J9 INT IMMUNOPHARMACOL JI Int. Immunopharmacol. PD APR PY 2002 VL 2 IS 5 BP 641 EP 651 AR PII S1567-5769(01)00192-8 DI 10.1016/S1567-5769(01)00192-8 PG 11 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 544UD UT WOS:000175179200003 PM 12013504 ER PT J AU Sopwith, WF Debrabant, A Yamage, M Dwyer, DM Bates, PA AF Sopwith, WF Debrabant, A Yamage, M Dwyer, DM Bates, PA TI Developmentally regulated expression of a cell surface class I nuclease in Leishmania mexicana SO INTERNATIONAL JOURNAL FOR PARASITOLOGY LA English DT Article DE Leishmania mexicana; 3 '-nucleotidase; nuclease; purine salvage ID MEMBRANE 3'-NUCLEOTIDASE NUCLEASE; CRITHIDIA-LUCILIAE; DONOVANI PROMASTIGOTES; PENICILLIUM-CITRINUM; TRYPANOSOMA-BRUCEI; DEFINED MEDIA; GENE; CULTIVATION; AMASTIGOTES; PURIFICATION AB Leishmania mexicana, like other trypanosomatid parasites, is a purine auxotroph and must obtain these essential nutrients from its sandfly and mammalian hosts. A single copy gene encoding its unique externally oriented, surface membrane, purine salvage enzyme 3'-nucleotidase/nuclease, was isolated. Structural features of the deduced protein included: an endoplasmic reticulum-directed signal peptide, several conserved class I catalytic and metal co-factor (Zn2+) binding domains, transmembrane anchor sequence and a C-terminal cytoplasmic tail. 3'-Nucleotidase/nuclease gene (mRNA) and protein (enzyme activity) expression were examined in three different L. mexicana developmental forms: procyclic promastigotes, metacyclic promastigotes and amastigotes. Results of both approaches demonstrated that the 3'-nucleotidase/nuclease was a stage-specific enzyme, being expressed by promastigote forms (stages restricted to the insect vector), but not by amastigotes (which produce disease in mammalian hosts). Starvation of these parasites for purines resulted in the significant up-regulation of both 3'-nucleotidase/nuclease mRNA and enzyme activity in promastigotes, but not in amastigotes. These results underscore the critical role that the 3'-nucleotidase/nuclease must play in purine salvage during the rapid multiplicative expansion of the parasite population within its insect vector. To our knowledge, the L. mexicana 3'-nucleotidase/nuclease is the first example of a nutrient-induced and developmentally regulated enzyme in any parasitic protozoan. (C) 2002 Australian Society fur parasitology Inc. Published by Elsevier Science Ltd. All rights reserved. C1 Univ Liverpool Liverpool Sch Trop Med, Div Mol Biol & Immunol, Liverpool L3 5QA, Merseyside, England. NIAID, Cell Biol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bates, PA (reprint author), Univ Liverpool Liverpool Sch Trop Med, Div Mol Biol & Immunol, Pembroke Pl, Liverpool L3 5QA, Merseyside, England. OI Bates, Paul/0000-0001-6861-5421 NR 47 TC 17 Z9 19 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0020-7519 J9 INT J PARASITOL JI Int. J. Parasit. PD APR PY 2002 VL 32 IS 4 BP 449 EP 459 AR PII S0020-7519(01)00372-1 DI 10.1016/S0020-7519(01)00372-1 PG 11 WC Parasitology SC Parasitology GA 538MD UT WOS:000174819000007 PM 11849641 ER PT J AU Idriss, HT Al-Assar, O Wilson, SH AF Idriss, HT Al-Assar, O Wilson, SH TI DNA polymerase beta SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Article DE DNA synthesis; DNA polymerase beta; base excision repair ID BASE EXCISION-REPAIR; DEOXYRIBOSE-PHOSPHATE RESIDUES; CRYSTAL-STRUCTURES; REPLICATION; PATHWAY; COMPLEXES; INSIGHTS AB Mammalian DNA polymerase beta(beta-pol) is a single polypeptide chain enzyme of 39kDa. beta-pol has enzymatic activities appropriate for roles in base excision repair and other DNA metabolism events involving gap-filling DNA synthesis. Many crystal structures of beta-pol complexed with dNTP and DNA substrates have been solved, and mouse fibroblast cell lines deleted in the beta-pol gene have been examined. These approaches have enhanced our understanding of structural and functional aspects of beta-pol's role in protecting genomic DNA. (C) 2002 Published by Elsevier Science Ltd. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC USA. Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Ctr, Dundee DD1 9SY, Scotland. RP Idriss, HT (reprint author), NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC USA. NR 23 TC 35 Z9 45 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD APR PY 2002 VL 34 IS 4 BP 321 EP 324 AR PII S1357-2725(01)00131-5 DI 10.1016/S1357-2725(01)00131-5 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 533HG UT WOS:000174523100003 PM 11854030 ER PT J AU Pearson, J Goldklang, D Striegel-Moore, RH AF Pearson, J Goldklang, D Striegel-Moore, RH TI Prevention of eating disorders: Challenges and opportunities SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article DE prevention science; research; risk factors ID BULIMIA-NERVOSA; INTERVENTIONS; BEHAVIOR; HEALTH; EPIDEMIOLOGY; ANOREXIA; ABUSE AB Objective and Methods: On April 25, 2000, the National Institute of Mental Health (NIMH) convened a Roundtable on the Prevention of Eating Disorders to review the state of prevention science in eating disorders and formulate recommendations regarding future steps to be taken in this area of research. Results and Discussion: This report summarizes the roundtable discussion. The discussion focused on four major areas: the state of the art of risk factors research, translational research, prevention research in related fields, and cutting-edge efforts in eating disorder prevention, Conclusions: The report concludes with specific recommendations. (C) 2002 by Wiley Periodicals, Inc. C1 NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. Wesleyan Univ, Dept Psychol, Middletown, CT USA. RP Pearson, J (reprint author), NIMH, Div Serv & Intervent Res, Rm 7160 MSC 9635, Bethesda, MD 20892 USA. NR 31 TC 28 Z9 28 U1 2 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0276-3478 J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD APR PY 2002 VL 31 IS 3 BP 233 EP 239 DI 10.1002/eat.10014 PG 7 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA 534GJ UT WOS:000174576500001 PM 11920984 ER PT J AU Moritani, S Ioffe, OB Sagae, S Dahmoush, L Silverberg, SG Hattori, T AF Moritani, S Ioffe, OB Sagae, S Dahmoush, L Silverberg, SG Hattori, T TI Mitotic activity and apoptosis in endocervical glandular lesions SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE uterine cervix; mitoses; apoptosis; AIS; glandular dysplasia; minimal deviation adenocarcinoma; microinvasive adenocarcinoma ID MINIMAL DEVIATION ADENOCARCINOMA; SQUAMOUS INTRAEPITHELIAL NEOPLASIA; UTERINE CERVIX; ADENOMA-MALIGNUM; IN-SITU; HUMAN-PAPILLOMAVIRUS; MICROINVASIVE ADENOCARCINOMA; TUBAL METAPLASIA; INSITU; HYPERPLASIA AB To evaluate the significance of mitotic activity and apoptosis in the differential diagnosis of endocervical glandular lesions, we examined the frequency of mitoses and apoptosis in 89 endocervical glandular lesions from 78 patients, which consisted of benign reactive changes (7 cases), lobular or diffuse laminar endocervical glandular hyperplasia (4), microglandular hyperplasia (3), tunnel clusters (7), nabothian cysts (2), mesonephric remnants (3), tubal metaplasia (3), endocervical glandular dysplasias (including atypical tubal metaplasia) (EGD) (7), adenocarcinoma in situ (AIS) (31), microinvasive adenocarcinoma (7), frankly invasive adenocarcinoma (12), and minimal deviation adenocarcinoma (3). Mitotic index (MI; mitotic figures per 1000 cells) was significantly higher in AIS, microinvasive adenocarcinoma, and frankly invasive adenocarcinoma than any other lesions examined. Microinvasive adenocarcinoma showed the highest MI. Apoptosis was detected consistently and frequently in AIS, microinvasive adenocarcinoma, and frankly invasive adenocarcinoma. AIS showed the highest apoptotic index (AI; apoptoses per 1000 cells). Frequent apoptotic bodies and mitotic figures are a common feature of endocervical glandular malignancies (except for minimal deviation adenocarcinoma) and are an important feature that can facilitate their differentiation from benign and borderline lesions. High MI in microinvasive adenocarcinoma might aid the distinction of microinvasive adenocarcinoma from AIS. Although both MI and Al of EGD were between those of benign reactive changes and of AIS, MI and AI alone are not sufficient to differentiate EGD from benign reactive changes. MI and AI are not helpful in the differential diagnosis between minimal deviation adenocarcinoma and its benign mimics. C1 Shiga Univ Med Sci, Dept Pathol, Otsu, Shiga 5202192, Japan. Univ Maryland, Med Syst, Dept Pathol, Baltimore, MD 21201 USA. Sapporo Med Univ, Dept Obstet & Gynecol, Sapporo, Hokkaido, Japan. NCI, Cytol Sect, NIH, Bethesda, MD 20892 USA. RP Moritani, S (reprint author), Shiga Univ Med Sci, Dept Pathol, Seta Tsukinowa Cho, Otsu, Shiga 5202192, Japan. NR 30 TC 17 Z9 18 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-1691 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD APR PY 2002 VL 21 IS 2 BP 125 EP 133 DI 10.1097/00004347-200204000-00004 PG 9 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA 535CY UT WOS:000174628700004 PM 11917221 ER PT J AU Roth, SM Schrager, MA Metter, EJ Riechman, SE Fleg, JL Hurley, BF Ferrell, RE AF Roth, SM Schrager, MA Metter, EJ Riechman, SE Fleg, JL Hurley, BF Ferrell, RE TI IGF2 genotype and obesity in men and women across the adult age span SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE Apal polymorphism; body mass index; body composition; fat mass; insulin-like growth factor II ID APAL POLYMORPHISM; MUSCLE MASS; LOCUS; PIGS; MAPS; GENE; QTL; DNA AB We studied a previously reported association between the IGF2 gene's Apal polymorphism and obesity in 500 healthy men and women (19 - 90 y). We hypothesized that individuals homozygous for the IGF2 A allele (A/A) would exhibit lower body mass, BMI and DEXA-measured fat mass compared to GIG homozygotes. Subjects were categorized as exhibiting the G/G (n = 241), G/A (n = 197) or A/A (n = 62) genotype. Contrary to our hypothesis, no difference was observed in body mass, body mass index (BMI) or fat mass between the GIG and A/A genotype groups in the entire cohort. Surprisingly, Caucasian A/A individuals (n = 427) exhibited significantly higher fat mass compared to Caucasian GIG individuals (P < 0.05). In summary, individuals homozygous for the IGF2 G allele do not exhibit higher body mass, BMI or fat mass compared to A/A individuals; however, Caucasians with the A/A genotype exhibit higher fat mass than GIG individuals. C1 Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA 15261 USA. Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. NIA, NIH, Baltimore, MD 21224 USA. RP Roth, SM (reprint author), Univ Pittsburgh, Dept Human Genet, A300 Crabtree Hall GSPH, Pittsburgh, PA 15261 USA. OI Roth, Stephen/0000-0002-7841-3695 FU NIA NIH HHS [AG-05893, AG-16205]; NIDDK NIH HHS [DK-46204] NR 12 TC 35 Z9 37 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD APR PY 2002 VL 26 IS 4 BP 585 EP 587 DI 10.1038/sj/ijo/0801927 PG 3 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 538KD UT WOS:000174814400022 PM 12075589 ER PT J AU Ashford, NA Castleman, B Frank, AL Giannasi, F Goldman, LR Greenberg, M Huff, J Joshi, TK LaDou, J Lemen, RA Maltoni, C O'Neill, R Righter, E Silbergeld, EK Teitelbaum, DT Thebaud-Mony, A Tomatis, L Watterson, A AF Ashford, NA Castleman, B Frank, AL Giannasi, F Goldman, LR Greenberg, M Huff, J Joshi, TK LaDou, J Lemen, RA Maltoni, C O'Neill, R Righter, E Silbergeld, EK Teitelbaum, DT Thebaud-Mony, A Tomatis, L Watterson, A TI The International Commission on Occupational Health (ICOH) and its influence on international organizations SO INTERNATIONAL JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH LA English DT Article DE ICOH; public policy AB The ICOH has played a key role in the development of some scientific documents and policy recommendations, but it has not always been scientifically objective, particularly in regard to asbestos and other fibers and some chemicals and pesticides. Many ICOH members are employees of corporations or consultants to industry, serving multinational corporate interests to influence public health policy in the guise of a professional scientific organization. ICOH members' conflicts of interest with the public health dominate the organization and damage the standing of the ICOH. Official recognition of the ICOH compromises the credibility of the WHO and the ILO. It is inappropriate for the ICOH to continue to receive WHO and ILO recognition unless the ICOH is recognized as an industry organization. C1 MIT, Cambridge, MA 02139 USA. Univ Texas, Ctr Hlth, Tyler, TX USA. Brazilian Labor Minist, Sao Paulo, Brazil. Johns Hopkins Univ, Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Ctr Environm & Occupat Hlth, New Delhi, India. NIOSH, Washington, DC USA. Hazards Publicat, London, England. Hebrew Univ Jerusalem, Sch Publ Hlth & Community Med, Jerusalem, Israel. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. Colorado Sch Mines, Golden, CO 80401 USA. Natl Inst Hlth & Med Res, INSERM, Val De Marne, France. Int Agcy Res Canc, F-69372 Lyon, France. Univ Stirling, Occupat & Environm Hlth Res Grp, Stirling FK9 4LA, Scotland. RP Ashford, NA (reprint author), MIT, Cambridge, MA 02139 USA. RI Goldman, Lynn/D-5372-2012 NR 27 TC 16 Z9 16 U1 0 U2 3 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1077-3525 J9 INT J OCCUP ENV HEAL JI Int. J. Occup. Environ. Health PD APR-JUN PY 2002 VL 8 IS 2 BP 156 EP 162 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 560VR UT WOS:000176102500012 PM 12019683 ER PT J AU Fletcher, CDM Berman, JJ Corless, C Gorstein, F Lasota, J Longley, BJ Miettinen, M O'Leary, TJ Remotti, H Rubin, BP Shmookler, B Sobin, LH Weiss, SW AF Fletcher, CDM Berman, JJ Corless, C Gorstein, F Lasota, J Longley, BJ Miettinen, M O'Leary, TJ Remotti, H Rubin, BP Shmookler, B Sobin, LH Weiss, SW TI Diagnosis of gastrointestinal stromal tumors: A consensus approach SO INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE gastrointestinal stromal tumor; GIST; sarcoma; diagnosis; guidelines; KIT; CD117 ID SMOOTH-MUSCLE TUMORS; INTERSTITIAL-CELLS; DIFFERENTIAL-DIAGNOSIS; TRACT; FEATURES; CAJAL; CD34; KIT; HISTOGENESIS; EXPRESSION AB As a result of major recent advances in understanding the biology of gastrointestinal stromal tumors (GIST), specifically recognition of the central role of activating KIT mutations and associated KIT protein expression in these lesions, and the development of novel and effective therapy for GISTs using the receptor tyrosine kinase inhibitor STI-571, these tumors have become the focus of considerable attention among pathologists, clinicians, and patients. Stromal/mesenchymal tumors of the gastrointestinal tract have long been a source of confusion and controversy with regard to classification, line(s) of differentiation, and prognostication. Characterization of the KIT pathway and its phenotypic implications has helped to resolve some but not all of these issues. Given the now critical role of accurate and reproducible pathologic diagnosis in ensuring appropriate treatment for patients with GIST, the National Institutes of Health (NIH) convened a GIST workshop in April 2001 with the goal of developing a consensus approach to diagnosis and morphologic prognostication. Key elements of the consensus, as described herein, are the defining role of KIT immunopositivity in diagnosis and a proposed scheme for estimating metastatic risk in these lesions, based on tumor size and mitotic count, recognizing that it is probably unwise to use the definitive term benign for any GIST, at least at the present time. C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. NCI, Canc Diagnosis Program, NIH, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Dept Pathol, Portland, OR 97201 USA. Thomas Jefferson Univ, Dept Pathol, Philadelphia, PA 19107 USA. Armed Forces Inst Pathol, Dept Soft Tissue Pathol, Washington, DC 20306 USA. Armed Forces Inst Pathol, Dept Cellular Pathol & Genet, Washington, DC 20306 USA. Armed Forces Inst Pathol, Dept Gastrointestinal Pathol, Washington, DC 20306 USA. Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY USA. Columbia Univ, Coll Phys & Surg, Dept Dermatol, New York, NY USA. Univ Washington, Med Ctr, Dept Pathol, Seattle, WA 98195 USA. Suburban Hosp, Dept Pathol, Bethesda, MD USA. Emory Univ Hosp, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. RP Fletcher, CDM (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. NR 38 TC 174 Z9 219 U1 0 U2 1 PU WESTMINSTER PUBL INC PI GLEN HEAD PA 708 GLEN COVE AVE, GLEN HEAD, NY 11545 USA SN 1066-8969 J9 INT J SURG PATHOL JI Int. J. Surg. Pathol. PD APR PY 2002 VL 10 IS 2 BP 81 EP 89 DI 10.1177/106689690201000201 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA 564QC UT WOS:000176324200001 PM 12075401 ER PT J AU Rex, TS Fariss, RN Lewis, GP Linberg, KA Sokal, I Fisher, SK AF Rex, TS Fariss, RN Lewis, GP Linberg, KA Sokal, I Fisher, SK TI A survey of molecular expression by photoreceptors after experimental retinal detachment SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID BINDING PROTEIN IRBP; NEURON-SPECIFIC ENOLASE; MONOCLONAL-ANTIBODIES; IMMUNOCYTOCHEMICAL LOCALIZATION; GUANYLATE-CYCLASE; SUBRETINAL FLUID; SURVIVAL FACTOR; CELL-DEATH; ROD; RHODOPSIN AB PURPOSE. To describe changes in the localization patterns and levels of rod and cone photoreceptor proteins after experimental retinal detachment (RD). METHODS. Cat retinas were detached for 1, 3, 7, or 28 days, at which time the eyecups were placed in fixative for immunocytochemical analysis or homogenized for biochemistry. Immunocytochemistry was performed using 19 probes for molecules known to be associated with photoreceptors. Protein concentrations were determined using enzyme-linked immunosorbent assay or Western blot analysis. Cone cell death was analyzed by double labeling with TdT-dUTP terminal nick-end labeling and cone-specific antibodies. RESULTS. Although some cones died, many survived long-term RD. Although their profiles may have changed, rod photoreceptors continued to express most of the molecules studied as long as they were alive. In contrast, the cones failed to label with almost all probes specific to them after 3 to 7 days of detachment. The exception was phosducin, which localized to both rods and cones and, in 28-day detachments, increased to 180% of the amount in normal retina. CONCLUSIONS. Rods and cones respond differently to RD. This difference may account for a faster return of rod vision and for the lingering changes in color vision and acuity that are often reported after successful reattachment surgeries. C1 Univ Calif Santa Barbara, Neurosci Res Inst, Santa Barbara, CA 93106 USA. Univ Calif Santa Barbara, Dept Mol Cellular & Dev Biol, Santa Barbara, CA 93106 USA. NEI, Biol Imaging Core Facil, NIH, Bethesda, MD 20892 USA. Univ Washington, Dept Ophthalmol, Seattle, WA USA. RP Fisher, SK (reprint author), Univ Calif Santa Barbara, Neurosci Res Inst, Santa Barbara, CA 93106 USA. EM fisher@lifesci.ucsb.edu FU NEI NIH HHS [EY-00888] NR 77 TC 36 Z9 38 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2002 VL 43 IS 4 BP 1234 EP 1247 PG 14 WC Ophthalmology SC Ophthalmology GA 536LE UT WOS:000174700900045 PM 11923271 ER PT J AU Aref, M Brechbiel, M Wiener, EC AF Aref, M Brechbiel, M Wiener, EC TI Identifying tumor vascular permeability heterogeneity with magnetic resonance imaging contrast agents SO INVESTIGATIVE RADIOLOGY LA English DT Article DE contrast agents; mammary tumors; permeability; MRI ID GD-DTPA ENHANCEMENT; BREAST-CANCER; MRI; MODEL; LESIONS; MACROMOLECULES; ANGIOGENESIS; LIMITATIONS; PARAMETERS; CARCINOMA AB RATIONALE AND OBJECTIVES. Dynamic contrast enhanced (DCE) MR mammography (MRM) uses tumor capillary density differences for prognosis. The heterogeneous response of permeability-surface area products (PS = Kp<---->t) was examined in mammary tumors, as a function of contrast agent size, to determine what effect ROI size might have on PS and prognosis. METHODS. DCE FLASH signal intensities were converted to gadolinium concentrations by a standard curve, which was fitted by a two-compartment model for the tumor's extravascular extracellular space (EES) volume fraction (v(e)), and the tumor volume normalized transfer rate between plasma and EES(Kp<---->tVT). RESULTS. For Gd-DTPA v(e) = 9% to 13% Kp<---->t/V-T = 0.01 to 0.06 minutes(-1), and the macromolecular agent, PAMAMTU-DTPA G = 4 v(e) = 0.8% to 1% Kp<---->t/V-T = 0.008 to 0.04 minutes(-1). Significant differences in Kp<---->t/V-T for local regions were found for both agents relative to the whole tumor and the macromolecular agent had greater dynamic range. CONCLUSIONS. Smaller ROI values or pixels should yield more accurate assessment of neovascularization. C1 Univ Illinois, Beckman Inst 4247, Urbana, IL 61801 USA. Univ Illinois, Dept Nucl Plasma & Radiol Engn, Urbana, IL 61801 USA. Univ Illinois, Biomed Magnet Resonance Facil, Urbana, IL 61801 USA. Univ Illinois, Dept Med Informat Sci, Urbana, IL 61801 USA. Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Wiener, EC (reprint author), Univ Illinois, Beckman Inst 4247, MC-251,405 N Mathews Dr, Urbana, IL 61801 USA. FU NCI NIH HHS [1R29CA61918, T32CA09067]; NCRR NIH HHS [5P41RR05964] NR 40 TC 20 Z9 20 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-9996 J9 INVEST RADIOL JI Invest. Radiol. PD APR PY 2002 VL 37 IS 4 BP 178 EP 192 DI 10.1097/00004424-200204000-00003 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 535UA UT WOS:000174663700003 PM 11923640 ER PT J AU Konda, SD Wang, S Brechbiel, M Wiener, EC AF Konda, SD Wang, S Brechbiel, M Wiener, EC TI Biodistribution of a Gd-153-folate dendrimer, generation=4, in mice with folate-receptor positive and negative ovarian tumor xenografts SO INVESTIGATIVE RADIOLOGY LA English DT Article DE folate; contrast agents; gadolinium; dendrimer; biodistribution ID MONOCLONAL-ANTIBODIES; NUDE-MICE; CANCER; PHARMACOKINETICS; LOCALIZATION; REACTIVITY; FRAGMENTS; CARCINOMA; PROTEIN; ASCITES AB RATIONALE AND OBJECTIVES. An important characteristic of targeted contrast agents is how they are tolerated in a biologic environment and their localization in the surrounding tissues in addition to target tissue. We evaluate the biodistribution of a gadolinium Gd 153-folate-dendrinier in high affinity folate-receptor (hFR) positive and negative ovarian tumor xenografts. METHODS. The Gd-foIate-dendrinjer chelate was prepared by exchanging Gd-153 with nonradioactive gadolinium for 1 week, followed by extensive filtration. Athymic mice with hFR-positive (n = 3) and negative tumors (n = 3) were injected intravenously and counted using a whole-body counting system with a 80 to 150 keV counting window. RESULTS. The hFR-positive tumors accumulate 3.6% +/- 2.8% injected dose/g, whereas only background counts were found in hFR-negative tumors. The folate-dendrimer's tumor-to-blood ratio of 12.6, in hFR-positive tumors, was similar to5.7 to 17.0 fold better than those obtained with monoclonal antibodies targeted to the folate receptor. CONCLUSIONS. Biodistribution studies confirm previous MRI findings and show that the accumulation of the folate-dendrimer requires the expression of the hFR. C1 Univ Illinois, Beckman Inst 4247, Urbana, IL 61801 USA. Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA. Univ Illinois, Dept Nucl Plasma & Radiol Engn, Urbana, IL 61801 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Wiener, EC (reprint author), Univ Illinois, Beckman Inst 4247, 405 N Mathews, Urbana, IL 61801 USA. FU NCI NIH HHS [1-R29-CA61918]; NCRR NIH HHS [5-P41-RR05964]; NIGMS NIH HHS [T32 GM07143] NR 30 TC 67 Z9 74 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-9996 J9 INVEST RADIOL JI Invest. Radiol. PD APR PY 2002 VL 37 IS 4 BP 199 EP 204 DI 10.1097/00004424-200204000-00005 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 535UA UT WOS:000174663700005 PM 11923642 ER PT J AU Olivero, OA Fernandez, JJ Antiochos, BB Wagner, JL St Claire, ME Poirier, MC AF Olivero, OA Fernandez, JJ Antiochos, BB Wagner, JL St Claire, ME Poirier, MC TI Transplacental genotoxicity of combined antiretroviral nucleoside analogue therapy in Erythrocebs patas monkeys SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV-1; zidovudine; lamivudine; nonhuman priniate; fetus/telomere; ZDV-DNA incorporation; 3TC-DNA incorporation ID 3'-AZIDO-2',3'-DIDEOXYTHYMIDINE AZT; DNA INCORPORATION; MUTANT FREQUENCY; CELLS; ZIDOVUDINE; 3'-AZIDO-3'-DEOXYTHYMIDINE; TRIPHOSPHATE; LAMIVUDINE; WOMEN AB Antiretroviral nucleoside analogue drugs are a major constituent of highly active antiretroviral therapy (HAART), the most advanced form of treatment for HIV-1 infection. Currently, HAART combinations that include zidovudine (ZDV) and lamivudine (3TC) are highly effective in preventing HIV-1 vertical transmission; most children are born with no evident adverse clinical effects. However, ZDV is a moderately strong transplacental carcinogen in mice, and potential long-term consequences of fetal exposure to most HAART combinations remain unknown. To model human transplacental ZDV and 3TC exposures, experiments were performed in Erythrocebus patas monkeys given human-equivalent drug exposure protocols. Pregnant monkeys were dosed with either no drug (n = 2), 40.0 mg ZDV/d (about 6 mg/kg body weight/d) for the last 50% (10 weeks) of gestation (n = 3), or with the same regimen of ZDV plus 24.0 mg 3TC/d (about 3.6 mg/kg body weight/d) for the last 20% (4 weeks) of gestation (n = 3). Multiple fetal organs were examined at term for DNA incorporation of ZDV and 3TC using two separate radioimmunoassays (RIAs). Values for ZDV-DNA incorporation were similar in fetuses exposed to ZDV alone and those exposed to ZDV plus 3TC. Values for 3TC-DNA in fetal organs were greater than or equal to values for ZDV-DNA, indicating that the total DNA damage sustained by fetuses exposed to both drugs was at least double that observed in fetuses exposed to ZDV alone. Telomere shortening, determined by Southern blot with a telomeric probe, was observed in most organs of the three animals exposed in utero to ZDV plus 3TC. No telomere shortening was evident in the unexposed fetuses, and occasional telomere shortening was found in fetuses exposed to ZDV alone. Overall, these studies demonstrate that monkey fetuses exposed in utero to the combination ZDV plus 3TC sustain a higher level of drug-DNA incorporation and show evidence of more telomere damage than monkey fetuses exposed to ZDV alone. C1 NCI, Carcinogen DNA Interact Sect, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. BioQual Inc, Rockville, MD USA. RP Olivero, OA (reprint author), NCI, Carcinogen DNA Interact Sect, Cellular Carcinogenesis & Tumor Promot Lab, NIH, 37 Convent Dr,MSC 4255,Bldg 37 Rm 2A 01, Bethesda, MD 20892 USA. NR 20 TC 48 Z9 50 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD APR 1 PY 2002 VL 29 IS 4 BP 323 EP 329 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 535TB UT WOS:000174661500001 PM 11917235 ER PT J AU Elbeik, T Alvord, WG Trichavaroj, T de Souza, M Dewar, R Brown, A Chernoff, D Michael, NL Nassos, P Hadley, K Elbeik, T AF Elbeik, T Alvord, WG Trichavaroj, T de Souza, M Dewar, R Brown, A Chernoff, D Michael, NL Nassos, P Hadley, K Elbeik, T TI Comparative analysis of HIV-1 viral load assays on subtype quantification: Bayer Versant HIV-1 RNA 3.0 versus Roche amplicor HIV-1 monitor version 1.5 SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE Amplicor; Branched DNA (bDNA); HIV-1subtypes; viral load ID IMMUNODEFICIENCY-VIRUS TYPE-1; NON-B SUBTYPES; GENETIC SUBTYPES; QUANTIPLEX VERSION-3.0; PLASMA; QUANTITATION; PERFORMANCE; DIVERSITY; INFECTION; AFRICA AB Quantification of HIV-1 subtypes is essential for appropriate clinical management. Whereas viral load assays were initially developed to accurately quantify Subtype B, the recent worldwide spread of non-B subtypes, and the introduction of treatment programs in regions with non-B subtypes have prompted adaptations of these assays. The Bayer Versant HIV-1 RNA 3.0 Assay (branched DNA [bDNA] 3.0) and the Roche Amplicor HIV-1 Monitor version 1.5 (Amplicor 1.5) assays are reported to quantify all subtypes in group M however, evaluation of performance characteristics remains limited. In this study, We evaluated the accuracy and reliability of bDNA 3.0 and Amplicor 1.5 on multiple serially diluted viral isolates from HIV-1 group M, subtypes A through F. Testing was conducted on both assay systems in two independent laboratories. Comparative pansubtype quantification from regression analysis showed that quantification by bDNA 3.0 was approximately 0.3 log-fold lower than that by Amplicor 1.5. Comparative pansubtype accuracy analysis showed data points more closely distributed about their respective regression lines and thus showing greater reliability by bDNA 3.0 than by Amplicor 1.5. C1 Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. San Francisco Gen Hosp, Clin Labs, San Francisco, CA 94110 USA. NCI, Data Management Serv, Frederick Canc Res & Dev Ctr, Frederick, MD USA. USA, Med Component, Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. Henry M Jackson Fdn, Bangkok, Thailand. SAIC Frederick Inc, Frederick, MD USA. Elan Pharmaceut, San Francisco, CA USA. Walter Reed Army Inst Res, Div Retrovirol, Dept Mol Diagnost & Pathogenesis, Rockville, MD USA. RP Elbeik, T (reprint author), San Francisco Gen Hosp, Dept Lab Med, 1001 Potrero Ave,NH,Room 2M35, San Francisco, CA 94110 USA. EM elbeik@itsa.ucsf.edu OI Elbeik, Tarek/0000-0001-5983-0867 NR 52 TC 47 Z9 48 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD APR 1 PY 2002 VL 29 IS 4 BP 330 EP 339 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 535TB UT WOS:000174661500002 PM 11917236 ER PT J AU Calabrese, LH Lederman, TM Spritzler, J Coombs, RW Fox, L Schock, B Yen-Lieberman, B Johnson, T Mildvan, T Parekh, N AF Calabrese, LH Lederman, TM Spritzler, J Coombs, RW Fox, L Schock, B Yen-Lieberman, B Johnson, T Mildvan, T Parekh, N CA AIDS Clin Trials Grp 334 Inv TI Placebo-controlled trial of cyclosporin-A in HIV-1 disease: Implications for solid organ transplantation SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE cyclosporine; immune activation; organ transplantation; HIV therapy ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL THERAPY; TYPE-1 RNA; RESPONSES; INFECTION; PLASMA; CELLS; AIDS AB Objective: Earlier open-label clinical trial, have provided conflicting data on the effects of cyclosporin-A (CsA) on the clinical course and immune status of patients with HIV disease. With the prospects for wider use of CsA in the setting of solid organ transplantation in HIV-infected persons, data on the safety and immunologic activity of this agent are needed. We report here the results of a randomized, double-blind, placebo-controlled trial to assess the safety and immunologic activity of CsA administration in early HIV disease. Methods: Twenty-eight patient, with confirmed HIV infection, CD4 cell counts greater than 500 x 10(6)/L, and plasma HIV RNA >600 copies/mL were randomized to receive 2 mg/kg of CsA (Neoral) twice daily or identical placebo fur 12 weeks. Subjects were stratified for the presence or absence of stable concomitant antiviral therapy. The primary end point was the effect of therapy on immune activation as assessed by the levels of soluble interleukin-2 receptors. Secondary end points included safety and effects of treatment on plasma HIV RNA, CD4 cell count, and other markers of immune activation and function. Results: The low dose of CsA used in this study did not suppress immune activation or increase circulating CD4 cell counts. Delayed-type hypersensitivity responses were not affected; however, lymphocyte proliferative responses tended to decrease, CsA-treated patients experienced a small but significant rise in plasma HIV RNA levels. Conclusions: Low-dose CsA has no benefit in patients with stable early HIV disease, and its administration may be associated with an increase in plasma HIV RNA. The use of CsA in HIV-infected patients undergoing organ transplantation should be undertaken with caution. C1 Cleveland Clin Fdn, Dept Rheumatol & Immunol, Cleveland, OH 44195 USA. Case Western Reserve Univ, Div Infect Dis, Sch Med, AIDS Res Ctr, Cleveland, OH USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. NIAID, Rockville, MD USA. Frontier Sci, Amherst, NY USA. Beth Israel Med Ctr, Div Infect Dis, New York, NY 10003 USA. RP Calabrese, LH (reprint author), Cleveland Clin Fdn, Dept Rheumatol & Immunol, 9500 Euclid Ave, Cleveland, OH 44195 USA. FU NCRR NIH HHS [RR 00080]; NIAID NIH HHS [AI 36219, AI 25879, AI-27664, AI-32910, AI 38858, 5 U01 AI38855, AI-27757] NR 20 TC 35 Z9 37 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD APR 1 PY 2002 VL 29 IS 4 BP 356 EP 362 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 535TB UT WOS:000174661500005 PM 11917239 ER PT J AU Mbulaiteye, SM Biggar, RJ Goedert, JJ Engels, EA AF Mbulaiteye, SM Biggar, RJ Goedert, JJ Engels, EA TI Pleural and peritoneal lymphoma among people with AIDS in the United States SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE pleura; peritoneum; non-Hodgkin lymphoma; AIDS; Kaposi sarcoma; Kaposi sarcoma-associated herpesvirus (KSHV); primary effusion lymphoma ID PRIMARY EFFUSION LYMPHOMA; DNA-SEQUENCES; KAPOSIS; SPECTRUM AB Objective: To describe the occurrence and characteristics of pleural and peritoneal lymphoma in a large cohort of persons with AIDS in I I regions in the United States, Methods: We used AIDS and cancer registries to identify cases of non-Hodgkin lymphoma (NHL) among 304,439 adults with AIDS. NHLs were categorized by site codes into pleural/peritoneal lymphoma and other NHLs. Data on age, sex, HIV exposure category, histology, history of Kaposi sarcoma (KS), CD4 counts, and survival were analyzed. Results: Fourteen lymphomas were identified (four within the pleura, 10 in the peritoneum) representing 0.13% (95% confidence interval [CI], 0.05-0.20) of 10,510 cases of NHL. Those with pleural/peritoneal lymphoma were similar to those with other NHLs in age (median, 43 years), race (79% white, 7% black, 14% Hispanic), and HIV transmission category (86% homosexual men), but they tended to have a higher prevalence of prior KS (29%, vs. 12% p = .06). More cases of pleural/peritoneal lymphoma had immunoblastic histology than did other NHLs (43% vs. 22%; p = .06). CD4 counts for pleural/peritoneal lymphomas were also higher than for other NHLs (median 203 vs. 65 cells/mm(3); P = .05), but post-NHL survival was similar (median 7.1 vs. 5.1 months, respectively; p = .32). Conclusions: Pleural and peritoneal lymphomas are a rare subtype of AIDS-associated NHL, occurring with less severe immune deficiency than for other NHLs, The increased frequency among persons with prior KS suggests a common etiology, presumably infection with KS-associated herpesvirus, as found in primary effusion lymphoma. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Mbulaiteye, SM (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8007, Rockville, MD 20852 USA. NR 10 TC 20 Z9 23 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD APR 1 PY 2002 VL 29 IS 4 BP 418 EP 421 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 535TB UT WOS:000174661500014 PM 11917248 ER PT J AU Johnson, EN Druey, KM AF Johnson, EN Druey, KM TI Heterotrimeric G protein signaling: Role in asthma and allergic inflammation SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Review DE asthma; allergic rhinitis; G proteins; inflammation; signal transduction ID AIRWAY SMOOTH-MUSCLE; GTPASE-ACTIVATING PROTEINS; LEUKOTRIENE B-4 RECEPTOR; BLOOD MONONUCLEAR-CELLS; NITRIC-OXIDE SYNTHASE; COUPLED RECEPTORS; T-CELL; TYROSINE KINASE; HYPERRESPONSIVE RATS; ATOPIC-DERMATITIS AB Asthma and rhinitis are pathophysiologic conditions associated with a prototypical allergic response to inhaled allergens consisting of both neuromechanical and inflammatory components. Heptahelical receptors that bind guanosine triphosphate-binding proteins (G proteins), referred to as G protein-coupled receptors (GPCRs), have been intimately linked with asthma and allergic inflammation for Man. years. G protein signaling mediates responses throughout the immune, nervous, and muscular systems that might contribute to the pathogenesis of allergic processes and asthma. For example, GPCR agonists or antagonists are used as therapies for asthma either by promoting airway smooth muscle relaxation (beta2 adrenergic receptor agonists) or by inhibiting inflammation in the nasal mucosa and airways (cysteinyl leukotriene receptor antagonists), The focus of this review is to explore how downstream signaling cascades elicited by GPCR activation contribute to the allergic phenotype and the mechanism by which pharmaceuticals alter signaling to generate a therapeutic effect. We also discuss physiologic modulators of G protein signaling, such as regulator of G protein signaling proteins and G protein receptor kinases, inasmuch as they represent potential new therapeutic targets in the treatment of atopy and other inflammatory conditions. C1 NIAID, Lab Allerg Dis, NIH, Rockville, MD 20852 USA. RP Druey, KM (reprint author), NIAID, Lab Allerg Dis, NIH, 12441 Parklawn Dr,Room 200E, Rockville, MD 20852 USA. NR 92 TC 41 Z9 43 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD APR PY 2002 VL 109 IS 4 BP 592 EP 602 DI 10.1067/mai.2002.122636 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA 543YZ UT WOS:000175132600002 PM 11941304 ER PT J AU Kino, T Chrousos, GP AF Kino, T Chrousos, GP TI Tissue-specific glucocorticoid resistance-hypersensitivity syndromes: Multifactorial states of clinical importance SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Editorial Material ID PITUITARY-ADRENAL AXIS; RECEPTOR TRANSCRIPTIONAL ACTIVATION; INHALED CORTICOSTEROID-THERAPY; BINDING AFFINITY; PROTEIN; SENSITIVITY; SUPPRESSION; COACTIVATOR; STRESS C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Kino, T (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Rm 9D42,10 Ctr Dr,MSC 1583, Bethesda, MD 20892 USA. NR 31 TC 28 Z9 30 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD APR PY 2002 VL 109 IS 4 BP 609 EP 613 DI 10.1067/mai.2002.123708 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA 543YZ UT WOS:000175132600005 PM 11941307 ER PT J AU Cohen, SG AF Cohen, SG TI Pioneers and milestones - Clemens von Pirquet, MD (1874-1929) SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Biographical-Item C1 NIAID, NIH, Bethesda, MD 20892 USA. NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Cohen, SG (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 5 TC 4 Z9 5 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD APR PY 2002 VL 109 IS 4 BP 722 EP 724 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA 543YZ UT WOS:000175132600029 PM 11941329 ER PT J AU Wang, ML Hauschka, PV Tuan, RS Steinbeck, MJ AF Wang, ML Hauschka, PV Tuan, RS Steinbeck, MJ TI Exposure to particles stimulates superoxide production by human THP-1 macrophages and avian HD-11EM osteoclasts activated by tumor necrosis factor-alpha and PMA SO JOURNAL OF ARTHROPLASTY LA English DT Article DE osteoclast; macrophage; wear particles; aseptic loosening; ceramics; tumor necrosis factor (TNF)-alpha; reactive oxygen species (ROS); superoxide; nitric oxide ID TNF-ALPHA; PROSTHESES; BONE AB Wear of orthopaedic implants generates particles capable of inducing bone resorption and aseptic loosening of the implant. The present study shows the combined effect of particles and cell activation on macrophage (THP-1) and osteoclast (HD-11EM) release of reactive oxygen and nitrogen species, providing insight into mechanisms that can lead to osteolysis. In the absence of cell activation, exposure of either cell type to submicron zirconia or latex particles did not elicit an increase in reactive oxygen and nitrogen species production. Suboptimal stimulation with 4beta-phorbol-12-myristate-13-acetate (PMA) plus particles resulted in a synergistic release of superoxide (O-2(-)), however, and a low-level production of nitric oxide (.) by THP-1 macrophages. Similarly, particle stimulation of tumor necrosis factor-alpha-activated THP-1 cells increased O-2(-) release. Our findings show the synergistic effect of cell activation and wear particles on O-2(-) production by activated macrophages and osteoclasts, suggesting O-2(-) involvement in mediating osteolysis. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. RP Steinbeck, MJ (reprint author), Thomas Jefferson Univ, Dept Orthopaed Surg, 1015 Walnut St,324 Curtis Bldg, Philadelphia, PA 19107 USA. EM marla.steinbeck@mail.tju.edu FU NIAMS NIH HHS [AR39740, AR44046, AR44501]; NIDCR NIH HHS [DE11082] NR 44 TC 29 Z9 29 U1 0 U2 4 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 J9 J ARTHROPLASTY JI J. Arthroplast. PD APR PY 2002 VL 17 IS 3 BP 335 EP 346 DI 10.1054/arth.2002.30416 PG 12 WC Orthopedics SC Orthopedics GA 540ZM UT WOS:000174960800012 PM 11938511 ER PT J AU Lacourciere, GM AF Lacourciere, GM TI Selenium is mobilized in vivo from free selenocysteine and is incorporated specifically into formate dehydrogenase H and tRNA Nucleosides SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ESCHERICHIA-COLI; CYSTEINE DESULFURASE; GLUTATHIONE REDUCTASE; GENE CLONING; NIFS; LYASE; PURIFICATION; ENZYME; SELENOPHOSPHATE; BIOSYNTHESIS AB Selenophosphate synthetase (SPS), the selD gene product from Escherichia coli, catalyzes the biosynthesis of monoselenophosphate, AMP, and orthophosphate in a 1:1:1 ratio from selenide and ATP. It was recently demonstrated that selenium delivered from selenocysteine by an E. coli NifS-like protein could replace free selenide in the in vitro SPS assay for selenophosphate formation (G. M. Lacourciere, H. Mihara, T. Kurihara, N. Esaki, and T. C. Stadtman, J. Biol. Chem. 275:23769-23773, 2000). During growth of E. coli in the presence of 0-1 muM (SeO32-)-Se-75 and increasing amounts Of L-selenocysteine, a concomitant decrease in Se-75 incorporation into formate dehydrogenase H and nucleosides of bulk tRNA was observed. This is consistent with the mobilization of selenium from L-selenocysteine in vivo and its use in selenophosphate formation. The ability of E. coli to utilize selenocysteine as a selenium source for selenophosphate biosynthesis in vivo supports the participation of the NifS-like proteins in selenium metabolism. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Lacourciere, GM (reprint author), NHLBI, Biochem Lab, NIH, 50 S Dr,Room 2126, Bethesda, MD 20892 USA. NR 22 TC 18 Z9 18 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD APR PY 2002 VL 184 IS 7 BP 1940 EP 1946 DI 10.1128/JB.184.7.1940-1946.2002 PG 7 WC Microbiology SC Microbiology GA 532CL UT WOS:000174454000018 PM 11889101 ER PT J AU Self, WT AF Self, WT TI Regulation of purine hydroxylase and xanthine dehydrogenase from Clostridium purinolyticum in response to purines, selenium, and molydenum SO JOURNAL OF BACTERIOLOGY LA English DT Article ID NICOTINIC-ACID HYDROXYLASE; ESCHERICHIA-COLI; MOLYBDENUM; SELENOCYSTEINE; EXPRESSION; MOLYBDATE; BARKERI; MODE; REQUIREMENT; REPRESSOR AB The discovery that two distinct enzyme catalysts, purine hydroxylase (PH) and xanthine dehydrogenase (XDH), are required for the overall conversion of hypoxanthine to uric acid by Clostridium purinolyticum was unexpected. In this reaction sequence, hypoxanthine is hydroxylated to xanthine by PH and then xanthine is hydroxylated to uric acid by XDH. PH and XDH, which contain a labile selenium cofactor in addition to a molybdenum cofactor, flavin adenine dinucleotide, and FeS centers, were purified and partially characterized as reported previously. In the present study, the activities of these two enzymes were measured in cells grown in media containing various concentrations of selenite, molybdate, and various purine substrates. The levels of PH protein in extracts were determined by immunoblot assay. The amount of PH protein, as well as the specific activities of PH and XDH, increased when either selenite or molybdate was added to the culture medium. PH levels were highest in the cells cultured in the presence of either adenine or purine. XDH activity increased dramatically in cells grown with either xanthine or uric acid. The apparent increases in protein levels and activities of PH and XDH in response to selenium, molybdenum, and purine substrates demonstrate that these enzymes are tightly regulated in response to these nutrients. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Self, WT (reprint author), NHLBI, Biochem Lab, NIH, 50 S Dr,Room 2126, Bethesda, MD 20892 USA. RI Self, William/A-6704-2008 NR 20 TC 9 Z9 10 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD APR PY 2002 VL 184 IS 7 BP 2039 EP 2044 DI 10.1128/JB.184.7.2039-2044.2002 PG 6 WC Microbiology SC Microbiology GA 532CL UT WOS:000174454000030 PM 11889113 ER PT J AU Boshoff, HI Mizrahi, V Barry, CE AF Boshoff, HI Mizrahi, V Barry, CE TI Effects of pyrazinamide on fatty acid synthesis by whole mycobacterial cells and purified fatty acid synthase I SO JOURNAL OF BACTERIOLOGY LA English DT Article ID CULTURED HUMAN MACROPHAGES; TUBERCULOSIS COMPLEX ORGANISMS; SHORT-COURSE CHEMOTHERAPY; ANTITUBERCULOSIS DRUGS; TUBERCLE-BACILLI; PYRAZINOIC ACID; SMEGMATIS; PNCA; RESISTANCE; MUTATIONS AB The effects of low extracellular pH and intracellular accumulation of weak organic acids were compared with respect to fatty acid synthesis by whole cells of Mycobacterium tuberculosis and Mycobacterium smegmatis. The profile of fatty acids synthesized during exposure to benzoic, nicotinic, or pyrazinoic acids, as well as that observed during intracellular hydrolysis of the corresponding amides, was not a direct consequence of modulation of fatty acid synthesis by these compounds but reflected the response to inorganic acid stress. Analysis of fatty acid synthesis in crude mycobacterial cell extracts demonstrated that pyrazinoic acid failed to directly modulate the fatty acid synthase activity catalyzed by fatty acid synthase I (FAS-I). However, fatty acid synthesis was irreversibly inhibited by 5-chloro-pyrazinamide in a time-dependent fashion. Moreover, we demonstrate that pyrazinoic acid does not inhibit purified mycobacterial FAS-I, suggesting that this enzyme is not the immediate target of pyrazinamide. C1 NIAID, Tuberculosis Res Sect, Rockville, MD 20852 USA. Univ Witwatersrand, South African Inst Med Res, Mol Mycobatericol Res Unit, Johannesburg, South Africa. Univ Witwatersrand, Sch Pathol, Johannesburg, South Africa. RP Barry, CE (reprint author), NIAID, Tuberculosis Res Sect, Twinbrook 2 Rm 239 12441 Parklawn Dr, Rockville, MD 20852 USA. RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000783-11] NR 43 TC 69 Z9 73 U1 1 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD APR PY 2002 VL 184 IS 8 BP 2167 EP 2172 DI 10.1128/JB.184.8.2167-2172.2002 PG 6 WC Microbiology SC Microbiology GA 535WJ UT WOS:000174669100014 PM 11914348 ER PT J AU Beutler, JA McMahon, JB Johnson, TR O'Keefe, BR Buzzell, RA Robbins, D Gardella, R Wilson, J Boyd, MR AF Beutler, JA McMahon, JB Johnson, TR O'Keefe, BR Buzzell, RA Robbins, D Gardella, R Wilson, J Boyd, MR TI High throughput screening for cyanovirin-N mimetics binding to HIV-1 gp41 SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article ID VIRUS-INACTIVATING PROTEIN; GP120; ENTRY; DISCOVERY; FUSION; GLYCOPROTEINS; INHIBITORS; BLOCKING; CD4 AB The human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein gp41 is an important mediator of viral entry into host cells. Previous studies showed that the virucidal protein cyanovirin-N (CV-N) bound to both gp120 and gp41, and that this binding was associated with its antiviral activity. We constructed an HTS assay based on the interaction of europium-labeled CV-N with recombinant glycosylated gp41 ectodomain to support identification of small-molecule mimetics of CV-N that might be developed as antiviral drug leads. Primary screening of over 107,000 natural product extracts in the assay yielded 347 confirmed hits. Secondary assays eliminated extracts that bound directly to labeled CV-N or for which the simple sugars mannose and N-acetylglucosamine blocked the interaction with gp41 (lectin activity). Extracts were further prioritized based on anti-HIV activity and other biological, biochemical, and chemical criteria. The distribution of source organism taxonomy of active extracts was analyzed, as was the cross-correlation of activity between the CV-N-gp41 binding competition assay and the previously reported CV-N-gp120 binding competition assay. A limited set of extracts was selected for bioassay-guided fractionation. C1 NCI, MTDDP, CCR, SAIC Frederick, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, CCR, SAIC Frederick, Frederick, MD 21702 USA. RP Beutler, JA (reprint author), NCI, MTDDP, CCR, SAIC Frederick, Bldg 1052,Room 121, Frederick, MD 21702 USA. RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 FU NCI NIH HHS [N01-CO-56000] NR 18 TC 10 Z9 11 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 J9 J BIOMOL SCREEN JI J. Biomol. Screen PD APR PY 2002 VL 7 IS 2 BP 105 EP 110 DI 10.1177/108705710200700202 PG 6 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA 548TA UT WOS:000175404800001 PM 12006108 ER PT J AU Potter, K Leapman, RD Basser, PJ Landis, WJ AF Potter, K Leapman, RD Basser, PJ Landis, WJ TI Cartilage calcification studied by proton nuclear magnetic resonance microscopy SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE nuclear magnetic resonance microscopy; cartilage; calcification; chondrocyte; bioreactor ID TRABECULAR BONE; RETINOIC ACID; EXTRACELLULAR-MATRIX; MINERAL PHASE; CHONDROCYTES; CALCIUM; TISSUE; DIFFRACTION; RELAXOMETRY; EXPRESSION AB A three-dimensional (3D) mineralizing culture system using hollow fiber bioreactors has been developed to study the early stages of endochondral ossification by proton nuclear magnetic resonance (NMR) microscopy. Chondrocytes harvested from the cephalic half of the sterna from 17-day-old chick embryos were terminally differentiated with 33 nM of retinoic acid for I week and mineralization was initiated by the addition of 1% beta-glycerophosphate to the culture medium. Histological sections taken after 6 weeks of development in culture confirmed calcification of the cartilage matrix formed in bioreactors. Calcium to phosphorus ratios (1.62-1.68) from X-ray microanalysis supported electron diffraction of thin tissue sections showing the presence of a poorly crystalline hydroxyapatite mineral phase in the cultures. After 4 weeks of culture, quantitative proton NMR images showed water proton magnetization transfer rate constants (km) were higher in premineralized cartilage compared with uncalcified cartilage, a result suggesting collagen enrichment of the matrix. Notably after 5 weeks mineral deposits formed in bioreactors principally in the collagen-enriched zones of the cartilage with increased km values. This caused marked reductions in water proton longitudinal (T-1) and transverse (T-2) relaxation times and water diffusion coefficients (D). These results support the hypothesis that mineralization proceeds in association with a collagen template. After 6 weeks of culture development, the water proton T2 values decreased by 13% and D increased by 7% in uncalcified areas, compared with the same regions of tissue examined 1 week earlier. These changes could be attributed to the formation of small mineral inclusions in the cartilage, possibly mediated by matrix vesicles, which may play an important role in cartilage calcification. In summary, NMR images acquired before and after the onset of mineralization of the same tissue provide unique insights into the matrix events leading to endochondral mineral formation. C1 NIH, Off Res Serv, Bethesda, MD 20892 USA. Armed Forces Inst Pathol Annex, Dept Cellular Pathol & Genet, Washington, DC USA. NICHHD, Sect Tissue Biophys & Biomimet, Bethesda, MD 20892 USA. NE Ohio Univ, Coll Med, Dept Biochem & Mol Pathol, Rootstown, OH 44272 USA. RP Potter, K (reprint author), Armed Forces Inst Pathol Annex, Dept Cellular Pathol & Genet, 1413 Res Blvd,Bldg 101,Room 1008, Rockville, MD 20850 USA. RI Basser, Peter/H-5477-2011 NR 38 TC 15 Z9 15 U1 1 U2 1 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD APR PY 2002 VL 17 IS 4 BP 652 EP 660 DI 10.1359/jbmr.2002.17.4.652 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 531UT UT WOS:000174436200012 PM 11918222 ER PT J AU Popescu, NC Zimonjic, DB AF Popescu, NC Zimonjic, DB TI Chromosome-mediated alterations of the MYC gene in human cancer SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Review DE breast cancer; Burkitt's lymphoma; hepatocellular carcinoma; MYC oncogene; chromosome alterations; viral integration; gene activation ID GROWTH-FACTOR-ALPHA; HUMAN-BREAST-CANCER; COMPARATIVE GENOMIC HYBRIDIZATION; VIRAL INTEGRATION SITES; CARCINOMA CELL-LINES; EXPRESSING C-MYC; HEPATOCELLULAR-CARCINOMA; BURKITT-LYMPHOMA; FRAGILE SITES; MOLECULAR-GENETICS AB The step-wise accumulation of genetic and epigenetic alterations in cancer development includes chromosome rearrangements and viral integration-mediated genetic alterations that frequently involve proto-oncogenes. Proto-oncogenes deregulation lead-to unlimited, self-sufficient cell growth and ultimately generates invasive and destructive tumors. C-MYC gene, the cellular homologue of the avian myelocitic leukemia virus, is implicated in a large number of human solid tumors, leukemias and lymphomas as well as in a variety of animal neoplasias. Deregulated WC expression is a common denominator in cancer. Chromosomal rearrangements and integration of oncogenic viruses frequently target MYC locus, causing structural or functional alterations of the gene. In this article, we illustrate how genomic rearrangements and viruses integration affect MYC locus in certain human lymphomas and solid tumors. C1 NCI, Canc Res Ctr, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Popescu, NC (reprint author), NCI, Canc Res Ctr, Expt Carcinogenesis Lab, 37 Convent Dr MSC 4258, Bethesda, MD 20892 USA. NR 55 TC 52 Z9 56 U1 0 U2 3 PU CAROL DAVILA UNIV PRESS PI BUCHARESST PA 8 EROILOR SANITARI BLVD, BUCHARESST 76241, ROMANIA SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD APR-JUN PY 2002 VL 6 IS 2 BP 151 EP 159 DI 10.1111/j.1582-4934.2002.tb00183.x PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 573VV UT WOS:000176853200001 PM 12169201 ER PT J AU Liu, D Lu, CB Wan, RQ Auyeung, WW Mattson, MP AF Liu, D Lu, CB Wan, RQ Auyeung, WW Mattson, MP TI Activation of mitochondrial, ATP-dependent potassium channels protects neurons against ischemia-induced death by a mechanism involving suppression of bax translocation and cytochrome c release SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE apoptosis; bax; Bcl2; cerebral cortex; cytochrome c; diazoxide; glibenclamide; hypoxia; hydroxydecanoate; preconditioning; staurosporine ID MANGANESE SUPEROXIDE-DISMUTASE; FOCAL CEREBRAL-ISCHEMIA; K+ CHANNEL; PEROXYNITRITE PRODUCTION; HIPPOCAMPAL-NEURONS; CELL-DEATH; APOPTOSIS; BRAIN; EXPRESSION; OPENERS AB Neurons express a variety of plasma-membrane potassium channels that play important roles in regulating neuronal excitability and synaptic transmission, but also contain mitochondrial ATP-sensitive potassium channels, the functions of which are unknown. Studies of cardiac cells suggest that similar mitochondrial ATP-sensitive potassium channels are involved in the process of ischemic preconditioning, suggesting a role in regulating cell survival. The authors report that mice given diazoxide, an activator of mitochondrial ATP-sensitive potassium channels, exhibited a large (60% to 70%) decrease in cortical infarct size after permanent occlusion of the middle cerebral artery. Diazoxide decreases neuronal apoptosis and increases astrocyte survival and activation in the penumbral region of the ischemic cortex. The neuroprotective effect of diazoxide is abolished by 5-hydroxydecanoate, a selective antagonist of mitochondrial ATP-sensitive potassium channels. Studies of cultured hippocampal neurons reveal that diazoxide depolarizes mitochondria, prevents cytochrome c release, and protects cells against death induced by staurosporine and chemical hypoxia. Diazoxide increased the levels of Bcl2 and inhibited the association of Bax with mitochondria in neurons exposed to an apoptotic insult, suggesting that activation of mitochondrial ATP-sensitive potassium channels may stabilize mitochondrial function by differentially modulating proapoptotic and antiapoptotic proteins. Collectively, the data suggest that mitochondrial ATP-sensitive potassium channels play a key role in modulating neuronal survival under ischemic conditions, and identify agents that activate mitochondrial ATP-sensitive potassium channels as potential therapeutics for stroke and related neurodegenerative conditions. C1 NIA, GRC 4F01, Lab Neurosci, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD USA. RP Mattson, MP (reprint author), NIA, GRC 4F01, Lab Neurosci, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 75 TC 154 Z9 185 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD APR PY 2002 VL 22 IS 4 BP 431 EP 443 PG 13 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 538EY UT WOS:000174802900007 PM 11919514 ER PT J AU Hiroi, N Ichijo, T Ueshiba, H Miyachi, Y AF Hiroi, N Ichijo, T Ueshiba, H Miyachi, Y TI Intranasal administration of adrenocorticotropin-(1-24) stimulates adrenocortical hormone secretion SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article; Proceedings Paper CT 82nd Annual Meeting of the Endocrine-Society CY JUN 21-24, 2000 CL TORONTO, CANADA SP Endocrine Soc ID DEHYDROEPIANDROSTERONE; RESPONSES; DHEA; REPLACEMENT; DEPRESSION; HUMANS; STRESS AB To determine the efficiency of transmucosal. absorption of ACTH, we measured serum cortisol, aldosterone, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEA-S) levels after intranasal (in) vs. iv administration of ACTH-(1-24) (250 mug) in 12 healthy adult men (mean age, 24.3 +/- 3.2 yr; range, 21-31 yr), who had received no prior medication and had no symptoms of rhinitis. Blood was collected at 0, 30, 60, 120, and 180 min after administration of ACTH-(1-24), and the levels of adrenocortical steroids were measured by specific RIAs. There were no side-effects associated with in or iv ACTH administration. After in administration, serum cortisol and aldosterone increased rapidly by 224.7 +/- 39.2% and 147.2 +/- 50.5%, respectively, peaking 30 min after ACTH-(1-24) administration, and decreasing to basal levels within 120 min. These increases in serum cortisol and aldosterone were lower than those obtained after iv administration. Thirty minutes after in or iv administration of ACTH-(1-24), DHEA increased by 49.1 +/- 27.2% and 81.6 +/- 17.1%, respectively, and remained elevated for 180 min. Serum DHEA-S levels did not change after in administration of ACTH.(1-24) and increased only slightly after iv injection. Adrenocortical steroid levels did not increase after in administration of saline. These data demonstrate that adrenocortical steroids are stimulated by in administration of ACTH-(1-24). We suggest that intranasal administration of ACTH offers both a diagnostic approach as an adrenal function test and a therapeutic approach as ACTH replacement therapy in patients with ACTH deficiency. The latter may be more physiological than glucocorticoid replacement. C1 Toho Univ, Sch Med, Dept Internal Med 1, Ota Ku, Tokyo 1430015, Japan. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Hiroi, N (reprint author), Toho Univ, Sch Med, Dept Internal Med 1, Ota Ku, 6-11-1 Omorinishi, Tokyo 1430015, Japan. EM n-hiroi@tkf.att.ne.jp NR 26 TC 2 Z9 3 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2002 VL 87 IS 4 BP 1750 EP 1753 DI 10.1210/jc.87.4.1750 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 541AM UT WOS:000174963100049 PM 11932311 ER PT J AU Mendonca, BB Leite, MV de Castro, M Kino, T Elias, LLK Bachega, TAS Arnhold, IJP Chrousos, GP Latronico, C AF Mendonca, BB Leite, MV de Castro, M Kino, T Elias, LLK Bachega, TAS Arnhold, IJP Chrousos, GP Latronico, C TI Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID HUMAN GLUCOCORTICOID RECEPTOR; 21-HYDROXYLASE DEFICIENCY; CORTISOL RESISTANCE; BRAZILIAN PATIENTS; SENSITIVITY; LYMPHOCYTES; FREQUENCY; CARRIERS AB Familial glucocorticoid resistance is characterized by increased cortisol secretion without clinical evidence of hyper-cortisolism, but with manifestations of androgen and miner. alocorticoid excess. This condition is mainly caused by mutations of the GR gene that cause inadequate transduction of the glucocorticoid signal in glucocorticoid target tissues. The clinical features of glucocorticoid. resistance in females include hirsutism, acne, male pattern baldness, oligomenorrhea, and oligoanovulation. We describe here a new phenotype, female pseudohermaphroditism and severe hypokalemia, caused by a homozygous inactivating mutation of the GR gene. The proband was born with ambiguous genitalia from consanguineous parents and was mistreated as a 21-hydroxylase deficiency case since the age of 5 yr. She had very high levels of plasma ACTH (759 pg/ml or 167 pmol/liter) and high levels of cortisol (28-54 mug/dl or 772-1490 nmol/liter), androstenedione (5-14 ng/ml or 17-48 nmol/liter), T (174-235 ng/dl or 7-8 nmol/liter), and 17-hydroxyprogesterone (8-12 ng/ml or 24-36 nmol/liter). Her cortisol and 17-hydroxyprogesterone levels were not compatible with the diagnosis of classic congenital adrenal hyperplasia; furthermore, cortisol was not properly suppressed after dexamethasone administration (28 mug/d or 772 nmol/liter). Her laboratory evaluation indicated a diagnosis of glucocorticoid resistance. To investigate this puzzling clinical and biochemical picture, we analyzed both GR and CYP21 genes. Indeed, a homozygous T to C substitution at nucleotide 1844 in exon 5 of the GR gene was identified in the patient that caused a valine to alanine substitution at amino acid 571 in the ligand domain of the receptor. Her parents and an older sister were heterozygous for this mutation. A whole Epstein-Barr virus-transformed cell dexamethasone-binding assay revealed that this Ala 511 mutant had a 6-fold reduction in binding affinity compared with the wild-type receptor. In a functional assay using mouse mammary tumor virus promoter-driven luciferase reporter gene, the mutant receptor displayed 10- to 50-fold less trans-activation activity than the wild-type receptor. In addition, a large heterozygous CYP21 conversion was identified in the patient and her father. In conclusion, we described the first case of female pseudohennaphroditism caused by a novel homozygous GR gene mutation. This phenotype indicates that pre- and postnatal virilization can occur in females with the glucocorticoid resistance syndrome. C1 Univ Sao Paulo, Fac Med, Hosp Clin, Lab Hormonios,Unidade Endocrinol Desenvolvimento, BR-05403900 Sao Paulo, Brazil. Univ Sao Paulo, Fac Med, Hosp Clin, Lab Hormonios & Genet Mol,Disciplina Endocrinol, BR-05403900 Sao Paulo, Brazil. Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Fisiol, BR-05403900 Sao Paulo, Brazil. Univ Fed Rio Grande Norte, BR-59022020 Natal, RN, Brazil. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20814 USA. RP Mendonca, BB (reprint author), Univ Sao Paulo, Fac Med, Hosp Clin, Lab Hormonios,Unidade Endocrinol Desenvolvimento, Ave Dr Eneas de Carvalho Aguiar 155 PAMB,2 Andar, BR-05403900 Sao Paulo, Brazil. EM beremen@usp.br RI Castro, Margaret/A-4918-2009; Mendonca, Berenice/C-2827-2012; ARNHOLD, IVO/D-2672-2012; Bachega, Tania/C-3361-2013; Elias, Lucila/P-6533-2015; OI Latronico Xavier, Ana Claudia/0000-0001-6782-693X NR 24 TC 61 Z9 69 U1 2 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2002 VL 87 IS 4 BP 1805 EP 1809 DI 10.1210/jc.87.4.1805 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 541AM UT WOS:000174963100057 PM 11932321 ER PT J AU Danilkovitch-Miagkova, A Zbar, B AF Danilkovitch-Miagkova, A Zbar, B TI Dysregulation of Met receptor tyrosine kinase activity in invasive tumors SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID GROWTH-FACTOR RECEPTOR; PAPILLARY RENAL CARCINOMAS; C-MET; SOMATIC MUTATIONS; CROSS-TALK; CONSTITUTIVE ACTIVATION; TRANSGENIC EXPRESSION; PROTOONCOGENE PRODUCT; ONCOGENE; CELLS C1 PPD Dev, Dept Immunochem, Richmond, VA 23230 USA. NCI, Frederick Canc Res & Dev Ctr, Immunobiol Lab, Frederick, MD 21701 USA. RP Danilkovitch-Miagkova, A (reprint author), PPD Dev, Dept Immunochem, 2244 Dabney Rd, Richmond, VA 23230 USA. NR 35 TC 178 Z9 185 U1 0 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD APR PY 2002 VL 109 IS 7 BP 863 EP 867 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 537KG UT WOS:000174757300003 PM 11927612 ER PT J AU Allegra, C AF Allegra, C TI Thymidylate synthase levels: Prognostic, predictive, or both? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID DISSEMINATED COLORECTAL-CANCER; ADJUVANT CHEMOTHERAPY; EXPRESSION; SURVIVAL; CARCINOMA C1 NCI, Bethesda, MD 20892 USA. RP Allegra, C (reprint author), NCI, Bethesda, MD 20892 USA. NR 16 TC 26 Z9 29 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 1 PY 2002 VL 20 IS 7 BP 1711 EP 1713 PG 3 WC Oncology SC Oncology GA 538ZP UT WOS:000174845200001 PM 11919223 ER PT J AU Allegra, CJ Parr, AL Wold, LE Mahoney, MR Sargent, DJ Johnston, P Klein, P Behan, K O'Connell, MJ Levitt, R Kugler, JW Tirona, MT Goldberg, RM AF Allegra, CJ Parr, AL Wold, LE Mahoney, MR Sargent, DJ Johnston, P Klein, P Behan, K O'Connell, MJ Levitt, R Kugler, JW Tirona, MT Goldberg, RM TI Investigation of the prognostic and predictive value of thymidylate synthase, p53, and Ki-67 in patients with locally advanced colon cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SURGICAL ADJUVANT THERAPY; COLORECTAL-CANCER; RECTAL-CARCINOMA; DNA-PLOIDY; NUCLEAR OVEREXPRESSION; KI-RAS; EXPRESSION; SURVIVAL; PROTEIN; CHEMOTHERAPY AB Purpose: To evaluate the value of thymidylate synthase (TS), Ki-67, and p53 as prognostic markers in patients with Dukes' B2 and C colon carcinoma. Methods: We conducted a retrospective analysis to evaluate the prognostic value of TS, Ki-67, and p53 in 465 patients with Dukes' B2 (220 patients) or Dukes' C (245 patients) colon carcinoma. Patients represent a nonrandom subset obtained from five randomized phase III trials and were treated with either surgery alone (151 patients) or surgery plus fluorouracil-based chemotherapy (314 patients). All three markers were assayed using immunohistochemical techniques. Results: With a minimum follow-up of 5 years, our retrospective analysis failed to demonstrate a consistent and significant association between TS, Ki-67, or p53 and either disease-free survival or overall survival. Exploratory analyses did not reveal a convincing explanation for these results that are in conflict with the published literature. Notable interactions were observed. In particular, high Ki-67 levels were associated with increased (decreased) survival in patients with low (high) TS intensity. Patients whose tumors stained positively for p53 seemed to benefit substantially from the use of adjuvant chemotherapy compared with those who were not treated (P = .05). Conclusion: This retrospective investigation failed to demonstrate a significant association between TS, Ki67, or p53 staining and clinical outcome. (C) 2002 by American Society of Clinical Oncology. C1 Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. NCI, Bethesda, MD 20892 USA. Meritcare Hosp Community, Clin Oncol Program, Fargo, ND USA. Illinois Oncol Res Assoc, Community Clin Oncol Program, Peoria, IL USA. Saskatoon Canc Ctr, Saskatoon, SK, Canada. Allan Blair Canc Ctr, Regina, SK, Canada. RP Goldberg, RM (reprint author), Mayo Clin & Mayo Fdn, 200 1st St SW, Rochester, MN 55905 USA. RI Goldberg , Richard/M-1311-2013; OI Sargent, Daniel/0000-0002-2684-4741 FU NCI NIH HHS [CA37417, CA15083, CA25224, CA35101, CA35103, CA35113, CA35195, CA35269, CA35272, CA35415, CA37404, CA52352, CA63848, CA63849] NR 55 TC 124 Z9 127 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 1 PY 2002 VL 20 IS 7 BP 1735 EP 1743 DI 10.1200/JCO.2002.07.080 PG 9 WC Oncology SC Oncology GA 538ZP UT WOS:000174845200007 PM 11919229 ER PT J AU Wilson, RH Lehky, T Thomas, RR Quinn, MG Floeter, MK Grem, JL AF Wilson, RH Lehky, T Thomas, RR Quinn, MG Floeter, MK Grem, JL TI Acute oxaliplatin-induced peripheral nerve hyperexcitability SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ADVANCED COLORECTAL-CANCER; FIRST-LINE TREATMENT; ACQUIRED NEUROMYOTONIA; CELL-LINES; PHASE-II; CARBAMAZEPINE; FLUOROURACIL; LEUCOVORIN; CISPLATIN; NEURONS AB Purpose: Oxaliplatin is a novel platinum compound with clinical activity in several malignancies. Neurotoxicity is dose-limiting and occurs in two distinct forms, an acute neurologic symptom complex that occurs within hours or days of therapy and a chronic, cumulative sensory neuropathy. Patients and Methods: Patients were treated in a phase I study designed to establish the maximum-tolerated dose of capecitabine given with oxaliplatin. Because of the unusual neurosensory toxicity of oxciliplatin, detailed neurologic examination, needle electromyography (EMG), and nerve conduction studies (NCS) were performed before and the day after oxaliplatin in a subset of 13 patients. Carbamazepine therapy was tried in 12 additional patients to determine whether the neurologic effects might be relieved. Results: All patients experienced acute, reversible neurotaxicities with oxaliplatin. Symptoms included paresthesias, dysesthesias, cold hypersensitivity, jaw pain, eye pain, pain in the arm used for drug infusion, ptosis, leg cramps, and visual and voice changes. Serial EMG and NCS revealed striking signs of hyperexcitability in motor nerves after oxaliplatin. In patients who achieved therapeutic levels, carbamazepine did not alter the clinical or electromyographic abnormalities. Conclusion. The acute neurotoxicity seen with oxaliplatin is characterized by peripheral-nerve hyperexcitability, and the findings are similar to the clinical manifestations of neuromyotonia. Carbamezepine, which provides symptomatic relief in acquired neuromytonia, did not seem to be beneficial. Efforts to identify a successful neuroprotectant strategy would have a major impact on improving patient quality of life and the ability to deliver full doses of oxaliplatin. (C) 2002 by American Society of Clinical Oncology. C1 NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NINCDS, Electromyog Sect, NIH, Bethesda, MD 20892 USA. RP Grem, JL (reprint author), Natl Naval Med Res Inst, NCI Navy Oncol, Bldg 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM gremj@mail.nih.gov NR 33 TC 175 Z9 183 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 1 PY 2002 VL 20 IS 7 BP 1767 EP 1774 DI 10.1200/JCO.2002.07.056 PG 8 WC Oncology SC Oncology GA 538ZP UT WOS:000174845200011 PM 11919233 ER PT J AU Harlan, LC Abrams, J Warren, JL Clegg, L Stevens, J Ballard-Barbash, R AF Harlan, LC Abrams, J Warren, JL Clegg, L Stevens, J Ballard-Barbash, R TI Adjuvant therapy for breast cancer: Practice patterns of community physicians SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID TAMOXIFEN; CARE; AMERICANS; CARCINOMA; ACCESS AB Purpose: We evaluated the use of adjuvant therapy for breast cancer using the National Institutes of Health (NIH) Consensus Development Conference statements as guideposts for assessing how rapidly community physicians adopt recommended therapies. Patients and Methods: Women with stage I through IIIA breast cancer diagnosed in 1987 through 1991 and in 1995 were randomly sampled from the population-based National Cancer Institute Surveillance, Epidemiology, and End-Results program. A total of 8,106 women were included in the study with younger women, less than or equal to 50 years, being oversampled. Their treating physicians were asked to verify whether chemotherapy, hormonal therapy, or both were given. Results: After adjusting for clinical and nonclinical factors, the use of 1985 recommendations for adjuvant therapy in women with node-positive disease was already high at 80% in 1987 and increased slightly to 84% by 1995. Use of combined multidrug chemotherapy plus tamoxifen increased. In contrast, the use of 1990 recommendations for adjuvant therapy for nodenegative disease was slightly less than 13% in 1987 and increased markedly to 57% by 1995. For women with node-negative tumors greater than or equal to 1 cm in size diagnosed in 1995, 40% received tomoxifen, 16% combination chemotherapy, and 7% both, an increase from 10%, 5%, and 0.4%, respectively, in 1987. Conclusion. Community physicians began prescribing-adjuvant chemotherapy and hormonal therapy in advance of publication of the NIH consensus statement in 1990. Adoption of recommended treatments for node-negative disease has been less complete compared with node-positive tumors, perhaps reflecting the more complex nature of the clinical trials data or the smaller anticipated benefit from adjuvant therapy for this disease subset. (C) 2002 by American Society of Clinical Oncology. C1 NCI, Appl Res Program, Bethesda, MD 20892 USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Harlan, LC (reprint author), NCI, Appl Res Program, 6130 Execut Blvd,EPN 4005, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-PC-67010, N01-PC-65107, N01-PC-67006, N01-PC-67009, N01-PC67007, N01-PC-65064, N01-PC-67005, N01-PC-67008] NR 23 TC 90 Z9 91 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 1 PY 2002 VL 20 IS 7 BP 1809 EP 1817 DI 10.1200/JCO.2002.07.052 PG 9 WC Oncology SC Oncology GA 538ZP UT WOS:000174845200016 PM 11919238 ER PT J AU Einat, H AF Einat, H TI Smoking in bipolar and schizophrenic patients - Dr. Einat replies SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Letter C1 NIMH, Bethesda, MD 20892 USA. RP Einat, H (reprint author), NIMH, Bethesda, MD 20892 USA. RI Einat, Haim/A-7203-2009 NR 5 TC 1 Z9 1 U1 0 U2 0 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD APR PY 2002 VL 63 IS 4 BP 369 EP 369 PG 1 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 541ZM UT WOS:000175017500019 ER PT J AU Turner, EH Schwartz, PJ Lowe, CH Nawab, SS Feldman-Naim, S Drake, CL Myers, FS Barnett, RL Rosenthal, NE AF Turner, EH Schwartz, PJ Lowe, CH Nawab, SS Feldman-Naim, S Drake, CL Myers, FS Barnett, RL Rosenthal, NE TI Double-blind, placebo-controlled study of single-dose metergoline in depressed patients with seasonal affective disorder SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID SEROTONIN RECEPTORS; LIGHT THERAPY; M-CHLOROPHENYLPIPERAZINE; BEHAVIORAL-RESPONSES; HEALTHY-VOLUNTEERS; HORMONAL RESPONSES; ANTAGONIST; BINDING; ANTIDEPRESSANT; EXPRESSION AB A role for serotonin in season affective disorder (SAD) has been explored with a variety of serotonergic pharmacologic agents. The authors initially hypothesized that metergoline, a nonspecific serotonin antagonist, would exacerbate depressive symptoms. In a small, open-label pilot study, the authors observed the opposite effect. They decided to follow up on this finding with this formal study. The study followed a double-blind, randomized crossover design. Sixteen untreated, depressed patients with SAD received single oral doses of metergoline 8 mg and of placebo, spaced 1 week apart. Fourteen patients were restudied after 2 weeks of fight treatment. Depression ratings using the Structured Interview Guide for the Hamilton Depression Rating Scale Seasonal Affective Disorder Version were performed at baseline and at 3 and 6 days after each intervention. These data were analyzed by baseline-corrected repeated measures with analysis of variance. In the off-lights condition, severity of depression was diminished after metergoline compared with placebo administration (p = 0.001). Patient daffy self-ratings suggested that the peak effect occurred 2 to 4 days after study drug administration. In contrast, after 2 weeks of treatment with bright artificial light, metergoline did not demonstrate a significant effect on mood. These data suggest that single doses of metergoline may have antidepressant effects that last several days. Possible mechanisms include 5-hydroxytryptamine2 receptor downregulation and dopamine agonism. C1 Vet Adm Med Ctr, Behav Hlth & Clin Neurosci Div, Portland, OR 97207 USA. NIMH, Sect Biol Rhythms Intramural Res Program, Bethesda, MD 20892 USA. RP Turner, EH (reprint author), Vet Adm Med Ctr, Behav Hlth & Clin Neurosci Div, P3MHDC,Box 1034, Portland, OR 97207 USA. OI Turner, Erick/0000-0002-3522-3357 NR 43 TC 10 Z9 10 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD APR PY 2002 VL 22 IS 2 BP 216 EP 220 DI 10.1097/00004714-200204000-00018 PG 5 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 538HB UT WOS:000174808400018 PM 11910270 ER PT J AU Wood, JN Romero, SG Makale, M Grafman, J AF Wood, JN Romero, SG Makale, M Grafman, J TI Category-specificity of representational knowledge in the human prefrontal cortex SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Meeting Abstract C1 Natl Inst Hlth, Bethesda, MD 20892 USA. Union Coll, Schenectady, NY 12308 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD APR PY 2002 SU S MA A40 BP 26 EP 26 PG 1 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 525LP UT WOS:000174072000050 ER PT J AU Busemeyer, J Stout, J Grant, S Finn, P Lin, A AF Busemeyer, J Stout, J Grant, S Finn, P Lin, A TI Cognitive modeling analyses of performance on the Bechara simulated gambling task by drug and alcohol abusing as compared to normal control participants SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Meeting Abstract C1 Indiana Univ, Bloomington, IN USA. NIDA, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD APR PY 2002 SU S BP 50 EP 50 PG 1 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 525LP UT WOS:000174072000159 ER PT J AU Husain, F Fromm, S Pursley, R Hosey, L Braun, A Horwitz, B AF Husain, F Fromm, S Pursley, R Hosey, L Braun, A Horwitz, B TI Lateralized brain activity during categorical perception for auditory stimuli: An fMRI study SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD APR PY 2002 SU S MA B101 BP 65 EP 65 PG 1 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 525LP UT WOS:000174072000230 ER PT J AU Greenwood, P Sunderland, T Friz, J Lambert, C Parasuraman, R AF Greenwood, P Sunderland, T Friz, J Lambert, C Parasuraman, R TI Focussing attention at the boundary of healthy and pathologic aging SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Meeting Abstract C1 NIMH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD APR PY 2002 SU S MA C18 BP 73 EP 73 PG 1 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 525LP UT WOS:000174072000266 ER PT J AU Dreher, JC Berman, K AF Dreher, JC Berman, K TI Dissociating the roles of the ventrolateral prefrontal and anterior cingulate cortex in cognitive control SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Meeting Abstract C1 NIMH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD APR PY 2002 SU S MA C35 BP 77 EP 77 PG 1 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 525LP UT WOS:000174072000283 ER PT J AU Rosen, V Friz, J Putnam, K Harwell, A Sunderland, T AF Rosen, V Friz, J Putnam, K Harwell, A Sunderland, T TI Working memory and apolipoprotein E: What's the connection? SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Meeting Abstract C1 NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD APR PY 2002 SU S MA C84 BP 88 EP 88 PG 1 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 525LP UT WOS:000174072000332 ER PT J AU Beauchamp, M Lee, K Haxby, J Martin, A AF Beauchamp, M Lee, K Haxby, J Martin, A TI Parallel visual motion processing streams in lateral temporal cortex for manipulable objects and human movements SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Meeting Abstract C1 NIMH, LBC, Bethesda, MD 20892 USA. RI martin, alex/B-6176-2009 NR 0 TC 1 Z9 1 U1 0 U2 1 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD APR PY 2002 SU S MA C106 BP 92 EP 93 PG 2 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 525LP UT WOS:000174072000354 ER PT J AU Van Boven, R Ingeholm, J Lee, K Ungerleider, L AF Van Boven, R Ingeholm, J Lee, K Ungerleider, L TI Functional MRI study of selective attention to discriminating tactile form or location SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Meeting Abstract C1 Lab Brain & Cognit, Bethesda, MD USA. NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD APR PY 2002 SU S MA C118 BP 95 EP 95 PG 1 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 525LP UT WOS:000174072000366 ER PT J AU Boemio, A Poeppel, D Fromm, S Braun, A Husain, F AF Boemio, A Poeppel, D Fromm, S Braun, A Husain, F TI Auditory cortical processing of complex time-varying stimuli SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Meeting Abstract C1 Univ Maryland, College Pk, MD 20742 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD APR PY 2002 SU S MA D105 BP 118 EP 118 PG 1 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 525LP UT WOS:000174072000472 ER PT J AU Ishai, A Haxby, J Ungerleider, L AF Ishai, A Haxby, J Ungerleider, L TI Imagery of famous faces: Effects of memory and attention revealed by fMRI SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Meeting Abstract C1 NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD APR PY 2002 SU S MA D113 BP 119 EP 119 PG 1 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 525LP UT WOS:000174072000480 ER PT J AU Jiang, X Parasuraman, R Jiang, Y AF Jiang, X Parasuraman, R Jiang, Y TI 3-D shape from motion can be primed SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Meeting Abstract C1 Catholic Univ Amer, Washington, DC 20064 USA. NIMH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD APR PY 2002 SU S MA D112 BP 119 EP 119 PG 1 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 525LP UT WOS:000174072000479 ER PT J AU de Haan, M Wyatt, J Roth, S Gadian, D AF de Haan, M Wyatt, J Roth, S Gadian, D TI Effects of birth asphyxia on episodic memory and hippocampal volume during childhood SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Meeting Abstract C1 UCL, Inst Child Hlth, London, England. NIMH, Bethesda, MD 20892 USA. RI de Haan, Michelle/C-5070-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MIT PRESS PI CAMBRIDGE PA 55 HAYWARD STREET, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD APR PY 2002 SU S MA E66 BP 135 EP 136 PG 2 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 525LP UT WOS:000174072000552 ER PT J AU Mell, T Heekeren, HR Marschner, A Wartenburger, I Kronfeldt, D Villringer, A Reischies, FM AF Mell, T Heekeren, HR Marschner, A Wartenburger, I Kronfeldt, D Villringer, A Reischies, FM TI Assessing the functional neuroanatomy of reward processing using the probabilistic object reversal test - Part 2: fMRI SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Meeting Abstract C1 Humboldt Univ, Charite, Fac Med, D-1086 Berlin, Germany. NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RI Heekeren, Hauke/B-7739-2008; Wartenburger, Isabell/A-2820-2013 OI Heekeren, Hauke/0000-0001-7912-6826; NR 0 TC 0 Z9 0 U1 0 U2 0 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD APR PY 2002 SU S MA F41 BP 156 EP 156 PG 1 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 525LP UT WOS:000174072000646 ER PT J AU McEleney, A Grafman, J Goel, V AF McEleney, A Grafman, J Goel, V TI Strategies in deductive reasoning: A functional magnetic resonance imaging study SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. York Univ, Toronto, ON M3J 2R7, Canada. NR 0 TC 0 Z9 0 U1 0 U2 1 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD APR PY 2002 SU S MA F44 BP 157 EP 157 PG 1 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 525LP UT WOS:000174072000649 ER PT J AU Zahajszky, J Bellgowan, P Weisberg, J Martin, A AF Zahajszky, J Bellgowan, P Weisberg, J Martin, A TI Repetition-related decreases in neural activity occur in both object priming and recognition memory tasks SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Meeting Abstract C1 NIH, HHMI, Res Scholar Program, Bethesda, MD 20892 USA. NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RI martin, alex/B-6176-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD APR PY 2002 SU S MA F66 BP 161 EP 162 PG 2 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 525LP UT WOS:000174072000671 ER PT J AU Heekeren, H Marrett, S Bandettini, P Ungerleider, L AF Heekeren, H Marrett, S Bandettini, P Ungerleider, L TI Nonmonotonic coherence tuning of BOLD FMRI signal to random dot kinematograms in human area MT SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Meeting Abstract C1 NIMH, NIH, Bethesda, MD USA. RI Heekeren, Hauke/B-7739-2008; Bandettini, Peter/F-5871-2012 OI Heekeren, Hauke/0000-0001-7912-6826; NR 0 TC 0 Z9 0 U1 0 U2 0 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD APR PY 2002 SU S MA F113 BP 172 EP 172 PG 1 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 525LP UT WOS:000174072000718 ER PT J AU Danis, M Goold, SD Williams, BC AF Danis, M Goold, SD Williams, BC TI A novel tool for teaching about limited resources and the clinical consequences. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2002 VL 17 SU 1 BP 91 EP 91 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 544LB UT WOS:000175158200299 ER PT J AU Mcdermott, MM Greenland, P Pearce, W Guralnik, JM Criqui, MH Taylor, L Schneider, J Liu, K Martin, GJ Ridker, P Rifai, N Green, D Chan, C Quann, M Fornage, M AF Mcdermott, MM Greenland, P Pearce, W Guralnik, JM Criqui, MH Taylor, L Schneider, J Liu, K Martin, GJ Ridker, P Rifai, N Green, D Chan, C Quann, M Fornage, M TI C-reactive protein and leg functioning in patients with and without peripheral arterial disease. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract C1 Northwestern Univ, Chicago, IL 60611 USA. NIA, Bethesda, MD 20892 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Oregon Hlth Sci Med Ctr, Portland, OR USA. Evanston Northwestern Hosp, Evanston, IL USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Texas, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2002 VL 17 SU 1 BP 116 EP 116 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 544LB UT WOS:000175158200410 ER PT J AU Murabito, JM Nam, B D'Agostino, RB Lloyd-Jones, DM O'Donnell, CJ Wilson, PW AF Murabito, JM Nam, B D'Agostino, RB Lloyd-Jones, DM O'Donnell, CJ Wilson, PW TI Accuracy of reported family history of cardiovascular disease and risk factors: The Framingham offspring study. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract C1 Boston Univ, Sch Med, Framingham Heart Dis Epidemiol Study, NHLBI, Framingham, MA USA. RI Lloyd-Jones, Donald/C-5899-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2002 VL 17 SU 1 BP 116 EP 116 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 544LB UT WOS:000175158200411 ER PT J AU Korn, LM Powe, NR Levine, MA Harris, TB Robbins, J Fitzpatrick, A Fried, LP AF Korn, LM Powe, NR Levine, MA Harris, TB Robbins, J Fitzpatrick, A Fried, LP TI Is screening for osteoporosis associated with fewer hip fractures? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD USA. NIA, Bethesda, MD 20892 USA. Calif State Univ Sacramento, Sacramento, CA 95819 USA. Univ Washington, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2002 VL 17 SU 1 BP 144 EP 144 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 544LB UT WOS:000175158200545 ER PT J AU Hoffman, RM Harlan, LC Klabunde, C Hunt, WC AF Hoffman, RM Harlan, LC Klabunde, C Hunt, WC TI Racial differences in initial treatment for clinically localized prostate cancer. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract C1 VA Med Ctr, Albuquerque, NM USA. NCI, Rockville, MD USA. New Mexico Tumor Registry, Albuquerque, NM USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2002 VL 17 SU 1 BP 161 EP 161 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 544LB UT WOS:000175158200625 ER PT J AU Mcdermott, MM Greenland, P Guralnik, J Criqui, M Liu, K Chan, C Taylor, L Quann, M AF Mcdermott, MM Greenland, P Guralnik, J Criqui, M Liu, K Chan, C Taylor, L Quann, M TI Depressive symptoms and lower extremity performance in patients with peripheral arterial disease. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract C1 Northwestern Univ, Chicago, IL 60611 USA. NIA, Bethesda, MD 20892 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Oregon Hlth Sci Med Ctr, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2002 VL 17 SU 1 BP 180 EP 181 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 544LB UT WOS:000175158200715 ER PT J AU Lynn, J Blanchard, J Campbell, D Jayes, RL Lunney, J AF Lynn, J Blanchard, J Campbell, D Jayes, RL Lunney, J TI The last three years of life through Medicare claims review. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract C1 RAND, Ctr Improve Care Dying, Arlington, VA USA. MORES, Thetford, VT USA. George Washington Univ, Washington, DC USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2002 VL 17 SU 1 BP 203 EP 203 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 544LB UT WOS:000175158200819 ER PT J AU Haviernik, P Festin, SM Opavsky, R Koller, RP Barr, NI Neil, JC Wolff, L AF Haviernik, P Festin, SM Opavsky, R Koller, RP Barr, NI Neil, JC Wolff, L TI Linkage on chromosome 10 of several murine retroviral integration loci associated with leukaemia SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID INDUCED PROMONOCYTIC LEUKEMIAS; C-MYB ACTIVATION; NUCLEAR MATRIX; MOUSE CHROMOSOME-10; CELLULAR ONCOGENES; CODING REGIONS; MLL PROTEIN; BALB/C MICE; DNA; ATTACHMENT AB Mml loci have been identified as provirus integration sites among a subset of monocytic tumours induced by murine leukaemia virus (MuLV) infection of BALB/c and DBA/2 mice. These myeloid leukaemias contain a retrovirus integrated on chromosome 10 in proximity to the c-myb locus; however, c-myb expression was not altered. Detailed physical mapping enabled placement of the retroviral integration sites similar to 25 kb (Mm/1), similar to 51 kb (Mm/2), and similar to 70 kb (Mm/3) upstream of the c-myb locus. Furthermore, the Fti1 (fit-1) locus, a common integration site in feline leukaemia virus-induced T cell lymphomas, was mapped upstream of Mm/3. Sequence analysis of Mm/1, Mm/2 and Mm/3 loci (39.6, 16.4 and 5.9 kb, respectively) in conjunction with the BLAST (basic local alignment search tool) homology searches against the expressed sequence tag (EST) database and the use of gene/exon prediction programs revealed potential coding sequences that were not confirmed by Northern analysis or RT-PCR. The sequences between c-myb and Fti1, which were shown to include two potential scaffold/matrix attachment regions (S/MARs), are most likely regulatory in nature. An extended search for transcribed sequences far upstream of Mm/3 revealed five genes, four of which were expressed in multiple tissues in mice. These genes could not be linked to tumour formation by the virus but their homologous sequences were found on human chromosome 6, thus allowing extension of the syntenic region on mouse chromosome 10 to approximately 250 kb. C1 NCI, Cellular Oncol Lab, Leukemogenesis Sect, NIH, Bethesda, MD 20892 USA. Univ Glasgow, Mol Oncol Lab, Glasgow G61 1QH, Lanark, Scotland. RP Wolff, L (reprint author), NCI, Cellular Oncol Lab, Leukemogenesis Sect, NIH, Bethesda, MD 20892 USA. NR 41 TC 10 Z9 10 U1 0 U2 0 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD APR PY 2002 VL 83 BP 819 EP 827 PN 4 PG 9 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 532YR UT WOS:000174503100012 PM 11907331 ER PT J AU Kiss, A Factor, V Novak, PK Conner, E Schaff, Z Thorgeirsson, S AF Kiss, A Factor, V Novak, PK Conner, E Schaff, Z Thorgeirsson, S TI HGF modifies but does not inhibit the hepatocarcinogenesis induced by diethylnitrosamine in transgenic mouse models SO JOURNAL OF HEPATOLOGY LA English DT Meeting Abstract C1 Semmelweis Univ, Inst Pathol 2, H-1085 Budapest, Hungary. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD APR PY 2002 VL 36 SU 1 MA 277 BP 81 EP 81 DI 10.1016/S0168-8278(02)80277-X PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 553YG UT WOS:000175704700274 ER PT J AU Egwuagu, CE Yu, CR Zhang, MF Mahdi, RM Kim, SJ Gery, I AF Egwuagu, CE Yu, CR Zhang, MF Mahdi, RM Kim, SJ Gery, I TI Suppressors of cytokine signaling proteins are differentially expressed in Th1 and Th2 cells: Implications for Th cell lineage commitment and maintenance SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NEGATIVE REGULATION; BINDING PROTEIN; SOCS PROTEINS; INHIBITOR; TRANSDUCTION; ACTIVATION; STAT6; MICE AB Positive regulatory factors induced by IL-12/STAT4 and IL-4/STAT6 signaling during T cell development contribute to polarized patterns of cytokine expression manifested by differentiated Th cells. These two critical and antagonistic signaling pathways are under negative feedback regulation by a multimember family of intracellular proteins called suppressor of cytokine signaling (SOCS). However, it is not known whether these negative regulatory factors also modulate Th1/Th2 lineage commitment and maintenance. We show here that CD4(+) naive T cells constitutively express low levels of SOCS1, SOCS2, and SOCS3 mRNAs. These mRNAs and their proteins increase significantly in nonpolarized Th cells after activation by TCR signaling. We further show that differentiation into Th1 or Th2 phenotype is accompanied by preferential expression of distinct SOCS mRNA transcripts and proteins. SOCS1 expression is 5-fold higher in Th1 than in Th2 cells, whereas Th2 cells contain 23-fold higher levels of SOCS3. We also demonstrate that IL-12-induced STAT4 activation is inhibited in Th2 cells that express high levels of SOCS3 whereas IL-4/STAT6 signaling is constitutively activated in Th2 cells, but not Th1 cells, with high SOCS1 expression. These results suggest that mutually exclusive use of STAT4 and STAT6 signaling pathways by differentiated Th cells may derive in part, from SOCS3- or SOCS1-mediated repression of IL-12/STAT4- or IL-4/STAT6 signaling in Th2 and Th1 cells, respectively. Given the strong correlation between distinct patterns of SOCS expression and differentiation into the Th1 or Th2 phenotype, SOCS1 and SOCS3 proteins are therefore Th lineage markers that can serve as therapeutic targets for immune modulation therapy. C1 NCI, Mol Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Egwuagu, CE (reprint author), NCI, Mol Immunol Sect, Immunol Lab, NIH, Bldg 10,Room 10N116,10 Ctr Dr, Bethesda, MD 20892 USA. NR 25 TC 167 Z9 180 U1 0 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 1 PY 2002 VL 168 IS 7 BP 3181 EP 3187 PG 7 WC Immunology SC Immunology GA 534CE UT WOS:000174566400010 PM 11907070 ER PT J AU Seki, N Brooks, AD Carter, CRD Back, TC Parsoneault, EM Smyth, MJ Wiltrout, RH Sayers, TJ AF Seki, N Brooks, AD Carter, CRD Back, TC Parsoneault, EM Smyth, MJ Wiltrout, RH Sayers, TJ TI Tumor-specific CTL kill murine renal cancer cells using both perforin and Fas ligand-mediated lysis in vitro, but cause tumor regression in vivo in the absence of perforin SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERFERON-INDUCIBLE PROTEIN-10; FLICE-INHIBITORY PROTEIN; CYTOTOXIC T-LYMPHOCYTES; IN-VIVO; NECROSIS-FACTOR; LYTIC PATHWAYS; DEFICIENT MICE; EXPRESSION; GAMMA; IFN AB Kidney cancer is a devastating disease; however, biological therapies have achieved sonic limited success. The murine renal cancer Renca has been used as a model for developing new preclinical approaches to the treatment of renal cell carcinoma. Successful cytokine-based approaches require CD8(+) T cells, but the exact mechanisms by which T cells mediate therapeutic benefit have not been completely identified. After successful biological therapy of Renca in BALB/c mice, we generated CTLs in vitro using mixed lymphocyte tumor cultures. These CTL mediated tumor-specific H-2K(d)-restricted lysis and production of IFN-gamma, TNF-alpha, and Fas ligand (FasL) in response to Renca. CTL used both granule- and FasL-mediated mechanisms to lyse Renca, although granule-mediated killing was the predominant lytic mechanism in vitro. The cytokines IFN-gamma and TNF-alpha increased the sensitivity of Renca cells to CTL lysis by both granule- and FasL-mediated death pathways. Adoptive transfer of these anti-Renca CTL into tumor-bearing mice cured most mice of established experimental pulmonary metastases, and successfully treated mice were immune to tumor rechallenge. Interestingly, we were able to establish Renca-specific CTL from mice gene targeted for perforin (pfp(-/-)) mice. Although these pfp(-/-) CTL showed reduced cytotoxic activity against Renca, their IFN-gamma production in the presence of Renca targets was equivalent to that of wild-type CTL, and adoptive transfer of pfp(-/-) CTL was as efficient as wild-type CTL in causing regression of established Renca pulmonary metastases. Therefore, although granule-mediated killing is of paramount importance for CTL-mediated lysis in vitro, some major in vivo effector mechanisms clearly are independent of perforin. C1 NCI, Sci Applicat Int Corp, Expt Immunol Lab, Ctr Canc Res, Frederick, MD 21702 USA. Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD 21702 USA. Peter MacCallum Canc Inst, Melbourne, Vic, Australia. RP Sayers, TJ (reprint author), NCI, Sci Applicat Int Corp, Expt Immunol Lab, Ctr Canc Res, Bldg 560,Room 31-93, Frederick, MD 21702 USA. RI Sayers, Thomas/G-4859-2015; Smyth, Mark/H-8709-2014 OI Smyth, Mark/0000-0001-7098-7240 FU NCI NIH HHS [N01-CO-56000] NR 42 TC 87 Z9 95 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 APR 1 PY 2002 VL 168 IS 7 BP 3484 EP 3492 PG 9 WC Immunology SC Immunology GA 534CE UT WOS:000174566400049 PM 11907109 ER PT J AU Samten, B Ghosh, P Yi, AK Weis, SE Lakey, DL Gonsky, R Pendurthi, U Wizel, B Zhang, YR Zhang, M Gong, JH Fernandez, M Safi, H Vankayalapati, R Young, HA Barnes, PF AF Samten, B Ghosh, P Yi, AK Weis, SE Lakey, DL Gonsky, R Pendurthi, U Wizel, B Zhang, YR Zhang, M Gong, JH Fernandez, M Safi, H Vankayalapati, R Young, HA Barnes, PF TI Reduced expression of nuclear cyclic adenosine 5 '-monophospate response element-binding proteins and IFN-gamma promoter function in disease due to an intracellular pathogen SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS INFECTION; CELL CYTOKINE RESPONSES; FACTOR-KAPPA-B; BLOOD T-CELLS; INTERFERON-GAMMA; MYCOBACTERIUM-TUBERCULOSIS; TRANSCRIPTIONAL REGULATION; PULMONARY TUBERCULOSIS; ACTIVATION; GENE AB Mycobacterium tuberculosis-induced IFN-gamma protein and mRNA expression have been shown to be reduced in tuberculosis patients, compared with healthy tuberculin reactors. To determine whether this decrease was associated with reduced activity, of the lFN-gamma promoter, we first studied binding of nuclear proteins to the radiolabeled proximal IFN-gamma promoter (-71 to -40 bp), using EMSAs with nuclear extracts of freshly isolated peripheral blood T cells. Nuclear extracts of T cells from most tuberculosis patients showed markedly reduced expression of proteins that bind to the proximal IFN-gamma promoter, compared with findings in nuclear extracts of T cells from healthy tuberculin reactors. These DNA-binding complexes contained CREB proteins, based on competitive EMSAs, supershift assays, and Western blotting with an anti-CREB Ab. Transient transfection of PBLs with a luciferase reporter construct under the control of the IFN-gamma promoter revealed reduced IFN-gamma promoter activity in tuberculosis patients. Transient transfection of Jurkat cells with a dominant-negative CREB repressor plasmid reduced IFN-gamma promoter activity. These data suggest that reduced expression of CREB nuclear proteins in tuberculosis patients results in decreased IFN-gamma promoter activity and reduced IFN-gamma production. C1 Univ Texas Hlth Ctr, Ctr Pulm & Infect Dis Control, Tyler, TX 75708 USA. Univ Texas Hlth Ctr, Dept Microbiol & Immunol, Tyler, TX 75708 USA. Univ Texas Hlth Ctr, Dept Med, Tyler, TX 75708 USA. Univ Texas Hlth Ctr, Dept Biochem, Tyler, TX 75708 USA. NIA, NIH, Baltimore, MD 21224 USA. Univ Tennessee, Hlth Sci Ctr, Dept Pediat, Memphis, TN 38103 USA. Le Bonheur Childrens Hosp, Crippled Childrens Fdn Res Ctr, Memphis, TN 38103 USA. Univ N Texas, Hlth Sci Ctr, Dept Internal Med, Ft Worth, TX 76107 USA. Cedars Sinai Med Ctr, Inflammatory Bowel Dis Res Ctr, Los Angeles, CA 90048 USA. Univ Miami, Sch Med, Dept Immunol & Microbiol, Coral Gables, FL 33124 USA. Natl Canc Inst, Expt Immunol Lab, Frederick, MD 21702 USA. RP Barnes, PF (reprint author), Univ Texas Hlth Ctr, Ctr Pulm & Infect Dis Control, 11937 US Highway 271, Tyler, TX 75708 USA. RI Young, Howard/A-6350-2008 OI Young, Howard/0000-0002-3118-5111 FU NHLBI NIH HHS [K08HL04298]; NIAID NIH HHS [AI27285] NR 37 TC 20 Z9 20 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 APR 1 PY 2002 VL 168 IS 7 BP 3520 EP 3526 PG 7 WC Immunology SC Immunology GA 534CE UT WOS:000174566400054 PM 11907114 ER PT J AU Ramirez, DM Leppla, S Schneerson, R Shiloach, J AF Ramirez, DM Leppla, S Schneerson, R Shiloach, J TI Production, recovery and immunogenicity of the protective antigen from a recombinant strain of Bacillus anthracis SO JOURNAL OF INDUSTRIAL MICROBIOLOGY & BIOTECHNOLOGY LA English DT Article DE Bacillus anthracis; protective antigen; expanded-bed adsorption; vaccine; immunogenicity ID LETHAL FACTOR; ESCHERICHIA-COLI; PURIFICATION; EXPRESSION; TOXIN; SUBTILIS; PROTEIN; GENE; EFFICACY; SURFACE AB The protective antigen (PA) is one of the three components of the anthrax toxin. It is a secreted nontoxic protein with a molecular weight of 83 kDa and is the major component of the currently licensed human vaccine for anthrax. Due to limitations found in the existing vaccine formulation, it has been proposed that genetically modified PA may be more effective as a vaccine. The expression and the stability of two recombinant PA (rPA) variants, PA-SNKE-DeltaFF-E308D and PA-N657A, were studied. These proteins were expressed in the nonsporogenic avirulent strain BH445. Initial results indicated that PA-SNKE-DeltaFF-E308D, which lacks two proteolysis-sensitive sites, is more stable than PA-N657A. Process development was conducted to establish an efficient production and purification process for PA-SNKE-DeltaFF-E308D. pH, media composition, growth strategy and protease inhibitors composition were analyzed. The production process chosen was based on batch growth of B. anthracis using tryptone and yeast extract as the only source of carbon, pH control at 7.5, and antifoam 289. Optimal harvest time was 14-18 h after inoculation, and EDTA (5 mM) was added upon harvest for proteolysis control. Recovery of the rPA was performed by expanded-bed adsorption (EBA) on a hydrophobic interaction chromatography (HIC) resin, eliminating the need for centrifugation, microfiltration and diafiltration. The EBA step was followed by ion exchange and gel filtration. rPA yields before and after purification were 130 and 90 mg/l, respectively. The purified rPA, without further treatment, treated with small amounts of formalin or adsorbed on alum, induced, high levels of IgG anti-PA with neutralization activities. C1 NIDDK, LCDB, Biotechnol Unit, NIH, Bethesda, MD 20892 USA. NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Dev & Mol Immun Lab, NIH, Bethesda, MD 20892 USA. RP Shiloach, J (reprint author), NIDDK, LCDB, Biotechnol Unit, NIH, Bethesda, MD 20892 USA. NR 36 TC 63 Z9 64 U1 2 U2 8 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1367-5435 J9 J IND MICROBIOL BIOT JI J. Ind. Microbiol. Biotechnol. PD APR PY 2002 VL 28 IS 4 BP 232 EP 238 DI 10.1038/sj/jim/700239 PG 7 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 537RJ UT WOS:000174773100008 PM 11986925 ER PT J AU Hauknes, HA Tanz, RR Thomson, RB Pierry, DK Kaplan, EL Beall, B Johnson, D Hoe, NP Musser, JM Shulman, ST AF Hauknes, HA Tanz, RR Thomson, RB Pierry, DK Kaplan, EL Beall, B Johnson, D Hoe, NP Musser, JM Shulman, ST TI The heterogeneity of endemic community pediatric group A streptococcal pharyngeal isolates and their relationship to invasive isolates SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Joint Meeting of the Pediatric-Academic-Societies/American-Academy-of-Pediatrics CY MAY 12-16, 2000 CL BOSTON, MASSACHUSETTS SP Pediat Acad Soc, Amer Acad Pediat ID GROUP-A STREPTOCOCCUS; COMPLEMENT-INHIBITING PROTEIN; TOXIC-SHOCK-SYNDROME; MOLECULAR EPIDEMIOLOGY; GEL-ELECTROPHORESIS; CLINICAL-FEATURES; INFECTIONS; PYOGENES; SEROTYPE; STRAINS AB By use of molecular techniques, the genetic heterogeneity of 63 community pediatric pharyngeal group A streptococcal (GAS) isolates circulating within a 3-week period were compared with 17 contemporaneous invasive pediatric isolates. Pharyngitis isolates represented 16 pulsed-field gel electrophoresis (PFGE) patterns with 12 emm serotypes, and invasive isolates represented 10 PFGE patterns with 9 emm serotypes. One-fourth of the pharyngeal isolates (16/63) were identical to at least 1 invasive isolate; conversely, 10 (59%) of 17 invasive isolates were identical to at least 1 pharyngeal strain. sic allele analysis of emm1 strains demonstrated additional heterogeneity and overlap. More pharyngeal (71%) than invasive isolates (35%) were positive for both speA and speC (P <.02). Many pharyngitis GAS strains circulate simultaneously. Most invasive pediatric GAS strains are identical to acute pharyngitis strains; thus, childhood pharyngitis is a major reservoir for strains with invasive potential. Pharyngeal isolates were more likely to be speA and speC positive than were the invasive isolates. C1 Northwestern Univ, Sch Med, Childrens Mem Hosp, Div Infect Dis, Chicago, IL 60614 USA. Northwestern Univ, Sch Med, Childrens Mem Hosp, Div Gen Med, Chicago, IL 60614 USA. Northwestern Univ, Sch Med, Childrens Mem Hosp, Div Med Acad Pediat, Chicago, IL 60614 USA. Northwestern Univ, Evanston Hosp, Dept Pathol & Microbiol, Evanston, IL 60201 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. Univ Minnesota, WHO, Collaborating Ctr Reference & Res Streptococci, Minneapolis, MN USA. NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Shulman, ST (reprint author), Northwestern Univ, Sch Med, Childrens Mem Hosp, Div Infect Dis, 2300 Childrens Plaza,Box 20, Chicago, IL 60614 USA. NR 31 TC 38 Z9 39 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD APR 1 PY 2002 VL 185 IS 7 BP 915 EP 920 DI 10.1086/339407 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 535QE UT WOS:000174654500009 PM 11920315 ER PT J AU Chernyak, A Kondo, S Wade, TK Meeks, MD Alzari, PM Fournier, JM Taylor, RK Kovac, P Wade, WF AF Chernyak, A Kondo, S Wade, TK Meeks, MD Alzari, PM Fournier, JM Taylor, RK Kovac, P Wade, WF TI Induction of protective immunity by synthetic Vibrio cholerae hexasaccharide derived from V-cholerae O1 ogawa lipopolysaccharide bound to a protein carrier SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID OUTER-MEMBRANE PROTEIN; PSEUDOMONAS-AERUGINOSA; SEROTYPE INABA; ANTIGENIC DETERMINANTS; CONJUGATE VACCINE; B POLYSACCHARIDE; ANTIBODIES; INFECTION; TOXIN; MICE AB Synthetic antigens that mimic the terminal hexasaccharide epitope of the O-specific polysaccharide of Vibrio cholerae O1, serotype Ogawa, were conjugated to bovine serum albumin (BSA). Conjugates with carbohydrate-to-carrier molar ratios of 15.5:1, 9.2: 1, and 4.6: 1 were tested for immunogenicity and efficacy in mice. The role of preimmunity to BSA and the use of adjuvant in the generation of the serologic response to the O-specific polysaccharide and protection against virulent V. cholerae was examined. Preimmunity to BSA did not affect the anti-Ogawa titers but seemed to enhance the protective capacity of antiserum. All 3 conjugates were immunogenic, but adjuvant was effective at inducing higher and earlier antibody responses. In tertiary serum samples, a correlation was found between vibriocidal activity and protection. The protective capacity of antiserum was evident in serum from mice immunized with all conjugates, but it was highest in the groups that received the conjugate with the lowest level of substitution. Further studies are required to increase understanding of the reason for differential protection. C1 NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. Dartmouth Coll Sch Med, Dept Microbiol & Immunol, Lebanon, NH 03755 USA. Josai Univ, Sch Pharmaceut Sci, Dept Microbiol, Sakado, Saitama 35002, Japan. Inst Pasteur, Unite Biochim Struct, CNRS, Unite Rech Associe 2185, Paris, France. Inst Pasteur, Unite Cholera & Vibr, Ctr Natl Reference Vibr & Cholera, Paris, France. RP Wade, WF (reprint author), Dartmouth Coll Sch Med, Dept Microbiol & Immunol, 630W Borwell Bldg, Lebanon, NH 03755 USA. FU NIAID NIH HHS [AI-47373, AI-25096] NR 47 TC 59 Z9 63 U1 0 U2 4 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD APR 1 PY 2002 VL 185 IS 7 BP 950 EP 962 DI 10.1086/339583 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 535QE UT WOS:000174654500014 PM 11920320 ER PT J AU Shevach, E AF Shevach, E TI Immunological mechanisms of self-tolerance SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 NIAID, Immunol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD APR PY 2002 VL 118 IS 4 MA 020 BP 738 EP 738 PG 1 WC Dermatology SC Dermatology GA 535LD UT WOS:000174645200048 ER PT J AU Fu, CL Horne, MK AF Fu, CL Horne, MK TI Histidine-rich glycoprotein plus zinc to neutralize heparin SO JOURNAL OF LABORATORY AND CLINICAL MEDICINE LA English DT Article ID ANTICOAGULANT ACTIVITY; EQUILIBRIUM DIALYSIS; ANTITHROMBIN-III; HUMAN-PLASMA; BINDING; PROLINE; METALS; SERUM; PLASMINOGEN; MODULATION AB Histidine-rich glycoprotein (HRG) binds heparin and neutralizes its anticoagulant effect. Because zinc greatly enhances this interaction, it is possible that the combination of HRG and zinc could be used as an antidote for heparin. We have determined the plasma concentrations of HRG and zinc necessary to neutralize clinically relevant concentrations of heparin. Using a thrombin-time assay, we found that HRG plus zinc can neutralize 0.2 to 4.5 units/mL. heparin, although the maximal effect requires an HRG plasma concentration about six times normal and a zinc concentration about 10 times normal. In a system using purified proteins and a thrombin-specific chromogenic substrate, we found that both the concentration of HRG and the molar ratio of HRG to zinc are important in determining the potency of the anti-heparin activity. Whether HRG and zinc can be administered as an antidote for heparin will depend on whether the requisite doses can be achieved without toxicity. C1 NIH, Warren G Magnuson Clin Ctr, Dept Lab Med, Hematol Serv, Bethesda, MD 20892 USA. RP Horne, MK (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Lab Med, Hematol Serv, Room 2C306,Bldg 10, Bethesda, MD 20892 USA. NR 30 TC 10 Z9 10 U1 0 U2 3 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0022-2143 J9 J LAB CLIN MED JI J. Lab. Clin. Med. PD APR PY 2002 VL 139 IS 4 BP 211 EP 217 DI 10.1067/mlc.2002.121854 PG 7 WC Medical Laboratory Technology; Medicine, General & Internal; Medicine, Research & Experimental SC Medical Laboratory Technology; General & Internal Medicine; Research & Experimental Medicine GA 558GN UT WOS:000175958100005 PM 12024108 ER PT J AU Murthy, M Hamilton, J Greiner, RS Moriguchi, T Salem, N Kim, HY AF Murthy, M Hamilton, J Greiner, RS Moriguchi, T Salem, N Kim, HY TI Differential effects of n-3 fatty acid deficiency on phospholipid molecular species composition in the rat hippocampus SO JOURNAL OF LIPID RESEARCH LA English DT Article DE diet; docosahexaenoic acid; essential fatty acids; mass spectrometry ID ALPHA-LINOLENIC ACID; DOCOSAHEXAENOIC ACID; CONTROLLED TRIAL; TERM INFANTS; BRAIN; PHOSPHATIDYLSERINE; DIET; PERFORMANCE; MELATONIN; AGE AB In this study, we have examined the effects of n-3 fatty acid deficient diets on the phospholipids (PL) molecular species composition in the hippocampus. Female rats were raised for two generations on diets containing linoleic acid (18:2n-6), with or without supplementation of alpha-linolenic acid (18:3n-3) or 18:3n-3 plus docosahexaenoic acid (22:6n-3). At 84 days of age, the hippocampal phospholipids were analyzed by reversed phase HPLC-electrospray ionization mass spectrometry. Depleting n-3 fatty acids from the diet led to a reduction of 22:6n-3 molecular species in phosphatidylcholine (PC), phosphatidylethanolamine (PE), PE-plasmalogens (PLE), and phosphatidylserine (PS) by 70-80%. In general, 22:6n-3 was replaced with 22:5n-6 but the replacement at the molecular species level did not always occur in a reciprocal manner, especially in PC and PLE. In PC, the 16:0,22:6n-3 species was replaced by 16:0122:5n-6 and 18:0.22:5n-6. In PIE, substantial increases of both 22:5n-6 and 22:4n-6 species compensated for the decreases in 22:6n-3 species in n-3 fatty acid deficient groups. While the total PL content was not affected by n-3 deficiency, the relative distribution of PS decreased by 28% with a concomitant increase in PC. The observed decrease of 22:6n-3 species along with PS reduction may represent key biochemical changes underlying losses in brain-hippocampal function associated with n-3 deficiency.-Murthy, M., J. Hamilton, R. S. Greiner, T. Moriguchi, N. Salem, Jr., and H-Y. Kim. Differential effects of n-3 fatty acid deficiency on phospholipid molecular species composition in the rat hippocampus. C1 NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, Div Intramural Clin & Biol Res,NIH, Rockville, MD 20852 USA. NIAAA, Sect Mass Spectrometry, Lab Membrane Biochem & Biophys, Div Intramural Clin & Biol Res,NIH, Rockville, MD 20852 USA. RP Kim, HY (reprint author), NIAAA, Sect Mass Spectrometry, Lab Membrane Biochem & Biophys, Div Intramural Clin & Biol Res,NIH, 12420 Parklawn Dr,Room 114, Rockville, MD 20852 USA. NR 47 TC 61 Z9 63 U1 1 U2 4 PU LIPID RESEARCH INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD APR PY 2002 VL 43 IS 4 BP 611 EP 617 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 535RP UT WOS:000174660200010 PM 11907144 ER PT J AU Petkova, AT Tycko, R AF Petkova, AT Tycko, R TI Sensitivity enhancement in structural measurements by solid state NMR through pulsed spin locking SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE dipolar recoupling; REDOR; magic angle spinning; solid state NMR; pulsed spin locking; sensitivity enhancement ID DYNAMIC NUCLEAR-POLARIZATION; OPTICALLY PUMPED NMR; TORSION ANGLE-PHI; MAGNETIC-RESONANCE; ROTATING SOLIDS; CHEMICAL-SHIFT; C-13 NMR; CORRELATION SPECTROSCOPY; MOLECULAR-STRUCTURE; INDIUM-PHOSPHIDE AB Free induction decay (FID) signals in solid state NMR measurements performed with magic angle spinning can often be extended in time by factors on the order of 10 by a simple pulsed spin locking technique. The sensitivity of a structural measurement in which the structural information is contained in the dependence of the integrated FID amplitude on a preceding evolution period can therefore be enhanced substantially by pulsed spin locking in the signal detection period. We demonstrate sensitivity enhancements in a variety of solid state NMR techniques that are applicable to selectively isotopically labeled samples, including C-13-N-15 rotational echo double resonance (REDOR), C-13-C-13 dipolar recoupling measurements using the constant-time finite-pulse radio-frequency-driven recoupling (fpRFDR-CT) and constant-time double-quantum-filtered dipolar recoupling (CTDQFD) techniques, and torsion angle measurements using the double quantum chemical shift anisotropy (DQCSA) technique. Further, we demonstrate that the structural information in the solid state NMR data is not distorted by pulsed spin locking in the detection period. (C) 2002 Elsevier Science (USA). C1 NIDDK, Chem Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDK, Chem Lab, NIH, Bethesda, MD 20892 USA. NR 62 TC 31 Z9 31 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE 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 APR PY 2002 VL 155 IS 2 BP 293 EP 299 DI 10.1006/jmre.2002.2519 PG 7 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 560GE UT WOS:000176073700010 PM 12036340 ER PT J AU Mouton, PR Gokhale, AM Ward, NL West, MJ AF Mouton, PR Gokhale, AM Ward, NL West, MJ TI Stereological length estimation using spherical probes SO JOURNAL OF MICROSCOPY-OXFORD LA English DT Article DE dentate gyrus; hippocampus; isotropic; space balls; stereology; unbiased ID SECTIONS; NEURONS; NUMBER; HIPPOCAMPUS; SLICES; CURVE; THICK AB Lineal structures in biological tissue support a wide variety of physiological functions, including membrane stabilization, vascular perfusion. and cell-to-cell communication. In 1953. Smith and Guttman demonstrated a stereological method to estimate the total length density (L-v) of linear objects based on random intersections with a two-dimensional sampling probe. Several methods have been developed to ensure the required isotropy of object-probe intersections, including isotropic-uniform-random (IUR) sections, vertical-uniform-random (VUR) slices, and isotropic virtual planes. The disadvantages of these methods are the requirements for inconvenient section orientations (IUR, VUR) or complex counting rules at multiple focal planes (isotropic virtual planes). To overcome these limitations we report a convenient and straightforward approach to estimate L-v and total length, L, for linear objects on tissue sections cut at any arbitrary orientation. The approach presented here uses spherical probes that are inherently isotropic, combined with unbiased fractionator Sampling, to demonstrate total L estimation for thin nerve fibres in dorsal hippocampus of the mouse brain. C1 NIA, Neurosci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Georgia Inst Technol, Sch Mat Sci & Engn, Atlanta, GA 30332 USA. Sunnybrook & Womens Mol & Cellular Hlth Sci Ctr, Div Coll Biol, Toronto, ON, Canada. Univ Aarhus, Inst Anat, Aarhus, Denmark. RP Mouton, PR (reprint author), Stereol Resource Ctr, 104 Ringneck Court, Chester, MD 21619 USA. OI Ward, Nicole L./0000-0003-1907-2621 FU NIA NIH HHS [AG05146]; NINDS NIH HHS [NS16735, NS 38377, NS10580] NR 21 TC 105 Z9 108 U1 1 U2 4 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-2720 J9 J MICROSC-OXFORD JI J. Microsc.-Oxf. PD APR PY 2002 VL 206 BP 54 EP 64 DI 10.1046/j.1365-2818.2002.01006.x PN 1 PG 11 WC Microscopy SC Microscopy GA 545QB UT WOS:000175227800006 PM 12000563 ER PT J AU Ting, KLH Jernigan, RL AF Ting, KLH Jernigan, RL TI Identifying a folding nucleus for the lysozyme/alpha-lactalbumin family from sequence conservation clusters SO JOURNAL OF MOLECULAR EVOLUTION LA English DT Article DE folding nucleus; "fast track" pathway; lysozyme; alpha-lactalbumin; phylogenetic; consensus conservation ID EGG-WHITE LYSOZYME; MOLTEN GLOBULE INTERMEDIATE; BOVINE ALPHA-LACTALBUMIN; 2 HYDROPHOBIC CORES; STRUCTURAL CHARACTERIZATION; CIRCULAR-DICHROISM; DISULFIDE BONDS; HEN LYSOZYME; GUINEA-PIG; VILLIN 14T AB Four subfamilies of c-type lysozyme and one subfamily of alpha-lactalbumin are defined from 78 sequences, and their folding nucleus is identified with a method based on conserved residues and native structural contacts between pairs of conserved residues. One large cluster of 19 conserved residues is found which is mostly nonpolar, buried, and nonfunctional. It can be subdivided into three subclusters: (1) conserved residues in four helices; (2) conserved residues that stabilize the connector between the a and the beta domains; and (3) a beta-turn, sitting in the middle of a bowl of alpha-helix residues. It is proposed that this folding nucleus initiates four helices, A, B, C, and D, three beta sheets, and the connector, which corresponds closely to the nucleation of the so-called fast folding track pathway. As the secondary structures propagate, nonconserved residues and functionally conserved residues would form additional contacts. The conserved residues are selected with a phylogenetic scheme in which single members of subfamilies are selected. Subfamilies are then equally weighted to obtain the consensus conservation. C1 NCI, Mol Struct Sect, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Ting, KLH (reprint author), NCI, Mol Struct Sect, Lab Expt & Computat Biol, NIH, MSC 5677,Room B-102,Bldg 12-B, Bethesda, MD 20892 USA. RI Jernigan, Robert/A-5421-2012 NR 67 TC 15 Z9 15 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0022-2844 J9 J MOL EVOL JI J. Mol. Evol. PD APR PY 2002 VL 54 IS 4 BP 425 EP 436 DI 10.1007/s00239-001-0033-x PG 12 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 537NQ UT WOS:000174765200001 PM 11956682 ER PT J AU Smith, BP Tyler, MJ Kaneko, T Garraffo, HM Spande, TF Daly, JW AF Smith, BP Tyler, MJ Kaneko, T Garraffo, HM Spande, TF Daly, JW TI Evidence for biosynthesis of pseudophrynamine alkaloids by an Australian myobatrachid frog (Pseudophryne) and for sequestration of dietary pumiliotoxins SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID SKIN ALKALOIDS; COMMON; ANTS AB Australian myobatrachid frogs of the genus Pseudophryne have only two classes of alkaloids in skin extracts, pseudophrynamines (PSs) and pumiliotoxins (PTXs). The former are unique to such Australian frogs, while the PTXs occur worldwide in all other genera of frogs/toads that contain lipophilic alkaloids. The major alkaloid of wild-caught frogs from one population of Pseudophryne semimarmorata was PTX 267C, while PSs were only minor or trace alkaloids. Captive-raised frogs from the same parental stock had no PTXs, but had larger amounts of PSs. A PTX fed to captive-raised frogs accumulated into skin along with dihydro and hydroxy metabolites. Thus, Pseudophryne frogs appear to biosynthesize PSs, but to sequester into skin dietary PTXs. In addition, biosynthesis of PSs appears reduced when high levels of dietary PTXs have accumulated into skin. This is the first evidence indicating that certain frogs are capable of synthesizing rather than merely sequestering alkaloids. A wide range of PSs, including many with molecular weights >500, were detected using both GC-mass spectral and LC-mass spectral analysis. C1 NIH, Bioorgan Chem Lab, Bethesda, MD 20892 USA. Univ Adelaide, Dept Environm Biol, Adelaide, SA 5005, Australia. RP Daly, JW (reprint author), NIH, Bioorgan Chem Lab, Bethesda, MD 20892 USA. NR 19 TC 54 Z9 58 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD APR PY 2002 VL 65 IS 4 BP 439 EP 447 DI 10.1021/np010506a PG 9 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 547HV UT WOS:000175327700002 PM 11975476 ER PT J AU Charan, RD McKee, TC Boyd, MR AF Charan, RD McKee, TC Boyd, MR TI Thorectandrols C, D, and E, new sesterterpenes from the marine sponge Thorectandra sp. SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID CHEMICAL-SHIFTS AB Extracts of the marine sponge Thorectandra sp. have been found to contain three new sesterterpenes, thorectandrols C (4), D (5), and E (6), together with the known compounds luffarin R (7), luffarin V (8), and palauolide (9). The structures were determined by extensive NMR spectral data analysis. Their relative stereochemistry was defined using NOE correlations and coupling constants, while CD data were used to suggest their absolute stereochemistry. Cytotoxicity data for compounds 4-9 as well as the previously reported compounds thorectandrols A and B and palauolol (1-3) against six or more human tumor cell lines are also reported. C1 NCI, Canc Res Ctr, Mol Targets Drug Discovery Program, Ft Detrick, MD 21702 USA. RP Boyd, MR (reprint author), NCI, Canc Res Ctr, Mol Targets Drug Discovery Program, Ft Detrick, MD 21702 USA. NR 14 TC 19 Z9 19 U1 1 U2 9 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 APR PY 2002 VL 65 IS 4 BP 492 EP 495 DI 10.1021/np010439k PG 4 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 547HV UT WOS:000175327700012 PM 11975486 ER PT J AU Chen, SN Li, WK Fabricant, DS Santarsiero, BD Mesecar, A Fitzloff, JF Fong, HHS Farnsworth, NR AF Chen, SN Li, WK Fabricant, DS Santarsiero, BD Mesecar, A Fitzloff, JF Fong, HHS Farnsworth, NR TI Isolation, structure elucidation, and absolute configuration of 26-deoxyactein from Cimicifuga racemosa and clarification of nomenclature associated with 27-deoxyactein SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID BLACK COHOSH; TRITERPENE GLYCOSIDES; SEQUENCE VARIATION; RHIZOME; ACTAEA; RANUNCULACEAE; PHYLOGENY; NRDNA AB A new triterpene glycoside, 26-deoxyactein (1), along with two known compounds, 23-epi-26-deoxyactein (2), previously designated as "27-deoxyactein", and actein (3), were isolated from the roots/rhizomes of Cimicifuga racemosa. The structures and absolute stereochemistry of 1 and 2 were established by spectroscopic methods (FABMS, H-1 and C-13 NMR) and single-crystal X-ray data analysis. C1 Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Program Collaborat Res Pharmaceut Sci MC877, Chicago, IL 60612 USA. Univ Illinois, Ctr Pharmaceut Biotechnol MC 870, Chicago, IL 60612 USA. Univ Illinois, Coll Pharm, UIC, NIH,Ctr Bot Dietary Supplements Res, Chicago, IL 60612 USA. RP Farnsworth, NR (reprint author), Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Program Collaborat Res Pharmaceut Sci MC877, 833 S Wood St, Chicago, IL 60612 USA. OI Mesecar, Andrew/0000-0002-1241-2577 NR 34 TC 77 Z9 82 U1 0 U2 5 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 APR PY 2002 VL 65 IS 4 BP 601 EP 605 DI 10.1021/np010494t PG 5 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 547HV UT WOS:000175327700039 PM 11975513 ER PT J AU Kuncl, RW Bilak, MM Bilak, SR Corse, AM Royal, W Becerra, SP AF Kuncl, RW Bilak, MM Bilak, SR Corse, AM Royal, W Becerra, SP TI Pigment epithelium-derived factor is elevated in CSF of patients with amyotrophic lateral sclerosis SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE amyotrophic lateral sclerosis; cerebrospinal fluid; neurotrophic factors; pigment epithelium-derived factor; serine protease inhibitors; spinal cord ID HUMAN CEREBROSPINAL-FLUID; CEREBELLAR GRANULE CELLS; MATRIX METALLOPROTEINASES; MOTOR-NEURONS; SPINAL-CORD; NEUROFILAMENT PHOSPHORYLATION; NEUROTROPHIC ACTIVITY; ALZHEIMERS-DISEASE; MOYAMOYA-DISEASE; BOVINE EYES AB Pigment epithelium-derived factor (PEDF), a recently defined retinal trophic factor and anti-angiogenic factor for the eye, is also present in the CNS and is a motor neuron protectant. We asked whether PEDF levels in CSF are altered in patients with amyotrophic lateral sclerosis (ALS). Pigment epithelium-derived factor protein was detected by quantitative western blot analysis with a PEDF-specific antiserum. Levels of PEDF in CSF, expressed as a ratio to total CSF protein, were significantly elevated 3.4-fold in 15 patients with ALS compared with neurologic disease controls (p < 0.0003). This increase does not seem likely to reflect up-regulation of PEDF synthesis in muscle in response to denervation, as CSF PEDF was not elevated in severe denervating diseases other than ALS. Nor does the increase represent some non-specific release in neurodegeneration, as CSF PEDF was not elevated in other neurodegenerative diseases. While the mechanism of this presumably reactive increase is not known, the distinctive, surprisingly elevated level of PEDF in the CSF may be an autoprotective reaction in ALS. C1 Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21218 USA. NEI, Bethesda, MD 20892 USA. RP Kuncl, RW (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, Garland 265,3400 N Charles St, Baltimore, MD 21218 USA. EM rkuncll@jhu.edu NR 47 TC 48 Z9 49 U1 0 U2 0 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 APR PY 2002 VL 81 IS 1 BP 178 EP 184 DI 10.1046/j.1471-4159.2002.00813.x PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 537XD UT WOS:000174784200018 PM 12067231 ER PT J AU Edelman, JA Goldberg, ME AF Edelman, JA Goldberg, ME TI Effect of short-term saccadic adaptation on saccades evoked by electrical stimulation in the primate superior colliculus SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID CAUDAL FASTIGIAL NUCLEUS; EYE-MOVEMENTS; GAIN ADAPTATION; ADAPTIVE-CONTROL; ALERT MONKEY; HUMANS; SYSTEM; MICROSTIMULATION; CONSTRAINTS; GENERATION AB The brain maintains the accuracy of visually guided movements by using visual feedback to correct for changes in the nervous system and musculature that would otherwise result in dysmetria. In monkeys, evidence suggests that an adaptive mechanism can compensate for weakness in an extraocular muscle by changing the gain of the neural signal to the weakened muscle. The visual effects of such neuromuscular changes have been simulated using a short-term saccade adaptation paradigm, in which the target spot jumps to a new location during the initial saccade. Under these circumstances, over several hundred trials, monkeys gradually change the amplitude of their saccades so that the eye lands closer to the final location of the target spot. There is considerable evidence from lesion and single-unit recording studies that the locus of such saccade adaptation is downstream of the superior colliculus in the cerebellum. Paradoxically, previous research has indicated that saccades evoked by electrical stimulation in the superior colliculus are not modified by short-term saccade adaptation, suggesting that adaptation occurs in the oculomotor system upstream of the superior colliculus or else in a pathway that bypasses the superior colliculus. We tested whether this result was due to using suprathreshold stimulation currents. Stimulating at 44 low-threshold sites in the superior colliculi of three monkeys revealed that using low current levels evoked saccades that were modified by adaptation. Adaptation for visually guided and electrically evoked saccades had similar time courses and tended to be accomplished by a reduction in saccade velocity rather than a decrease in duration. Moreover, the more similar the velocity of electrically evoked and visually guided saccades prior to the start of saccadic adaptation the greater the effect of adaptation on electrically evoked saccades. These results suggest that the superior colliculus is indeed upstream of the locus of adaptation, corroborating previous lesion and single-cell recording studies, but that the mechanism mediating saccade adaptation is sensitive to the parameters of electrical stimulation. C1 NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. RP Edelman, JA (reprint author), Harvard Univ, Dept Psychol, 33 Kirkland St,7th Floor, Cambridge, MA 02138 USA. NR 50 TC 41 Z9 41 U1 1 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 APR PY 2002 VL 87 IS 4 BP 1915 EP 1923 DI 10.1152/jn.00805.2000 PG 9 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 537BC UT WOS:000174736000024 PM 11929911 ER PT J AU Partridge, JG Apparsundaram, S Gerhardt, GA Ronesi, J Lovinger, DM AF Partridge, JG Apparsundaram, S Gerhardt, GA Ronesi, J Lovinger, DM TI Nicotinic acetylcholine receptors interact with dopamine in induction of striatal long-term depression SO JOURNAL OF NEUROSCIENCE LA English DT Article DE striatum; synaptic plasticity; acetylcholine; dopamine; habit learning; drug addiction ID SYNAPTIC DEPRESSION; RAT NEOSTRIATUM; CORTICOSTRIATAL SYNAPSES; NEURONS INVITRO; CAUDATE-NUCLEUS; DORSAL STRIATUM; CELL-BODIES; IN-VITRO; RELEASE; BRAIN AB The dorsal striatum participates in motor function and stimulus-response or "habit" learning. Acetylcholine (ACh) is a prominent neurotransmitter in the striatum and exerts part of its actions through nicotinic cholinergic receptors. Activation of these receptors has been associated with the enhancement of learning and certainly is instrumental in habitual use of nicotine. Nicotinic receptors have also been suggested to be a possible therapeutic target for disorders of the basal ganglia. In this report we show that the activation of nicotinic acetylcholine receptors in the dorsal striatum contributes to dopamine (DA) and activity-dependent changes in synaptic efficacy. High-frequency activation of glutamatergic synapses onto striatal neurons results in a long-term depression (LTD) of synaptic efficacy that is dependent on the activation of dopamine receptors. This stimulation also produces robust increases in extracellular dopamine concentration as well as strong activation of cholinergic striatal interneurons. Antagonists of nicotinic acetylcholine receptors inhibit striatal LTD. However, on coapplication of dopamine reuptake inhibitors with nicotinic receptor antagonists, activity-induced striatal LTD is restored. Dopamine release is modulated by activation of nicotinic receptors in the dorsal striatum, and activation of nicotinic receptors during high-frequency synaptic activation appears to be capable of interacting with dopaminergic actions that lead to striatal LTD. Our results suggest that stimulation of mechanisms involved in striatal synaptic plasticity is an important role for striatal nicotinic acetylcholine receptors and that these mechanisms may contribute to the enhancement of learning and habit formation produced by nicotine intake. C1 Vanderbilt Univ, Dept Pharmacol, Sch Med, Nashville, TN 37232 USA. Vanderbilt Univ, Dept Mol Physiol & Biophys, Sch Med, Nashville, TN 37232 USA. Vanderbilt Ctr Mol Neurosci, Nashville, TN 37232 USA. Univ Kentucky, Sch Med, Dept Anat & Neurobiol, Lexington, KY 40536 USA. Ctr Sensor Technol, Lexington, KY 40536 USA. RP Lovinger, DM (reprint author), NIAAA, Lab Integrat Neurosci, Room 158H Pk 5 Bldg,12420 Parklawn Dr, Rockville, MD 20852 USA. RI yu, yan/C-2322-2012 FU NINDS NIH HHS [NS30470] NR 46 TC 71 Z9 71 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 APR 1 PY 2002 VL 22 IS 7 BP 2541 EP 2549 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 535BU UT WOS:000174626000017 PM 11923419 ER PT J AU Moll, J de Oliveira-Souza, R Eslinger, PJ Bramati, IE Mourao-Miranda, J Andreiuolo, PA Pessoa, L AF Moll, J de Oliveira-Souza, R Eslinger, PJ Bramati, IE Mourao-Miranda, J Andreiuolo, PA Pessoa, L TI The neural correlates of moral sensitivity: A functional magnetic resonance imaging investigation of basic and moral emotions SO JOURNAL OF NEUROSCIENCE LA English DT Article DE moral judgment; fMRI; emotion; orbitofrontal; sociopathy; frontal lobes ID FRONTAL-LOBE DAMAGE; FACE PERCEPTION; ACTIVATION; BRAIN; PSYCHOPATH; COGNITION; BEHAVIOR; PATIENT; DISGUST; CORTEX AB Humans are endowed with a natural sense of fairness that permeates social perceptions and interactions. This moral stance is so ubiquitous that we may not notice it as a fundamental component of daily decision making and in the workings of many legal, political, and social systems. Emotion plays a pivotal role in moral experience by assigning human values to events, objects, and actions. Although the brain correlates of basic emotions have been explored, the neural organization of "moral emotions" in the human brain remains poorly understood. Using functional magnetic resonance imaging and a passive visual task, we show that both basic and moral emotions activate the amygdala, thalamus, and upper midbrain. The orbital and medial prefrontal cortex and the superior temporal sulcus are also recruited by viewing scenes evocative of moral emotions. Our results indicate that the orbital and medial sectors of the prefrontal cortex and the superior temporal sulcus region, which are critical regions for social behavior and perception, play a central role in moral appraisals. We suggest that the automatic tagging of ordinary social events with moral values may be an important mechanism for implicit social behaviors in humans. C1 Hosp DOr & LABS, Neuroimaging & Behav Neurol Grp, BR-22281081 Rio De Janeiro, Brazil. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Med,Div Neurol, Hershey, PA 17033 USA. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Pediat, Hershey, PA 17033 USA. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Behav Sci, Hershey, PA 17033 USA. Fed Univ Rio De Janeiro, Inst Biofis Carlos Chagas Filho, BR-21941 Rio De Janeiro, Brazil. NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Moll, J (reprint author), Hosp DOr & LABS, Neuroimaging & Behav Neurol Grp, R Pinheiro Guimaraes 22,4th Floor, BR-22281081 Rio De Janeiro, Brazil. RI Moll, Jorge/B-2654-2013 NR 38 TC 330 Z9 345 U1 9 U2 75 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 APR 1 PY 2002 VL 22 IS 7 BP 2730 EP 2736 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 535BU UT WOS:000174626000036 PM 11923438 ER PT J AU Lipska, BK Halim, ND Segal, PN Weinberger, DR AF Lipska, BK Halim, ND Segal, PN Weinberger, DR TI Effects of reversible inactivation of the neonatal ventral hippocampus on behavior in the adult rat SO JOURNAL OF NEUROSCIENCE LA English DT Article DE tetrodotoxin; animal model; schizophrenia; amphetamine; MK-801; locomotion ID MEDIAL TEMPORAL-LOBE; PREFRONTAL CORTEX; NEURONAL-ACTIVITY; SOCIAL-BEHAVIOR; DENTATE GYRUS; SCHIZOPHRENIA; DAMAGE; LESIONS; CELLS; HYPERRESPONSIVENESS AB Rats with neonatal excitotoxic damage of the ventral hippocampus display in adulthood a variety of abnormalities reminiscent of schizophrenia and are used as an animal model of this disorder. In the present study, we hypothesized that transient inactivation of ventral hippocampal activity during a critical developmental period may be sufficient to disrupt normal maturation of relevant brain systems and produce similar lasting behavioral changes. We infused tetrodotoxin (TTX) or artificial CSF into the ventral hippocampus on postnatal day 7 (P7) and assessed behavioral changes in response to stress, amphetamine, and (+)- 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine maleate in juvenile (P35) and young adult (P56) rats. In adulthood, rats infused neonatally with TTX displayed motor hyperactivity after pharmacological stimulation and after stress compared with sham controls. Analogous TTX infusions in adult animals did not alter these behaviors later in life. These data suggest that transient loss of ventral hippocampal function during a critical time in maturation of intracortical connections permanently changes the development of neural circuits mediating certain dopamine- and NMDA-related behaviors. These results represent a potential new model of aspects of schizophrenia without involving a gross anatomic lesion. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Lipska, BK (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, 10 Ctr Dr,Bldg 10,Room 4N306, Bethesda, MD 20892 USA. RI Lipska, Barbara/E-4569-2017 NR 48 TC 76 Z9 77 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 APR 1 PY 2002 VL 22 IS 7 BP 2835 EP 2842 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 535BU UT WOS:000174626000046 PM 11923448 ER PT J AU Cardenas, AM Allen, DD Arriagada, C Olivares, A Bennett, LB Caviedes, R Dagnino-Subiabre, A Mendoza, IE Segura-Aguilar, J Rapoport, SI Caviedes, P AF Cardenas, AM Allen, DD Arriagada, C Olivares, A Bennett, LB Caviedes, R Dagnino-Subiabre, A Mendoza, IE Segura-Aguilar, J Rapoport, SI Caviedes, P TI Establishment and characterization of immortalized neuronal cell lines derived from the spinal cord of normal and trisomy 16 fetal mice, an animal model of Down syndrome SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE calcium; glutamate; nicotine; spinal cord; trisomy 21; Down syndrome ID ROOT GANGLION NEURONS; CHOLINE-ACETYLTRANSFERASE; HIPPOCAMPAL-NEURONS; CEREBRAL-CORTEX; SYNDROME BRAINS; MESSENGER-RNA; ION CHANNELS; MOUSE; GENE; MUSCLE AB We report the establishment of continuously growing cell lines from spinal cords of normal and trisomy 16 fetal mice. We show that both cell lines, named Mob (derived from a normal animal) and MTh (trisomic) possess neurological markers by immunohistochemistry (neuron specific enolase, synaptophysin, microtubule associated protein-2 [MAP-2], and choline acetyltransferase) and lack glial traits (glial fibrillary acidic protein and S100). MTh cells were shown to overexpress mRNA of Cu/Zn superoxide dismutase, whose gene is present in autosome 16. We also studied intracellular Ca2+ signals ([Ca2+](i)) induced by different agonists in Indo-1 loaded cells. Basal [Ca2+](i) was significantly higher in MTh cells compared to Mob cells. Glutamate (200 muM) and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACDP) (100 muM) induced rapid, transient increases in [Ca2+]; in Mob and MTh cells, indicating the presence of glutamatergic metabotropic receptors. N-methyl-D-aspartate (NMDA) and kainate, but not alphaamino-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), produced [Ca2+]; rises in both cell types. MTh cells exhibited faster time-dependent decay phase kinetics in glutamate-induced responses compared to Mob cells. Nicotine induced a transient increase in [Ca2+]; in Mob and MTh cells, with significantly greater amplitudes in the latter compared to the former. Further, both cell types responded to noradrenaline. Finally, we examined cholinergic function in both cell lines and found no significant differences in the [H-3]-choline uptake, but fractional acetylcholine release induced by either K+, glutamate or nicotine was significantly higher in MTh cells. These results show that Mob and MTh cells have neuronal characteristics and the MTh line shows differences which could be related to neuronal pathophysiology in Down's syndrome. (C) 2002 Wiley-Liss, Inc. C1 Univ Chile, Fac Med, ICBM, Program Mol & Clin Pharmacol, Santiago 7, Chile. Univ Chile, Fac Med, ICBM, Program Morphol, Santiago 7, Chile. NIA, Sect Brain Physiol & Metab, NIH, Bethesda, MD 20892 USA. Sansum Med Res Inst, Santa Barbara, CA USA. Texas Tech Univ, Hlth Sci Ctr, Dept Pharmaceut Sci, Amarillo, TX USA. Univ Valparaiso, Sch Med, Pharmacol Lab, Valparaiso, Chile. Univ Valparaiso, Valparaiso Ctr Cellular & Mol Neurosci, Valparaiso, Chile. RP Caviedes, P (reprint author), Univ Chile, Fac Med, ICBM, Program Mol & Clin Pharmacol, Casilla 70000,Correo 7, Santiago 7, Chile. EM pcaviede@machi.med.uchile.cl RI Segura-Aguilar, Juan/H-8839-2013 OI Segura-Aguilar, Juan/0000-0002-1018-673X NR 40 TC 11 Z9 11 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD APR 1 PY 2002 VL 68 IS 1 BP 46 EP 58 DI 10.1002/jnr.10205 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 538AW UT WOS:000174792700006 PM 11933048 ER EF