FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Kuehl, WM Bergsagel, PL AF Kuehl, WM Bergsagel, PL TI Multiple myeloma: Evolving genetic events and host interactions SO NATURE REVIEWS CANCER LA English DT Review ID PLASMA-CELL LEUKEMIA; IN-SITU HYBRIDIZATION; ENDOTHELIAL GROWTH-FACTOR; COMPARATIVE GENOMIC HYBRIDIZATION; MARROW STROMAL CELLS; MURINE MONOCLONAL-ANTIBODY; TUMOR-SUPPRESSOR GENES; HIGH-DOSE THERAPY; K-RAS ONCOGENES; C-MYC ONCOGENE AB Multiple myeloma is a neoplasm of terminally differentiated B cells (plasma cells) in which chromosome translocations frequently place oncogenes under the control of immunoglobulin enhancers. Unlike most haematopoietic cancers, multiple myeloma often has complex chromosomal abnormalities that are reminiscent of epithelial tumours. What causes full-blown myeloma? And can our molecular understanding of this common haematological malignancy be used to develop effective preventive and treatment strategies? C1 Bethesda Naval Hosp, Genet Branch, Ctr Canc Res, NCI,NIH, Bethesda, MD 20889 USA. Cornell Univ, Weill Med Coll, New York, NY 10021 USA. RP Kuehl, WM (reprint author), Bethesda Naval Hosp, Genet Branch, Ctr Canc Res, NCI,NIH, Bldg 8,Rm 5105, Bethesda, MD 20889 USA. RI Bergsagel, Peter/A-7842-2011 OI Bergsagel, Peter/0000-0003-1523-7388 NR 164 TC 479 Z9 487 U1 2 U2 33 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD MAR PY 2002 VL 2 IS 3 BP 175 EP 187 DI 10.1038/nrc746 PG 13 WC Oncology SC Oncology GA 635QU UT WOS:000180411000011 PM 11990854 ER PT J AU Engel, LW Straus, SE AF Engel, LW Straus, SE TI Development of therapeutics: opportunities within complementary and alternative medicine SO NATURE REVIEWS DRUG DISCOVERY LA English DT Article ID ARTEMISININ; PRODUCTS; DRUG AB Whereas other components of the National Institutes of Health support the discovery and subsequent development of novel chemical entities into drugs, the National Center for Complementary and Alternative Medicine (NCCAM) studies complex natural products that are marketed as dietary supplements. This article contrasts the regulatory framework for dietary supplements and drugs, outlines the challenges of evaluating dietary supplements for safety and clinical effectiveness, and describes the evolving drug model for botanicals. C1 NIH, NCCAM, Bethesda, MD 20892 USA. RP Engel, LW (reprint author), NIH, NCCAM, 31 Ctr Dr, Bethesda, MD 20892 USA. NR 21 TC 50 Z9 51 U1 8 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD MAR PY 2002 VL 1 IS 3 BP 229 EP 237 DI 10.1038/nrd750 PG 9 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 607DZ UT WOS:000178777500016 PM 12120507 ER PT J AU Killen, J Grady, C Folkers, GK Fauci, AS AF Killen, J Grady, C Folkers, GK Fauci, AS TI Ethics of clinical research in the developing world SO NATURE REVIEWS IMMUNOLOGY LA English DT Editorial Material ID DEVELOPING-COUNTRIES; HIV/AIDS; TRIALS; ISSUES C1 NIH, Bethesda, MD 20892 USA. RP Killen, J (reprint author), NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 29 TC 19 Z9 19 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD MAR PY 2002 VL 2 IS 3 BP 210 EP 215 DI 10.1038/nri.gov PG 6 WC Immunology SC Immunology GA 636CZ UT WOS:000180438100024 PM 11913072 ER PT J AU Forster, K Groner, F Goitzsch, S Birnbaumer, L Koch, W Herzig, S AF Forster, K Groner, F Goitzsch, S Birnbaumer, L Koch, W Herzig, S TI Gi(alpha 2) protein increases survival of mice overexpressing the human beta(2)-adrenoceptor in the heart SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract C1 Univ Cologne, Dept Pharmacol, D-50931 Cologne, Germany. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Duke Univ, Durham, NC 27706 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2002 VL 365 SU 1 MA 358 BP R93 EP R93 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 542EQ UT WOS:000175030900367 ER PT J AU Hesslinger, C Parravicini, V Romer, I Turchanowa, L Ziegler, I Rivera, J Pfeilschifter, J AF Hesslinger, C Parravicini, V Romer, I Turchanowa, L Ziegler, I Rivera, J Pfeilschifter, J TI Regulation of the pteridine pathway by protein kinase C modulates degranulation of mast cells SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract C1 Klinikum J W Goethe Univ, Pharmazentrum Frankfurt, D-60590 Frankfurt, Germany. NIAMS, Mol Inflammat Sect, NIH, Bethesda, MD 20892 USA. GSF Forschungszentrum Umwelt & Gesundheit, Inst Klin Mol Biol, D-81377 Munich, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2002 VL 365 SU 1 MA 43 BP R14 EP R14 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 542EQ UT WOS:000175030900053 ER PT J AU Schwarz, M Radeke, HH Murphy, PM AF Schwarz, M Radeke, HH Murphy, PM TI Dual signaling by Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor: Agonist-independent and agonist-dependent pathways SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract C1 Univ Frankfurt Klinikum, Pharmazentrum Frankfurt, D-60590 Frankfurt, Germany. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RI Radeke, Heinfried/E-3772-2013 OI Radeke, Heinfried/0000-0002-4499-2510 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2002 VL 365 SU 1 MA 295 BP R77 EP R77 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 542EQ UT WOS:000175030900304 ER PT J AU Thiefes, A Wolter, S Mushinsky, F Hoffmann, E Dorrie, A Graue, N Holtman, H Resch, K Kracht, M AF Thiefes, A Wolter, S Mushinsky, F Hoffmann, E Dorrie, A Graue, N Holtman, H Resch, K Kracht, M TI A kinase-negative mutant of the MAPK kinase kinase TAK1 inhibits stress signalling and sensitizes NIH3T3 cells to TNF-alpha induced apoptosis SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract C1 Hannover Med Sch, Inst Pharmacol, D-30625 Hannover, Germany. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2002 VL 365 SU 1 MA 213 BP R57 EP R57 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 542EQ UT WOS:000175030900222 ER PT J AU Trendelenburg, AU Wess, J Gomeza, J Zhou, H Meyer, A Klebroff, W Starke, K AF Trendelenburg, AU Wess, J Gomeza, J Zhou, H Meyer, A Klebroff, W Starke, K TI Muscarinic receptors on sympathetic axons studied with muscarinic receptor-deficient mice SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract C1 Univ Freiburg, Inst Pharmakol, D-7800 Freiburg, Germany. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2002 VL 365 SU 1 MA 76 BP R22 EP R22 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 542EQ UT WOS:000175030900086 ER PT J AU Shibata, MA Shibata, MA Green, JE Jorcyk, CL AF Shibata, MA Shibata, MA Green, JE Jorcyk, CL TI Development of PIN and prostate adenocarcinoma cell lines: A model system for multistage tumor progression SO NEOPLASIA LA English DT Article DE prostate; PIN; adenocarcinoma; cell lines; mouse ID TRANSGENIC MOUSE MODEL; LARGE T-ANTIGEN; INTRAEPITHELIAL NEOPLASIA; CANCER; CARCINOMA; MICE; EXPRESSION; MAMMARY; GROWTH; ESTABLISHMENT AB Existing prostate cancer cell lines have been derived from late stages of human prostate cancer. In this paper, we present two cell lines generated from prostatic intraepithelial neoplasia (PIN), the precursor lesion for prostate adenocarcinoma. Pr-111 and Pr-117 were established from PIN lesions that developed in the C3(1)/Tag transgenic model of prostate cancer. Pr-111 and Pr-117 cells express simian virus 40 large T antigen (SV40 Tag) and are immortalized in culture, distinguishing them from normal prostate cells. The growth rates of these two cell lines are quite different; with Pr-111 cells growing much more slowly (doubling time approximately 40 hours) compared to Pr-117 cells (doubling time approximately 22 hours), and also show significantly different growth rates in different media. Both prostate cell lines express cytokeratin and androgen receptor (AR) with Pr-111 cells demonstrating androgen-dependent growth and Pr-117 cells exhibiting androgen-responsive growth characteristics. Athymic nude mice injected with Pr-111 cells either do not develop tumors or develop tumors after a long latency period of 14 weeks. Pr-117 cells, however, develop tumors by 3 to 6 weeks, suggesting that Pr-117 cells represent a later stage of tumor progression. These two novel cell lines will. be useful for studying early stages of prostate tumor development and androgen responsiveness. C1 Boise State Univ, Dept Biol, Boise, ID 83725 USA. Osaka Med Coll, Osaka, Japan. NCI, Lab Cell Regulat & Carcinogenesis, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Shibata, MA (reprint author), Boise State Univ, Dept Biol, Sci Nursing Bldg,Room 227,1910 Univ Dr, Boise, ID 83725 USA. NR 29 TC 0 Z9 0 U1 0 U2 0 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD MAR-APR PY 2002 VL 4 IS 2 BP 112 EP 120 PG 9 WC Oncology SC Oncology GA 529LD UT WOS:000174300200003 ER PT J AU Krajewska, M Zapata, JM Meinhold-Heerlein, I Hedayat, H Monks, A Bettendorf, H Shabaik, A Bubendorf, L Kallioniemi, OP Kim, H Reifenberger, G Reed, JC Krajewski, S AF Krajewska, M Zapata, JM Meinhold-Heerlein, I Hedayat, H Monks, A Bettendorf, H Shabaik, A Bubendorf, L Kallioniemi, OP Kim, H Reifenberger, G Reed, JC Krajewski, S TI Expression of Bcl-2 family member bid in normal and malignant tissues SO NEOPLASIA LA English DT Article DE Bid; Bcl-2; apoptosis; cancer; tissue microarrays ID CYTOCHROME-C RELEASE; DRUG-INDUCED APOPTOSIS; SURVIVAL-PROMOTING PROTEINS; TUMOR-CELL LINES; CASPASE ACTIVATION; LEUKEMIA-CELLS; DEATH AGONIST; BH3 DOMAIN; X-L; BAX AB Bid is the only known Bcl-2 family member that can function as an agonist of proapoptotic Bcl-2-related proteins such as Bax and Bak. Expression of the proapoptotic Bcl-2 family protein Bid was assessed by immunoblotting and immunohistochemical methods in normal murine and human tissues, and in several types of human cancers and tumor cell lines. Bid expression in normal tissues varied widely, with prominent Bid immunostaining occurring in several types of short-lived cells (e.g., germinal center B cells, peripheral blood granulocytes, differentiated keratinocytes) and in apoptosis-sensitive cells (e.g., adult neurons). Analysis of Bid expression by immunostaining of 100 colon, 95 ovarian, and 254 prostate cancers, as well as 59 brain tumors and 50 lymphomas, revealed evidence of altered Bid regulation in some types of cancers. Correlations with clinical outcome data revealed association of higher levels of Bid with longer recurrence-free survival in men with locally advanced (T3 stage) prostate cancer(P=0.04). Immunoblot analysis of Bid protein levels in the NCl's panel of 60 human tumor cell lines revealed a correlation between higher levels of Bid and sensitivity to ribonucleotide reductase (RR)-inhibiting drugs (P<0.0005). Overexpression of Bid in a model tumor cell line by gene transfection resulted in increased sensitivity to apoptosis induction by a RR inhibitor. Taken together, these observations suggest a potential role for Bid in tumor responses to specific chemotherapeutic drugs, and lay a foundation for future investigations of this member of the Bcl-2 family in healthy and diseased tissues. C1 Burnham Inst, Program Apoptosis & Cell Death Regulat, La Jolla, CA 92037 USA. SAIC Frederick Inc, MCI Frederick, Frederick, MD 21702 USA. Univ Calif Davis, Dept Pathol, Davis, CA 95616 USA. Univ Basel, Inst Pathol, CH-4051 Basel, Switzerland. NHGRI, Canc Genet Lab, NIH, Bethesda, MD 20892 USA. Yonsei Univ, Coll Med, Dept Pathol, Seoul 120749, South Korea. Univ Dusseldorf, Dept Neuropathol, D-40225 Dusseldorf, Germany. RP Krajewska, M (reprint author), Burnham Inst, Program Apoptosis & Cell Death Regulat, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. RI Kallioniemi, Olli/H-5111-2011; Bubendorfl, Lukas/H-5880-2011; Kallioniemi, Olli/H-4738-2012; Zapata, Juan/J-6304-2014; OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332; Zapata, Juan/0000-0002-0110-0009; Shabaik, Ahmed/0000-0003-1987-3453 FU NIGMS NIH HHS [GM60554, R01 GM060554]; NINDS NIH HHS [NS36821, R01 NS036821] NR 68 TC 57 Z9 59 U1 0 U2 1 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD MAR-APR PY 2002 VL 4 IS 2 BP 129 EP 140 DI 10.1038/sj.neo.7900222 PG 12 WC Oncology SC Oncology GA 529LD UT WOS:000174300200005 PM 11896568 ER PT J AU McDoniels-Silvers, AL Stoner, GD Lubet, RA Ming, Y AF McDoniels-Silvers, AL Stoner, GD Lubet, RA Ming, Y TI Differential expression of critical cellular genes in human lung adenocarcinomas and squamous cell carcinomas in comparison to normal lung tissues SO NEOPLASIA LA English DT Article DE non -small cell lung cancer; cDNA microarray; expression profile; differential changes; cancer genes ID HEPATOCYTE GROWTH-FACTOR; RETINOBLASTOMA PROTEIN EXPRESSION; FACTOR SCATTER FACTOR; C-KIT; BCL-2 PROTEIN; EPH RECEPTORS; CANCER; APOPTOSIS; P53; CASPASE-8 AB The Atlas human cDNA expression array was used to evaluate gene expression profile changes in the genesis of human lung adenocarcinomas and squamous cell carcinomas. Gene expression changes between adenocarcinomas and squamous cell carcinomas were also analyzed. Of the 588 gene targets, 262 genes were expressed in these tissues and, of these, 45 genes were differentially expressed by at least two-fold in tumor tissues compared to corresponding normal tissues. Semiquantitative reverse-transcriptase polymerase chain reaction was used to confirm gene expression changes. Only those genes that reflected changes in >50% of the analyzed tissues were included in the final analysis. Ultimately, 26 genes were evaluated with 14 genes overexpressed and 12 genes underexpressed compared to matching normal lung tissues. Although similar expression changes were detected in adenocarcinomas and squamous cell carcinomas for most of the genes analyzed, some subtype-specific differences were also found. Genes encoding cell cycle regulators, intracellular signal transducers, cell receptor and adhesion molecules, growth factors, oncogenes, and apoptotic effectors were differentially expressed in this study. These gene expression changes may directly contribute to the initiation or progression of human lung cancer or may be secondary effects of the tumori-genesis process. Regardless, many of these differences may be useful in the diagnosis and/or treatment of this deadly disease. C1 Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Med Res Facil 514, Columbus, OH 43210 USA. Med Coll Ohio, Dept Pathol, Toledo, OH 43614 USA. Ohio State Univ, Ctr Comprehens Canc, Sch Publ Hlth, Columbus, OH 43210 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP McDoniels-Silvers, AL (reprint author), Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Med Res Facil 514, 420 W 12th Ave, Columbus, OH 43210 USA. FU NCI NIH HHS [CN05113, P30 CA016058, P30CA16058, R01 CA058554, R01CA58554, R01CA78797] NR 62 TC 27 Z9 27 U1 0 U2 1 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD MAR-APR PY 2002 VL 4 IS 2 BP 141 EP 150 DI 10.1038/sj.neo.7900217 PG 10 WC Oncology SC Oncology GA 529LD UT WOS:000174300200006 PM 11896569 ER PT J AU Bressloff, PC Cowan, JD Golubitsky, M Thomas, PJ Wiener, MC AF Bressloff, PC Cowan, JD Golubitsky, M Thomas, PJ Wiener, MC TI What geometric visual hallucinations tell us about the visual cortex SO NEURAL COMPUTATION LA English DT Editorial Material ID MONKEY STRIATE CORTEX; HORIZONTAL CONNECTIONS; INTRINSIC CONNECTIONS; MATHEMATICAL-THEORY; ORIENTATION; PROJECTION; PATTERNS; COLUMNS AB Many observers see geometric visual hallucinations after taking hallucinogens such as LSD, cannabis, mescaline or psilocybin; on viewing bright flickering lights; on waking up or falling asleep; in "near-death" experiences; and in many other syndromes. Kluver organized the images into four groups called form constants: (I) tunnels and funnels, (11) spirals, (III) lattices, including honeycombs and triangles, and (IV) cobwebs. In most cases, the images are seen in both eyes and move with them. We interpret this to mean that they are generated in the brain. Here, we summarize a theory of their origin in visual cortex (area VI), based on the assumption that the form of the retino-cortical map and the architecture of V1 determine their geometry. (A much longer and more detailed mathematical version has been published in Philosophical Transactions of the Royal Society B, 356 [2001].) We model V1 as the continuum limit of a lattice of interconnected hypercolumns, each comprising a number of interconnected iso-orientation columns. Based on anatomical evidence, we assume that the lateral connectivity between hypercolumns exhibits symmetries, rendering it invariant under the action of the Euclidean group E(2), composed of reflections and translations in the plane, and a (novel) shift-twist action. Using this symmetry, we show that the various patterns of activity that spontaneously emerge when V1's spatially uniform resting state becomes unstable correspond to the form constants when transformed to the visual field using the retino-cortical map. The results are sensitive to the detailed specification of the lateral connectivity and suggest that the cortical mechanisms that generate geometric visual hallucinations are closely related to those used to process edges, contours, surfaces, and textures. C1 Univ Utah, Dept Math, Salt Lake City, UT 84112 USA. Univ Chicago, Dept Math, Chicago, IL 60637 USA. Univ Houston, Dept Math, Houston, TX 77204 USA. Salk Inst Biol Studies, Computat Neurobiol Lab, San Diego, CA 92186 USA. NIH, Lab Neuropsychol, Bethesda, MD 20892 USA. RP Bressloff, PC (reprint author), Univ Utah, Dept Math, Salt Lake City, UT 84112 USA. OI Thomas, Peter/0000-0001-7533-6770 NR 49 TC 82 Z9 83 U1 7 U2 36 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0899-7667 J9 NEURAL COMPUT JI Neural Comput. PD MAR PY 2002 VL 14 IS 3 BP 473 EP 491 DI 10.1162/089976602317250861 PG 19 WC Computer Science, Artificial Intelligence SC Computer Science GA 518EC UT WOS:000173652800001 PM 11860679 ER PT J AU Borchelt, DR Lee, MK Gonzales, V Slunt, HH Ratovitski, T Jenkins, NA Copeland, NG Price, DL Sisodia, SS AF Borchelt, DR Lee, MK Gonzales, V Slunt, HH Ratovitski, T Jenkins, NA Copeland, NG Price, DL Sisodia, SS TI Accumulation of proteolytic fragments of mutant presenilin 1 and accelerated amyloid deposition are co-regulated in transgenic mice SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer; mutant presenilin; transgenic mice; amyloid deposition; neuropathology ID FAMILIAL ALZHEIMERS-DISEASE; BETA-PROTEIN-PRECURSOR; GAMMA-SECRETASE INHIBITORS; IN-VIVO; TERMINAL FRAGMENTS; MISSENSE MUTATIONS; CULTURED-CELLS; WILD-TYPE; ENDOPROTEOLYSIS; DEFICIENCY AB The activities of prosenilin 1 (PS1) and 2 modulate the protcolytic processing of amyloid precursor proteins to produce Abeta1-42, and mutations in these proteins are associated with an accelerated rate of Abeta deposition. PS1 and PS2 themselves are subject to a highly-regulated endoproteolytic cleavage to generate stable 27 kDa N-terminal and 17 kDa C-terminal fragments. Here, we examined the relationship between the regulated cleavage of PS1 and the acceleration of Abeta deposition in transgenic mice that co-express Mo/Hu APPswe and varied levels mutant PS1 (A246E variant). The steady-state levels of the N- and C-terminal fragments of mutant PS1 in mice expressing low levels of mRNA were similar to that of mice expressing high levels of mRNA. Only mice expressing high levels of transgene mRNA accumulated uncleaved full-length protein. In mice co-expressing low levels of PS1A246E mRNA with Mo/Hu APPswe the age of appearance of Abeta deposits was similar to that of mice co-expressing expressing Mo/Hu APPswe with very high levels of mutant PS1. Our findings demonstrate that the levels of accumulated human PS1 N- and C-terminal fragments do not increase in proportion to the level of transgene mRNA and that similarly, the magnitude by which mutant PS1 accelerates the deposition of beta-amyloid is not proportional to the level of transgene expression. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. NCI, Frederick Canc Res & Dev Ctr, Mouse Canc Genet Program, Frederick, MD 21702 USA. Univ Chicago, Dept Neurobiol Pharmacol & Physiol, Chicago, IL 60637 USA. RP Borchelt, DR (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, 720 Rutland Ave,Ross Bldg,Room 558, Baltimore, MD 21205 USA. RI Lee, Michael/D-9491-2013 OI Lee, Michael/0000-0001-5865-9682 FU NIA NIH HHS [1 P01 AG14248, P01 AG-98-003] NR 55 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR-APR PY 2002 VL 23 IS 2 BP 171 EP 177 DI 10.1016/S0197-4580(01)00280-9 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 516WY UT WOS:000173580800002 PM 11804700 ER PT J AU Baysal, BE Willett-Brozick, JE Badner, JA Corona, W Ferrell, RE Nimgaonkar, VL Detera-Wadleigh, SD AF Baysal, BE Willett-Brozick, JE Badner, JA Corona, W Ferrell, RE Nimgaonkar, VL Detera-Wadleigh, SD TI A mannosyltransferase gene at 11q23 is disrupted by a translocation breakpoint that co-segregates with bipolar affective disorder in a small family SO NEUROGENETICS LA English DT Article DE protein glycosylation; glycan; single nucleotide polymorphism; molecular evolution; complex genetic disorder ID CHROMOSOME BAND 11Q23; SUSCEPTIBILITY LOCUS; SIGNIFICANT LINKAGE; SCHIZOPHRENIA; MARKERS; REGION; VULNERABILITY; PEDIGREES; DISEASE; TESTS AB Bipolar affective disorder (BPAD) is a complex neuropsychiatric disease characterized by extreme mood swings. Genetic influences affect the disease susceptibility substantially, yet the underlying mechanisms are unknown. We previously described a pedigree in which all five individuals with BPAD and one individual with recurrent major depression were carriers of a reciprocal chromosomal translocation t(9;11)(p24;q23). Gene content analyses of the breakpoint junctions revealed disruption of a gene (DIBD1) at 11q23, a genomic region that has also been implicated in schizophrenia and Tourette syndrome. DIBD1 is predicted to encode a mannosyltransferase similar to Saccaromyces cerevisiae Alg9p of the protein N-glycosylation pathway. The inborn errors of protein N-glycosylation cause congenital disorders of glycosylation in humans. DIBD1 shows uniform expression in the tested subregions of the brain by Northern analysis. Sequence analysis revealed four intragenic single nucleotide polymorphisms. The valine residue at V289I was conserved in other eukaryotic species, whereas its frequency was approximately 65% in humans. We performed linkage and linkage disequilibrium analyses in two NIMH bipolar pedigree series using, four tightly linked simple tandem repeat polymorphisms (STRPs) and the V289I. These analyses overall failed to support a role for DIBD1 in disease susceptibility. The most-significant finding was a lod score of 1.18 (P=0.0098), obtained by an intronic STRP D11S5025, in the subset of 22 multiplex pedigrees. In conclusion, we found that a mannosyltransferase gene at 11q23 is disrupted by a translocation breakpoint co-segregating with BPAD in a family. However, its role in the disease susceptibility remains unconfirmed. C1 Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Med Ctr, Dept Otolaryngol, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Dept Human Genet, Pittsburgh, PA USA. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. NIMH, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA 15213 USA. RP Baysal, BE (reprint author), Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA 15260 USA. NR 48 TC 22 Z9 23 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1364-6745 J9 NEUROGENETICS JI Neurogenetics PD MAR PY 2002 VL 4 IS 1 BP 43 EP 53 DI 10.1007/s10048-001-0129-x PG 11 WC Genetics & Heredity; Clinical Neurology SC Genetics & Heredity; Neurosciences & Neurology GA 542KK UT WOS:000175042400006 PM 12030331 ER PT J AU Braga, MFM Aroniadou-Anderjaska, V Post, RM Li, H AF Braga, MFM Aroniadou-Anderjaska, V Post, RM Li, H TI Lamotrigine reduces spontaneous and evoked GABA(A) receptor-mediated synaptic transmission in the basolateral amygdala: implications for its effects in seizure and affective disorders SO NEUROPHARMACOLOGY LA English DT Article DE lamotrigine; amygdala; GABA(A); inhibition; affective disorders; bipolar depression ID PAIRED-PULSE FACILITATION; BIPOLAR DISORDER; RAT HIPPOCAMPUS; ANTICONVULSANT LAMOTRIGINE; GENERALIZED EPILEPSIES; ANTIEPILEPTIC DRUG; CALCIUM CURRENTS; MOOD DISORDERS; IN-VITRO; NEURONS AB Lamotrigine (LTG) is an antiepileptic drug that is also effective in the treatment of certain psychiatric disorders. Its anticonvulsant action has been attributed to its ability to block voltage-gated Na+ channels and reduce glutamate release. LTG also affects GABA-mediated synaptic transmission, but there are conflicting reports as to whether inhibitory transmission is enhanced or suppressed by LTG. We examined the effects of LTG on GABA(A), receptor-mediated synaptic transmission in slices from rat amygdala, it brain area that is particularly important in epileptogenesis and affective disorders. In intracellular recordings, LTG (100 muM) reduced GABA(A), reccptor-mediated IPSPs evoked by electrical stimulation in neurons of the basolateral nucleus. In whole-cell recordings LTG (10.50 and 100 muM) decreased the frequency and amplitude of spontaneous IPSCs, as well as the amplitude of evoked IPSCs, but had no effect on the kinetics of these Currents. LTG also had no effects on the frequency, amplitude or kinetics of miniature IPSCs recorded in the presence of TTX. These results suggest that in the basolateral amygdala. LTG Suppresses GABA(A) receptor-mediated synaptic transmission by a direct and/or indirect effect oil presynaptic Ca++ influx. The modulation of inhibitory synaptic transmission may be an important mechanism Underlying the psychotropic effects of LTG. Published by Elsevier Science Ltd. C1 Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. NIMH, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Braga, MFM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Psychiat, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. NR 39 TC 42 Z9 42 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD MAR PY 2002 VL 42 IS 4 BP 522 EP 529 AR PII S0038-3908(01)00198-8 DI 10.1016/S0028-3908(01)00198-8 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 551VT UT WOS:000175583800008 PM 11955522 ER PT J AU Adler, CM Malhotra, AK Elman, I Pickar, D Breier, A AF Adler, CM Malhotra, AK Elman, I Pickar, D Breier, A TI Amphetamine-induced dopamine release and post-synaptic specific binding in patients with mild tardive dyskinesia SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE tardive dyskinesia; amphetamine; striatum; dopamine; raclopride; PET ID C-11 RACLOPRIDE; H-3-SPIPERONE BINDING; RISK-FACTORS; IN-VIVO; PET; SCHIZOPHRENIA; RECEPTORS; SUPERSENSITIVITY; QUANTIFICATION; HALOPERIDOL AB Several lines of evidence suggest that changes in dopamine release and/or post-synaptic sensitivity may be involved in the pathogenesis of tardive dyskinesia (TD). Preclinically, increased D-2 receptor sensitivity and dopamine turnover are associated with D-2 receptor antagonism. Clinically, development of TD is associated with D-2 receptor antagonist administration. Eight Patients With mild evidence of TD (AIMS ratings greater than or equal to 14) and six without (AIMS = 10), underwent [C-11]raclopride PET scans. Baseline and amphetamine-induced decrements in striatal specific binding were assessed. Baseline and amphetamine-induced decrements in specific binding did not differ between patients with and without evidence of mild TD (p = .53). AIMS ratings did not significantly correlate with baseline (p = .76) or decrements in specific binding (p = .45). This study provides evidence that TD is not associated with increased amphetamine-induced presynaptic dopamine release and/or D-2 receptor binding as measured by [C-11]raclopride PET. More research is needed to unravel the neurobiology of this debilitating disorder. (C) 2002 American College of Neuropsychopharmacology. Published by Elsevier Science Inc. C1 NIMH, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Adler, CM (reprint author), Univ Cincinnati, Coll Med, Dept Psychiat, Bipolar & Psychot Disorders Res Program, 231 Albert Sabin Way, Cincinnati, OH 45267 USA. NR 40 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2002 VL 26 IS 3 BP 295 EP 300 DI 10.1016/S0893-133X(01)00309-8 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 523UU UT WOS:000173976300003 PM 11850144 ER PT J AU Bonson, KR Grant, SJ Contoreggi, CS Links, JM Metcalfe, J Weyl, HL Kurian, V Ernst, M London, ED AF Bonson, KR Grant, SJ Contoreggi, CS Links, JM Metcalfe, J Weyl, HL Kurian, V Ernst, M London, ED TI Neural systems and cue-induced cocaine craving SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE craving; cocaine; cognitive; brain imaging; positron emission tomography (PET); cerebral glucose metabolism ID POSITRON-EMISSION-TOMOGRAPHY; HUMAN PREFRONTAL CORTEX; OBSESSIVE-COMPULSIVE DISORDER; PRIMATE ORBITOFRONTAL CORTEX; ANTERIOR CINGULATE CORTEX; WORKING-MEMORY; HUMAN BRAIN; BASOLATERAL AMYGDALA; HIERARCHICAL ORGANIZATION; SYMPTOM PROVOCATION AB We have extended our previous work investigating the neural correlates of cue-induced cocaine craving through the use of positron emission tomography with greater spatial resolution (<4.6 mm), an evocative script, and a pixel-by-pixel analysis. Craving and cerebral glucose metabolism were measured after presentation of cocaine-related or neutral cues to 11 cocaine abusers. Cocaine cues elicited a higher degree of craving titan has been previously reported and resulted in left hemispheric activation of lateral amygdala, lateral orbitofrontal cortex, and rhinal cortex and right hemispheric activation of dorsolateral prefrontal cortex and cerebellum. The intensity of activation in these areas (except cerebellum), as well its left insula, was also correlated with craving. Deactivation occurred in left ventral pole and left medial prefrontal cortex. The results suggest that induction of drug craving involves a neural network that assigns incentive motivational value to environmental stimuli through the coactivation of brain regions that process information about memories and emotions. (C) 2002 American College of Neuropsychopharmacology. Published by Elsevier Science Inc. C1 Natl Inst Drug Abuse, Brain Imaging Ctr, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD 21205 USA. Columbia Univ, Dept Psychol, New York, NY 10027 USA. RP Bonson, KR (reprint author), US FDA, Controlled Substance Staff, HFD-009,5600 Fishers Lane, Rockville, MD 20857 USA. NR 74 TC 281 Z9 294 U1 12 U2 21 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2002 VL 26 IS 3 BP 376 EP 386 AR PII S0893-133X(01)00371-2 DI 10.1016/S0893-133X(01)00371-2 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 523UU UT WOS:000173976300011 PM 11850152 ER PT J AU Zhang, JZ Dyer, KD Rosenberg, HF AF Zhang, JZ Dyer, KD Rosenberg, HF TI RNase 8, a novel RNase A superfamily ribonuclease expressed uniquely in placenta SO NUCLEIC ACIDS RESEARCH LA English DT Article ID EOSINOPHIL CATIONIC PROTEIN; RESPIRATORY SYNCYTIAL VIRUS; TISSUE-SPECIFIC EXPRESSION; GENE FAMILY; EVOLUTIONARY HISTORY; ANGIOGENIN; SELECTION AB We report the identification and characterization of the gene encoding the eighth and final human ribonuclease (RNase) of the highly diversified RNase A superfamily. The RNase 8 gene is linked to seven other RNase A superfamily genes on chromosome 14. It is expressed prominently in the placenta, but is not detected in any other tissues examined. Phylogenetic analysis suggests that RNase 7 is the closest relative of RNase 8 and that the pair likely resulted from a recent gene duplication event in primates. Further analysis reveals that the RNase 8 gene has incorporated non-silent mutations at an elevated rate (1.3 x 10(-9) substitutions/site/year) and that orthologous RNase 8 genes from 6 of 10 primate species examined have been deactivated by frameshifting deletions or point mutations at crucial structural or catalytic residues. The ribonucleolytic activity of recombinant human RNase 8 is among the lowest of members of this superfamily and it exhibits neither antiviral nor antibacterial activities characteristic of some other RNase A ribonucleases. The rapid evolution, species-limited deactivation and tissue-specific expression of RNase 8 suggest a unique physiological function and reiterates the evolutionary plasticity of the RNase A superfamily. C1 Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Zhang, JZ (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, 3003 Nat Sci Bldg,830 N Univ Ave, Ann Arbor, MI 48109 USA. EM jianzhi@umich.edu NR 36 TC 54 Z9 67 U1 2 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 1 PY 2002 VL 30 IS 5 BP 1169 EP 1175 DI 10.1093/nar/30.5.1169 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 528DV UT WOS:000174229900011 PM 11861908 ER PT J AU Debethune, L Kohlhagen, G Grandas, A Pommier, Y AF Debethune, L Kohlhagen, G Grandas, A Pommier, Y TI Processing of nucleopeptides mimicking the topoisomerase I-DNA covalent complex by tyrosyl-DNA phosphodiesterase SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SOLID-PHASE SYNTHESIS; DIOL EPOXIDE ADDUCTS; CLEAVAGE COMPLEXES; EUKARYOTIC TOPOISOMERASE; CAMPTOTHECIN; SITE; INHIBITORS; INDUCTION AB Tyrosyl-DNA phosphodiesterase-1 (Tdp1) is the only known enzyme to remove tyrosine from complexes in which the amino acid is linked to the 3'-end of DNA fragments. Such complexes can be produced following DNA processing by topoisomerase I, and recent studies in yeast have demonstrated the importance of TDP1 for cell survival following topoisomerase I-mediated DNA damage. In the present study, we used synthetic oligodeoxynucleotide-peptide conjugates (nucleopeptides) and recombinant yeast Tdp1 to investigate the molecular determinants for Tdp1 activity. We find that Tdp1 can process nucleopeptides with up to 13 amino acid residues but is poorly active with a 70 kDa fragment of topoisomerase I covalently linked to a suicide DNA substrate. Furthermore, Tdp1 was more effective with nucleopeptides with one to four amino acids than 15 amino acids. Tdp1 was also more effective with nucleopeptides containing 15 nt than with homolog nucleopeptides containing 4 nt. These results suggest that DNA binding contributes to the activity of Tdp1 and that Tdp1 would be most effective after topoisomerase I has been proteolyzed in vivo. C1 Univ Barcelona, Fac Chem, Dept Organ Chem, E-08028 Barcelona, Spain. NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), Univ Barcelona, Fac Chem, Dept Organ Chem, Marti & Franques 1-11, E-08028 Barcelona, Spain. RI Grandas, Anna/K-6419-2014 OI Grandas, Anna/0000-0001-6517-4018 NR 31 TC 68 Z9 68 U1 2 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 1 PY 2002 VL 30 IS 5 BP 1198 EP 1204 DI 10.1093/nar/30.5.1198 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 528DV UT WOS:000174229900015 PM 11861912 ER PT J AU Tan, DP Nonaka, K Nuckolls, GH Liu, YH Maxson, RE Slavkin, HC Shum, L AF Tan, DP Nonaka, K Nuckolls, GH Liu, YH Maxson, RE Slavkin, HC Shum, L TI YY1 activates Msx2 gene independent of bone morphogenetic protein signaling SO NUCLEIC ACIDS RESEARCH LA English DT Article ID APICAL ECTODERMAL RIDGE; PROGRAMMED CELL-DEATH; GROWTH-FACTOR-BETA; TRANSCRIPTION FACTOR; ECTOPIC EXPRESSION; BINDING PROTEIN; NEURAL CREST; TRANSACTIVATION DOMAIN; TARGETED DISRUPTION; LIMB MORPHOGENESIS AB Msx2 is a homeobox gene expressed in multiple embryonic tissues which functions as a key mediator of numerous developmental processes: YY1 is a bi-functional zinc finger protein that serves as a repressor or activator to a variety of promoters. The role of YY1 during embryogenesis remains unknown. In this study, we report that Msx2 is regulated by YY1 through protein-DNA interactions. During embryogenesis, the expression pattern of YY1 was observed to overlap in part with that of Msx2. Most notably, during first branchial arch and limb development, both YY1 and Msx2 were highly expressed, and their patterns were complementary. To test the hypothesis that YY1 regulates Msx2 gene expression, P19 embryonal cells were used in a number of expression and binding assays. We discovered that, in these cells, YY1 activated endogenous Msx2 gene expression as well as Msx2 promoter-luciferase fusion gene activity. These biological activities were dependent on both the DNA binding and activation domains of YY1. In addition, YY1 bound specifically to three YY1 binding sites on the proximal promoter of Msx2 that accounted for this transactivation. Mutations introduced to these sites reduced the level of YY1 transactivation. As bone morphogenetic protein type 4 (BMP4) regulates Msx2 expression in embryonic tissues and in P19 cells, we further tested whether YY1 is the mediator of this BMP4 activity. BMP4 did not induce the expression of YY1 in early mouse mandibular explants, nor in P19 cells, suggesting that YY1 is not a required mediator of the BMP4 pathway in these tissues at this developmental stage. Taken together, these findings suggest that YY1 functions as an activator for the Msx2 gene, and that this regulation, which is independent of the BMP4 pathway, may be required during early mouse craniofacial and limb morphogenesis. C1 NIAMSD, Craniofacial Dev Sect, NIH, Bethesda, MD 20892 USA. Univ So Calif, Ctr Craniofacial Mol Biol, Los Angeles, CA 90033 USA. Univ So Calif, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA. RP NIAMSD, Craniofacial Dev Sect, NIH, 6 Ctr Dr,MSC 2745,Bldg 6,Room 324, Bethesda, MD 20892 USA. EM lillian.shum@nih.gov NR 73 TC 17 Z9 19 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 1 PY 2002 VL 30 IS 5 BP 1213 EP 1223 DI 10.1093/nar/30.5.1213 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 528DV UT WOS:000174229900017 PM 11861914 ER PT J AU Webb, CT Shabalina, SA Ogurtsov, AY Kondrashov, AS AF Webb, CT Shabalina, SA Ogurtsov, AY Kondrashov, AS TI Analysis of similarity within 142 pairs of orthologous intergenic regions of Caenorhabditis elegans and Caenorhabditis briggsae SO NUCLEIC ACIDS RESEARCH LA English DT Article ID REGULATORY ELEMENTS; MOUSE GENOME; C-ELEGANS; SEQUENCES; STATISTICS; ALIGNMENTS; NUCLEOTIDE; GENE; DNA; RNA AB Patterns of similarity between genomes of related species reflect the distribution of selective constraint within DNA. We analyzed alignments of 142 orthologous intergenic regions of Caenorhabditis elegans and Caenorhabditis briggsae and found a mosaic pattern with regions of high similarity (phylogenetic footprints) interspersed with non-alignable sequences. Footprints cover similar to20% of intergenic regions, often occur in clumps and are rare within 5' UTRs but common within 3' UTRs. The footprints have a higher ratio of transitions to transversions than expected at random and a higher GC content than the rest of the intergenic region. The number of footprints and the GC content of footprints within an intergenic region are higher when genes are oriented so that their 5' ends form the boundaries of the intergenic region. Overall, the patterns and characteristics identified here, along with other comparative and experimental studies, suggest that many footprints have a regulatory function, although other types of function are also possible. These conclusions may be quite general across eukaryotes, and the characteristics of conserved regulatory elements determined from genomic comparisons can be useful in prediction of regulation sites within individual DNA sequences. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM ctwebb@princeton.edu RI Shabalina, Svetlana/N-8939-2013 OI Shabalina, Svetlana/0000-0003-2272-7473 NR 41 TC 33 Z9 33 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 1 PY 2002 VL 30 IS 5 BP 1233 EP 1239 DI 10.1093/nar/30.5.1233 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 528DV UT WOS:000174229900019 PM 11861916 ER PT J AU Moll, JR Acharya, A Gal, J Mir, AA Vinson, C AF Moll, JR Acharya, A Gal, J Mir, AA Vinson, C TI Magnesium is required for specific DNA binding of the CREB B-ZIP domain SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TRANSCRIPTION FACTOR; CRYSTAL-STRUCTURE; PROTEIN INTERACTIONS; BASIC REGION; C-FOS; COMPLEX; JUN; DIMERIZATION; RECOGNITION; NEURONS AB We have examined binding of the CREB B-ZIP protein domain to double-stranded DNA containing a consensus CRE sequence (5'-TGACGTCA-3'), the related PAR, C/EBP and AP-1 sequences and the unrelated SP1 sequence. DNA binding was assayed in the presence or absence of MgCl2 and/or KCl using two methods: circular dichroism (CD) spectroscopy and electrophoretic mobility shift assay (EMSA). The CD assay allows us to measure equilibrium binding in solution. Thermal denaturation in 150 mM KCl indicates that the CREB B-ZIP domain binds all the DNA sequences, with highest affinity for the CRE site, followed by the PAR (5'-TAACGTTA-3'), C/EBP (5'-TTGCGCAA-3') and AP-1 (5'-TGAGTCA-3') sites. The addition of 10 MM MgCl2 diminished DNA binding to the CRE and PAR DNA sequences and abolished binding to the C/EBP and AP-1 DNA sequences, resulting in more sequence-specific DNA binding. Using 'standard' EMSA conditions (0.25x TBE), CREB bound all the DNA sequences examined. The CREB-CRE complex had an apparent K-d of similar to300 pM, PAR of similar to1 nM, C/EBP and AP-1 of similar to3 nM and SP1 of similar to30 nM. The addition of 10 MM MgCl2 to the polyacrylamide gel dramatically altered sequence-specific DNA binding. CREB binding affinity for CRE DNA decreased 3-fold, but binding to the other DNA sequences decreased >1000-fold. In the EMSA, addition of 150 mM KCl to the gels had an effect similar to MgCl2. The magnesium concentration needed to prevent non-specific electrostatic interactions between CRIES and DNA in solution is in the physiological range and thus changes in magnesium concentration may be a cellular signal that regulates gene expression. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Vinson, C (reprint author), NCI, Lab Metab, NIH, Bldg 37,Room 4D06, Bethesda, MD 20892 USA. NR 40 TC 34 Z9 36 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 1 PY 2002 VL 30 IS 5 BP 1240 EP 1246 DI 10.1093/nar/30.5.1240 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 528DV UT WOS:000174229900020 PM 11861917 ER PT J AU Ulrich, CM Wallen, GR Grady, C AF Ulrich, CM Wallen, GR Grady, C TI Research vulnerability and patient advocacy - Balance-seeking perspectives for the clinical nurse scientist? SO NURSING RESEARCH LA English DT Editorial Material C1 NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. NR 5 TC 8 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-6562 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2002 VL 51 IS 2 BP 71 EP 71 DI 10.1097/00006199-200203000-00001 PG 1 WC Nursing SC Nursing GA 534GV UT WOS:000174577500001 PM 11984375 ER PT J AU Smith, MA Murgo, AJ Wright, JJ Schoenfeldt, M Cheson, BD AF Smith, MA Murgo, AJ Wright, JJ Schoenfeldt, M Cheson, BD TI Clinical trials referral resource: Current clinical trials of molecularly targeted agents in children with cancer SO ONCOLOGY-NEW YORK LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Smith, MA (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD MAR PY 2002 VL 16 IS 3 BP 328 EP 328 PG 1 WC Oncology SC Oncology GA 531WX UT WOS:000174441200012 PM 15046391 ER PT J AU Smith, JA Chan, CC Goldin, E Schiffmann, R AF Smith, JA Chan, CC Goldin, E Schiffmann, R TI Noninvasive diagnosis and ophthalmic features of mucolipidosis type IV SO OPHTHALMOLOGY LA English DT Article ID NATURAL-HISTORY AB Objective: To comprehensively describe the ophthalmic characteristics of patients with mucolipidosis type IV. Design: Prospective natural history study. Participants: Twenty-two patients with confirmed mucolipidosis type IV. Methods or Testing: External and slit-lamp examination with dilated funduscopy, photography of corneal and retinal lesions, and exfoliative conjunctival cytology were performed. Main Outcome Measures: Grading of corneal, optic nerve, retinal vasculature, and pigmentary abnormalities. Results: All patients exhibited some degree of corneal epithelial haze, optic nerve pallor, retinal vascular attenuation, and retinal pigment epithelial changes. The associated ocular findings observed in decreasing order of frequency were strabismus, corneal erosion, cataract, corneal abnormalities, fundus abnormalities, and ptosis. The older patients were significantly more likely to demonstrate severe optic nerve pallor, retinal vascular attenuation, and corneal epithelial haze. Conjunctival cytologic studies showed characteristic lysosomal inclusions on light and electron microscopy. Conclusions: Patients with mucolipidosis type IV have characteristic ophthalmic features, most of which have a progressive course. Conjunctival cytologic studies help confirm the diagnosis of this disorder. Ophthalmology 2002;109:588-594 (C) 2002 by the American Academy of Ophthalmology. C1 NEI, NIH, Bethesda, MD 20892 USA. NINCDS, NIH, Bethesda, MD 20892 USA. RP Smith, JA (reprint author), NEI, NIH, 10 Ctr Dr,MSC 1857, Bethesda, MD 20892 USA. NR 22 TC 17 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD MAR PY 2002 VL 109 IS 3 BP 588 EP 594 AR PII S0161-6420(01)00968-X DI 10.1016/S0161-6420(01)00968-X PG 7 WC Ophthalmology SC Ophthalmology GA 525VV UT WOS:000174095500040 PM 11874766 ER PT J AU Nansel, TR Weaver, N Donlin, M Jacobsen, H Kreuter, MW Simons-Morton, B AF Nansel, TR Weaver, N Donlin, M Jacobsen, H Kreuter, MW Simons-Morton, B TI Baby, be safe: the effect of tailored communications for pediatric injury prevention provided in a primary care setting SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE injury prevention; tailored communications; anticipator guidance ID PHYSICIAN ADVICE; COMPUTER; CHILDHOOD; EDUCATION; SMOKING; IMPACT; EPIDEMIOLOGY; ATTITUDES; KNOWLEDGE; BEHAVIOR AB Injuries are a major cause of morbidity and mortality in young children. The provision of individually tailored educational materials in primary care settings may be an effective and efficient way to promote adoption of injury prevention measures by parents. A randomized controlled study compared the effectiveness of tailored and generic persuasive communications delivered in a primary care setting on the adoption of home and car safety behaviors. During routine well-child, visits, a primarily African-American sample of parents of children ages 6-20 months (n = 213) was randomized to receive either tailored or generic information regarding the prevention of injuries to their child. At follow-up, participants who received tailored information reported greater adoption of home and car safety behaviors than those receiving generic information. In addition, within the tailored information group, those who discussed the information with their physician showed significantly greater change than those who did not. However. this difference A as not observed among those receiving generic information. Findings support the use of office-based tailored injury prevention education as a component of routine A ell-child care. Published by Elsevier Science Ireland Ltd. C1 NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. St Louis Univ, Hlth Commun Res Lab, St Louis, MO 63103 USA. RP Nansel, TR (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B05,MSC 7510, Bethesda, MD 20892 USA. OI Nansel, Tonja/0000-0002-8298-7595; Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural NIH HHS [Z01 HD002402-09] NR 51 TC 47 Z9 47 U1 5 U2 9 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD MAR PY 2002 VL 46 IS 3 SI SI BP 175 EP 190 AR PII S0738-3991(01)00211-7 DI 10.1016/S0738-3991(01)00211-7 PG 16 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 550XD UT WOS:000175529600004 PM 11932115 ER PT J AU Favara, BE Jaffe, R Egeler, RM AF Favara, BE Jaffe, R Egeler, RM TI Macrophage activation and hemophagocytic syndrome in Langerhans cell histiocytosis: Report of 30 cases SO PEDIATRIC AND DEVELOPMENTAL PATHOLOGY LA English DT Article DE histiocytosis; Langerhans cell histiocytosis; hemophagocytic syndrome; pediatric ID EPSTEIN-BARR-VIRUS; SOLUBLE INTERLEUKIN-2 RECEPTOR; TUMOR-NECROSIS-FACTOR; INTERFERON-GAMMA; T-CELLS; ABUNDANT EXPRESSION; DISEASE-ACTIVITY; DENDRITIC CELLS; UP-REGULATION; LYMPHOHISTIOCYTOSIS AB Macrophage activation and secondary hemophagocytic syndrome are rarely reported in association with Langerhans cell histiocytosis (LCH). The authors reviewed their pathology files for cases of LCH in which evidence of macrophage activation coexisted and report 30 such cases indicating that the association is not that rare and may even be underdiagnosed unless specifically sought. Available clinical data were collected and correlated with pathological findings. Of the 30 cases of LCH with varying degrees of macrophage activation, 29 had multisystem disease. The cases were graded from I to V on the basis of evidence for, and severity of, macrophage activation; cases in category I had evidence of fully developed hemophagocytic syndrome whereas those in category V had limited evidence of macrophage activation. There were seven cases with fully developed hemophagocytic syndrome (category I) and an additional five with hemophagocytosis and some but not all of the features of hemophagocytic syndrome (category II). Most of these 12 cases were young children with high-risk LCH and poor prognosis; 4 are known to have died. Coexisting hemophagocytic syndrome in these cases of LCH may have contributed to their poor prognosis. The association of LCH with macrophage activation, though more than coincidental, is of unknown pathogenesis, but the role of T lymphocytes and cytokines is prominent in both disorders and is presumed to link the two. C1 NIH, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. Univ Utah, Dept Pathol, Salt Lake City, UT USA. Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. Childrens Hosp Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. Leiden Univ, Med Ctr, Dept Pediat Immunol, Leiden, Netherlands. Leiden Univ, Med Ctr, Dept Hematol, Leiden, Netherlands. Leiden Univ, Med Ctr, Dept Oncol, Leiden, Netherlands. Leiden Univ, Med Ctr, Dept Bone Marrow Transplantat & Autoimmune Dis, Leiden, Netherlands. Alberta Childrens Prov Gen Hosp, Tom Baker Canc Ctr, So Alberta Childrens Canc Program, Calgary, AB, Canada. Univ Calgary, Dept Oncol & Pediat, Calgary, AB, Canada. RP Favara, BE (reprint author), 1114 W Main St, Hamilton, MT 59840 USA. NR 55 TC 38 Z9 38 U1 0 U2 5 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1093-5266 J9 PEDIATR DEVEL PATHOL JI Pediatr. Dev. Pathol. PD MAR-APR PY 2002 VL 5 IS 2 BP 130 EP 140 DI 10.1007/s10024-001-0159-2 PG 11 WC Pathology; Pediatrics SC Pathology; Pediatrics GA 532DP UT WOS:000174456600003 PM 11910507 ER PT J AU Walsh, TJ Lutsar, I Driscoll, T Dupont, B Roden, M Ghahramani, P Hodges, M Groll, AH Perfect, JR AF Walsh, TJ Lutsar, I Driscoll, T Dupont, B Roden, M Ghahramani, P Hodges, M Groll, AH Perfect, JR TI Voriconazole in the treatment of aspergillosis, scedosporiosis and other invasive fungal infections in children SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE voriconazole; aspergillosis; scedosporiosis; candidiasis ID CENTRAL-NERVOUS-SYSTEM; 10 YEARS EXPERIENCE; IN-VITRO ACTIVITY; PSEUDALLESCHERIA-BOYDII; ANTIFUNGAL AGENTS; MARROW TRANSPLANTATION; CANCER CENTER; PROLIFICANS; APIOSPERMUM; MANAGEMENT AB Objective. To describe the safety and efficacy of voriconazole in children treated within the compassionate release program. Methods. Children received voriconazole on a compassionate basis for treatment of an invasive fungal infection if they were refractory to or intolerant of conventional antifungal therapy. Voriconazole was administered as a loading dose of 6 mg/kg every 12 h iv on Day 1 followed by 4 mg/kg every 12 h iv thereafter. When feasible the route of administration of voriconazole was changed from iv to oral (100 or 200 mg twice a day for patients weighing < 40 or &GE;40 kg, respectively). Outcome was assessed by investigators at the end of therapy or at the last visit as success (complete or partial response), stable infection, or failure, based on protocol-defined criteria. Results. Sixty-nine children (ages 9 months to 15 years; median, 7 years) received voriconazole; 58 had a proven or probable fungal infection. Among these 58 patients 27 had hematologic malignancies and 13 had chronic granulomatous disease as the most frequent underlying conditions. Forty-two patients had aspergillosis, 8 had scedosporiosis, 4 had invasive candidiasis and 4 had other invasive fungal infections. The median duration of voriconazole therapy was 93 days. At the end of therapy 26 patients (45%) had a complete or partial response. Four patients (7%) had a stable response, 25 (43%) failed therapy and 4 (7%) were discontinued from voriconazole because of intolerance. Success rates were highest in patients with chronic granulomatous disease (62%) and lowest in patients with hematologic malignancies (33%). Two patients experienced treatment-related serious adverse events (ulcerated lips with rash, elevated hepatic transaminases or bilirubin). A total of 23 patients had voriconazole-related adverse events, 3 (13%) of which caused discontinuation of voriconazole therapy. The most commonly reported adverse events included elevation in hepatic transaminases or bilirubin (n = 8), skin rash (n = 8), abnormal vision (n = 3) and a photosensitivity reaction (n = 3). Conclusion. These data support the use of voriconazole for treatment of invasive fungal infections in pediatric patients who are intolerant of or refractory to conventional antifungal therapy. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. Pfizer Ltd, Sandwich CT13 9NJ, Kent, England. Duke Univ, Div Hematol Oncol, Raleigh, NC USA. Duke Univ, Div Infect Dis, Raleigh, NC USA. Inst Pasteur, Paris, France. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bldg 10,Room 13N240, Bethesda, MD 20892 USA. RI lutsar, irja/H-3177-2015 NR 38 TC 279 Z9 295 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD MAR PY 2002 VL 21 IS 3 BP 240 EP 248 DI 10.1097/00006454-200203000-00015 PG 9 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 531WD UT WOS:000174439500013 PM 12005089 ER PT J AU Sommerfelt, K Sonnander, K Skranes, J Andersson, HW Ahlsten, G Ellertsen, B Markestad, T Jacobsen, G Hoffman, HJ Bakketeig, LS AF Sommerfelt, K Sonnander, K Skranes, J Andersson, HW Ahlsten, G Ellertsen, B Markestad, T Jacobsen, G Hoffman, HJ Bakketeig, LS TI Neuropsychologic and motor function in small-for-gestation preschoolers SO PEDIATRIC NEUROLOGY LA English DT Article ID LOW-BIRTH-WEIGHT; DEVELOPMENTAL STATUS; AGE CHILDREN; INFANTS; PERFORMANCE AB The aim of this study was to evaluate neuropsychologic and motor performance in term small-for-gestation preschool children. A patient-based sample of 311 5-year-old children with birth weights less than the fifteenth percentile for gestation was compared with a random sample of 321 appropriate-for-gestation control subjects. The main assessment tools were subscales from the Wechsler Preschool and Primary Scale of Intelligence Revised, subscales from the Illinois Test of Psycholinguistic Abilities, tests of manual dexterity and figure copying, and the Peabody Developmental Motor Scales. The small-for-gestation children had mean scores on tests of visuospatial and visuomotor abilities that were one fourth standard deviation lower than appropriate-for-gestation control subjects and slightly lower scores on manual dexterity. The small-for-gestation children were comparable to appropriate-for-gestation children regarding motor performance. We therefore conclude that the neuropsychologic and neuromotor performance in preschool years of term small-for-gestation children is reassuring. (C) 2002 by Elsevier Science Inc. All rights reserved. C1 Univ Bergen, Dept Pediat, Bergen, Norway. Univ Uppsala, Dept Neurosci, Psychiat Ulleraker, Uppsala, Sweden. Univ Trondheim, Dept Pediat, Trondheim, Norway. Univ Trondheim, Dept Psychol, Trondheim, Norway. Univ Uppsala, Dept Pediat, Uppsala, Sweden. Univ Bergen, Dept Biol & Med Psychol, Bergen, Norway. Univ Trondheim, Dept Community Med & Gen Practice, Trondheim, Norway. NIDCD, Stat & Data Syst Branch, NIH, Bethesda, MD USA. RP Sommerfelt, K (reprint author), Haukeland Hosp, Dept Pediat, Barneklinikken, N-5021 Bergen, Norway. NR 30 TC 19 Z9 22 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD MAR PY 2002 VL 26 IS 3 BP 186 EP 191 AR PII S0887-8994(01)00381-2 DI 10.1016/S0887-8994(01)00381-2 PG 6 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 543AD UT WOS:000175077500002 PM 11955924 ER PT J AU Ahmad, A Moriguchi, T Salem, N AF Ahmad, A Moriguchi, T Salem, N TI Decrease in neuron size in docosahexaenoic acid-deficient brain SO PEDIATRIC NEUROLOGY LA English DT Article ID ALPHA-LINOLENIC ACID; NERVE GROWTH-FACTOR; POLYUNSATURATED FATTY-ACIDS; VISUAL-ACUITY DEVELOPMENT; AGE-RELATED-CHANGES; RAT FRONTAL-CORTEX; PRETERM INFANTS; CEREBRAL-CORTEX; DIET; SUPPLEMENTATION AB Docosahexaenoic acid is an important fatty acid for neuronal function because its deficiency leads to many behavioral and functional deficits. In a previous study, we reported that docosahexaenoic acid deficiency caused a reduction in the size of neurons of the CA1 region in the hippocampus. To extend these results to other regions of the brain, the present study entailed a morphologic analysis of neuronal size in hippocampus, hypothalamus, piriform cortex, and parietal cortex in rats that were raised on docosahexaenoic acid-deficient and supplemented diets for three generations. Neuron size in these regions was measured both at weaning (21 days) and maturity (68 days), and docosahexaenoic acid content in the brain was measured on a separate set of sibling rats using fatty acid analysis. Neuron size in hippocampus, hypothalamus, and parietal cortex decreased in weanling and in piriform cortex in mature rats raised on the docosahexaenoic acid-deficient diet. The brains of these rats exhibited a nearly 90% decrease of docosahexaenoic acid. Decrease of neuron size has been linked to a loss of optimal function in neurons. In the United States, human infant-milk formulas use vegetable oils as fat sources that lack docosahexaenoic acid. If docosahexaenoic acid deficiency reduces neuron size, then human infants raised on these formulas may also have smaller neurons relative to breast-fed infants. (C) 2002 by Elsevier Science Inc. All rights reserved. C1 NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, Div Intramural Clin & Biol Res,NIH, Bethesda, MD USA. RP Salem, N (reprint author), 12420 Parklawn Dr,Room 1-14, Rockville, MD 20852 USA. NR 55 TC 83 Z9 92 U1 4 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD MAR PY 2002 VL 26 IS 3 BP 210 EP 218 AR PII S0887-8994(01)00383-6 DI 10.1016/S0887-8994(01)00383-6 PG 9 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 543AD UT WOS:000175077500007 PM 11955929 ER PT J AU Champoux, M Hibbeln, JR Shannon, C Majchrzak, S Suomi, SJ Salem, N Higley, JD AF Champoux, M Hibbeln, JR Shannon, C Majchrzak, S Suomi, SJ Salem, N Higley, JD TI Fatty acid formula supplementation and neuromotor development in rhesus monkey Neonates SO PEDIATRIC RESEARCH LA English DT Article ID INFANTS MACACA-MULATTA; VISUAL RESOLUTION ACUITY; HEALTHY PRETERM INFANTS; FULL-TERM INFANTS; FED BREAST-MILK; DOCOSAHEXAENOIC ACID; RANDOMIZED TRIAL; BIRTH-WEIGHT; CEREBRAL-CORTEX; BRAIN AB Docosahexaenoic acid (DIIA) is an omega-3 fatty acid that is highly concentrated in CNS tissues. Although breast milk contains the fatty acids DHA and arachidonic acid, infant formulas marketed in North America do not contain these nutrients. The potential deleterious effects of rearing infants with formulas devoid of these nutrients was assessed by comparing nursery-reared rhesus macaque infants (Macaca mulatta) fed standard formula with infants fed standard formula supplemented with physiologically relevant concentrations of DHA (1.0%) and arachidonic acid (1.0%). Neurobehavioral assessments were conducted on d 7, 14, 21, and 30 of life using blinded raters. The 30-min assessment consisted of 45 test items measuring orienting, temperament, reflex capabilities, and motor skills. Plasma concentrations of DHA in standard formula-fed infants were significantly lower than those fed supplemented formula or mother-raised (breast-fed) infants; however, infants fed the supplemented formula exhibited higher arachidonic acid levels than either mother-reared infants or infants fed standard formula. Infant monkeys fed the supplemented formula exhibited stronger orienting and motor skills than infants fed the standard formula, with the differences most pronounced during d 7 and 14. This pattern suggests an earlier maturation of specific visual and motor abilities in the supplemented infants. Supplementation did not affect measures of activity or state control, indicating no effect on temperament. These data support the assertion that preformed DHA and arachidonic acid in infant formulas are required for optimal development. C1 NICHHD, Comparat Ethol Lab, Poolesville, MD 20837 USA. NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. NIAAA, Clin Studies Lab, Primate Unit, Bethesda, MD 20892 USA. RP Champoux, M (reprint author), NIH, Anim Ctr, POB 529, Poolesville, MD 20837 USA. RI Wilkinson, Stuart/C-2802-2013 NR 73 TC 45 Z9 47 U1 5 U2 6 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD MAR PY 2002 VL 51 IS 3 BP 273 EP 281 DI 10.1203/00006450-200203000-00003 PG 9 WC Pediatrics SC Pediatrics GA 525RH UT WOS:000174084400003 PM 11861930 ER PT J AU Lamba, JK Lin, YS Thummel, K Daly, A Watkins, PB Strom, S Zhang, J Schuetz, EG AF Lamba, JK Lin, YS Thummel, K Daly, A Watkins, PB Strom, S Zhang, J Schuetz, EG TI Common allelic variants of cytochrome P4503A4 and their prevalence in different populations SO PHARMACOGENETICS LA English DT Article DE single nucleotide polymorphisms; cytochrome P450 3A4; ethnic; pharmacogenetics ID SINGLE-NUCLEOTIDE POLYMORPHISMS; FUNCTIONAL-CHARACTERIZATION; ETHNIC-DIFFERENCES; DRUG-METABOLISM; ORAL NIFEDIPINE; GENETIC VARIANT; HUMAN-LIVER; CYP3A4; IDENTIFICATION; REGION AB Marked interindividual variability in expression of CYP3A4 influences the disposition of many endo- and xenobiotics, including the metabolism of steroids, environmental toxins and therapeutically useful drugs. The present study was designed to determine the genetic basis of CYP3A4 variability. We analysed DNA from 82 individuals with known CYP3A4 phenotype including 53 Caucasians and 21 African-American liver donors, seven individuals who were outliers in CYP3A4 metabolism and five individuals in a family of a poor nifedipine metabolizer. In addition, we analysed DNA from the eight person DNA Polymorphism Discovery Resource subset (Coriell Institute) and 89 individuals representing nine ethnic groups. Five non-synonymous mutations in the coding region of CYP3A4 were observed. CYP3A4* 14 (T44C) in exon 1 resulted in an L15P change; CYP3A4* 15 (G14387A) in exon 6 resulted in a R162Q substitution; CYP3A4* 10 (G14422C) in exon 6 resulted in a D174H substitution; CYP3A4* 16 (Cl 5721 G) in exon 7 resulted in a T185S amino acid substitution; and CYP3A4* 12 (C22002T) in exon 11 resulted in a L373F change in the CYP3A4 protein. An additional six single nucleotide polymorphisms (SNPs) in the 5'-UTR, 13 SNPs in the introns and three SNPs in the 3'-UTR were observed. Extensive population differences were observed in the frequencies of various CYP3A4 alleles. None of the 28 CYP3A4 SNPs identified in CYP3A4 phenotyped persons (most individuals being heterozygous for any CYP3A4 variant) was associated with low hepatic CYP3A4 protein expression or low CYP3A4 activity in vivo. C1 St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA. Newcastle Univ, Dept Pharmaceut Sci, Newcastle Upon Tyne, Tyne & Wear, England. Univ N Carolina, Chapel Hill, NC USA. Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. Natl Ctr Biotechnol Informat, NIH, Bethesda, MD USA. Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA. RP Schuetz, EG (reprint author), St Jude Childrens Res Hosp, Dept Pharmaceut Sci, 332 N Lauderdale St, Memphis, TN 38105 USA. EM erin.schuetz@stjude.org RI Strom, Stephen/A-6501-2008; Daly, Ann/H-3144-2011 OI Daly, Ann/0000-0002-7321-0629 FU NCI NIH HHS [P30 CA21765]; NIEHS NIH HHS [ES08658]; NIGMS NIH HHS [GM07750, GM32165, GM38147, GM60346, U01 GM61393, U01GM61374] NR 34 TC 202 Z9 222 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-314X J9 PHARMACOGENETICS JI Pharmacogenetics PD MAR PY 2002 VL 12 IS 2 BP 121 EP 132 DI 10.1097/00008571-200203000-00006 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 540UE UT WOS:000174947200006 PM 11875366 ER PT J AU Ishibe, N Sinha, R Hein, DW Kulldorff, M Strickland, P Fretland, AJ Chow, WH Kadlubar, FF Lang, NP Rothman, N AF Ishibe, N Sinha, R Hein, DW Kulldorff, M Strickland, P Fretland, AJ Chow, WH Kadlubar, FF Lang, NP Rothman, N TI Genetic polymorphisms in heterocyclic amine metabolism and risk of colorectal adenomas SO PHARMACOGENETICS LA English DT Article DE heterocyclic amines; MelQx; colorectal adenomas; N-acetyltransferases ID ARYLAMINE N-ACETYLTRANSFERASE; UNITED-STATES; COLON-CANCER; RED MEAT; POLYADENYLATION POLYMORPHISM; ACETYLATOR PHENOTYPE; FAMILY HISTORY; COOKING METHOD; WELL-DONE; DIET AB High red meat intake has been linked with an increased risk of colorectal cancer and adenomas. During high temperature cooking of red meats, heterocyclic amines (HCAs) are generated; however, to be carcinogenic, they must be metabolized by enzymes including cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase 1 (NAT1) and/or N-acetyltransferase 2 (NAT2). We have conducted a clinic-based case-control study of colorectal adenomas that focused on assessment of exposure to HCAs (estimated by use of a HCA database and meat cooking module) and modification of these exposures by genetic factors. We have previously reported that intake of MelQx was associated with an increased risk of colorectal adenomas [overall association at 80th percentile, > 27.00 ng/day: odds ratio (OR) = 2.68,95% confidence interval (CI) 1.58-4.55]. Here, we report our evaluation of whether variation in CYP1A2, NAT1 and/or NAT2 modify the association between HCAs and colorectal adenoma formation in 146 cases and 228 frequency-matched controls. The NAT1* 10 allele was associated with a nonsignificant increased risk of colorectal adenomas (OR = 1.43; 95% Cl 0.86-2.36). Further, when we analysed 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MelQx) intake as a categorical variable, we observed a six-fold increase in adenoma risk among rapid NAT1 acetylators who consumed more than 27 ng a day (OR = 6.50; 95% Cl 2.16-19.7), whereas among slow NAT1 acetylators, the increase in risk was two-fold (OR = 2.32; 95% Cl 1.12-4.81). While suggestive, the results were not significantly different from each other on either an additive or multiplicative scale. In contrast, NAT2 genotype and CYP1A2 and NAT2 hepatic activity measured by caffeine urinary metabolites were not associated with adenoma risk, although an increase in risk with rapid CYP1A2 activity could not be ruled out (OR = 1.46; 95% Cl 0.76-2.81). Moreover, there was no evidence that the effect of MeIQx was enhanced among subjects in any subgroup defined by variation in these measures. These results are compatible with the hypothesis that high HCA exposure is associated with an increased risk of colorectal adenomas, particularly in genetically susceptible subgroups. Further study of larger populations is needed to confirm and extend these observations. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. Univ Connecticut, Sch Med, Div Biostat, Dept Community Med & Hlth Care, Farmington, CT USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. Natl Ctr Toxicol Res, Div Mol Epidemiol, Jefferson, AR 72079 USA. RP Ishibe, N (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,MSC 7236, Bethesda, MD 20892 USA. RI Hein, David/A-9707-2008; Kulldorff, Martin/H-4282-2011; Sinha, Rashmi/G-7446-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Kulldorff, Martin/0000-0002-5284-2993 FU NCI NIH HHS [CA-34627, R01 CA034627, R01 CA034627-16]; NIEHS NIH HHS [ES06052] NR 58 TC 87 Z9 88 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-314X J9 PHARMACOGENETICS JI Pharmacogenetics PD MAR PY 2002 VL 12 IS 2 BP 145 EP 150 DI 10.1097/00008571-200203000-00008 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 540UE UT WOS:000174947200008 PM 11875368 ER PT J AU Shalev, U Grimm, JW Shaham, Y AF Shalev, U Grimm, JW Shaham, Y TI Neurobiology of relapse to heroin and cocaine seeking: A review SO PHARMACOLOGICAL REVIEWS LA English DT Review ID CORTICOTROPIN-RELEASING-FACTOR; CONDITIONED PLACE PREFERENCE; STRESS-INDUCED RELAPSE; SELF-ADMINISTRATION BEHAVIOR; VENTRAL TEGMENTAL AREA; DRUG-INDUCED REINSTATEMENT; EXTRACELLULAR DOPAMINE LEVELS; DEPENDENT PROTEIN-KINASE; ACOUSTIC STARTLE REFLEX; OPPONENT-PROCESS THEORY AB The objective of this article is to review data from studies that used a reinstatement model in rats to elucidate the neural mechanisms underlying relapse to heroin and cocaine seeking induced by exposure to the self-administered drug (drug priming), conditioned drug cues, and stressors. These factors were reported to contribute to relapse to drug use in humans following prolonged abstinence periods. In the reinstatement model, the ability of acute exposure to drug or nondrug stimuli to reinstate drug seeking is determined following training for drug self-administration and subsequent extinction of the drug-reinforced behavior. We will review studies in which pharmacological agents were injected systemically or intracranially to block (or mimic) reinstatement by drug priming, drug cues, and stressors. We also will review studies in which brain lesions, in vivo microdialysis and electrochemistry, and gene expression methods were used to map brain sites involved in relapse to drug seeking. Subsequently, we will discuss theoretical issues related to the processes underlying relapse to drugs and address methodological issues in studies on reinstatement of drug seeking. Finally, the implications of the findings from the studies reviewed for addiction theories and treatment will be discussed. The main conclusion of this review is that the neuronal mechanisms involved in relapse to heroin and cocaine seeking induced by drug priming, drug cues, and stressors are to a large degree dissociable. The data reviewed also suggest that the neuronal events mediating drug-induced reinstatement are to some degree dissociable from those mediating drug reinforcement. C1 NIDA, Behav Neurosci Branch, IRP, NIH, Baltimore, MD 21224 USA. RP Shaham, Y (reprint author), NIDA, Behav Neurosci Branch, IRP, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM Yshaham@intra.nida.nih.gov RI Kipke, Daryl/A-2167-2009; shaham, yavin/G-1306-2014 NR 330 TC 559 Z9 583 U1 12 U2 66 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 EI 1521-0081 J9 PHARMACOL REV JI Pharmacol. Rev. PD MAR PY 2002 VL 54 IS 1 BP 1 EP 42 DI 10.1124/pr.54.1.1 PG 42 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 530NT UT WOS:000174365500001 PM 11870259 ER PT J AU Drevets, WC Price, JL Bardgett, ME Reich, T Todd, RD Raichle, ME AF Drevets, WC Price, JL Bardgett, ME Reich, T Todd, RD Raichle, ME TI Glucose metabolism in the amygdala in depression: Relationship to diagnostic subtype and plasma cortisol levels SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Review DE positron emission tomography; major depression; bipolar disorder; amygdala; cortisol ID CORTICOTROPIN-RELEASING FACTOR; MEDIAL PREFRONTAL CORTEX; EMISSION COMPUTED-TOMOGRAPHY; FACTOR-LIKE IMMUNOREACTIVITY; RECURRENT MAJOR DEPRESSION; CEREBRAL BLOOD-FLOW; BIPOLAR DISORDER; PARAVENTRICULAR NUCLEUS; UNIPOLAR DEPRESSION; MOOD DISORDERS AB In a previous positron emission tomography (PET) study of major depression, we demonstrated that cerebral blood flow was increased in the left amygdala, in unipolar depressives with familial pure depressive disease (FPDD) relative to healthy controls [J. Neurosci. 12 (1992) 3628.]. These measures were obtained from relatively low-resolution PET images using a stereotaxic method based upon skull X-ray landmarks. The current experiments aimed to replicate and extend these results using higher-resolution glucose metabolism images and magnetic resonance imaging (MRI)-based region-of-interest (ROI) analysis. The specificity of this finding to FPDD was also investigated by assessing depressed samples with bipolar disorder (BD-D) and depression spectrum disease (DSD). Finally, the relationship between amygdala metabolism and plasma cortisol levels obtained during the scanning procedure was assessed. Glucose metabolism was measured using PET and F-18-fluorodeoxyglucose ((18)FDG) in healthy control (n = 12), FPDD (n = 12), DSD (n = 9) and BD-D (n = 7) samples in the amygdala and the adjacent hippocampus. The left amygdala metabolism differed across groups (P<.001), being increased in both the FPDD and BD-D groups relative to the control group. The left amygdala metabolism was positively correlated with stressed plasma cortisol levels in both the unipolar (r =.69; P<,005) and the bipolar depressives (r = 0.68;. 195% pure as determined by Coomassie blue-stained sodium dodecyl sulfate-polyacrylamide gel electrophoresis, high-pressure size-exclusion chromatography, and capillary zonal electrophoresis. The endotoxin level was <0.6 EU/mg. Final estimated yield of purified rSEB was 147 mg/L of starting culture. Purified rSEB was stable, elicited an immune response in mice, and protected mice against a lethal challenge with the native toxin. (C) 2002 Elsevier Science (USA). C1 NCI, SAIC Frederick, Biopharmaceut Dev Program, Frederick, MD 21702 USA. USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. RP Giardina, SL (reprint author), NCI, SAIC Frederick, Biopharmaceut Dev Program, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 27 TC 24 Z9 27 U1 2 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD MAR PY 2002 VL 24 IS 2 BP 302 EP 312 DI 10.1006/prep.2001.1556 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 526ZP UT WOS:000174159800017 PM 11858726 ER PT J AU Ma, C Marassi, FM Jones, DH Straus, SK Bour, S Strebel, K Schubert, U Oblatt-Montal, M Montal, M Opella, SJ AF Ma, C Marassi, FM Jones, DH Straus, SK Bour, S Strebel, K Schubert, U Oblatt-Montal, M Montal, M Opella, SJ TI Expression, purification, and activities of full-length and truncated versions of the integral membrane protein Vpu from HIV-1 SO PROTEIN SCIENCE LA English DT Article DE HIV-1; Vpu; membrane proteins; overexpression; NMR spectroscopy; ion channel activity ID VIRUS TYPE-1 VPU; TRIPLE-RESONANCE NMR; PARTICLE RELEASE; CYTOPLASMIC DOMAIN; HIGH-SENSITIVITY; ION CHANNELS; AIDS VIRUS; IMMUNODEFICIENCY; CD4; DEGRADATION AB Vpu is an 81-residue accessory protein of HIV-1. Because it is a membrane protein, it presents substantial technical challenges for the characterization of its structure and function, which are of considerable interest because the protein enhances the release of new virus particles from cells infected with HIV-1 and induces the intracellular degradation of the CD4 receptor protein. The Vpu-mediated enhancement of the virus release rate from HIV-1-infected cells is correlated with the expression of an ion channel activity associated with the transmembrane hydrophobic helical domain. Vpu-induced CD4 degradation and, to a lesser extent, enhancement of particle release are both dependent on the phosphorylation of two highly conserved serine residues in the cytoplasmic domain of Vpu. To define the minimal folding units of Vpu and to identify their activities, we prepared three truncated forms of Vpu and compared their structural and functional properties to those of full-length Vpu (residues 2-81). Vpu(2-37) encompasses the N-terminal transmembrane alpha-helix; Vpu(2-51) spans the N-terminal transmembrane helix and the first cytoplasmic alpha-helix; Vpu(28-81) includes the entire cytoplasmic domain containing the two C-terminal amphipathic alpha-helices without the transmembrane helix. Uniformly isotopically labeled samples of the polypeptides derived from Vpu were prepared by expression of fusion proteins in E. coli and were studied in the model membrane environments of lipid micelles by solution NMR spectroscopy and oriented lipid bilayers by solid-state NMR spectroscopy. The assignment of backbone resonances enabled the secondary structure of the constructs corresponding to the transmembrane and the cytoplasmic domains of Vpu to be defined in micelle samples by solution NMR spectroscopy. Solid-state NMR spectra of the polypeptides in oriented lipid bilayers demonstrated that the topology of the domains is retained in the truncated polypeptides. The biological activities of the constructs of Vpu were evaluated. The ion channel activity is confined to the transmembrane alpha-helix. The C-terminal alpha-helices modulate or promote the oligomerization of Vpu in the membrane and stabilize the conductive state of the channel, in addition to their involvement in CD4 degradation. C1 Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. Univ Calif San Diego, Div Biol, Neurobiol Sect, La Jolla, CA 92093 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Burnham Inst, La Jolla, CA 92037 USA. RP Opella, SJ (reprint author), Univ Calif San Diego, Dept Chem & Biochem, 9500 Gilman Dr, La Jolla, CA 92093 USA. FU NCI NIH HHS [R01 CA082864, R01 CA082864-05]; NCRR NIH HHS [P41RR09731]; NIGMS NIH HHS [P01GM56538] NR 45 TC 93 Z9 99 U1 0 U2 4 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD MAR PY 2002 VL 11 IS 3 BP 546 EP 557 DI 10.1110/ps.37302 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 523BR UT WOS:000173931900011 PM 11847278 ER PT J AU Aravind, L Koonin, EV AF Aravind, L Koonin, EV TI Classification of the caspase-hemoglobinase fold: Detection of new families and implications for the origin of the eukaryotic separins SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE caspase; apoptosis; mitosis; proteobacteria; cyanobacteria; cysteine-protease ID ASPARAGINYL ENDOPEPTIDASE; CRYSTAL-STRUCTURE; ACTIVE-SITE; PSI-BLAST; IDENTIFICATION; ALIGNMENT; APOPTOSIS; SEQUENCE; PREDICTION; EVOLUTION AB A comprehensive sequence and structural comparative analysis of the caspase-hemoglobinase, protein fold resulted in the delineation of the minimal structural core of the protease domain and the identification of numerous, previously undetected members, including a new protease family typified by the HetF protein from the cyanobacterium Nostoc. The first bacterial homologs of legumains and hemoglobinases were also identified. Most proteins containing this fold are known or predicted to be active proteases, but multiple, independent inactivations were noticed in nearly all lineages. Together with the tendency of caspase-related proteases to form intramolecular or intermolecular dimers, this suggests a widespread regulatory role for the inactive forms. A classification of the caspase-hemoglobinase fold was developed to reflect the inferred evolutionary relationships between the constituent protein families. Proteins containing this domain were so far detected almost exclusively in bacteria and eukaryotes. This analysis indicates that caspase-hemoglobinase-fold proteases and their inactivated derivatives are widespread in diverse bacteria, particularly those with a complex development, such as Streptomyces, Anabaena, Mesorhizobium, and Myxococcus. The eukaryotic separin family was shown to be most closely related to the mainly prokaryotic HetF family. The phyletic patterns and evolutionary relationships between these proteins suggest that they probably were acquired by eukaryotes from bacteria during the primary, promitochondrial endosymbiosis. A similar scenario, supported by phylogenetic analysis, seems to apply to metacaspases and paracaspases, with the latter, perhaps, being acquired in an independent horizontal transfer to the eukaryotes. The acquisition of the caspase-hemoglobinase-fold domains by eukaryotes might have been critical in the evolution of important eukaryotic processes, such as mitosis and programmed cell death. (C) 2002 Wiley-Liss, Inc. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. NR 48 TC 98 Z9 101 U1 2 U2 11 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-3585 J9 PROTEINS JI Proteins PD MAR 1 PY 2002 VL 46 IS 4 BP 355 EP 367 DI 10.1002/prot.10060 PG 13 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 525XA UT WOS:000174098300002 PM 11835511 ER PT J AU Bhatara, VS Feil, M Hoagwood, K Vitiello, B Zima, B AF Bhatara, VS Feil, M Hoagwood, K Vitiello, B Zima, B TI Trends in combined pharmacotherapy with stimulants for children SO PSYCHIATRIC SERVICES LA English DT Editorial Material ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER C1 Univ S Dakota, Dept Psychiat, Vermillion, SD USA. Natl Inst Mental Hlth, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Hlth Serv Res Ctr, Los Angeles, CA 90024 USA. RP Bhatara, VS (reprint author), 2601 W Nicole Dr, Sioux Falls, SD 57105 USA. NR 4 TC 11 Z9 11 U1 0 U2 0 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1075-2730 J9 PSYCHIATR SERV JI Psychiatr. Serv. PD MAR PY 2002 VL 53 IS 3 BP 244 EP 244 DI 10.1176/appi.ps.53.3.244 PG 1 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 527AN UT WOS:000174162700002 PM 11875215 ER PT J AU Heinssen, RK AF Heinssen, RK TI Improving medication compliance of a patient with schizophrenia through collaborative behavioral therapy SO PSYCHIATRIC SERVICES LA English DT Editorial Material ID OUTPATIENTS C1 NIMH, Psychot Disorders Res Program, Div Mental Disorders Behav Res & AIDS, Bethesda, MD 20892 USA. RP Heinssen, RK (reprint author), NIMH, Psychot Disorders Res Program, Div Mental Disorders Behav Res & AIDS, 6001 Execut Blvd, Bethesda, MD 20892 USA. NR 9 TC 7 Z9 7 U1 0 U2 0 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1075-2730 J9 PSYCHIATR SERV JI Psychiatr. Serv. PD MAR PY 2002 VL 53 IS 3 BP 255 EP 257 DI 10.1176/appi.ps.53.3.255 PG 3 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 527AN UT WOS:000174162700003 PM 11875216 ER PT J AU Wenzel, LB Donnelly, JP Fowler, JM Habbal, R Taylor, TH AF Wenzel, LB Donnelly, JP Fowler, JM Habbal, R Taylor, TH TI Resilience, reflection, and residual stress in ovarian cancer survivorship: A Gynecologic Oncology Group study SO PSYCHO-ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; RANDOMIZED TRIALS; HEALTH SURVEY; CISPLATIN; SCALE; QUESTIONNAIRE; MANAGEMENT; VALIDATION; MORBIDITY; THERAPY AB Ovarian cancer is a life-threatening diagnosis which poses multiple challenges. The purpose of this study is to describe the quality of life (QOL) concerns and survivorship sequelae of long-term (>5yr) early-stage ovarian cancer survivors accrued through the clinical cooperative Gynecologic Oncology Group. Forty-nine ovarian cancer survivors with a mean age at diagnosis of 55.9yr (range 30 76) completed a telephone interview assessing QOL, psychosocial status, sexual functioning and late-effects of treatment. Results indicate that this disease-free early-stage sample enjoys a good QOL, with physical, emotional, and social well-being comparable to other survivors and same-aged noncancer cohorts. However, 20% of survivors indicated the presence of long-term treatment side effects, with a subset reporting problems related to abdominal and gynecologic symptoms, and neurotoxicity. Spiritual wellbeing was significantly positively associated with personal growth and mental health, and negatively associated with a declining health status. Lingering psychological survivorship sequelae included fear of follow-up diagnostic tests and fear of recurrence. Forty-three percent of respondents expressed that they would likely participate in a counseling program today to discuss pychosocial issues raised by having had ovarian cancer, and 56% stated that they would have attended a support program during the initial treatment if it had been offered. This information provides some insight into the complex survivorship relationships between quality of life, long-term physical and sexual sequelae, and factors of resilience and growth which appear to promote a sense of well-being as a result of the cancer experience. Copyright (C) 2002 John Wiley Sons, Ltd. C1 Univ Calif Irvine, Coll Med, Div Epidemiol, Irvine, CA 92697 USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Ohio State Univ, Columbus, OH 43210 USA. Natl Canc Inst, Bethesda, MD 20892 USA. Northwestern Univ, Evanston, IL 60208 USA. RP Wenzel, LB (reprint author), Univ Calif Irvine, Coll Med, Div Epidemiol, 224 Irvine Hall, Irvine, CA 92697 USA. FU NCI NIH HHS [1R01CA79039-01] NR 45 TC 136 Z9 139 U1 3 U2 14 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD MAR-APR PY 2002 VL 11 IS 2 BP 142 EP 153 DI 10.1002/pon.567 PG 12 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 533CB UT WOS:000174510900007 PM 11921330 ER PT J AU Umhau, JC George, DT Reed, S Petrulis, SG Rawlings, R Porges, SW AF Umhau, JC George, DT Reed, S Petrulis, SG Rawlings, R Porges, SW TI Atypical autonomic regulation in perpetrators of violent domestic abuse SO PSYCHOPHYSIOLOGY LA English DT Article DE domestic violence; respiratory sinus arrhythmia; autonomic nervous system; alcoholism; cardiac vagal tone; heart rate ID RESPIRATORY SINUS ARRHYTHMIA; HEART-RATE; POLYVAGAL THEORY; NERVOUS-SYSTEM; PLASMA NOREPINEPHRINE; PANIC DISORDER; BEHAVIOR; ALCOHOL; ANXIETY; RESPONSIVITY AB Perpetrators of domestic violence describe symptoms that are compatible with exaggerated autonomic arousal at the time of the domestic violence. This inappropriate arousal may be reflected in altered heart rate regulation. If heart rate is systematically regulated by vagal mechanisms, then increases in heart rate should correlate with decreases in cardiac vagal activity, as indexed by respiratory sinus arrhythmia (RSA). We hypothesized that perpetrators of domestic violence have an alteration in heart rate regulation. To test this hypothesis we compared the results of a postural shift performed on perpetrators, healthy volunteers, and nonviolent alcoholics. Results showed there were no significant differences in heart rate, RSA, or catecholamines. However, the significant inverse relationship between posture-elicited changes in RSA and heart rate present in the healthy volunteers was not found in perpetrators. These differences in the covariation between heart rate and RSA may represent differences in the neural regulation of heart rate and may be related to difficulties in controlling autonomic state. C1 NIAAA, Clin Studies Lab, DICBR, Bethesda, MD 20892 USA. Univ Maryland, Inst Child Study, Dept Human Dev, College Pk, MD 20742 USA. RP Umhau, JC (reprint author), NIAAA, Clin Studies Lab, DICBR, 10 Ctr Dr MSC-1610,Bldg 10,Room 6S-240, Bethesda, MD 20892 USA. NR 58 TC 11 Z9 11 U1 3 U2 9 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD MAR PY 2002 VL 39 IS 2 BP 117 EP 123 DI 10.1017/S0048577201392016 PG 7 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 535UU UT WOS:000174665400001 PM 12212660 ER PT J AU Katz, DG Dutcher, GA Toigo, TA Bates, R Temple, F Cadden, CG AF Katz, DG Dutcher, GA Toigo, TA Bates, R Temple, F Cadden, CG TI The AIDS Clinical Trials Information Service (ACTIS): A decade of providing clinical trials information SO PUBLIC HEALTH REPORTS LA English DT Article ID PREVENTION; CALLERS; HOTLINE; IMPACT; HEALTH AB The AIDS Clinical Trials Information Service (ACTIS) is a central resource for information about federally and privately funded HIV/AIDS clinical trials. Sponsored by four components of the U.S. Department of Health and Human Services, ACTIS has been a key part of U.S. HIV/AIDS information and education services since 1989. ACTIS offers a toll-free telephone service, through which trained information specialists can provide callers with information about AIDS clinical trials in English or Spanish, and a website that provides access to clinical trials databases and a variety of educational resources. Future priorities include the development of new resources to target diverse and underserved populations. In addition, research needs to be conducted on the use of telephone services vs. Web-based information exchange to ensure the broadest possible dissemination of up-to-date information on HIV infection and clinical trials. C1 NIAID, DMID, NIH, Bethesda, MD 20892 USA. Food & Drug Adm, Off Special Hlth Issues, Washington, DC USA. Aspen Syst Corp, Rockville, MD USA. RP Katz, DG (reprint author), NIAID, DMID, NIH, 6700B Rockledge Dr, Bethesda, MD 20892 USA. NR 17 TC 2 Z9 2 U1 0 U2 0 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 0033-3549 J9 PUBLIC HEALTH REP JI Public Health Rep. PD MAR-APR PY 2002 VL 117 IS 2 BP 123 EP 130 DI 10.1093/phr/117.2.123 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 605MC UT WOS:000178680800004 PM 12356996 ER PT J AU Schmidt, KC Turkheimer, FE AF Schmidt, KC Turkheimer, FE TI Kinetic modeling in positron emission tomography SO QUARTERLY JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE tomography, emission computed, instrumentation; radiopharmaceuticals; tomography, emission computed, methods ID CEREBRAL-BLOOD-FLOW; BRAIN TRANSFER CONSTANTS; GLUCOSE METABOLIC-RATE; TIME UPTAKE DATA; GRAPHICAL ANALYSIS; SPECTRAL-ANALYSIS; F-18 FLUORODEOXYGLUCOSE; HETEROGENEOUS TISSUES; DYNAMIC PET; INTRAVENOUS (H2O)-O-15 AB Most PET kinetic modeling approaches have at their basis a compartmental model that has first-order, constant coefficients. The present article outlines the one-, two-, and three-compartment models used to measure cerebral blood flow, cerebral glucose metabolism, and receptor binding, respectively. The number of compartments of each model is based on specific knowledge of the physiological and/or biochemical compartments into which the tracer distributes. Additional physical and biochemical properties of the tracer distribution are considered in specifying the use of first-order rate constants. For example, in cerebral blood flow and receptor binding studies transport across the bloodbrain barrier by diffusion can be modeled as a first-order process. A saturable carrier-mediated process or saturable enyzme catalyzed reaction, when tracer doses of the labeled substrate are used and the natural substrate is in steady-state, also results in first-order rate constants, as in glucose metabolism studies. The rate of ligand binding, on the other hand, depends on the concentrations of both substrate and available receptors. In order to appropriately model the reaction as pseudo first-order during a specified experimental interval, protocols are carefully designed to assure that the number of available binding sites remains approximately constant throughout the given interval. A broad array of scanning protocols is employed for kinetic analyses. These include single-scan approaches, which function like their autoradiographic counterparts in animal studies and are often called "autoradiographic" methods, which allow estimation of a single parameter. Dynamic scanning to obtain the time course of tissue activity allows simultaneous estimation of multiple parameters. Scanning may be conducted during a period of tracer uptake or after attainment of steady-state conditions. All quantitative modeling approaches share the common requirement that an arterial Input function be measured or an appropriate surrogate be found. A vast array of methods is available for estimation of model parameters, both micro and macro. In the final analysis, it is the interaction among all elements of the PET study, including careful tracer selection, model specification, experimental protocol design, and sound parameter estimation methods, that determines the quantitative accuracy of the estimates of the physiological or biochemical process under study. C1 NIMH, Cerebral Metab Lab, Bethesda, MD 20892 USA. Hammersmith Hosp, Imaging Res Solut Ltd, London, England. RP NIMH, Cerebral Metab Lab, Bldg 36,Room 1 A-07,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Kathy@shiloh.nimh.nih.gov RI Turkheimer, Federico/B-9485-2012 OI Turkheimer, Federico/0000-0002-3766-3815 NR 80 TC 52 Z9 53 U1 1 U2 9 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 1125-0135 J9 Q J NUCL MED JI Q. J. Nucl. Med. PD MAR PY 2002 VL 46 IS 1 BP 70 EP 85 PG 16 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 573ZD UT WOS:000176862600009 PM 12072847 ER PT J AU Koshurnikova, NA Gilbert, ES Shilnikova, NS Sokolnikov, M Preston, DL Kreisheimer, M Ron, E Okatenko, P Romanov, SA AF Koshurnikova, NA Gilbert, ES Shilnikova, NS Sokolnikov, M Preston, DL Kreisheimer, M Ron, E Okatenko, P Romanov, SA TI Studies on the Mayak nuclear workers: health effects SO RADIATION AND ENVIRONMENTAL BIOPHYSICS LA English DT Article ID PLUTONIUM; CANCERS C1 NCI, Radiat Epidemiol Branch, Div Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. So Urals Biophys Inst, Ozyorsk 456780, Russia. Radiat Effects Res Fdn, Dept Stat, Minami Ku, Hiroshima 732, Japan. Radiat Effects Res Fdn, Dept Epidemiol, Minami Ku, Hiroshima 732, Japan. Univ Munich, Inst Radiobiol, D-30336 Munich, Germany. RP Gilbert, ES (reprint author), NCI, Radiat Epidemiol Branch, Div Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NR 8 TC 12 Z9 13 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0301-634X J9 RADIAT ENVIRON BIOPH JI Radiat. Environ. Biophys. PD MAR PY 2002 VL 41 IS 1 BP 29 EP 31 DI 10.1007/s00411-001-0130-7 PG 3 WC Biology; Biophysics; Environmental Sciences; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Environmental Sciences & Ecology; Radiology, Nuclear Medicine & Medical Imaging GA 541HM UT WOS:000174979200006 PM 12014404 ER PT J AU Khokhryakov, VV Drozhko, EG Glagolenko, YV Rovny, SI Vasilenko, EK Suslov, A Anspaugh, LR Napier, BA Bouville, A Khokhryakov, VF Suslova, KG Romanov, SA AF Khokhryakov, VV Drozhko, EG Glagolenko, YV Rovny, SI Vasilenko, EK Suslov, A Anspaugh, LR Napier, BA Bouville, A Khokhryakov, VF Suslova, KG Romanov, SA TI Studies on the Ozyorsk population: dosimetry SO RADIATION AND ENVIRONMENTAL BIOPHYSICS LA English DT Article C1 Univ Utah, Dept Radiol, Div Radiobiol, Salt Lake City, UT 84108 USA. Mayak Prod Assoc, Ozyorsk 456780, Russia. Pacific NW Natl Lab, Richland, WA 99352 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. So Urals Biophys Inst, Ozyorsk 456780, Russia. RP Anspaugh, LR (reprint author), Univ Utah, Dept Radiol, Div Radiobiol, Salt Lake City, UT 84108 USA. NR 6 TC 10 Z9 11 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0301-634X J9 RADIAT ENVIRON BIOPH JI Radiat. Environ. Biophys. PD MAR PY 2002 VL 41 IS 1 BP 33 EP 35 DI 10.1007/S00411-002-0147-6 PG 3 WC Biology; Biophysics; Environmental Sciences; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Environmental Sciences & Ecology; Radiology, Nuclear Medicine & Medical Imaging GA 541HM UT WOS:000174979200007 PM 12014405 ER PT J AU Koshurnikova, NA Mushkacheva, GS Shilnikova, NS Rabinovich, EI Petrushkina, NP Hall, P Bolotnikova, MG Preston, DL Ron, E AF Koshurnikova, NA Mushkacheva, GS Shilnikova, NS Rabinovich, EI Petrushkina, NP Hall, P Bolotnikova, MG Preston, DL Ron, E TI Studies on the Ozyorsk population: health effects SO RADIATION AND ENVIRONMENTAL BIOPHYSICS LA English DT Article C1 NCI, Div Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. So Urals Biophys Inst, Epidemiol Lab, Ozyorsk 456780, Russia. So Urals Biophys Inst, Lab Screening Studies, Ozyorsk 456780, Russia. Karolinska Inst, Dept Med Epidemiol, S-17177 Stockholm, Sweden. Radiat Effects Res Fdn, Dept Stat, Minami Ku, Hiroshima 732, Japan. Radiat Effects Res Fdn, Dept Epidemiol, Minami Ku, Hiroshima 732, Japan. RP Ron, E (reprint author), NCI, Div Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NR 7 TC 7 Z9 9 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0301-634X J9 RADIAT ENVIRON BIOPH JI Radiat. Environ. Biophys. PD MAR PY 2002 VL 41 IS 1 BP 37 EP 39 DI 10.1007/s00411-001-0133-4 PG 3 WC Biology; Biophysics; Environmental Sciences; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Environmental Sciences & Ecology; Radiology, Nuclear Medicine & Medical Imaging GA 541HM UT WOS:000174979200008 PM 12014406 ER PT J AU Kossenko, MM Preston, DL Krestinina, LY Degteva, MO Startsev, NV Thomas, T Vyushkova, OV Anspaugh, LR Napier, BA Kozheurov, VP Ron, E Akleyev, AV AF Kossenko, MM Preston, DL Krestinina, LY Degteva, MO Startsev, NV Thomas, T Vyushkova, OV Anspaugh, LR Napier, BA Kozheurov, VP Ron, E Akleyev, AV TI Studies on the extended Techa river cohort: cancer risk estimation SO RADIATION AND ENVIRONMENTAL BIOPHYSICS LA English DT Article ID POPULATION; MORTALITY; SYSTEM C1 Radiat Effects Res Fdn, Dept Stat, Minami Ku, Hiroshima 732, Japan. Radiat Effects Res Fdn, Dept Epidemiol, Minami Ku, Hiroshima 732, Japan. Urals Res Ctr Radiat Med, Chelyabinsk 454076, Russia. Univ Utah, Dept Radiol, Div Radiobiol, Salt Lake City, UT 84108 USA. Pacific NW Natl Lab, Richland, WA 99352 USA. NCI, Radiat Epidemiol Branch, Div Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Preston, DL (reprint author), Radiat Effects Res Fdn, Dept Stat, Minami Ku, 5-2 Hijiyama Pk, Hiroshima 732, Japan. FU NCI NIH HHS [N01-CP-81034, NIH-CP-51025] NR 7 TC 16 Z9 18 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0301-634X J9 RADIAT ENVIRON BIOPH JI Radiat. Environ. Biophys. PD MAR PY 2002 VL 41 IS 1 BP 45 EP 48 DI 10.1007/s00411-001-0132-5 PG 4 WC Biology; Biophysics; Environmental Sciences; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Environmental Sciences & Ecology; Radiology, Nuclear Medicine & Medical Imaging GA 541HM UT WOS:000174979200010 PM 12014408 ER PT J AU Gordeev, K Vasilenko, I Lebedev, A Bouville, A Luckyanov, N Simon, SL Stepanov, Y Shinkarev, S Anspaugh, L AF Gordeev, K Vasilenko, I Lebedev, A Bouville, A Luckyanov, N Simon, SL Stepanov, Y Shinkarev, S Anspaugh, L TI Fallout from nuclear tests: dosimetry in Kazakhstan SO RADIATION AND ENVIRONMENTAL BIOPHYSICS LA English DT Article C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Minist Hlth, Inst Biophys, State Res Ctr, Moscow, Russia. Univ Utah, Dept Radiol, Salt Lake City, UT 84108 USA. RP Bouville, A (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RI Shinkarev, Sergey /B-3254-2017 NR 7 TC 43 Z9 47 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0301-634X J9 RADIAT ENVIRON BIOPH JI Radiat. Environ. Biophys. PD MAR PY 2002 VL 41 IS 1 BP 61 EP 67 DI 10.1007/s00411-011-0139-y PG 7 WC Biology; Biophysics; Environmental Sciences; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Environmental Sciences & Ecology; Radiology, Nuclear Medicine & Medical Imaging GA 541HM UT WOS:000174979200014 PM 12014413 ER PT J AU Grosche, B Land, C Bauer, S Pivina, LM Abylkassimova, ZN Gusev, BI AF Grosche, B Land, C Bauer, S Pivina, LM Abylkassimova, ZN Gusev, BI TI Fallout from nuclear tests: health effects in Kazakhstan SO RADIATION AND ENVIRONMENTAL BIOPHYSICS LA English DT Article ID TEST-RELATED RADIATION; TEST-SITE; CANCER C1 Fed Off Radiat Protect, Inst Radiat Hyg, D-85762 Oberschleissheim, Germany. NCI, Bethesda, MD 20892 USA. Kazakh Res Inst Radiat Med & Ecol, Semipalatinsk 490046, Kazakhstan. RP Fed Off Radiat Protect, Inst Radiat Hyg, D-85762 Oberschleissheim, Germany. EM bgrosche@bfs.de OI Grosche, Bernd/0000-0003-2024-3555 NR 5 TC 26 Z9 28 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-634X EI 1432-2099 J9 RADIAT ENVIRON BIOPH JI Radiat. Environ. Biophys. PD MAR PY 2002 VL 41 IS 1 BP 75 EP 80 DI 10.1007/s00411-001-0136-1 PG 6 WC Biology; Biophysics; Environmental Sciences; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Environmental Sciences & Ecology; Radiology, Nuclear Medicine & Medical Imaging GA 541HM UT WOS:000174979200016 PM 12014415 ER PT J AU Farb, RI Kim, JK Willinsky, RA Montanera, WJ terBrugge, K Derbyshire, JA van Dijk, JMC Wright, GA AF Farb, RI Kim, JK Willinsky, RA Montanera, WJ terBrugge, K Derbyshire, JA van Dijk, JMC Wright, GA TI Spinal dural arteriovenous fistula localization with a technique of first-pass gadolinium-enhanced MR angiography: Initial experience SO RADIOLOGY LA English DT Article DE arteriovenous malformations, dural; dura; dura, MR; fistula, arteriovenous; magnetic resonance (MR), vascular studies; spinal cord, abnormalities ID VASCULAR MALFORMATIONS; ORDER AB Nine patients with initial magnetic resonance (MR) imaging and clinical findings suggestive of spinal dural arteriovenous fistula (AVF) underwent spinal MR angiography with an autotriggered elliptic centric ordered three-dimensional gadolinium-enhanced technique (hereafter, this MR angiographic technique) before conventional intraarterial angiography. In all nine patients, findings with this MR angiographic technique correctly and precisely localized the spinal dural AVF. Observer error resulted in one case in which the site of the fistula was not prospectively reported but was easily identified retrospectively on the spinal MR angiogram. (C) RSNA, 2002. C1 Toronto Western Hosp, Dept Med Imaging, Div Neuroradiol, Toronto, ON M5T 2S8, Canada. NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. Leiden Univ, Med Ctr, Dept Neurosurg, Leiden, Netherlands. Univ Toronto, Sunnybrook & Womens Coll Hlth Sci Ctr, Dept Med Res, Toronto, ON, Canada. RP Farb, RI (reprint author), Toronto Western Hosp, Dept Med Imaging, Div Neuroradiol, Fell Pavil 3-404,399 Bathurst St, Toronto, ON M5T 2S8, Canada. RI van Dijk, J. Marc C./C-1078-2013 OI van Dijk, J. Marc C./0000-0002-0814-5680 NR 23 TC 79 Z9 81 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAR PY 2002 VL 222 IS 3 BP 843 EP 850 DI 10.1148/radiol.2223010826 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 524TX UT WOS:000174029900039 PM 11867811 ER PT J AU Alter, BP AF Alter, BP TI Radiosensitivity in Fanconi's anemia patients SO RADIOTHERAPY AND ONCOLOGY LA English DT Article DE Fanconi's anemia; radiation sensitivity; head and neck cancer ID BONE-MARROW TRANSPLANTATION; SQUAMOUS-CELL CARCINOMA; TONGUE AB The risks of radiation therapy in patients with Fanconi's anemia who have cancer are not clear. Possible toxicity was reported in six of 14 patients: 1/1 with vaginal cancer, 4/10 with head and neck or esophageal cancer, and 1/3 with oral cancer following bone marrow transplant. Published by Elsevier Science Ireland Ltd. C1 NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Alter, BP (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7020, Rockville, MD 20852 USA. NR 24 TC 66 Z9 69 U1 1 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0167-8140 J9 RADIOTHER ONCOL JI Radiother. Oncol. PD MAR PY 2002 VL 62 IS 3 BP 345 EP 347 AR PII S0167-8140(01)00474-1 DI 10.1016/S0167-8140(01)00474-1 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 561TQ UT WOS:000176159100012 PM 12175566 ER PT J AU Algire, MA Maag, D Savio, P Acker, MG Tarun, SZ Sachs, AB Asano, K Nielsen, KH Olsen, DS Phan, L Hinnebusch, AG Lorsch, JR AF Algire, MA Maag, D Savio, P Acker, MG Tarun, SZ Sachs, AB Asano, K Nielsen, KH Olsen, DS Phan, L Hinnebusch, AG Lorsch, JR TI Development and characterization of a reconstituted yeast translation initiation system SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE elF; eukaryotic initiation factor; kinetics; mechanism; mRNA; ribosome; tRNA ID PROTEIN-SYNTHESIS; SACCHAROMYCES-CEREVISIAE; RABBIT RETICULOCYTES; RIBOSOMAL-SUBUNITS; START CODON; MECHANISM; COMPLEX; EIF2B; RNA; 1A AB To provide a bridge between in vivo and in vitro studies of eukaryotic translation initiation, we have developed a reconstituted translation initiation system using components from the yeast Saccharomyces cerevisiae. We have purified a minimal set of initiation factors (eIFs) that, together with yeast 80S ribosomes, GTP, and initiator methionyl-tRNA, are sufficient to assemble active initiation complexes on a minimal mRNA template. The kinetics of various steps in the pathway of initiation complex assembly and the formation of the first peptide bond in vitro have been explored. The formation of active initiation complexes in this system is dependent on ribosomes, mRNA, Met-tRNA(i), GTP hydrolysis, eIF1, eIF1 A, eIF2, eIF5, and eIF5B. Our data indicate that eIF1 and eIF1 A both facilitate the binding of the eIF2.GTP.Met-tRNA(i) complex to the 40S ribosomal subunit to form the 43S complex. eIF5 stimulates a step after 43S complex formation, consistent with its proposed role in activating GTP hydrolysis by eIF2 upon initiation codon recognition. The presence of eIF5B is required for the joining of the 40S and 60S subunits to form the 80S initiation complex. The step at which each of these factors acts in this reconstituted system is in agreement with previous data from in vivo studies and work using reconstituted mammalian systems, indicating that the system recapitulates fundamental events in translation initiation in eukaryotic cells. This system should allow us to couple powerful yeast genetic and molecular biological experiments with in vitro kinetic and biophysical experiments, yielding a better understanding of the molecular mechanics of this central, complex process. C1 Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. NICHHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Lorsch, JR (reprint author), Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, 725 N Wolfe St, Baltimore, MD 21205 USA. OI Lorsch, Jon/0000-0002-4521-4999 NR 27 TC 93 Z9 95 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD MAR PY 2002 VL 8 IS 3 BP 382 EP 397 DI 10.1017/S1355838202029527 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 544JY UT WOS:000175155500011 PM 12008673 ER PT J AU Ferguson, AD Chakraborty, R Smith, BS Esser, L van der Helm, D Deisenhofer, J AF Ferguson, AD Chakraborty, R Smith, BS Esser, L van der Helm, D Deisenhofer, J TI Structural basis of gating by the outer membrane transporter FecA SO SCIENCE LA English DT Article ID INDUCED CONFORMATIONAL CHANGE; ENTEROBACTIN RECEPTOR FEPA; FERRIC CITRATE TRANSPORT; ELECTRON-DENSITY MAPS; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; ANOMALOUS DIFFRACTION; IRON TRANSPORT; PROTEIN TONB; FHUA AB Siderophore-mediated acquisition systems facilitate iron uptake. We present the crystallographic structure of the integral outer membrane receptor FecA from Escherichia coli with and without ferric citrate at 2.5 and 2.0 angstrom resolution. FecA is composed of three distinct domains: the barrel, plug, and NH2-terminal extension. Binding of ferric citrate triggers a conformational change of the extracellular loops that close the external pocket of FecA. Ligand-induced allosteric transitions are propagated through the outer membrane by the plug domain, signaling the occupancy of the receptor in the periplasm. These data establish the structural basis of gating for receptors dependent on the cytoplasmic membrane protein TonB. By compiling available data for this family of receptors, we propose a mechanism for the energy-dependent transport of siderophores. C1 Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA. Univ Oklahoma, Dept Chem & Biochem, Norman, OK 73019 USA. E Tennessee State Univ, Coll Publ & Allied Hlth, Dept Hlth Sci, Johnson City, TN 37614 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Victoria, Dept Biochem & Microbiol, Victoria, BC V8W 3P6, Canada. RP Deisenhofer, J (reprint author), Univ Texas, SW Med Ctr, Howard Hughes Med Inst, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. NR 40 TC 243 Z9 248 U1 0 U2 14 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 MAR 1 PY 2002 VL 295 IS 5560 BP 1715 EP 1719 DI 10.1126/science.1067313 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 527XH UT WOS:000174212900047 PM 11872840 ER PT J AU Castle, PE Shields, T Kirnbauer, R Manos, MM Burk, RD Glass, AG Scott, DR Sherman, ME Schiffman, M AF Castle, PE Shields, T Kirnbauer, R Manos, MM Burk, RD Glass, AG Scott, DR Sherman, ME Schiffman, M TI Sexual behavior, human papillomavirus type 16 (HPV 16) infection, and HPV 16 seropositivity SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID VIRUS-LIKE PARTICLES; SQUAMOUS INTRAEPITHELIAL LESIONS; CYTOLOGICALLY NORMAL WOMEN; EPIDEMIOLOGIC EVIDENCE; CERVICAL NEOPLASIA; SEROREACTIVITY; DNA; CANCER AB Background. Sexual behaviors have been linked to seropositivity for human papilloma-virus (HPV) but not with the magnitude of the seroreactivity. Goals: The objective of this analysis was to examine the association of sexual behavior, cervical HPV 16 DNA positivity at enrollment (past) and at diagnosis (current), and other potential determinants with the likelihood and magnitude of HPV 16 seropositivity at diagnosis. Study Design: With use of stored specimens from an incidence case-control study at Kaiser Permanente (Portland, OR), women were tested for seroreactivity to HPV 16 by enzyme-linked immunosorbent assay with virus-like particles at diagnosis and were tested for past and concurrent cervical HPV 16 DNA positivity with MY09/MY11 L1 consensus primer PCR. Questionnaire data were used to ascertain past sexual behavior. Results: Increased lifetime number of sex partners (P-Trend < 0.001), past FIPV 16 DNA positivity (odds ratio = 6.9; 95% confidence interval = 1.5-31), and a current cytologic diagnosis (P-Trend < 0.03) were independently associated with HPV 16 seropositivity. Among the seropositive, only lifetime number of sex partners (P-Trend < 0.001) and past HPV 16 DNA positivity (P = 0.003) were independently associated with mean signal strength (optical density) in an age-adjusted analysis. Women negative for past and concurrent HPV 16 DNA had a significant trend of increasing optical densities associated with greater numbers of lifetime partners (P-Trend < 0.001). Conversely, the mean signal strength for those women who were ever HPV 16 DNA-positive during the study did not depend on lifetime numbers of sex partners (P-Trend = 0.36). Conclusions: HPV 16 seropositivity is a surrogate for past HPV 16 infection. Circulating levels of antibodies to HPV 16 may reflect recent HPV 16 infection or the frequency of past HPV 16 infection. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Vienna, Sch Med, Dept Dermatol, Div Immunol Allergy & Infect Dis, Vienna, Austria. Permanente Med Grp Inc, Div Res, Oakland, CA USA. Albert Einstein Coll Med, New York, NY USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7234, Bethesda, MD 20892 USA. NR 22 TC 23 Z9 24 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD MAR PY 2002 VL 29 IS 3 BP 182 EP 187 DI 10.1097/00007435-200203000-00009 PG 6 WC Infectious Diseases SC Infectious Diseases GA 527RQ UT WOS:000174201000009 PM 11875380 ER PT J AU Cohen, PN Casper, LM AF Cohen, PN Casper, LM TI In whose home? Multigenerational families in the United States, 1998-2000 SO SOCIOLOGICAL PERSPECTIVES LA English DT Article ID LIVING ARRANGEMENTS; HOUSEHOLD STRUCTURE; KIN NETWORKS; RACE; MARRIAGE; MOTHERS; PARENT; DETERMINANTS; CORESIDENCE; BLACK AB This article examines multigenerational living arrangements of white, black, and Latino individuals using data from the Current Population Surveys. We describe people in multigenerational households as "hosts" or "guests." In terms of resources, guests have no home of their own, whereas hosts maintain an important source of independence. By age, the proportion of adults living as guests peaks in the late twenties, then declines until the late seventies, In contrast, hosting rates peak in the fifties. Men have higher guest rates and women haze higher host rates at almost all ages. While blacks and Latinos are more likely than whites to live in multigenerational households, those with higher incomes are less likely to live in multigenerational households and if they are living in multigenerational households are less likely to be guests, regardless of race-ethnicity. We interpret this as consistent with the assumption that residential independence is generally preferred. C1 Univ Calif Irvine, Dept Sociol, Irvine, CA 92697 USA. NICHHD, Bethesda, MD 20892 USA. RP Cohen, PN (reprint author), Univ Calif Irvine, Dept Sociol, Irvine, CA 92697 USA. RI Cohen, Philip/H-2269-2016 OI Cohen, Philip/0000-0003-2839-3144 NR 47 TC 33 Z9 33 U1 3 U2 8 PU UNIV CALIF PRESS PI BERKELEY PA C/O JOURNALS DIVISION, 2000 CENTER ST, STE 303, BERKELEY, CA 94704-1223 USA SN 0731-1214 J9 SOCIOL PERSPECT JI Sociol. Perspect. PD SPR PY 2002 VL 45 IS 1 BP 1 EP 20 DI 10.1525/sop.2002.45.1.1 PG 20 WC Sociology SC Sociology GA 542EN UT WOS:000175030700001 ER PT J AU Hodes, RJ AF Hodes, RJ TI The effects of aging on lymphocyte development and function: Introduction SO SPRINGER SEMINARS IN IMMUNOPATHOLOGY LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Hodes, RJ (reprint author), NIH, Bldg 31,Rm 5C35, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-4325 J9 SPRINGER SEMIN IMMUN JI Springer Semin. Immunopathol. PD MAR PY 2002 VL 24 IS 1 BP 1 EP 5 DI 10.1007/s00281-001-0091-6 PG 5 WC Immunology; Pathology SC Immunology; Pathology GA 536JJ UT WOS:000174696700001 PM 11974578 ER PT J AU Fry, TJ Mackall, CL AF Fry, TJ Mackall, CL TI Current concepts of thymic aging SO SPRINGER SEMINARS IN IMMUNOPATHOLOGY LA English DT Article ID T-CELL DEVELOPMENT; BONE-MARROW TRANSPLANTATION; AGE-RELATED-CHANGES; CYCLIN D1; MICE; REGENERATION; REPERTOIRE; INVOLUTION; EXPANSION; RECEPTOR C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Mackall, CL (reprint author), NCI, Pediat Oncol Branch, Bldg 10,Rm 13N240,10 Ctr Dr,MSC 1928, Bethesda, MD 20892 USA. NR 70 TC 37 Z9 38 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-4325 J9 SPRINGER SEMIN IMMUN JI Springer Semin. Immunopathol. PD MAR PY 2002 VL 24 IS 1 BP 7 EP 22 DI 10.1007/s00281-001-0092-5 PG 16 WC Immunology; Pathology SC Immunology; Pathology GA 536JJ UT WOS:000174696700002 PM 11974583 ER PT J AU Weng, NP AF Weng, NP TI Regulation of telomerase expression in human lymphocytes SO SPRINGER SEMINARS IN IMMUNOPATHOLOGY LA English DT Article ID REVERSE-TRANSCRIPTASE HTERT; CATALYTIC SUBUNIT GENE; B-LYMPHOCYTES; T-CELL; TERMINAL TRANSFERASE; HEMATOPOIETIC-CELLS; ANTIGEN RECEPTOR; UP-REGULATION; TUMOR-CELLS; ACTIVATION AB The function of lymphocytes is highly dependent on the ability of cell to divide. Among the various factors that regulate this cellular process. telomerase-dependent maintenance of telomere length has recently drawn considerable attention. Unlike most normal human somatic cells that express telomerase only during development but not after differentiation., lymphocytes express telomerase during development and retain the ability to express telomerase after maturation in response to antigenic challenge. How telomerase is regulated and its precise role in lymphocytes is not fully understood. The recent progress in characterizing regulation of telomerase expression in human lymphocytes is discussed. C1 NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. RP Weng, NP (reprint author), NIA, Immunol Lab, NIH, 5600 Nathan Shock Dr,Box 21, Baltimore, MD 21224 USA. NR 56 TC 19 Z9 20 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-4325 J9 SPRINGER SEMIN IMMUN JI Springer Semin. Immunopathol. PD MAR PY 2002 VL 24 IS 1 BP 23 EP 33 DI 10.1007/s00281-001-0093-4 PG 11 WC Immunology; Pathology SC Immunology; Pathology GA 536JJ UT WOS:000174696700003 PM 11974579 ER PT J AU Nam, JM Blackwelder, WC AF Nam, JM Blackwelder, WC TI Analysis of the ratio of marginal probabilities in a matched-pair setting SO STATISTICS IN MEDICINE LA English DT Article DE constrained maximum likelihood estimator; efficiency of matching; equivalence test in matched-pair studies; power; ratio of marginal probabilities; sample size determination ID SAMPLE-SIZE REQUIREMENTS; UNITY RELATIVE RISK; NULL HYPOTHESIS; MCNEMARS TEST; EQUIVALENCE; PROPORTIONS; DIFFERENCE; DESIGN AB Statistical methods for testing and interval estimation of the ratio of marginal probabilities in the matched-pair setting are considered in this paper. We are especially interested in the situation where the null value is not one, as in one-sided equivalence trials. We propose a Fieller-type statistic based on constrained maximum likelihood (CML) estimation of nuisance parameters. For a series of examples, the significance level of the CML test is satisfactorily close to the nominal level, while a Wald-type test is anticonservative for reasonable sample sizes. We present formulae for approximate power and sample size for the CML and Wald tests. The matched design is seen to have a clear advantage over the unmatched design in terms of asymptotic efficiency when the two responses of the pair are highly positively correlated. We recommend the CML method over the Wald method, especially for small or moderate sample sizes. Published in 2002 by John Wiley Sons, Ltd. C1 NCI, Biostat Branch, Rockville, MD 20852 USA. NIAID, Div Microbiol & Infect Dis, Bethesda, MD 20892 USA. RP Nam, JM (reprint author), NCI, Biostat Branch, Execut Plaza S,Room 8028,6120 Execut Blvd,MSC 724, Rockville, MD 20852 USA. NR 14 TC 23 Z9 25 U1 1 U2 4 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD MAR PY 2002 VL 21 IS 5 BP 689 EP 699 DI 10.1002/sim.1017 PG 11 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 525LW UT WOS:000174074100005 PM 11870810 ER PT J AU Dorgan, JF Fears, TR McMahon, RP Friedman, LA Patterson, BH Greenhut, SF AF Dorgan, JF Fears, TR McMahon, RP Friedman, LA Patterson, BH Greenhut, SF TI Measurement of steroid sex hormones in serum: a comparison of radioimmunoassay and mass spectrometry SO STEROIDS LA English DT Article DE steroid; androgens; estrogens; radioimmunoassays; mass spectrometry; quality control ID REPRODUCIBILITY; ESTROGENS; SULFATE; ASSAYS AB Concern has been raised about the adequacy of radioimmunoassays to measure steroid sex hormones in population studies. We compared steroid sex hormone measurements in serum by radioimmunoassay with mass spectrometry. Four male and four female serum pools with known relative concentrations of steroid sex hormones were measured multiple times by both methods. Because measurements are expected to increase linearly with concentration for each sex, we examined whether the linear regressions of hormone measurements on concentration were the same for radioimmunoassay and mass spectrometry. Estradiol, estrone, androstenedione, testosterone, and dehydroepiandrosterone sulfate were measured in female pools; testosterone, dihydrotestosterone, androstenedione, and dehydroepiandrosterone sulfate were measured in male pools. Regression slopes for radioimmunoassay and mass spectrometry measurements were comparable for all hormones except androstenedione, which had a steeper slope when measured by mass spectrometry (P less than or equal to 0.02). Intercepts for radioimmunoassay and mass spectrometry were similar and close to zero for estradiol, androstenedione, dehydroepiandrosterone sulfate, and in male samples, testosterone, For testosterone in female samples, estrone, and dihydrotestosterone, radioimmunoassay and mass spectrometry intercepts differed significantly. Standard deviations of individual measurements by radioimmunoassay and mass spectrometry differed by hormone and serum concentration; neither method consistently measured hormone concentrations with less variability. Our findings suggest that although absolute concentrations may differ for some hormones, radioimmunoassay and mass spectrometry can yield similar estimates of between subject differences in serum concentrations of most steroid sex hormones commonly measured in population studies. Relative power of studies using radioimmunoassay and mass spectrometry will depend on the hormones measured and their serum concentrations. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Maryland Med Res Inst, Baltimore, MD 21210 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. McKesson BioServ, Rockville, MD 20850 USA. RP Dorgan, JF (reprint author), Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. RI McMahon, Robert/C-5462-2009 NR 10 TC 69 Z9 71 U1 0 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X J9 STEROIDS JI Steroids PD MAR PY 2002 VL 67 IS 3-4 BP 151 EP 158 AR PII S0039-128X(01)00147-7 DI 10.1016/S0039-128X(01)00147-7 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 525AM UT WOS:000174045100001 PM 11856538 ER PT J AU Garman, SC Hannick, L Zhu, A Garboczi, DN AF Garman, SC Hannick, L Zhu, A Garboczi, DN TI The 1.9 angstrom structure of alpha-N-acetylgalactosaminidase: Molecular basis of glycosidase deficiency diseases SO STRUCTURE LA English DT Article ID ANGIOKERATOMA CORPORIS DIFFUSUM; LECTIN-CARBOHYDRATE-RECOGNITION; GROUP-B ERYTHROCYTES; FULL-LENGTH CDNA; GALACTOSIDASE-B; HUMAN-LIVER; GROUP-O; CATALYTIC NUCLEOPHILE; NEUROAXONAL DYSTROPHY; GLYCOSYL HYDROLASES AB In the lysosome, glycosidases degrade glycolipids, glycoproteins, and oligosaccharides. Mutations in glycosidases cause disorders characterized by the deposition of undegraded carbohydrates. Schindler and Fabry diseases are caused by the incomplete degradation of carbohydrates with terminal alpha-N-acetylgalactosamine and alpha-galactose, respectively. Here we present the X-ray structure of alpha-N-acetylgalactosaminidase (alpha-NAGAL), the glycosidase that removes alpha-N-acetylgalactosamine, and the structure with bound ligand. The active site residues of alpha-NAGAL are conserved in the closely related enzyme alpha-galactosidase A (alpha-GAL). The structure demonstrates the catalytic mechanisms of both enzymes and reveals the structural basis of mutations causing Schindler and Fabry diseases. As alpha-NAGAL and alpha-GAL produce type O "universal donor" blood from type A and type B blood, the alpha-NAGAL structure will aid in the engineering of improved enzymes for blood conversion. C1 NIAID, Struct Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. New York Blood Ctr, Lindsley F Kimball Res Inst, New York, NY 10021 USA. RP Garman, SC (reprint author), NIAID, Struct Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. NR 70 TC 56 Z9 58 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD MAR PY 2002 VL 10 IS 3 BP 425 EP 434 AR PII S0969-2126(02)00726-8 DI 10.1016/S0969-2126(02)00726-8 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 531HH UT WOS:000174409600017 PM 12005440 ER PT J AU Umegaki, H Ishiwata, K Ogawa, O Ingram, DK Roth, GS Yoshimura, J Oda, K Matsui-Hirai, H Ikari, H Iguchi, A Senda, M AF Umegaki, H Ishiwata, K Ogawa, O Ingram, DK Roth, GS Yoshimura, J Oda, K Matsui-Hirai, H Ikari, H Iguchi, A Senda, M TI In vivo assessment of adenoviral vector-mediated gene expression of dopamine D-2 receptors in the rat striatum by positron emission tomography SO SYNAPSE LA English DT Article DE autoradiography; raclopride; aging; binding potential ID HIGH-RESOLUTION PET; C-11 RACLOPRIDE; BRAIN; THERAPY; AGE; NEMONAPRIDE; SENESCENCE; BEHAVIOR; DISEASE; LIGANDS AB For functional assessment of gene therapy in experimental animals, in vivo assessment of transferred genes will provide a major advance over an in vitro analysis which must be done post-hoc. In the current study we conducted positron emission tomography (PET) analysis in rats following injection of the adenoviral vector encoding the cDNA for the rat dopamine D-2 receptors (D2R) (AdCMV.DopD(2)R) into rat brain to provide a quantitative evaluation of D2R overexpression. Quantitative measurements as well as images by PET and ex vivo autoradiography demonstrated the significant increase of D2R binding of [C-11]raclopride, a specific D2R radioligand, in the AdCMV.DopD(2)R-injected rat striatum 2 or 3 days after vector injection. Longitudinal in vivo assessment of the gene expression by PET demonstrated decreased binding of [C-11]raclopride with time, which was in agreement with the observation in a cross-sectional autoradiographic study. The results of the current study demonstrate that PET can be used for longitudinal in vivo assessment of D2R expression mediated by adenoviral vector in rat brain. Synapse 43:195-200, 2002. (C) 2002 Wiley-Liss, Inc. C1 Nagoya Univ, Grad Sch Med, Dept Geriatr, Showa Ku, Aichi 4668550, Japan. Tokyo Metropolitan Inst Gerontol, Positron Med Ctr, Tokyo 1730022, Japan. NIA, Gerontol Res Ctr, Neurosci Lab, NIH, Baltimore, MD 21224 USA. Fukushimura Hosp, Choju Med Inst, Aichi 4418124, Japan. RP Umegaki, H (reprint author), Nagoya Univ, Grad Sch Med, Dept Geriatr, Showa Ku, 65 Tsuruma Cho, Aichi 4668550, Japan. NR 32 TC 20 Z9 21 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD MAR 1 PY 2002 VL 43 IS 3 BP 195 EP 200 DI 10.1002/syn.10035 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 514AT UT WOS:000173414400006 PM 11793425 ER PT J AU Ackerman, M Craft, R Ferrante, F Kratz, M Mandil, S Sapci, H AF Ackerman, M Craft, R Ferrante, F Kratz, M Mandil, S Sapci, H TI Telemedicine technology SO TELEMEDICINE JOURNAL AND E-HEALTH LA English DT Article; Proceedings Paper CT Symposium on State-of-the-Art Telemedicine/Telehealth CY AUG, 2001 CL UNIV MICHIGAN, ANN ARBOR, MICHIGAN SP WHO HO UNIV MICHIGAN C1 Natl Lib Med, Bethesda, MD 20894 USA. Sandia Natl Labs, Livermore, CA 94550 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. WHO, CH-1211 Geneva, Switzerland. Univ Michigan, Ann Arbor, MI 48109 USA. RP Ackerman, M (reprint author), Care of Bashshur RL, Univ Michigan Hlth Syst, C201 Medinn Bldg,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. NR 11 TC 16 Z9 16 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1530-5627 J9 TELEMED J E-HEALTH JI Telemed. J. e-Health PD SPR PY 2002 VL 8 IS 1 BP 71 EP 78 DI 10.1089/15305620252933419 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 552UF UT WOS:000175637900007 PM 12020407 ER PT J AU Chriqui, JF Frosh, M Brownson, RC Shelton, DM Sciandra, RC Hobart, R Fisher, PH el Arculli, R Alciati, MH AF Chriqui, JF Frosh, M Brownson, RC Shelton, DM Sciandra, RC Hobart, R Fisher, PH el Arculli, R Alciati, MH TI Application of a rating system to state clean indoor air laws (USA) SO TOBACCO CONTROL LA English DT Article ID ENVIRONMENTAL TOBACCO-SMOKE; UNITED-STATES; NATIONAL SURVEY; YOUTH-ACCESS; WORKPLACE; EXPOSURE; IMPACT; BANS; RESTRICTIONS; RESTAURANTS AB Objective: To develop and implement a system for rating state clean indoor air laws. Design: The public health interest of state clean indoor air laws is to limit non-smoker exposure to environmental tobacco smoke (ETS). Current estimates of health risks and methods available for con trolling ETS provided a framework for devising a ratings scale. An advisory committee applied this scale to each of seven site specific smoking restrictions and two enforcement related items. For each item, a target score of +4 was identified. The nine items were then combined to produce a summary score for each state. A state that achieved the target across all nine items would receive a summary score of 36 points and be eligible to receive an additional 6 points for exceeding the target on six of the nine items, resulting in a maximum summary score of 42 points. Individual scores were also adjusted to reflect state level preemption measures. Each state's law was evaluated annually from 1993 through 1999. Setting: USA. Main outcome measure: A summary score measuring the extensiveness of the state's clean indoor air law. Results: State laws restricting smoking in the seven individual locations of interest were relatively weak. The overall mean score across the location restrictions ranged from 0.72 in 1993 to 0.98 in 1999. Mean scores were higher for the enforcement items than for the location restrictions. Summary scores ranged from 0 to 20 in 1993 and 0 to 31 in 1994 through 1999. Average summary scores ranged S from 8.71 in 1993 to 10.98 in 1999. By the end of 1999, scores increased for 22 states; however between 1995 and 1997 there were no changes in the summary scores. Three states scored zero, points across all years, From 1993 through 1999, there was a 41% increase in the number of states that had in place state level preemption measures. Conclusion: The number of newly enacted state clean indoor air laws has remained relatively stagnant since 1995. With a few exceptions, as of the end of 1999, progress in enacting state laws to meet specified public health targets for reducing exposure to ETS was relatively low. Thus, state laws in the USA provide, on average, only minimal protection in specified areas and, given the increase in preemption, are increasingly undermining those passed in localities. C1 MayaTech Corp, Silver Spring, MD 20910 USA. St Louis Univ, Sch Publ Hlth, Prevent Res Ctr, St Louis, MO 63103 USA. St Louis Univ, Sch Publ Hlth, Dept Community Hlth, St Louis, MO 63103 USA. Ctr Dis Control & Prevent, Natl Ctr HIV STD & TB Prevent, Div STD Prevent, Atlanta, GA USA. Ctr Tobacco Free New York, Loudonville, NY USA. Campaign Tobacco Free Kids, Washington, DC USA. NCI, NIH, Bethesda, MD 20892 USA. Management Solut Hlth, Reston, VA USA. RP Chriqui, JF (reprint author), MayaTech Corp, 8737 Colesville Rd,7th Floor, Silver Spring, MD 20910 USA. OI Alciati, Marianne/0000-0001-6294-1090 NR 56 TC 41 Z9 41 U1 1 U2 2 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 J9 TOB CONTROL JI Tob. Control PD MAR PY 2002 VL 11 IS 1 BP 26 EP 34 DI 10.1136/tc.11.1.26 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 533BV UT WOS:000174510300018 PM 11891365 ER PT J AU Marcy, TW Solomon, LJ Dana, GS Secker-Walker, R Skelly, JM AF Marcy, TW Solomon, LJ Dana, GS Secker-Walker, R Skelly, JM TI A smoking cessation telephone resource: feasibility and preliminary evidence on the effect on health care provider adherence to smoking cessation guidelines SO TOBACCO CONTROL LA English DT Letter ID PHYSICIANS C1 Univ Vermont, Vermont Canc Ctr, Burlington, VT 05405 USA. Univ Vermont, Coll Med, Off Hlth Promot Res, Burlington, VT USA. NCI, Div Canc Prevent, Off Prevent Oncol, Rockville, MD USA. RP Marcy, TW (reprint author), Univ Vermont, Vermont Canc Ctr, Burlington, VT 05405 USA. NR 4 TC 6 Z9 6 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 J9 TOB CONTROL JI Tob. Control PD MAR PY 2002 VL 11 IS 1 BP 84 EP 84 DI 10.1136/tc.11.1.84 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 533BV UT WOS:000174510300031 PM 11891379 ER PT J AU Nyska, A Nold, JB Johnson, JD Abdo, K AF Nyska, A Nold, JB Johnson, JD Abdo, K TI Lysosomal-storage disorder induced by Elmiron following 90-days gavage administration in rats and mice SO TOXICOLOGIC PATHOLOGY LA English DT Article DE sodium pentosan polysulfate; polysaccharide; rodents; rectum; macrophage ID PENTOSAN POLYSULFATE; DRUG STORAGE; REVERSIBILITY; MECHANISMS; AGENT AB Elmiron, a highly sulfated, semisynthetic pentose polysaccharide with properties similar to heparin, is used for the treatment of interstitial cystitis. Thirteen-week gavage studies were conducted by administering the drug in deionized water to F344/N rats and B6C3F(1) mice once daily, 5 days per week for up to 13 consecutive weeks, at doses of 0, 63, 125, 250, 500, and 1,000 mg/kg body weight. No significant drug-related effects were observed in body weight, survival, clinical, and necropsy results. Significant organ weight increases were seen in the liver, lungs, and spleen of both species and the kidneys of rats, mainly in groups treated with 250 mg/kg/day and above. Hematological analysis indicated increases for both species in the white blood cell and lymphocyte counts. Sites of toxicity identified histopathologically were the rectum, liver, mesenteric and mandibular lymph nodes (both sexes), spleen (mice only), and lungs and kidneys (rats only). Lesions consisted mainly of infiltration into multiple tissues of vacuolated histiocytes, which, by histochemical investigation, indicated the presence of neutral and acidic mucins and lipidic material within the vacuoles. Transmission electron microscopy identified these vacuoles as lysosomal structures that exhibited a variety of contents. On the basis of our findings, we propose that Elmiron was absorbed through the focally disrupted rectal mucosa, was deposited in the lamina propria, accumulated within macrophages, and then was distributed by these cells or as a free chemical via the lymphatics and blood, to the various organ sites manifesting histiocytic infiltration. The cytoplasmic membrane-bound structures within macrophages were lysosomes containing membranous material of cellular origin and, perhaps, remnants of the deposited test material, Elmiron. C1 NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Environm Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. Pathol Associates Inc, Durham, NC 27713 USA. Battelle Mem Inst, Columbus Labs, Columbus, OH 43201 USA. RP Nyska, A (reprint author), NIEHS, Lab Expt Pathol, NIH, MD B3-06,POB 12233, Res Triangle Pk, NC 27709 USA. NR 22 TC 11 Z9 11 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD MAR PY 2002 VL 30 IS 2 BP 178 EP 187 DI 10.1080/019262302753559515 PG 10 WC Pathology; Toxicology SC Pathology; Toxicology GA 558EL UT WOS:000175953300003 PM 11950161 ER PT J AU Suwa, T Nyska, A Haseman, JK Mahler, JF Maronpot, RR AF Suwa, T Nyska, A Haseman, JK Mahler, JF Maronpot, RR TI Spontaneous lesions in control B6C3F(1) mice and recommended sectioning of male accessory sex organs SO TOXICOLOGIC PATHOLOGY LA English DT Article DE background; pathology; prostate; seminal vesicle; rodent ID SPONTANEOUS TUMORS; PROSTATE; MOUSE AB Because sampling of the paired lobes (ventral, dorsal, lateral, and anterior) of the mouse prostate has often been inconsistent, comparisons among different investigations have lacked validity. The absence of site identification for prostatic lesions has made reported incidences relatively nonspecific. We present here the lobe-specific incidences and degree of severity of spontaneous lesions in prostate, coagulating gland (anterior prostatic lobe), seminal vesicles, and ampullary glands in 612 control B6C3F(1) mice from 12 recent National Toxicology Program 2-year carcinogenicity and toxicity studies conducted in 1 of 4 different laboratories. Lymphocytic infiltration, inflammation, epithelial hyperplasia, mucinous cyst, and mucinous metaplasia were observed in the dorsolateral lobes. Lymphocytic infiltration, inflammation, epithelial hyperplasia, and edema were present in the ventral lobes. Lymphocytic infiltration, acinar dilatation, inflammation, epithelial hyperplasia, and atrophy occurred in the coagulating glands. No neoplastic lesions were observed in the prostate or coagulating gland. Lymphocytic infiltration, acinar dilatation, inflammation, atrophy, adenoma, adenocarcinoma, and a granular cell tumor were observed in the seminal vesicles. Lymphocytic infiltration was also present in the ampullary glands. The results of our survey indicate that the amounts of glandular tissues were not present consistently in slides from the different laboratories. Landmarks for uniform tissue trimming are needed. We therefore suggest an optimal trimming and embedding method for mouse prostate and seminal vesicles to ensure adequate, consistent sampling. C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Nyska, A (reprint author), NIEHS, Lab Expt Pathol, POB 12233, Res Triangle Pk, NC 27709 USA. NR 23 TC 29 Z9 29 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD MAR PY 2002 VL 30 IS 2 BP 228 EP 234 DI 10.1080/019262302753559560 PG 7 WC Pathology; Toxicology SC Pathology; Toxicology GA 558EL UT WOS:000175953300008 PM 11950166 ER PT J AU Diwan, BA Gladwin, MT Noguchi, CT Ward, JM Fitzhugh, AL Buzard, GS AF Diwan, BA Gladwin, MT Noguchi, CT Ward, JM Fitzhugh, AL Buzard, GS TI Renal pathology in hemizygous sickle cell mice SO TOXICOLOGIC PATHOLOGY LA English DT Article; Proceedings Paper CT 40th Annual Meeting of the Society-of-Toxicology CY MAR 24-29, 2001 CL SAN FRANCISCO, CALIFORNIA SP Soc Toxicol DE sickle cell disease; sickle cell trait; mouse; homozygous; hemizygous; kidney; pathology; immunohistochemistry ID NITRIC-OXIDE SYNTHASE; ACUTE CHEST SYNDROME; ADHESION MOLECULE-1; VASOOCCLUSIVE CRISIS; ENDOTHELIAL-CELLS; MOUSE KIDNEYS; DISEASE; EXPRESSION; HYPOXIA; ALPHA AB Transgenic mice have been developed that express exclusively human sickle cell beta hemoglobin and have major pathological features found in humans with sickle cell disease. These mice provide a unique opportunity to investigate the fundamental mechanisms of this disease and to design new strategies to correct the associated genetic defect(s). We found that in breeding males expressing only adult human alpha-globin and sickle beta-globin (homozygous SS mice) with females containing these transgenes plus one copy of the mouse beta-globin gene (hemizygous SS mice) greater than expected numbers of hemizygous offspring were produced than homozygous mice (carrying no mouse beta-globin gene). These hemizygous mice, expressing the human alpha and sickle beta(s) transgenes in combination with mouse beta(+/-), were used for our preliminary studies of their renal pathology. No kidney lesions were found in the control (129/Sv) mice, whereas about 50% of the hemizygous SS mice showed mild-to-severe kidney lesions, including glomerulonephritis, cystic atypical hyperplastic tubules, and general nephropathy. Kidneys of some hemizygous mice were normal or showed minimal nephropathy, yet those of the susceptible phenotype developed a mild-to-more-severe form of renal lesions. The tubular epithelium of kidneys of hemizygous mice of the more affected phenotype exhibited increased expression of inducible nitric oxide synthase with an increased 3-nitrotyrosine in close proximity. There was also a stronger immunostaining for vascular cell adhesion molecule-1 in the interstitial capillary cells as well as the tubular epithelial cells of the renal cortex, compared with normal control mice. The occurrence of a high incidence of renal abnormalities in our hemizygous SS mice suggests that these mice may provide a suitable model to study the pathogenesis of nephropathy resulting from altered blood flow and/or insufficient oxygen delivery. C1 NCI, IRSP, SAIC Frederick, Frederick, MD 21702 USA. NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. NIDDK, Biol Chem Lab, NIH, Bethesda, MD USA. NCI, Vet & Tumor Pathol Sect, Frederick, MD 21701 USA. RP Diwan, BA (reprint author), NCI, IRSP, SAIC Frederick, Bldg 538,Rm 2051, Frederick, MD 21702 USA. NR 35 TC 12 Z9 12 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD MAR PY 2002 VL 30 IS 2 BP 254 EP 262 DI 10.1080/019262302753559597 PG 9 WC Pathology; Toxicology SC Pathology; Toxicology GA 558EL UT WOS:000175953300011 PM 11950169 ER PT J AU Ozaki, K Haseman, JK Hailey, JR Maronpot, RR Nyska, A AF Ozaki, K Haseman, JK Hailey, JR Maronpot, RR Nyska, A TI Association of adrenal pheochromocytoma and lung pathology in inhalation studies with particulate compounds in the male F344 rat - The national toxicology program experience SO TOXICOLOGIC PATHOLOGY LA English DT Article DE pheochromocytoma; adrenal medulla; lung; fibrosis; inflammation; F344 rat; inhalation; particulate ID CHROMAFFIN CELL-PROLIFERATION; HYPOXIA-INDUCIBLE FACTOR-1; TYROSINE-HYDROXYLASE; CARCINOGENICITY; MEDULLA; GLAND; STIMULATION; INHIBITION; MECHANISMS; LESIONS AB Systemic hypoxemia, occurring in space-occupying lung pathologies such as inflammation and neoplasms, reduces the gas exchange area and stimulates catecholamine secretion from the adrenal medulla where chronic endocrine hyperactivity may lead to hyperplasia and neoplasia. We investigated the possible correlation between nonneoplastic chronic pulmonary lesions and adrenal pheochromocytoma in 9 recent, NTP, 2-year particulate inhalation studies in male F344 rats. Re-evaluation for chronic active inflammation, interstitial fibrosis, alveolar epithelial hyperplasia, squamous metaplasia, proteinosis, and histiocytosis revealed significant associations of pheochromocytoma only with the severity of inflammation and fibrosis. Nickel oxide, cobalt sulfate, indium phosphide, talc, and nickel subsulfide studies showed chemical-related incidences of adrenal pheochromocytoma and significant (p < 0.01) associations with inflammation and fibrosis. Gallium arsenide, vanadium pentoxide, molybdenum trioxide, and nickel sulfate hexahydrate studies revealed an increased incidence and/or severity of nonneoplastic lung lesions, but no increased incidence of pheochromocytoma. Although gallium arsenide and molybdenum trioxide showed no dose-related increase in pheochromocytoma, a significant (p < 0.01) correlation of the latter with the severity of fibrosis and inflammation occurred. In the vanadium pentoxide and nickel sulfate hexahydrate studies, no relationship between nonneoplastic lung lesions and pheochromocytoma was manifested. Our investigation assessed the strength of these various associations and supports the possible roles of 2 chronic pulmonary lesions-fibrosis and inflammation-and hypoxemia in the induction of pheochromocytoma in the F344 male rat. C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Nyska, A (reprint author), NIEHS, Lab Expt Pathol, POB 12233, Res Triangle Pk, NC 27709 USA. NR 45 TC 19 Z9 19 U1 0 U2 5 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD MAR PY 2002 VL 30 IS 2 BP 263 EP 270 DI 10.1080/019262302753559605 PG 8 WC Pathology; Toxicology SC Pathology; Toxicology GA 558EL UT WOS:000175953300012 PM 11950170 ER PT J AU Nyska, A Dayan, A Maronpot, RR AF Nyska, A Dayan, A Maronpot, RR TI New tools in therapeutic research - Prostatic cancer and models SO TOXICOLOGIC PATHOLOGY LA English DT Article ID TISSUE MICROARRAYS; ANIMAL-MODELS; GROWTH-FACTOR; NOBLE RATS; CELLS; EXPRESSION; CARCINOMA; ESTRADIOL-17-BETA; ADENOCARCINOMAS; TESTOSTERONE C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. RP Nyska, A (reprint author), NIEHS, Lab Expt Pathol, 111 T W Alexander Dr,MD B3-06, Res Triangle Pk, NC 27709 USA. NR 44 TC 2 Z9 2 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD MAR PY 2002 VL 30 IS 2 BP 283 EP 287 DI 10.1080/019262302753559623 PG 5 WC Pathology; Toxicology SC Pathology; Toxicology GA 558EL UT WOS:000175953300017 PM 11950172 ER PT J AU Buchanan, DL Ohsako, S Tohyama, C Cooke, PS Iguchi, T AF Buchanan, DL Ohsako, S Tohyama, C Cooke, PS Iguchi, T TI Dioxin inhibition of estrogen-induced mouse uterine epithelial mitogenesis involves changes in cyclin and transforming growth factor-beta expression SO TOXICOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT 40th Annual Meeting of the Society-of-Toxicology CY MAR 24-29, 2001 CL SAN FRANCISCO, CALIFORNIA SP Soc Toxicol DE cytokine; uterus; estrogen; proliferation; antiestrogen; aryl hydrocarbon receptor; ovariectomy ID ARYL-HYDROCARBON RECEPTOR; CELL-PROLIFERATION; AH-RECEPTOR; GENE-EXPRESSION; DOWN-REGULATION; MCF-7 CELLS; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN; UTERUS; PROTEIN; TRANSCRIPTION AB A single dose of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin or TCDD; 5 mug/kg, ip) inhibits 17beta-estradiol (E2)-induced uterine epithelial mitogenesis, apparently through disruption of stromal-epithelial interactions. To understand if TCDD alters early uterine (Ut) responses to E2, young adult C57BL/6J mice were ovariectomized and given (ip) either oil or 5 mug/kg TCDD. After 24 h, TCDD-treated mice received E2, and oil-treated mice were given E2 or oil. Body and Ut weights were collected 6 and 18 h later. Ut were flash-frozen at 6 h. E2 increased Ut weight (p < 0.0001) and Ut/body weight ratio (p < 0.0001), compared to mice given oil alone. Ut cyclin expression was assessed by an RNase protection assay. E2 increased mRNA expression for cyclin A2 and B1 (p < 0.05), in addition to D1, D2, and D3 (p < 0.001), while cyclin C was unchanged from oil controls and cyclins A1 and B2 were undetectable. In contrast, TCDD completely abolished E2-induced cyclin A2, which has been associated with S phase initiation, and reduced B1 and D2 (p < 0.05). Interestingly, TCDD did not alter E2-induced Ut weight increases at 6 h, but inhibited E2-induced Ut weight gain at 18 h. A 10-μg/kg TCDD dose was necessary for attenuation of the early E2-induced Ut weight increases (p < 0.01). Since TGF-beta regulates cyclins, Ut TGF-beta was also assessed in TCDD + E2-treated and control mice. TGF-beta mRNA levels were increased after TCDD compared to E2 alone (p < 0.01), suggesting a possible mechanism for TCDD inhibition of Ut cyclin A2. Thus, TCDD alters specific E2-regulated Ut G(1) phase activities and may inhibit E2-induced Ut epithelial mitogenesis by disrupting specific cell signaling mechanisms necessary for S phase initiation in vivo. C1 Okazaki Natl Res Inst, Ctr Integrat Biosci, Aichi 4448585, Japan. Japan Sci & Technol Corp, CREST, Kawaguchi, Saitama 3320012, Japan. Natl Inst Environm Studies, Tsukuba, Ibaraki 3058506, Japan. Univ Illinois, Dept Vet Biosci, Urbana, IL 61802 USA. Univ Illinois, Div Nutr Sci, Urbana, IL 61802 USA. RP Buchanan, DL (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 42 TC 18 Z9 20 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD MAR PY 2002 VL 66 IS 1 BP 62 EP 68 DI 10.1093/toxsci/66.1.62 PG 7 WC Toxicology SC Toxicology GA 524LG UT WOS:000174014300008 PM 11861973 ER PT J AU Liu, YC Gu, H AF Liu, YC Gu, H TI Cbl and Cbl-b in T-cell regulation SO TRENDS IN IMMUNOLOGY LA English DT Editorial Material ID NEGATIVE REGULATOR; SIGNAL-TRANSDUCTION; C-CBL; TRANSCRIPTION FACTOR; TYROSINE KINASE; DEFICIENT MICE; ACTIVATION; RECEPTOR; VAV; UBIQUITINATION AB Genetic studies indicate that Cbl and Cbl-b, two highly homologous adaptor proteins, are involved in the negative regulation of thymocyte development and peripheral T-cell activation, respectively. The recent identification of Cbl proteins as RING-type E3 ubiquitin ligases might provide insights into their distinct immune regulatory functions, involving the targeting of different substrates for ubiquitination. The structural similarity and ubiquitous expression of Cbl and Cbl-b suggest, however, that they might also have overlapping functions in setting the thresholds for thymocyte selection and mature T-cell signaling. C1 La Jolla Inst Allergy & Immunol, Div Cell Biol, Sci Ctr 10355, San Diego, CA 92121 USA. NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Liu, YC (reprint author), La Jolla Inst Allergy & Immunol, Div Cell Biol, Sci Ctr 10355, San Diego, CA 92121 USA. FU NIDDK NIH HHS [R01DK56588] NR 34 TC 51 Z9 52 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD MAR PY 2002 VL 23 IS 3 BP 140 EP 143 DI 10.1016/S1471-4906(01)02157-3 PG 4 WC Immunology SC Immunology GA 525VK UT WOS:000174094600009 PM 11864842 ER PT J AU Bachelior, R Vincent, A Mathevet, P Magdinier, F Lenoir, GM Frappart, L AF Bachelior, R Vincent, A Mathevet, P Magdinier, F Lenoir, GM Frappart, L TI Retroviral transduction of splice variant Brca1-Delta 11 or mutant Brca1-W1777Stop causes mouse epithelial mammary atypical duct hyperplasia SO VIRCHOWS ARCHIV LA English DT Article DE Brca1; mammary gland morphogenesis; tumorigenesis ID SPORADIC BREAST-CANCER; TRANSCRIPTIONAL ACTIVATION; SUBCELLULAR-LOCALIZATION; BRCA1 EXPRESSION; GENE BRCA1; TUMOR; MICE; DIFFERENTIATION; SUSCEPTIBILITY; ISOFORMS AB We have investigated the effects of the expression of wild-type and mutant Brca1 alleles on the murine mammary gland morphogenesis and carcinogenesis. Primary cultures of mammary cells from BALB/cByJIco mice were infected with recombinant Babe Puro retroviruses expressing lacZ, full-length Brca1, splice variant Brca1-Delta11, or mutant Brca1-W1777Stop alleles. Infected cells were reinjected into the mammary fat pad of a syngeneic virgin mouse whose endogenous epithelium had previously been removed. Four months after reinjection, nulliparous and postlactating mice were checked for the reconstitution of the mammary gland. Stable expression of beta-galactosidase was observed in the ducts formed by epithelial mammary cells infected with Babe Puro/lacZ retrovirus. Epithelial mammary cells transduced with full-length Brca1 developed normally, whereas those transduced with Brca1-Delta11 or Brca1-W1777Stop formed atypical duct hyperplasia associated with reduced branching. These results suggest that ectopically expressed splice variant Brca1-Delta11 and mutant Brca1-W1777Stop have dominant negative effects. C1 Univ Lyon 1, Fac Med, Genet Lab, UMR 5641 CNRS, F-69373 Lyon 08, France. Hop Edouard Herriot, F-69437 Lyon, France. NIH, Bethesda, MD 20892 USA. RP Vincent, A (reprint author), Univ Lyon 1, Fac Med, Genet Lab, UMR 5641 CNRS, 8 Ave Rockefeller, F-69373 Lyon 08, France. RI Magdinier, Frederique/I-4735-2016 OI Magdinier, Frederique/0000-0002-0159-9559 NR 21 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0945-6317 J9 VIRCHOWS ARCH JI Virchows Arch. PD MAR PY 2002 VL 440 IS 3 BP 261 EP 266 DI 10.1007/s004280100500 PG 6 WC Pathology SC Pathology GA 539TU UT WOS:000174887800003 PM 11889595 ER PT J AU Golinelli, MP Hughes, SH AF Golinelli, MP Hughes, SH TI Nontemplated base addition by HIV-1 RT can induce nonspecific strand transfer in vitro SO VIROLOGY LA English DT Article DE nontemplated base addition; strand transfer; fidelity; reverse transcription ID IMMUNODEFICIENCY-VIRUS TYPE-1; MURINE LEUKEMIA-VIRUS; HAMMERHEAD RIBOZYME CATALYSIS; STRONG-STOP DNA; REVERSE-TRANSCRIPTASE; NUCLEOCAPSID PROTEIN; VECTOR REPLICATION; MOLECULAR-CLONING; ESCHERICHIA-COLI; RETROVIRAL DNA AB After minus-strand strong-stop DNA (-sssDNA) synthesis, the RNA template is degraded by the RNase H activity of reverse transcriptase (RT), generating a single-stranded DNA. The genomes of some retroviruses contain sequences that could lead to self-priming of their -sssDNA. Self-priming was prevented by annealing a DNA oligonucleotide to the 3' end of model DNAs that corresponded to the 3' ends of the -sssDNAs (-R ssDNA) from human immunodeficiency virus type 1 (HIV-1), type 2 (HIV-2), and human T-cell leukemia virus type 1 (HTLV-1) but nonspecific strand transfer to ssDNA molecules in solution was induced in vitro (Golinelli and Hughes, 2001). This nonspecific strand transfer involved the addition of a nontemplated base to the 3' end of -R ssDNAs that was part of a blunt-ended duplex. In the case of HIV-2 -R ssDNA, A and C were added more efficiently than G and T Strand transfer to ssDNA in solution occurred only if the nontemplated base could form a basepair with the last base at the 3' end of the ssDNA. If there was a mismatch, strand transfer did not occur. There was no detectable strand transfer to internal sites in the target ssDNA except to the second position from the 3' end of the DNA acceptor when the sequences at the 3' ends of the two DNAs allowed the formation of two basepairs. The nontemplated base addition and the one-basepair strand transfer were both affected by the salt concentration in the reaction, the nature of the reverse transcriptase (HIV-1 versus Moloney murine leukemia virus), and the sequence at the 3' end of -R ssDNA. NC reduced the efficiency of nonspecific strand transfer in vitro, suggesting that NC may have a role in reducing nonspecific strand transfer in vivo. (C) 2002 Elsevier Science (USA). C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, POB B, Frederick, MD 21702 USA. RI Golinelli, Marie-Pierre/K-4287-2013 OI Golinelli, Marie-Pierre/0000-0002-6738-8631 NR 48 TC 14 Z9 14 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 1 PY 2002 VL 294 IS 1 BP 122 EP 134 DI 10.1006/viro.2001.1322 PG 13 WC Virology SC Virology GA 532DK UT WOS:000174456200012 PM 11886271 ER PT J AU Gedat, E Schreiber, A Albrecht, J Emmler, T Shenderovich, I Findenegg, GH Limbach, HH Buntkowsky, G AF Gedat, E Schreiber, A Albrecht, J Emmler, T Shenderovich, I Findenegg, GH Limbach, HH Buntkowsky, G TI H-2-solid-state NMR study of benzene-d(6) confined in mesoporous silica SBA-15 SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID H-2 NMR; MAGNETIC-RESONANCE; WATER-MOLECULES; RABBIT LENS; N-HEXANE; SPECTROSCOPY; DIFFUSION; DYNAMICS; SURFACE; H-1-NMR AB Benzene-d(6) confined in the hexagonal ordered cylindrical pores of mesoporous silica SBA-15 (pore diameter 8.0 nm) was studied by low-temperature H-2-solid-state NMR spectroscopy in the temperature range between 236 and 19 K and compared to bulk benzene-d(6). The solid-state spectra of the bulk benzene-d(6) exhibit quadrupolar Pake patterns at high and low temperatures, and in the intermediate temperature regime the typical line shape changes caused by rotational jumps around the 6-fold axis. At all temperatures the benzene molecules are characterized by a single rotational correlation time. For benzene-d6 confined in SBA-15, however, these exchange dominated line shapes are not found. At all temperatures below the freezing point the spectra of benzene in the silica show the coexistence of two states with temperature-dependent intensity ratios. This behavior is the result of a Gaussian distributions of activation energies for the rotational jumps inside the pores. For the solid I-solid 11 (fast 6-fold jump to slow 6-fold jump) transition the center of the distribution is at 40 K (6.0 kJ/mol) with a width of 19.5 K (2.9 kJ/mol). For the liquid-solid I (liquidlike to fast 6-fold jump) transition the center of the distribution is at 204 K (30.6 kJ/mol) and the width is 15 K (2.2 kJ/mol). From the pore volume and the filling factor, a thickness of four molecular layers of this surface phase is estimated. C1 Free Univ Berlin, Inst Chem, D-14195 Berlin, Germany. Tech Univ Berlin, Stranski Lab Phys & Theoret Chem, D-10623 Berlin, Germany. RP Buntkowsky, G (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. RI Shenderovich, Ilya/C-4301-2011; Buntkowsky, Gerd/B-3206-2010; Limbach, Hans-Heinrich/G-8858-2011; Emmler, Thomas/H-3508-2011 OI Shenderovich, Ilya/0000-0001-6713-9080; Buntkowsky, Gerd/0000-0003-1304-9762; Limbach, Hans-Heinrich/0000-0002-2084-6359; Emmler, Thomas/0000-0002-0674-7880 NR 47 TC 83 Z9 83 U1 1 U2 9 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 FEB 28 PY 2002 VL 106 IS 8 BP 1977 EP 1984 DI 10.1021/jp012391p PG 8 WC Chemistry, Physical SC Chemistry GA 527MC UT WOS:000174189000022 ER PT J AU Braddock, DT Louis, JM Baber, JL Levens, D Clore, GM AF Braddock, DT Louis, JM Baber, JL Levens, D Clore, GM TI Structure and dynamics of KH domains from FBP bound to single-stranded DNA SO NATURE LA English DT Article ID RESIDUAL DIPOLAR COUPLINGS; FAR UPSTREAM ELEMENT; FRAGILE-X-SYNDROME; C-MYC; TRANSCRIPTION FACTOR; STRUCTURE REFINEMENT; RNA-BINDING; NMR; PROTEINS; EXPRESSION AB Gene regulation can be tightly controlled by recognition of DNA deformations that are induced by stress generated during transcription(1-3). The KH domains of the FUSE-binding protein (FBP), a regulator of c-myc expression(1,4), bind in vivo and in vitro to the single-stranded far-upstream element (FUSE), 1,500 base pairs upstream from the c-myc promoter(4-6). FBP bound to FUSE acts through TFIIH at the promoter(4). Here we report the solution structure of a complex between the KH3 and KH4 domains of FBP and a 29-base single-stranded DNA from FUSE. The KH domains recognize two sites, 9-10 bases in length, separated by 5 bases, with KH4 bound to the 5' site and KH3 to the 3' site. The central portion of each site comprises a tetrad of sequence 5'd-ATTC for KH4 and 5'd-TTTT for KH3. Dynamics measurements show that the two KH domains bind as articulated modules to single-stranded DNA, providing a flexible framework with which to recognize transient, moving targets. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008; Levens, David/C-9216-2009 OI Clore, G. Marius/0000-0003-3809-1027; Levens, David/0000-0002-7616-922X NR 31 TC 121 Z9 126 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 28 PY 2002 VL 415 IS 6875 BP 1051 EP 1056 DI 10.1038/4151051a PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 525MF UT WOS:000174075000052 PM 11875576 ER PT J AU Bal, W Kasprzak, KS AF Bal, W Kasprzak, KS TI Induction of oxidative DNA damage by carcinogenic metals SO TOXICOLOGY LETTERS LA English DT Article; Proceedings Paper CT 39th Congress of the European-Societies-of-Toxicology CY SEP 13-16, 2001 CL ISTANBUL, TURKEY SP European Soc Toxicol DE carcinogenesis; DNA histories; metals; oxidative damage; oxygen radicals ID N-TERMINAL SEQUENCE; HUMAN PROTAMINE HP2; HYDROGEN-PEROXIDE; PEPTIDE COMPLEXES; HISTONE H2A; SPECIFICALLY CLEAVES; CRYSTAL-STRUCTURE; TRIVALENT NICKEL; MAMMALIAN-CELLS; SPERM CHROMATIN AB The metal ions carcinogenic to humans are As, Be, Cd, Cr and Ni, and the candidates also include Co, Cu, Fe and Pt. A range of molecular mechanisms was proposed for these metals, reflecting their diverse chemical properties. The oxidative concept in metal carcinogenesis proposes that some complexes of the above metals (Co, Cr, Cu, Fe, Ni) formed in vivo undergo redox cycling, yielding reactive oxygen species and/or high valence metal ions which oxidize DNA. Some of the products of oxidative DNA damage, including 8-oxoguanine and strand breaks, induce mutations, which may lead to neoplastic transformation. The establishment of metal-binding modes in the cell nucleus and of their reactivity is crucial for the understanding of molecular events in metal carcinogenesis. We have proposed the binding sites for Ni(II) and Cu(II) in core histones (H3, H2A) and sperm protamines (HP2) and, using molecular models, provided evidence for the generation of promutagenic oxidative DNA damage by the bound metals. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Wroclaw, Fac Chem, PL-50383 Wroclaw, Poland. Polish Acad Sci, Inst Biochem & Biophys, PL-02532 Warsaw, Poland. NCI, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. RP Bal, W (reprint author), Univ Wroclaw, Fac Chem, Ul F Joliot Curie 14, PL-50383 Wroclaw, Poland. EM wbal@wchuwr.chem.uni.wroc.pl NR 67 TC 117 Z9 125 U1 1 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD FEB 28 PY 2002 VL 127 IS 1-3 BP 55 EP 62 AR PII S0378-4274(01)00483-0 DI 10.1016/S0378-4274(01)00483-0 PG 8 WC Toxicology SC Toxicology GA 632GG UT WOS:000180215100008 PM 12052641 ER PT J AU Goodnough, MC Oyler, G Fishman, PS Johnson, EA Neale, EA Keller, JE Tepp, WH Clark, M Hartz, S Adler, M AF Goodnough, MC Oyler, G Fishman, PS Johnson, EA Neale, EA Keller, JE Tepp, WH Clark, M Hartz, S Adler, M TI Development of a delivery vehicle for intracellular transport of botulinum neurotoxin antagonists SO FEBS LETTERS LA English DT Article DE botulinum neurotoxin; targeted drug dell-very; laser confocal microscopy; fluorescent probe ID BIOLOGICAL WARFARE; LIGHT-CHAIN; HEAVY; TOXIN; INTERNALIZATION; PURIFICATION; EFFICACY; TETANUS; NEURONS AB A targeted delivery vehicle (DV) was developed for intracellular transport of emerging botulinum neurotoxin (BoNT) antagonists. The DV consisted of the isolated heavy chain (HC) of BoNT/A coupled to a 10-kDa amino dextran via the heterobifunctional linker 3-(2-pyridylthio)-propionyl hydrazide. The HC served to target BoNT-sensitive cells and promote internalization of the complex, while the dextran served as a platform to deliver model therapeutic molecules to the targeted cells. To determine the ability of this chimeric glycoprotein to enter neurons, dextran and HC were labeled independently with the fluorescent dyes Oregon green 488 and Cy3, respectively. Internalization of DV was monitored in primary cortical cells using laser confocal microscopy. Incubation of cells for 24 h with DV resulted in discrete punctate labeling of both soma and processes. The Cy3 and Oregon green 488 signals were generally co-localized, suggesting that the complex remained in the same intracellular compartment during the initial 24 h. The DV-associated fluorescence was reduced progressively by co-application of increasing concentrations of unlabeled BoNT/A holotoxin. The results suggest that the BoNT/A HC is able to mediate internalization of a coupled dextran, even though the latter bears no resemblance to the BoNT/A light chain (LC). The HC of BoNT/A thus offers promise as a selective carrier to deliver BoNT antagonists to the nerve terminal cytoplasm for inhibiting the proteolytic activity of internalized BoNT/A LC. (C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. C1 USA, Med Res Inst Chem Def, Neurotoxicol Branch, Aberdeen Proving Ground, MD 21010 USA. Univ Wisconsin, Food Res Inst, Dept Food Microbiol, Madison, WI 53706 USA. Univ Maryland, Sch Med, Dept Neurol, Vet Affairs Med Ctr, Baltimore, MD 21201 USA. NICHHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Metabiol, Madison, WI 53719 USA. RP Adler, M (reprint author), USA, Med Res Inst Chem Def, Neurotoxicol Branch, Aberdeen Proving Ground, MD 21010 USA. NR 24 TC 31 Z9 33 U1 2 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD FEB 27 PY 2002 VL 513 IS 2-3 BP 163 EP 168 AR PII S0014-5793(02)02268-8 DI 10.1016/S0014-5793(02)02268-8 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 534QM UT WOS:000174597900005 PM 11904143 ER PT J AU Borio, LL AF Borio, LL TI Evaluation of inhalational anthrax - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Johns Hopkins Univ, Sch Med, Johns Hopkins Ctr Civilian Biodef Strategies, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Borio, LL (reprint author), Johns Hopkins Univ, Sch Med, Johns Hopkins Ctr Civilian Biodef Strategies, Baltimore, MD 21218 USA. NR 1 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 27 PY 2002 VL 287 IS 8 BP 985 EP 985 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 525CX UT WOS:000174052100016 ER PT J AU Vasan, RS Beiser, A Seshadri, S Larson, MG Kannel, WB D'Agostino, RB Levy, D AF Vasan, RS Beiser, A Seshadri, S Larson, MG Kannel, WB D'Agostino, RB Levy, D TI Residual lifetime risk for developing hypertension in middle-aged women and men - The Framingham Heart Study SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BLOOD-PRESSURE; ALZHEIMERS-DISEASE; UNITED-STATES; TRENDS; MORTALITY; PREVALENCE; POPULATION; COMMUNITY; EPIDEMIC; STROKE AB Context The long-term risk for developing hypertension is best described by the lifetime risk statistic. The lifetime risk for hypertension and trends in this risk over time are unknown. Objectives To estimate the residual lifetime risk for hypertension in older US adults and to evaluate temporal trends in this risk. Design, Setting, and Participants Community-based prospective cohort study of 1298 participants from the Framingham Heart Study who were aged 55 to 65 years and free of hypertension at baseline 1976-1998). Main Outcome Measures Residual lifetime risk (lifetime cumulative incidence not adjusted for competing causes of mortality) for hypertension, defined as blood pressure of 140/90 mm Hg or greater or use of anti hypertensive medications. Results The residual lifetime risks for developing hypertension and stage 1 high blood pressure or higher (greater than or equal to140/90 mm Hg regardless of treatment) were 90% in both 55- and 65-year-old participants. The lifetime probability of receiving anti hypertensive medication was 60%. The risk for hypertension remained unchanged for women, but it was approximately 60% higher for men in the contemporary 1976-1998 period compared with an earlier 1952-1975 period. In contrast, the residual lifetime risk for stage 2 high blood pressure or higher greater than or equal to160/100 mm Hg regardless of treatment) was considerably lower in both sexes in the recent period (35%-57% in 1952-1975 vs 35%-44% in 1976-1998), likely due to a marked increase in treatment of individuals with substantially elevated blood pressure. Conclusion The residual lifetime risk for hypertension for middle-aged and elderly individuals is 90%, indicating a huge public health burden. Although the decline in lifetime risk for stage 2 high blood pressure or higher represents a major achievement, efforts should be directed at the primary prevention of hypertension. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Boston, MA USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Div Clin Epidemiol, Boston, MA 02215 USA. NHLBI, Bethesda, MD 20892 USA. RP Vasan, RS (reprint author), NHLBI, Framingham Heart Study, 5 Thurber St, Framingham, MA 01702 USA. OI Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [K24 HL 04334-01A1, N01-HC-38038]; NINDS NIH HHS [NS17950] NR 34 TC 615 Z9 673 U1 3 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 FEB 27 PY 2002 VL 287 IS 8 BP 1003 EP 1010 DI 10.1001/jama.287.8.1003 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 525CX UT WOS:000174052100028 PM 11866648 ER PT J AU Sharrett, AR Coady, SA Sorlie, PD Ballantyne, CM Heiss, G Catellier, D Patsch, W AF Sharrett, AR Coady, SA Sorlie, PD Ballantyne, CM Heiss, G Catellier, D Patsch, W TI Serum triglyceride concentration and coronary heart disease - Response SO CIRCULATION LA English DT Letter C1 NHLBI, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. Landeskrankenstalten, Dept Lab Med, Salzburg, Austria. RP Sharrett, AR (reprint author), NHLBI, Epidemiol & Biometry Program, Bldg 10, Bethesda, MD 20892 USA. RI Ballantyne, Christie/A-6599-2008 NR 1 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 26 PY 2002 VL 105 IS 8 BP E54 EP E54 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 526QP UT WOS:000174141400005 ER PT J AU Scacheri, PC Gillanders, EM Subramony, SH Vedanarayanan, V Crowe, CA Thakore, N Bingler, M Hoffman, EP AF Scacheri, PC Gillanders, EM Subramony, SH Vedanarayanan, V Crowe, CA Thakore, N Bingler, M Hoffman, EP TI Novel mutations in collagen VI genes - Expansion of the Bethlem myopathy phenotype SO NEUROLOGY LA English DT Article ID GIRDLE MUSCULAR-DYSTROPHY; AUTOSOMAL-DOMINANT MYOPATHY; SKELETAL-MUSCLE; LAMININ BETA-1; COL6A2 GENES; CHAIN; CONTRACTURES; FAMILY; IDENTIFICATION; EXPRESSION AB Objective: To investigate the molecular basis of autosomal dominant limb-girdle muscular dystrophy (ADLGMD) in three large new families. Methods and Results: Genome-wide linkage was performed to show that the causative gene in all three families localized to chromosome 21q22.3 (Zmax = 10.3; theta = 0). This region contained the collagen VI alpha1 and alpha2 genes, which have been previously shown to harbor mutations causing a relatively mild congenital myopathy with contractures (Bethlem myopathy). Screening of the collagen VI alpha1 and alpha2 genes revealed novel, causative mutations in each family (COL6A1-K121R, G341D); COL6A2-D620N); two of these mutations were in novel regions of the proteins not previously associated with disease. Collagen VI is a ubiquitously expressed component of connective tissue; however, both limb-girdle muscular dystrophy and Bethlem myopathy patients show symptoms restricted to skeletal muscle. To address the muscle-specific symptoms resulting from collagen VI mutations, the authors studied three patient muscle biopsies at the molecular level (protein expression). A marked reduction of laminin beta1 protein in the myofiber basal lamina in all biopsies was found, although this protein was expressed normally in the neighboring capillary basal laminae. Conclusions: The authors' studies widen the clinical spectrum of Bethlem myopathy and suggest collagen VI etiology should be investigated in dominant limb-girdle muscular dystrophy. The authors hypothesize that collagen VI mutations lead to muscle-specific defects of the basal lamina, and may explain the muscle-specific symptoms of Bethlem and limb-girdle muscular dystrophy patients with collagen VI mutations. C1 George Washington Univ, Childrens Natl Med Ctr, Res Ctr Genet Med, Washington, DC 20010 USA. Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA USA. NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. Univ Mississippi, Med Ctr, Dept Neurol, Jackson, MS 39216 USA. Metrohlth Med Ctr, Div Genet, Cleveland, OH USA. RP Hoffman, EP (reprint author), George Washington Univ, Childrens Natl Med Ctr, Res Ctr Genet Med, 111 Michigan Ave NW, Washington, DC 20010 USA. FU NINDS NIH HHS [2 R01 NS29525-08] NR 32 TC 55 Z9 59 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 FEB 26 PY 2002 VL 58 IS 4 BP 593 EP 602 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 524KP UT WOS:000174012600016 PM 11865138 ER PT J AU Mattay, VS Fera, F Tessitore, A Hariri, AR Das, S Callicott, JH Weinberger, DR AF Mattay, VS Fera, F Tessitore, A Hariri, AR Das, S Callicott, JH Weinberger, DR TI Neurophysiological correlates of age-related changes in human motor function SO NEUROLOGY LA English DT Article ID CEREBRAL BLOOD-FLOW; POSITRON EMISSION TOMOGRAPHY; NEURAL ACTIVITY; BASAL GANGLIA; BRAIN; ACTIVATION; MOVEMENTS; MEMORY; RETRIEVAL; RECEPTORS AB Background: There are well-defined and characteristic age-related deficits in motor abilities that may reflect structural and chemical changes in the aging brain. Objective: To delineate age-related changes in the physiology of brain systems subserving simple motor behavior. Methods: Ten strongly right-handed young (<35 years of age) and 12 strongly right-handed elderly (>50 years of age) subjects with no evidence of cognitive or motor deficits participated in the study. Whole-brain functional imaging was performed on a 1.5-T MRI scanner using a spiral pulse sequence while the subjects performed a visually paced "button-press" motor task with their dominant right hand alternating with a rest state. Results: Although the groups did not differ in accuracy, there was an increase in reaction time in the elderly subjects (mean score +/- SD, young subjects = 547 +/- 97 ins, elderly subjects = 794 280 ms, p < 0.03). There was a greater extent of activation in the contralateral sensorimotor cortex, lateral premotor area, supplementary motor area, and ipsilateral cerebellum in the elderly subjects relative to the young subjects (p < 0.001). Additional areas of activation, absent in the young subjects, were seen in the ipsilateral sensorimotor cortex, putamen (left > right), and contralateral cerebellum of the elderly subjects. Conclusions: The results of this study show that elderly subjects recruit additional cortical and subcortical areas even for the performance of a simple motor task. These changes may represent compensatory mechanisms invoked by the aging brain, such as reorganization and redistribution of functional networks to compensate for age-related structural and neurochemical changes. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Mattay, VS (reprint author), Bldg 10,Ctr Dr,Rm 4S-235, Bethesda, MD 20982 USA. RI Hariri, Ahmad/D-5761-2011; Callicott, Joseph/C-9102-2009 OI Callicott, Joseph/0000-0003-1298-3334 NR 45 TC 263 Z9 268 U1 1 U2 22 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 26 PY 2002 VL 58 IS 4 BP 630 EP 635 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 524KP UT WOS:000174012600022 PM 11865144 ER PT J AU Scott, DR Hagmar, B Maddox, P Hjerpe, A Dillner, J Cuzick, J Sherman, ME Stoler, MH Kurman, RJ Kiviat, NB Manos, MM Schiffman, M AF Scott, DR Hagmar, B Maddox, P Hjerpe, A Dillner, J Cuzick, J Sherman, ME Stoler, MH Kurman, RJ Kiviat, NB Manos, MM Schiffman, M TI Use of human papillomavirus DNA testing to compare equivocal cervical cytologic interpretations in the United States, Scandinavia, and the United Kingdom SO CANCER CYTOPATHOLOGY LA English DT Article; Proceedings Paper CT Meeting of the British-Society-of-Colposcopy CY MAR, 2000 CL BIRMINGHAM, ENGLAND SP British Soc Colposcopy DE cervical cytology; Papanicolaou tests; atypical squamous cells of undetermined significance (ASCUS); reproducibility; the Bethesda System; human papillomavirus (HPV) ID ATYPICAL SQUAMOUS CELLS; INTRAEPITHELIAL NEOPLASIA; UNDETERMINED SIGNIFICANCE; NORMAL WOMEN; INFECTION; LESIONS; SMEARS; CANCER AB BACKGROUND. Human papillomavirus (HPV) DNA testing may be useful in clarifying equivocal cervical cytologic interpretations. One application might be to standardize the meaning of equivocal interpretations from laboratories in various regions. Because international differences may be particularly marked, international comparisons of emerging data will require clear translations of "equivocal" and similar terms. METHODS. To perform a three-country comparison, the authors selected a morphologically diverse set of 188 conventional Papanicolaou tests initially classified as "squamous atypia" from a study of more than 20,000 women in Portland, Oregon (1989-1990). Previously, five U.S. expert cytopathologists independently interpreted the slides with screening cytotechnologists' marks in place. For this comparison, one British and two Scandinavian reviewers involved in HPV research reviewed the slides after original marks had been removed. The authors compared all eight reviewers' classifications of negative, equivocal, or abnormal in a series of pairwise comparisons using the kappa statistic. They then compared cytologic interpretations with HPV DNA testing. RESULTS. Oncogenic HPV DNA detection was significantly associated with increasingly abnormal interpretations for each reader. The British reader tended to rate tests as more abnormal than the American pathologists did, whereas the Scandinavians tended to rate tests as more normal. Reference to the HPV DNA standard clarified the tendency of readers to render systematically more or less severe interpretations. For example, the Scandinavian cytologists discounted subtle (often HPV-associated) changes in favor of cytologic certainty, making HPV triage of equivocal tests less applicable there. CONCLUSIONS. international research on cytopathology, particularly on the possible uses of HPV DNA testing, will require calibration of local cytologic definitions. (C) 2002 American Cancer Society. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Kaiser Permanente, Dept Pathol, Portland, OR USA. Norwegian Natl Hosp, Dept Pathol, Div Cytol, Oslo, Norway. Imperial Canc Res Fund, Dept Math Stat & Epidemiol, London WC2A 3PX, England. Huddinge Hosp, Karolinska Inst, Div Pathol, Dept Immunol Microbiol Pathol & Infect Dis, Stockholm, Sweden. Karolinska Inst, Ctr Microbiol & Tumor Biol, Stockholm, Sweden. RP Schiffman, M (reprint author), NCI, Div Canc Epidemiol & Genet, Room 7066,6120 Execut Blvd, Rockville, MD 20852 USA. NR 28 TC 33 Z9 35 U1 1 U2 1 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 FEB 25 PY 2002 VL 96 IS 1 BP 14 EP 20 DI 10.1002/cncr.10317 PG 7 WC Oncology; Pathology SC Oncology; Pathology GA 524NE UT WOS:000174019100003 PM 11836698 ER PT J AU Hui, AM Shi, YZ Li, X Sun, L Guido, T Takayama, T Makuuchi, M AF Hui, AM Shi, YZ Li, X Sun, L Guido, T Takayama, T Makuuchi, M TI Proliferative marker Ki-67 in gallbladder carcinomas: high expression level predicts early recurrence after surgical resection SO CANCER LETTERS LA English DT Article DE gallbladder cancer; proliferation; prognosis ID SQUAMOUS-CELL CARCINOMA; PROGNOSTIC-SIGNIFICANCE; COLORECTAL-CARCINOMA; BREAST-CARCINOMA; OVER-EXPRESSION; GASTRIC-CANCER; INHIBITOR P27; INDEX; P53; KI67 AB To evaluate the prognostic value of proliferative maker Ki-67, its expression was determined immunohistochemically in 37 gallbladder carcinomas (GBCs). A high Ki-67 index was significantly correlated with tumor lymphatic invasion (P = 0.007) and vascular invasion (P = 0.04). High Ki-67 index group and low Ki-67 index group showed different clinical courses. Five patients who experienced recurrences in high Ki-67 index group developed their recurrent diseases within one year after surgery and died soon after recurrence, while the recurrences (five cases) in low Ki-67 index group were distributed all stages after surgery. In conclusion, high Ki-67 index predicts early recurrence after surgery for GBCs. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Tokyo, Grad Sch Med, Dept Surg, Hepato Biliary Pancreat Surg Div,Bunkyo Ku, Tokyo 1130033, Japan. RP Hui, AM (reprint author), NCI, NIH, 36 Convent Dr,Bldg 36,Room 3B05,MSC 4089, Bethesda, MD 20892 USA. RI 幕内, 雅敏/A-2140-2012 NR 33 TC 11 Z9 13 U1 1 U2 2 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 FEB 25 PY 2002 VL 176 IS 2 BP 191 EP 198 DI 10.1016/S0304-3835(01)00749-2 PG 8 WC Oncology SC Oncology GA 520PJ UT WOS:000173790000010 PM 11804747 ER PT J AU Moaddel, R Lu, LL Baynham, M Wainer, IW AF Moaddel, R Lu, LL Baynham, M Wainer, IW TI Immobilized receptor- and transporter-based liquid chromatographic phases for on-line pharmacological and biochemical studies: a mini-review SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Review DE reviews; P-glycoprotein; estrogen receptor; nicotine receptor ID PROTEOLIPOSOME AFFINITY-CHROMATOGRAPHY; RECONSTITUTED P-GLYCOPROTEIN; MULTIDRUG-RESISTANCE; STATIONARY-PHASE; FUNCTIONAL RECONSTITUTION; GLUCOSE-TRANSPORTER; ATPASE ACTIVITY; CYTOCHALASIN-B; BREAST-CANCER; BINDING AB This review addresses the synthesis and characterization of two different types of receptor-based liquid chromatographic supports, one based upon a trans-membrane ligand gated ion channel receptor (the nicotinic acetylcholine receptor) and the other a soluble nuclear receptor (the estrogen receptor). In addition. studies with the P-glycoprotein transporter are also reported. The nicotinic receptor was immobilized via hydrophobic insertion into the interstitial spaces of an immobilized artificial membrane (IAM) stationary phase, the estrogen receptor was tethered to a hydrophilic stationary phase and the membranes containing the Pgp transporter were coated on the surface of the IAM stationary phase. The stationary phases were characterized using known ligands and substrates for the respective non-immobilized proteins. The results from zonal and frontal chromatographic experiments demonstrated that the stationary phases could be used to determine binding affinities (expressed as dissociation constants, K-d's) and to resolve mixtures of ligands according to their relative affinities. In addition, competitive ligand binding studies on the P-glycoprotein-based stationary phase have established that this phase can be used to identify and characterize competitive displacement and allosteric interactions. These studies demonstrate that immobilized-receptor phases can be used for on-line pharmacological studies and as rapid screens for the isolation and identification of lead drug candidates from complex biological or chemical mixtures. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Georgetown Univ, Sch Med, Dept Pharmacol, Washington, DC 20007 USA. RP Wainer, IW (reprint author), NIA, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 43 TC 49 Z9 52 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD FEB 25 PY 2002 VL 768 IS 1 BP 41 EP 53 AR PII S0378-4347(01)00484-4 DI 10.1016/S0378-4347(01)00484-4 PG 13 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 522YZ UT WOS:000173925700004 PM 11939557 ER PT J AU Attardi, BJ Burgenson, J Hild, SA Reel, JR Blye, RP AF Attardi, BJ Burgenson, J Hild, SA Reel, JR Blye, RP TI CDB-4124 and its putative monodemethylated metabolite, CDB-4453, are potent antiprogestins with reduced antiglucocorticoid activity: in vitro comparison to mifepristone and CDB-2914 SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE alkaline phosphatase; transactivation; progestin receptor; glucocorticoid receptor; (T47D-CO cells); (HepG2 cells) ID PROGESTERONE-RECEPTOR MODULATORS; AGONIST ACTIVITY; SIGNALING PATHWAYS; BREAST-CANCER; ANTAGONIST; BINDING; RU486; CELLS; GENE; MECHANISMS AB To obtain selective antiprogestins, we have examined the in vitro antiprogestational/antiglucocorticoid properties of two novel compounds, CDB-4124 and the putative monodemethylated metabolite, CDB-4453, in transcription and receptor binding assays and compared them to CDB-2914 and mifepristone. All four antiprogestins bound with high affinity to rabbit uterine progestin receptors (PR) and recombinant human PR-A and PR-B (rhPR-A, rhPR-B) and were potent inhibitors of R5020-induced transactivation of the PRE2-tk-luciferase (PRE2-tk-LUC) reporter plasmid and endogenous alkaline phosphatase production in T47D-CO human breast cancer cells. None of these compounds exhibited agonist activity in these cells. Induction of luciferase activity was potentiated about five-fold by 8-Br-cAMP under basal conditions and to the same extent in the presence of the PR antagonists. Mifepristone bound to rabbit thymic glucocorticoid receptors (GR) with approximately twice the avidity of the CDB antiprogestins. Inhibition of GR-mediated transcription of PRE2-tk-LUC was assessed in HepG2 human hepatoblastoma cells. Mifepristone exhibited greater antiglucocorticoid activity than CDB-2914, 4124, and 4453, about 12-, 22-, and 185-fold, respectively. Thus, while there was a good correlation between binding to PR and functional activity of these antiprogestins, GR binding was not predictive of their glucocorticoid antagonist activity. In agreement with our in vivo results, CDB-4124 and CDB-4453, as well as CDB-2914, are potent antiprogestins in vitro, but show considerably less antiglucocorticoid activity than mifepristone. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 BIOQUAL Inc, Mol Endocrinol Lab, Rockville, MD 20850 USA. NICHHD, Contracept & Reprod Hlth Branch, Rockville, MD 20852 USA. RP Attardi, BJ (reprint author), BIOQUAL Inc, Mol Endocrinol Lab, 9600 Med Ctr Dr, Rockville, MD 20850 USA. FU NICHD NIH HHS [N01-HD-6-3259] NR 36 TC 67 Z9 69 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD FEB 25 PY 2002 VL 188 IS 1-2 BP 111 EP 123 AR PII S0303-7207(01)00743-2 DI 10.1016/S0303-7207(01)00743-2 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 538CA UT WOS:000174795400013 PM 11911951 ER PT J AU de Alba, E Tjandra, N AF de Alba, E Tjandra, N TI NMR dipolar couplings for the structure determination of biopolymers in solution SO PROGRESS IN NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY LA English DT Review DE nucleic acid; J coupling; structure refinement; protein; liquid crystal ID LIQUID-CRYSTALLINE MEDIUM; PROTEIN-STRUCTURE DETERMINATION; MALTODEXTRIN-BINDING-PROTEIN; COMPLETE CROSS-VALIDATION; HIGH-RESOLUTION NMR; BIOLOGICAL MACROMOLECULES; HYDROGEN-BONDS; MAGNETIC-FIELD; ORIENTED MACROMOLECULES; ACCURATE MEASUREMENT C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 50,Room 3513, Bethesda, MD 20892 USA. NR 109 TC 115 Z9 115 U1 1 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0079-6565 J9 PROG NUCL MAG RES SP JI Prog. Nucl. Magn. Reson. Spectrosc. PD FEB 25 PY 2002 VL 40 IS 2 BP 175 EP 197 AR PII S0079-6565(01)00042-5 DI 10.1016/S0079-6565(01)00042-5 PG 23 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Chemistry; Physics; Spectroscopy GA 523DR UT WOS:000173938100003 ER PT J AU Porciuncula, LO Vinade, L Wofchuk, S Souza, DO AF Porciuncula, LO Vinade, L Wofchuk, S Souza, DO TI Guanine based purines inhibit [H-3]glutamate and [H-3]AMPA binding at postsynaptic densities from cerebral cortex of rats SO BRAIN RESEARCH LA English DT Article DE guanine-based purine; glutamate bindings; AMPA bindings; postynaptic density ID METHYL-D-ASPARTATE; KAINIC ACID-BINDING; CHICK OPTIC TECTUM; GLUTAMATE RECEPTORS; SIGNAL-TRANSDUCTION; ADENYLATE-CYCLASE; QUINOLINIC ACID; AMPA RECEPTORS; NERVOUS-SYSTEM; NUCLEOTIDES AB Extracellular guanine-based purines (GBPs) have been implicated in neuroprotective effects against glutamate toxicity by modulating the glutamatergic system through mechanisms without the involvement of G proteins. Accordingly, GBPs have been shown to inhibit the binding of glutamate and its analogs in different brain membrane preparations. However, brain membrane preparations used for these studies are comprised of both post- and pro-neuronal and glial synaptic components. In this study we investigated the ability of GBPs to displaced glutamate and AMPA binding at postsynaptic densities (PSDs). PSDs are markedly prominent in glutamatergic synapses and retains the native apposition of membrane components and post synaptic receptors. The PSD fraction was prepared from cerebral cortex of Wistar rats and it was characterized as PSDs by electron microscopy and by an enrichment of PSD-95, a protein marker of PSDS (90% of immunodetection). Moreover. we detected an enrichment of glutamate receptors subunits that including NR1 subunit of NMDA receptors and GluR1 subunit of AMPA receptors. GppNp (poor hydrolyzable GTP analog) and GMP displaced 40 and 36% of glutamate binding. respectively. and guanosine only 23%. AMPA binding was not affected by guanosine and was inhibited 21 and 25% by GppNp and GMP. respectively. Hence, this studs demonstrates that guanine based purines inhibited glutamate and AMPA binding at postsynaptic membrane preparations, contributing for a better understanding of the mechanisms by which GBPs antagonize glutamatergic neurotoxicicity, e.g. the possible involvement of glutamatergic postsynaptic receptors in their neuroprotective roles. (C) 2002 Elsevier Science B.V. All rights reserved. C1 UFRGS, ICBS, Dept Bioquim, BR-90035003 Porto Alegre, RS, Brazil. NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Souza, DO (reprint author), UFRGS, ICBS, Dept Bioquim, Rua Ramiro Barcelos,2600 Anexo, BR-90035003 Porto Alegre, RS, Brazil. RI Souza, Diogo/J-8894-2014 OI Souza, Diogo/0000-0002-4322-0404 NR 44 TC 15 Z9 15 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD FEB 22 PY 2002 VL 928 IS 1-2 BP 106 EP 112 AR PII S0006-8993(01)03368-6 DI 10.1016/S0006-8993(01)03368-6 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 530TJ UT WOS:000174374800012 PM 11844477 ER PT J AU Dever, TE AF Dever, TE TI Gene-specific regulation by general translation factors SO CELL LA English DT Review ID GUANINE-NUCLEOTIDE EXCHANGE; UNFOLDED-PROTEIN RESPONSE; EUKARYOTIC INITIATION-FACTORS; OPEN READING FRAMES; MESSENGER-RNA; KINASE PKR; IN-VIVO; NEUROSPORA-CRASSA; BINDING; ACTIVATION AB Protein synthesis is the ultimate step of gene expression and a key control point for regulation. In particular, it enables cells to rapidly manipulate protein production without new mRNA synthesis, processing, or export. Recent studies have enhanced our understanding of the translation initiation process and helped elucidate how modifications of the general translational machinery regulate gene-specific protein production. C1 NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Dever, TE (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RI Marion-Poll, Frederic/D-8882-2011 OI Marion-Poll, Frederic/0000-0001-6824-0180 NR 99 TC 503 Z9 518 U1 3 U2 24 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD FEB 22 PY 2002 VL 108 IS 4 BP 545 EP 556 DI 10.1016/S0092-8674(02)00642-6 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 524XW UT WOS:000174039000012 PM 11909525 ER PT J AU Ginjala, V Holmgren, C Ulleras, E Kanduri, C Pant, V Lobanenkov, V Franklin, G Ohlsson, R AF Ginjala, V Holmgren, C Ulleras, E Kanduri, C Pant, V Lobanenkov, V Franklin, G Ohlsson, R TI Multiple cis elements within the Igf2/H19 insulator domain organize a distance-dependent silencer - A cautionary note SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMPRINTED EXPRESSION; HISTONE ACETYLATION; CHROMATIN STRUCTURE; H19/IGF2 LOCUS; MOUSE H19; METHYLATION; CTCF; GENE AB The 5'-flank of the H19 gene harbors a differentially methylated imprinting control region that represses the maternally derived Igf2 and paternally derived H19 alleles. Here we show that the H19 imprinting control region (ICR) is a potent silencer when positioned in a promoter-proximal position. The silencing effect is not alleviated by trichostatin A treatment, suggesting that it does not involve histone deacetylase functions. When the H19 ICR is separated from the promoter by more than 1.2 +/- 0.3 kb, however, trichostatin A stimulates promoter activity 10-fold. Deletion analyses revealed that the silencing feature extended throughout the ICR segment. Finally, chromatin immunopurification analyses revealed that the H19 ICR prevented trichostatin A-dependent reacetylation of histones in the promoter region in a proximal but not in a distal position. We argue that these features are likely to be side effects of the H19 ICR, rather than explaining the mechanism of silencing of the paternal H19 allele. We issue a cautionary note, therefore, that the interpretation of insulator/ silencer data could be erroneous should the distance issue not be taken into consideration. C1 Uppsala Univ, Dept Dev & Genet Evolut Biol Ctr, S-75236 Uppsala, Sweden. NIAID, Lab Immunopathol, NIH, Bethesda, MD 20892 USA. RP Ohlsson, R (reprint author), Uppsala Univ, Dept Dev & Genet Evolut Biol Ctr, Norbyvagen 18A, S-75236 Uppsala, Sweden. OI Lobanenkov, Victor/0000-0001-6665-3635 NR 16 TC 5 Z9 5 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 FEB 22 PY 2002 VL 277 IS 8 BP 5707 EP 5710 DI 10.1074/jbc.C100552200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 524AF UT WOS:000173989200003 PM 11777900 ER PT J AU Gatanaga, H Suzuki, Y Tsang, H Yoshimura, K Kavlick, MF Nagashima, K Gorelick, RJ Mardy, S Tang, C Summers, MF Mitsuya, H AF Gatanaga, H Suzuki, Y Tsang, H Yoshimura, K Kavlick, MF Nagashima, K Gorelick, RJ Mardy, S Tang, C Summers, MF Mitsuya, H TI Amino acid substitutions in Gag protein at non-cleavage sites are indispensable for the development of a high multitude of HIV-1 resistance against protease inhibitors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CYCLOPHILIN-A; POL POLYPROTEINS; MATRIX PROTEIN; TYPE-1; REPLICATION; ALLOPHENYLNORSTATINE; TARGET; DOMAIN; GENE AB Amino acid substitutions in human immunodeficiency virus type 1 (HIV-1) Gag cleavage sites have been identified in HIV-1 isolated from patients with AIDS failing chemotherapy containing protease inhibitors (PIs). However, a number of highly PI-resistant HIV-1 variants lack cleavage site amino acid substitutions. In this study we identified multiple novel amino acid substitutions including L75R, H219Q V390D/V390A, R409K, and E468K in the Gag protein at non-cleavage sites in common among HIV-1 variants selected against the following four PIs: amprenavir, JE-2147, RNI-272, and UIC-94003. Analyses of replication profiles of various mutant clones including competitive HIV-1 replication assays demonstrated that these mutations were indispensable for HIV-1 replication in the presence of PIs. When some of these mutations were reverted to wild type amino acids, such HIV-1 clones failed to replicate. However, virtually the same Gag cleavage pattern was seen, indicating that the mutations affected Gag protein functions but not their cleavage sensitivity to protease. These data strongly suggest that non-cleavage site amino acid substitutions in the Gag protein recover the reduced replicative fitness of HIV-1 caused by mutations in the viral protease and may open a new avenue for designing PIs that resist the emergence of PI-resistant HIV-1. C1 NCI, HIV & AIDS Malignancy Branch, Expt Retrovirol Sect, NIH, Bethesda, MD 20892 USA. Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 860, Japan. NCI, Sci Applicat Int Corp, AIDS Vaccine Program, Frederick, MD 21701 USA. NCI, Sci Applicat Int Corp, Image Anal Lab, Frederick, MD 21701 USA. Univ Maryland, Howard Hughes Med Inst, Baltimore, MD 21250 USA. Univ Maryland, Dept Chem & Biochem, Baltimore, MD 21250 USA. RP Mitsuya, H (reprint author), NCI, HIV & AIDS Malignancy Branch, Expt Retrovirol Sect, NIH, Bldg 10,Rm 5A11,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Tsang, Hsinyi/C-9547-2011 FU NCI NIH HHS [N01-CO 56000] NR 31 TC 98 Z9 101 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 FEB 22 PY 2002 VL 277 IS 8 BP 5952 EP 5961 DI 10.1074/jbc.M108005200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 524AF UT WOS:000173989200034 PM 11741936 ER PT J AU Guo, Q Corbett, JT Yue, GH Fann, YC Qian, SY Tomer, KB Mason, RP AF Guo, Q Corbett, JT Yue, GH Fann, YC Qian, SY Tomer, KB Mason, RP TI Electron spin resonance investigation of semiquinone radicals formed from the reaction of ubiquinone 0 with human oxyhemoglobin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MITOCHONDRIAL PERMEABILITY TRANSITION; VITAMIN-E HOMOLOG; RESPIRATORY-CHAIN; SUPEROXIDE ANION; COENZYME Q(0); GLUTATHIONE; HEMOGLOBIN; ANTIOXIDANT; OXIDATION; QUINONES AB The redox properties and thiol reactivity of quinones play critical roles in their therapeutic and toxicological properties. The present study was undertaken to investigate the binding activity of ubiquinone 0 (UQ(0)) to human oxyhemoglobin (HbO(2)) using electron spin resonance (ESR). Addition of UQ(0) to HbO(2) resulted in the immediate detection of a five-line ESR spectrum characteristic of the semiquinone radical of UQ(0) (UQ ((0)) over bar). With time the HbO(2) adduct with UQ(0), which was characterized by a broad immobilized ESR spectrum, was gradually formed. Matrix-assisted laser desorption/ionization time-of-flight mass spectra analysis showed that UQ(0) bound to the beta-chain of HbO(2). Superoxide dismutase dose-dependently suppressed the intensity of the broad spectrum and accelerated its formation. However, N-ethylmaleimide, a thiol-blocking agent, completely eliminated its formation. The nonspecific protease mixture pronase also prevented its formation and resulted in the gradual appearance of a 4-line spectrum from the 5-line spectrum of UQ ((0)) over bar. The structure of the species responsible for the 4-line spectrum was confirmed and identified by the reaction of UQ(0) with reduced glutathione. In human red blood cells, UQ(0) rapidly bound to glutathione but more slowly to HbO(2). These results suggest that UQO reacted with both ferrous heme and the reactive beta-93 cysteinyl residue of HbO(2) to generate its corresponding semiquinone radical. Subsequently UQ(0) bound to the beta-93 cysteinyl residue of HbO(2) to form a covalent-binding adduct responsible for the broad spectrum. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Guo, Q (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Tomer, Kenneth/E-8018-2013 NR 45 TC 17 Z9 17 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 22 PY 2002 VL 277 IS 8 BP 6104 EP 6110 DI 10.1074/jbc.M106395200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 524AF UT WOS:000173989200055 PM 11748217 ER PT J AU Schrager, JA Minassian, VD Marsh, JW AF Schrager, JA Minassian, VD Marsh, JW TI HIV Nef increases T cell ERK MAP kinase activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVATED PROTEIN-KINASE; SIGNAL-REGULATED KINASE-2; TERNARY COMPLEX FACTORS; TYPE-1 NEF; ANTIGEN-RECEPTOR; TRANSCRIPTION FACTOR; EFFECTOR FUNCTIONS; ALPHA PROTEOLYSIS AB The human immunodeficiency regulatory protein Nef enhances viral replication and is central to viral pathogenesis. Although Nef has displayed a capacity to associate with a diverse assortment of cellular molecules and to increase T cell activity, the biochemical activity of Nef in T cells remains poorly defined. In this report we examine the bioactivity of Nef in primary CD4 T cells and, in particular, focus on the biochemical pathways known to be central to T cell activity. The extracellular signal-regulated kinase (ERK) mitogen-activated protein (ALAP) kinase pathway was dramatically affected by Nef expression with increases in ERK, MEK, and Elk induction. The capacity of Nef to increase the MAP kinase pathway activity was dependent on T cell receptor stimulation. By increasing ERK MAP kinase activity, Nef is functionally associated with a kinase known to affect T cell activity, viral replication, and viral infectivity. C1 NIMH, LMB, Bethesda, MD 20892 USA. RP Marsh, JW (reprint author), NIMH, LMB, BLdg 36,Rm 1B08,36 Convent Dr,MSC 4034, Bethesda, MD 20892 USA. NR 90 TC 46 Z9 47 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 FEB 22 PY 2002 VL 277 IS 8 BP 6137 EP 6142 DI 10.1074/jbc.M107322200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 524AF UT WOS:000173989200060 PM 11726657 ER PT J AU Fujimoto, T Parry, S Urbanek, M Sammel, M Macones, G Kuivaniemi, H Romero, R Strauss, JF AF Fujimoto, T Parry, S Urbanek, M Sammel, M Macones, G Kuivaniemi, H Romero, R Strauss, JF TI A single nucleotide polymorphism in the matrix metalloproteinase-1 (MMP-1) promoter influences amnion cell MMP-1 expression and risk for preterm premature rupture of the fetal membranes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NEUTROPHIL COLLAGENASE; CHROMOSOME 11Q22.3; GENE; ORGANIZATION; MECHANISMS; ACTIVATION; TRANSCRIPTION; LOCALIZATION; PARTURITION; ASSIGNMENT AB Interstitial collagen gives fetal membranes tensile strength, and membrane rupture has been attributed to collagen degradation. A polymorphism at -1607 in the matrix metalloproteinase-1 (MMP-1) promoter (an insertion of a guanine (G)) creates a core Ets binding site and increases promoter activity. We investigated whether this polymorphism is functionally significant for MMP-1 expression in amnion cells and whether it is associated with preterm premature rupture of the membranes (PPROM). The 2G promoter had >2-fold greater activity than the 1G allele in amnion mesenchymal cells and WISH amnion cells. Phorbol 12-myristate 13-acetate (PMA) increased mesenchymal cell nuclear protein binding with greater affinity to the 2G allele. Induction of MMP-1 mRNA by PMA was significantly greater in cells with a 1G/2G or 2G/2G genotype compared with cells homozygous for the 1G allele. When treated with PMA, the 1G/2G and 2G/2G cells produced greater amounts of MMP-1 protein than 1G/1G cells. A significant association was found between fetal carriage of a 2G allele and PPROM. We conclude that the 2G allele has stronger promoter activity in amnion cells, that it confers increased responsiveness of amnion cells to stimuli that induce MMP-1, and that this polymorphism contributes to the risk of PPROM. C1 Univ Penn, Med Ctr, Ctr Res Reprod & Womens Hlth, Philadelphia, PA 19104 USA. Univ Penn, Med Ctr, Dept Genet, Philadelphia, PA 19104 USA. Univ Penn, Med Ctr, Dept Biostat & Clin Epidemiol, Philadelphia, PA 19104 USA. Hutzel Hosp, Perinatol Res Branch, NIH, NICHHD, Detroit, MI 48201 USA. RP Strauss, JF (reprint author), 1354 BRB II,421 Curie Blvd, Philadelphia, PA 19104 USA. OI Kuivaniemi, Helena/0000-0001-5753-8766 FU NICHD NIH HHS [HD34612] NR 41 TC 110 Z9 115 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 FEB 22 PY 2002 VL 277 IS 8 BP 6296 EP 6302 DI 10.1074/jbc.M107865200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 524AF UT WOS:000173989200080 PM 11741975 ER PT J AU Cole, NB Murphy, DD Grider, T Rueter, S Brasaemle, D Nussbaum, RL AF Cole, NB Murphy, DD Grider, T Rueter, S Brasaemle, D Nussbaum, RL TI Lipid droplet binding and oligomerization properties of the Parkinson's disease protein alpha-synuclein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LEWY BODIES; SYNAPSIN-I; NACP/ALPHA-SYNUCLEIN; SYNAPTIC VESICLES; OXIDATIVE STRESS; NERVOUS-SYSTEM; BRAIN; LOCALIZATION; EXPRESSION; PERILIPIN AB alpha-Synuclein is a major component of the fibrillary lesion known as Lewy bodies and Lewy neurites that are the pathologic hallmarks of Parkinson's disease (PD). In addition, point mutations in the alpha-synuclein gene imply a-synuclein dysfunction in the pathology of inherited forms of PD. alpha-Synuclein is a member of a family of proteins found primarily in the brain and is concentrated within presynaptic terminals. Here, we address the localization and membrane binding characteristics of wild type and PD mutants of alpha-synuclein in cultured cells. In cells treated with high concentrations of fatty acids, wild type alpha-synuclein accumulated on phospholipid monolayers surrounding triglyceride-rich lipid droplets and was able to protect stored triglycerides from hydrolysis. PD mutant synucleins showed variable distributions on lipid droplets and were less effective in regulating triglyceride turnover. Chemical cross-linking demonstrated that synuclein formed small oligomers within cells, primarily dimers and trimers, that preferentially associated with lipid droplets and cell membranes. Our results suggest that the initial phases of synuclein aggregation may occur on the surfaces of membranes and that pathological conditions that induce cross-linking of synuclein may enhance the propensity for subsequent synuclein aggregation. C1 NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. NINCDS, Div Extramural Activ, NIH, Bethesda, MD 20982 USA. Univ Penn, Sch Med, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA. Rutgers State Univ, Dept Nutr Sci, New Brunswick, NJ 08901 USA. RP Cole, NB (reprint author), NHGRI, Genet Dis Res Branch, NIH, Rm 4B67,49 Convent Dr, Bethesda, MD 20892 USA. OI Brasaemle, Dawn/0000-0002-8553-8285 NR 61 TC 228 Z9 231 U1 0 U2 14 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 22 PY 2002 VL 277 IS 8 BP 6344 EP 6352 DI 10.1074/jbc.M108414200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 524AF UT WOS:000173989200086 PM 11744721 ER PT J AU Cardona, CM Gawley, RE AF Cardona, CM Gawley, RE TI An improved synthesis of a trifurcated Newkome-type monomer and orthogonally protected two-generation dendrons SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID SUPRAMOLECULAR CHEMISTRY; PHOTOPHYSICAL PROPERTIES; CASCADE POLYMERS; DENDRIMERS; ELECTROCHEMISTRY; DERIVATIVES; MIMICS; CORE AB The one-step synthesis of amino-polyether tritert-butyl ester monomer 2, by condensation of TRIS with tert-butyl acrylate, is reported. The nitrogen of the monomer can be protected with a Cbz group; subsequent removal of the tert-butyl esters with formic acid affords a triacid that is coupled to three monomers to afford an orthogonally protected two-generation, trifurcated polyether-polyamide dendron. The Cbz protecting group may be removed from the second-generation dendron without disturbing the tertbutyl esters of the periphery. C1 Univ Miami, Dept Chem, Coral Gables, FL 33124 USA. Univ Miami, NIEHS Marine & Freshwater Biomed Sci Ctr, Coral Gables, FL 33124 USA. RP Gawley, RE (reprint author), Univ Miami, Dept Chem, POB 249118, Coral Gables, FL 33124 USA. FU NIEHS NIH HHS [ES05705, ES05931, ES07320] NR 27 TC 30 Z9 31 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD FEB 22 PY 2002 VL 67 IS 4 BP 1411 EP 1413 DI 10.1021/jo0161678 PG 3 WC Chemistry, Organic SC Chemistry GA 522MT UT WOS:000173901700057 PM 11846699 ER PT J AU Bergasa, NV Rothman, RB Mukerjee, E Vergalla, J Jones, EA AF Bergasa, NV Rothman, RB Mukerjee, E Vergalla, J Jones, EA TI Up-regulation of central mu-opioid receptors in a model of hepatic encephalopathy: A potential mechanism for increased sensitivity to morphine in liver failure SO LIFE SCIENCES LA English DT Article DE hepatic encephalopathy; opioids; morphine; mu-opioid receptors ID RAT-BRAIN; OPIATE RECEPTOR; BINDING; NEUROTRANSMISSION; SUPERSENSITIVITY; CHOLESTASIS; ENKEPHALIN AB Increased GABA-mediated neurotransmission, reported to occur in hepatic encephalopathy (HE), is associated with a decrease in the release of Met-enkephalin and the expression of its coding gene in the brain. Furthermore, patients with cirrhosis and a history of HE exhibit increased sensitivity to the neuroinhibitory effects of morphine. Thus, there is a rationale to study the status of the endogenous opioid system in HE. The aim of this study was to determine whether mu-opioid receptors in the brain are up-regulated in a well characterized model of HE. Binding parameters of mu-opioid receptors were derived by assaying the binding of the opiate agonist [H-3]-tyr-D-Ala-Gly-N-Methyl-Phe-Gly-ol (DAMGO) to brain membranes from rats with precisely defined stages of HE and control animals. The mean density of mu-opioid receptor sites (Bmax) in rats with stage II, III, and IV HE was 15, 29, and 33% higher, respectively, than the corresponding control value (p < 0.01). In addition, the affinity of mu opioid receptors for the agonist (1/Kd) also increased with progression of HE (mean for stage IV HE vs. corresponding control mean, p < 0.01). In conclusion, in liver failure, increased density and affinity of central mu-opioid receptors in the brain may: (i) be the basis for the documented increased sensitivity to opiate agonists; and (ii) occur as a consequence of increased GABAergic tone reducing neuronal synthesis and release of opioid agonist peptides. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Natl Inst Hlth, Liver Dis Sect, Bethesda, MD USA. Natl Inst Drug Abuse, Addict Res Ctr, Baltimore, MD 21224 USA. Acad Med Ctr, Dept Gastrointestinal & Liver Dis, Amsterdam, Netherlands. RP Bergasa, NV (reprint author), Columbia Univ, Coll Phys & Surg, Div Digest & Liver Dis, 630 W 168 St,P&S 10-508, New York, NY 10032 USA. NR 27 TC 15 Z9 15 U1 0 U2 3 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 FEB 22 PY 2002 VL 70 IS 14 BP 1701 EP 1708 AR PII S0024-3205(02)01487-X DI 10.1016/S0024-3205(02)01487-X PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 537GN UT WOS:000174750700010 PM 11991257 ER PT J AU Nemukhin, AV Topol, IA Grigorenko, BL Burt, SK AF Nemukhin, AV Topol, IA Grigorenko, BL Burt, SK TI On the origin of potential barrier for the reaction OH-+CO2 -> HCO3- in water: Studies by using continuum and cluster solvation methods SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID GAS-PHASE; CARBONIC-ANHYDRASE; HYDROXIDE ION; FREE-ENERGY; MODEL; EQUILIBRIA; DYNAMICS; SYSTEM AB The energy profiles for the reaction OH- + CO2 --> HCO3- are analyzed following the results of calculations carried out using both a continuum solvation model and a cluster approach. The minimum energy path, computed with the quantum chemistry LMP2 and B3LYP approximations, corresponds to the activation-less process in the gas phase but shows a barrier on the way from the reactants to the product in the dielectric continuum medium. In the cluster approach, the reacting species were completely surrounded by 30 water molecules, each considered as an effective fragment potential (EFP) acting on the quantum system. Positions of all particles were optimized along the reaction coordinate in this quantum mechanical-molecular mechanical (QM/MM) approximation. The energy profile obtained with the QM/MM(EFP) approach is in remarkable agreement with the results of the continuum model, showing the barrier in the same region. An analysis of the arrangements of the water molecules around the reacting species, as well as changes in geometry configurations and electronic distributions of the solute species, allows us to conclude that on the segment of the reaction path close to the potential barrier a considerable fraction of the negative charge on OH- transfers to CO2, accompanied by a sharp bending of the O-C-O species. As a result, the hydroxide anion loses water molecules from its hydration shell. We show that the height of the barrier on the free energy curve for the reaction OH- + CO2 --> HCO3- in water can be estimated within the limits 8-13 kcal/mol, and its precise quantity depends on the reference value of experimental free energy of solvation of OH-. 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 NR 30 TC 29 Z9 29 U1 2 U2 15 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 FEB 21 PY 2002 VL 106 IS 7 BP 1734 EP 1740 DI 10.1021/jp0141629 PG 7 WC Chemistry, Physical SC Chemistry GA 523XB UT WOS:000173981900032 ER PT J AU Misra, S Puertollano, R Kato, Y Bonifacino, JS Hurley, JH AF Misra, S Puertollano, R Kato, Y Bonifacino, JS Hurley, JH TI Structural basis for acidic-cluster-dileucine sorting-signal recognition by VHS domains SO NATURE LA English DT Article ID ELECTRON-DENSITY MAPS; TRANS-GOLGI NETWORK; FACTOR-II RECEPTOR; GAMMA-ADAPTIN; PROTEINS; FAMILY; TRAFFICKING AB Specific sorting signals direct transmembrane proteins to the compartments of the endosomal-lysosomal system(1). Acidic-cluster-dileucine signals present within the cytoplasmic tails of sorting receptors, such as the cation-independent and cation-dependent mannose-6-phosphate receptors, are recognized by the GGA (Golgi-localized, gamma-ear-containing, ADP-ribosylation-factor-binding) proteins(2-5). The VHS (Vps27p, Hrs and STAM) domains(6) of the GGA proteins are responsible for the highly specific recognition of these acidic-cluster-dileucine signals(7-10). Here we report the structures of the VHS domain of human GGA3 complexed with signals from both mannose-6-phosphate receptors. The signals bind in an extended conformation to helices 6 and 8 of the VHS domain. The structures highlight an Asp residue separated by two residues from a dileucine sequence as critical recognition elements. The side chains of the Asp-X-X-Leu-Leu sequence interact with subsites consisting of one electropositive and two shallow hydrophobic pockets, respectively. The rigid spatial alignment of the three binding subsites leads to high specificity. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RI KATO, Yukio/D-8396-2015; OI Misra, Saurav/0000-0002-1385-8554; Bonifacino, Juan S./0000-0002-5673-6370 NR 26 TC 128 Z9 129 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 21 PY 2002 VL 415 IS 6874 BP 933 EP 937 DI 10.1038/415933a PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 523EL UT WOS:000173941000051 PM 11859375 ER PT J AU Oral, EA Simha, V Ruiz, E Andewelt, A Premkumar, A Snell, P Wagner, AJ DePaoli, AM Reitman, ML Taylor, SI Gorden, P Garg, A AF Oral, EA Simha, V Ruiz, E Andewelt, A Premkumar, A Snell, P Wagner, AJ DePaoli, AM Reitman, ML Taylor, SI Gorden, P Garg, A TI Leptin-replacement therapy for lipodystrophy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CONGENITAL GENERALIZED LIPODYSTROPHY; FAMILIAL PARTIAL LIPODYSTROPHY; ADIPOSE-TISSUE; OBESE GENE; RECOMBINANT LEPTIN; INSULIN-RESISTANCE; DIABETES-MELLITUS; WEIGHT; MICE; MOUSE AB Background: The adipocyte hormone leptin is important in regulating energy homeostasis. Since severe lipodystrophy is associated with leptin deficiency, insulin resistance, hypertriglyceridemia, and hepatic steatosis, we assessed whether leptin replacement would ameliorate this condition. Methods: Nine female patients (age range, 15 to 42 years; eight with diabetes mellitus) who had lipodystrophy and serum leptin levels of less than 4 ng per milliliter (0.32 nmol per milliliter) received recombinant methionyl human leptin (recombinant leptin). Recombinant leptin was administered subcutaneously twice a day for four months at escalating doses to achieve low, intermediate, and high physiologic replacement levels of leptin. Results: During treatment with recombinant leptin, the serum leptin level increased from a mean (+/-SE) of 1.3+/-0.3 ng per milliliter to 11.1+/-2.5 ng per milliliter (0.1+/-0.02 to 0.9+/-0.2 nmol per milliliter). The absolute decrease in the glycosylated hemoglobin value was 1.9 percent (95 percent confidence interval, 1.1 to 2.7 percent; P=0.001) in the eight patients with diabetes. Four months of therapy decreased average triglyceride levels by 60 percent (95 percent confidence interval, 43 to 77 percent; P<0.001) and liver volume by an average of 28 percent (95 percent confidence interval, 20 to 36 percent; P=0.002) in all nine patients and led to the discontinuation of or a large reduction in antidiabetes therapy. Self-reported daily caloric intake and the measured resting metabolic rate also decreased significantly with therapy. Overall, recombinant leptin therapy was well tolerated. Conclusions: Leptin-replacement therapy improved glycemic control and decreased triglyceride levels in patients with lipodystrophy and leptin deficiency. Leptin deficiency contributes to the insulin resistance and other metabolic abnormalities associated with severe lipodystrophy. Copyright (C) 2002 Massachusetts Medical Society. C1 NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Amgen Inc, Thousand Oaks, CA USA. RP Oral, EA (reprint author), NIDDK, Diabet Branch, NIH, Bldg 10,Rm 8D20, Bethesda, MD 20892 USA. RI Reitman, Marc/B-4448-2013; OI Reitman, Marc/0000-0002-0426-9475; Oral, Elif/0000-0002-9171-1144 FU NCRR NIH HHS [M01-RR00633]; NIDDK NIH HHS [R01-DK54387] NR 45 TC 651 Z9 676 U1 2 U2 17 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 FEB 21 PY 2002 VL 346 IS 8 BP 570 EP 578 DI 10.1056/NEJMoa012437 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 522ZK UT WOS:000173926700005 PM 11856796 ER PT J AU Yanovski, SZ Yanovski, JA AF Yanovski, SZ Yanovski, JA TI Drug therapy - Obesity SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID TERM WEIGHT CONTROL; FENFLURAMINE PLUS PHENTERMINE; CONGENITAL LEPTIN DEFICIENCY; PLACEBO-CONTROLLED TRIAL; VALVULAR HEART-DISEASE; DOUBLE-BLIND; BEHAVIOR-MODIFICATION; DIETARY-SUPPLEMENTS; CALORIC RESTRICTION; RECOMBINANT LEPTIN C1 NIDDK, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. NICHHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Yanovski, SZ (reprint author), NIDDK, Obest & Eating Disorders Program, 6707 Democracy Blvd, Bethesda, MD 20892 USA. NR 109 TC 406 Z9 430 U1 5 U2 25 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 FEB 21 PY 2002 VL 346 IS 8 BP 591 EP 602 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 522ZK UT WOS:000173926700008 PM 11856799 ER PT J AU Warren, JL Brown, ML AF Warren, JL Brown, ML TI Chemotherapy in the elderly SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Warren, JL (reprint author), NCI, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 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 FEB 21 PY 2002 VL 346 IS 8 BP 622 EP 623 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 522ZK UT WOS:000173926700015 PM 11858266 ER PT J AU Sattler, M Pride, YB Quinnan, LR Verma, S Malouf, NA Husson, H Salgia, R Lipkowitz, S Griffin, JD AF Sattler, M Pride, YB Quinnan, LR Verma, S Malouf, NA Husson, H Salgia, R Lipkowitz, S Griffin, JD TI Differential expression and signaling of CBL and CBL-B in BCR/ABL transformed cells SO ONCOGENE LA English DT Article DE CBL-B; BCR/ABL; gene expression; cell migration; signal transduction ID GROWTH-FACTOR RECEPTOR; ADAPTER PROTEINS CRKL; C-CBL; TYROSINE PHOSPHORYLATION; PHOSPHATIDYLINOSITOL 3-KINASE; PROTOONCOGENE PRODUCT; HEMATOPOIETIC-CELLS; NEGATIVE REGULATOR; ANTIGEN RECEPTOR; BINDING-PROTEIN AB CBL and the related CBL-B protein are two members of a family of RING finger type ubiquitin E3 ligases that are believed to function as negative regulators of signal transduction in hematopoietic and immune cells. In mice, expression of v-Cbl causes lymphomas, and targeted disruption of either the CBL gene or the CBL-B gene can result in a lymphoproliferative disorder or hypersensitivity of lymphocytes. CBL is one of the most prominent targets of the BCR/ABL tyrosine kinase oncogene. We compared the role of CBL and CBL-B in signal transduction of BCR/ABL using pairs of cell lines before and after expression of BCR/ABL. In contrast to CBL, BCR/ABL was found to rapidly downregulate the expression of CBL-B protein. The decrease in CBL-B protein induced by BCR/ABL was associated with down-regulation of CBL-B mRNA. Downregulation and tyrosine phosphorylation of CBL-B required BCR/ABL kinase activity. However, despite their known similarities in structure and function, we found CBL and CBL-B proteins to be involved in distinct signaling complexes. CBL was predominantly in a complex with phosphatidylinositol 3'-kinase and CRKL, while CBL-B was not associated with any significant phosphatidylinositol 3'-kinase activity. A major CBL-B associated protein was identified as mono-ubiquitinated Vav, a nucleotide exchange factor for Rac1. These results demonstrate that BCR/ABL signals differentially through CBL and CBL-B, with downregulation of the CBL-B protein potentially contributing to BCR/ABL-mediated transformation. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Natl Naval Med Res Inst, Med Branch, Genet Dept, NCI, Bethesda, MD 20889 USA. RP Sattler, M (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. EM martin_sattler@dfci.harvard.edu FU NCI NIH HHS [CA78348]; NIDDK NIH HHS [DK50654] NR 49 TC 22 Z9 23 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 21 PY 2002 VL 21 IS 9 BP 1423 EP 1433 DI 10.1038/sj/onc/1205202 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 521VA UT WOS:000173861000012 PM 11857085 ER PT J AU Choi, Y George, C Strazewski, P Marquez, VE AF Choi, Y George, C Strazewski, P Marquez, VE TI Synthesis of a conformationally locked version of puromycin amino nucleoside SO ORGANIC LETTERS LA English DT Article ID CARBOCYCLIC NUCLEOSIDES; ADENOSINE-DEAMINASE; NEPLANOCIN-C; SUGAR RING; OLIGONUCLEOTIDES; TEMPLATE; ANALOGS AB [GRAPHICS] A conformationally locked carbocyclic version of puromycin amino nucleoside was synthesized via Mitsunobu coupling of a 3-azido-substituted carbocyclic moiety with 6-chloropurine without interference from the azido group reacting with triphenylphosphine. The requisite 3-azido-substituted carbocyclic pseudosugar was prepared by a double inversion of configuration at C3' (nucleoside numbering) involving a nucleophilic displacement with azide. C1 NCI, Med Chem Lab, Canc Res Ctr, Frederick, MD 21702 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. Univ Lyon 1, Lab Syntheses Biomol, F-69622 Villeurbanne, France. RP Marquez, VE (reprint author), NCI, Med Chem Lab, Canc Res Ctr, Frederick, MD 21702 USA. RI Choi, Yongseok/F-8375-2012 OI Choi, Yongseok/0000-0002-3622-3439 NR 19 TC 23 Z9 23 U1 0 U2 7 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 FEB 21 PY 2002 VL 4 IS 4 BP 589 EP 592 DI 10.1021/ol010288c PG 4 WC Chemistry, Organic SC Chemistry GA 522FR UT WOS:000173885800030 PM 11843598 ER PT J AU Aasland, R Abrams, C Ampe, C Ball, LJ Bedford, MT Cesareni, G Gimona, M Hurley, JH Jarchau, T Lehto, VP Lemmon, MA Linding, R Mayer, BJ Nagai, M Sudol, M Walter, U Winder, SJ AF Aasland, R Abrams, C Ampe, C Ball, LJ Bedford, MT Cesareni, G Gimona, M Hurley, JH Jarchau, T Lehto, VP Lemmon, MA Linding, R Mayer, BJ Nagai, M Sudol, M Walter, U Winder, SJ TI Normalization of nomenclature for peptide motifs as ligands of modular protein domains SO FEBS LETTERS LA English DT Review DE protein-protein interaction; peptide motif; protein domain, specificity and recognition; proteomics; glossary; nomenclature; ASCII format AB We propose a normalization of symbols and terms used to describe, accurately and succinctly, the detailed interactions between amino acid residues of pairs of interacting proteins at protein:protein (or protein: peptide) interfaces. Our aim is to unify several diverse descriptions currently in use in order to facilitate communication in the rapidly progressing field of signaling by protein domains. In order for the nomenclature to be convenient and widely used, we also suggest a parallel set of symbols restricted to the ASCII format allowing accurate parsing of the nomenclature to a computer-readable form. This proposal will be reviewed in the future and will therefore be open for the inclusion of new rules, modifications and changes. (C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. C1 Univ Bergen, Dept Biol Mol, N-5020 Bergen, Norway. Univ Penn, Div Hematol & Oncol, Philadelphia, PA 19014 USA. State Univ Ghent, Dept Biochem, B-9000 Ghent, Belgium. FMP, Res Inst Mol Pharmacol, Dept NMR & Struct Biol, FMP, D-13125 Berlin, Germany. Univ Texas, Dept Carcinogenesis, Smithville, TX 78957 USA. Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy. Austrian Acad Sci, Dept Cell Biol, A-5020 Salzburg, Austria. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Inst Klin Biochem & Pathobiochem, D-97078 Wurzburg, Germany. Oulu Univ, Dept Pathol, Oulu, Finland. Univ Penn, Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. European Mol Biol Lab, Biocomp Unit, D-69117 Heidelberg, Germany. Univ Connecticut, Dept Genet & Dev Biol, Farmington, CT 06030 USA. Mt Sinai Med Ctr, Dept Med, New York, NY 10029 USA. Univ Glasgow, Div Biochem & Mol Biol, Glasgow G12 8QQ, Lanark, Scotland. RP Aasland, R (reprint author), Univ Bergen, Dept Biol Mol, N-5020 Bergen, Norway. RI Bedford, Mark/E-7856-2011; Ampe, Christophe/B-5534-2012 NR 7 TC 76 Z9 78 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD FEB 20 PY 2002 VL 513 IS 1 SI SI BP 141 EP 144 AR PII S0014-5793(01)03295-1 DI 10.1016/S0014-5793(01)03295-1 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 527VN UT WOS:000174208800023 PM 11911894 ER PT J AU Roy, S Sahu, A Adhya, S AF Roy, S Sahu, A Adhya, S TI Evolution of DNA binding motifs and operators SO GENE LA English DT Article DE helix-turn-helix; evolution; regulator; auto-regulation ID HARVEYI LUX-OPERON; ESCHERICHIA-COLI; GENETIC-CODE; REPRESSOR; GAL; AUTOREGULATION; TRANSCRIPTION; PROMOTER; PROTEIN; ISOREPRESSOR AB A gene regulatory protein with helix-turn-helix (HTH) DNA-binding motif, GalS contains a functional operator within the DNA sequences encoding the HTH region (Nature 369 (1994) 314). We searched for operator-like sequences within the DNA sequences encoding the DNA binding motifs of other regulatory proteins. Five such proteins, DeoR, CytR, LRP, LuxR and PurR, were found to have actual operator or operator-like sequences in the DNA sequences encoding the DNA-binding motif. Except DeoR, all of them including GalS, are known to be auto-regulated. Auto-regulation in case of DeoR has not been investigated. Seven other proteins containing a HTH motif, do not have operator-like sequences in the DNA sequences encoding the HTH motif, none of them, except MerR, are known to be auto-regulated. The DNA binding proteins may have evolved from a common ancestor containing a DNA binding site within its gene segment that encodes the DNA-binding motif to facilitate auto-regulation. We have discussed current evidence for monophyletic or polyphyletic origin of such sequences. Published by Elsevier Science B.V. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Bose Inst, Dept Biophys, Kolkata 700054, W Bengal, India. RP Adhya, S (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Room 5138,37 Convent Dr MSC 4264, Bethesda, MD 20892 USA. EM sadhya@helix.nih.gov NR 27 TC 14 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 EI 1879-0038 J9 GENE JI Gene PD FEB 20 PY 2002 VL 285 IS 1-2 BP 169 EP 173 AR PII S0378-1119(02)00413-4 DI 10.1016/S0378-1119(02)00413-4 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 542WH UT WOS:000175066900016 PM 12039043 ER PT J AU Durmowicz, MC Cui, CY Schlessinger, D AF Durmowicz, MC Cui, CY Schlessinger, D TI The EDA gene is a target of, but does not regulate Wnt signaling SO GENE LA English DT Article DE ectodysplasin; anhidrotic ectodermal dysplasia transcription; ectodermal development; lymphocyte enhancer factor 1/beta-catenin ID HYPOHIDROTIC ECTODERMAL DYSPLASIA; HAIR FOLLICLE DEVELOPMENT; GROWTH-FACTOR RECEPTOR; BETA-CATENIN; ECTODYSPLASIN-A; PROTEIN; TRANSCRIPTION; HOMOLOG; ACTIVATION; MUTATIONS AB Lesions in the anhidrotic ectodermal dysplasia (EDA) gene cause the recessive human genetic disorder X-linked anhidrotic ectodermal dysplasia, which is characterized by the poor development of ectoderm-derived structures. Ectodysplasin-A, the protein encoded by the EDA gene, is a member of the tumor necrosis factor ligand superfamily that forms a collagen triple helix, suggesting functions in signal transduction and cell adhesion. In an effort to elucidate the function of EDA in pathways regulating ectodermal development, we have analyzed promoter elements of the gene, We show here that a binding site for the lymphocyte enhancer factor I (Lef-1) transcription factor is active. In electrophoretic mobility shift assays, Lef-1 specifically bound to its site in the EDA promoter. Over-expression of both Lef-1 and beta-catenin significantly increased EDA transcription in co-transfection studies. In addition, indirect stabilization of endogenous beta-catenin stimulated EDA transcription 4- to 13-fold. This is the first direct evidence of a relationship between EDA and the Wnt pathway. We have also investigated whether EDA might function in a feedback loop to modulate Wnt signaling. Over-expression of EDA neither stimulated basal transcription of Wnt-dependent genes, nor inhibited Wnt-dependent activation of transcription. Taken together, our results demonstrate that Wnt signaling does control EDA gene expression, but ectodysplasin-A does not feedback on the Wnt pathway. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIA, Triad Technol Ctr, Lab Genet, Baltimore, MD 21224 USA. RP Durmowicz, MC (reprint author), NIA, Triad Technol Ctr, Lab Genet, Suite 4000 333 Cassell Dr, Baltimore, MD 21224 USA. NR 35 TC 35 Z9 37 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD FEB 20 PY 2002 VL 285 IS 1-2 BP 203 EP 211 AR PII S0378-1119(02)00407-9 DI 10.1016/S0378-1119(02)00407-9 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 542WH UT WOS:000175066900020 PM 12039047 ER PT J AU Stein, U Lage, H Jordan, A Walther, W Bates, SE Litman, T Hohenberger, P Dietel, M AF Stein, U Lage, H Jordan, A Walther, W Bates, SE Litman, T Hohenberger, P Dietel, M TI Impact of BCRP/MXR, MRP1 and MDR1/P-glycoprotein on thermoresistant variants of atypical and classical multidrug resistant cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE thermoresistance; multidrug resistance; BCRP/MXR; MRP1; P-glycoprotein ID HUMAN GASTRIC-CANCER; CARCINOMA CELL-LINES; P-GLYCOPROTEIN; GENE-EXPRESSION; PROTEIN MRP; HEAT-SHOCK; MESSENGER-RNA; QUANTITATIVE-ANALYSIS; MITOMYCIN-C; IN-VITRO AB The impact of the ABC transporters breast cancer resistance protein/mitoxantrone resistance associated transporter (BCRP/MXR), multidrug resistance-associated protein 1 (MRP1) and multidrug resistance gene-1/P-glycoprotein (MDR1/PGP) on the multidrug resistance (MDR) phenotype in chemoresistance and thermoresistance was investigated in the parental human gastric carcinoma cell line EPG85-257P, the atypical MDR sublime EPG85-257RNOV, the classical MDR sublime EPG85-257RDB and their thermoresistant counterparts EPG85-257P-TR, EPG85-257RNOV-TR and EPG85-257RDB-TR. Within the atypical MDR sublime EPG85-257RNOV expression of BCRP/MXR and of MRP1 were clearly enhanced (vs. parental and classical MDR lines). MDR1/PGP expression was distinctly elevated in the classical MDR sublime EPG85-257RDB (vs. parental and atypical MDR sublimes). In ail thermoresistant counterparts basal expression of BCRP/MXR, MRP1 and MDR1/PGP was increased relative to thermosensitive sublines. Although it could be shown that the overexpressed ABC transporters were functionally active, however, no decreased drug accumulations of doxorubicin, mitoxantrone and rhodamine 123 were observed. Thus, expression of BCRP/MXR, MRP1 and MDR1/PGP was found to be dependent on the appropriate type of chemoresistance; correlating with a classical or atypical MDR phenotype. Within the thermoresistant variants, however, the increase in ABC transporter expression did obviously not influence the MDR phenotype. (C) 2002 Wiley-Liss, Inc. C1 Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany. Humboldt Univ, Inst Pathol, Charite, Berlin, Germany. Humboldt Univ, Dept Radiat Oncol, Charite, Berlin, Germany. NCI, Mol Therapeut Sect, Bethesda, MD 20892 USA. Univ Copenhagen, Panum Inst, Dept Med Physiol, DK-2200 Copenhagen, Denmark. Humboldt Univ, Robert Rossle Clin, Dept Surg Surg Oncol, Charite, Berlin, Germany. RP Stein, U (reprint author), Max Delbruck Ctr Mol Med, Robert Rossle Str 10, D-13092 Berlin, Germany. NR 70 TC 22 Z9 25 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 20 PY 2002 VL 97 IS 6 BP 751 EP 760 DI 10.1002/ijc.10131 PG 10 WC Oncology SC Oncology GA 515EU UT WOS:000173483100006 PM 11857350 ER PT J AU Fine, HA AF Fine, HA TI Polyomavirus and medulloblastoma: A smoking gun or guilt by association? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID BRAIN-TUMORS C1 NCI, Neurooncol Branch, NINDS, NIH, Bethesda, MD 20892 USA. RP Fine, HA (reprint author), NCI, Neurooncol Branch, NINDS, NIH, Bethesda, MD 20892 USA. NR 10 TC 7 Z9 7 U1 0 U2 0 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 FEB 20 PY 2002 VL 94 IS 4 BP 240 EP 241 PG 2 WC Oncology SC Oncology GA 522ZA UT WOS:000173925800001 PM 11854380 ER PT J AU Stefanek, M Hartmann, L Nelson, W AF Stefanek, M Hartmann, L Nelson, W TI Re: Risk-reduction mastectomy: Clinical issues and research needs - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Mayo Clin, Div Med Oncol, Rochester, MN USA. RP Stefanek, M (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN 4066,MSC 7363, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 1 U1 0 U2 0 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 FEB 20 PY 2002 VL 94 IS 4 BP 307 EP 308 PG 2 WC Oncology SC Oncology GA 522ZA UT WOS:000173925800014 ER PT J AU Petrache, HI Zuckerman, DM Sachs, JN Killian, JA Koeppe, RE Woolf, TB AF Petrache, HI Zuckerman, DM Sachs, JN Killian, JA Koeppe, RE Woolf, TB TI Hydrophobic matching mechanism investigated by molecular dynamics simulations SO LANGMUIR LA English DT Article ID LIPID-PROTEIN INTERACTIONS; INDUCED BILAYER DEFORMATIONS; INDIVIDUAL ALPHA-HELICES; TRANSMEMBRANE HELIX; GRAMICIDIN-A; COMPONENT VOLUMES; AROMATIC RESIDUES; FLUID MEMBRANES; SURFACE-TENSION; MODEL MEMBRANES AB Membrane protein structure and function are influenced by the interaction with the lipid bilayer environment. The lipid bilayer structure and dynamics are in turn perturbed by the protein insertion. To study this mechanism, a number of experimental studies have used a series of model peptides (WALP) which consist of sequences of alternating alanine and leucine amino acids terminated by a pair of tryptophans at both ends. It has been shown that, due to hydrophobic mismatch, these peptides can assume tilted conformations with respect to the bilayer normal and also perturb the bilayer thickness. In an attempt to rationalize experimental results we performed a series of all-atom molecular dynamics simulations comprising five WALP lengths (16, 17, 19, 21, and 23 residues) and two lipid types (dimyristoyl- and dipalmitoylphosphatidylcholine). The peptide:lipid ratio was in all cases 1:30. We find that the bilayer boundary thickness increases monotonically with WALP length, as expected based on the WALP hydrophobicity. Other structural properties, including peptide tilt, appear to also be modulated by the tryptophan arrangement around the helical axis. These results suggest an important role for tryptophan-environment interactions in both microscopic and mesoscopic properties of the lipid bilayer. We discuss the role of the lipid bilayer density gradient on the dynamic structure of the peptide-lipid bilayer system and show the dependence of peptide side chain interactions and side chain volumes on the location along the bilayer normal. We find that WALP sequences with the tryptophan residues on opposite sides of the helix have an overall looser packing with the surrounding lipids and larger peptide tilts than peptides with the tryptophans on the same side. C1 Johns Hopkins Univ, Dept Physiol, Sch Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Biomed Engn, Sch Med, Baltimore, MD 21205 USA. Univ Utrecht, Dept Biochem & Membranes, Utrecht, Netherlands. Univ Arkansas, Dept Chem, Fayetteville, AR 72701 USA. RP Petrache, HI (reprint author), NICHHD, LPSB, NIH, Bldg 12A,Rm 2041, Bethesda, MD 20892 USA. RI Killian, J. Antoinette/I-3001-2016; OI Zuckerman, Daniel/0000-0001-7662-2031 NR 75 TC 70 Z9 72 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD FEB 19 PY 2002 VL 18 IS 4 BP 1340 EP 1351 DI 10.1021/la011338p PG 12 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 524JK UT WOS:000174009300058 ER PT J AU Farber, JM Berger, EA AF Farber, JM Berger, EA TI HIV's response to a CCR5 inhibitor: I'd rather tighten than switch! Commentary SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID IMMUNODEFICIENCY-VIRUS TYPE-1; CHEMOKINE RECEPTORS; MACROPHAGE-TROPISM; INFECTION; DISEASE C1 NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Berger, EA (reprint author), NIAID, Clin Invest Lab, NIH, Bldg 4,Room 237, Bethesda, MD 20892 USA. NR 14 TC 29 Z9 31 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 19 PY 2002 VL 99 IS 4 BP 1749 EP 1751 DI 10.1073/pnas.042708299 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524UK UT WOS:000174031100001 PM 11854476 ER PT J AU Bifulco, M Laezza, C Stingo, S Wolff, J AF Bifulco, M Laezza, C Stingo, S Wolff, J TI 2 ',3 '-Cyclic nucleotide 3 '-phosphodiesterase: A membrane-bound, microtubule-associated protein and membrane anchor for tubulin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID EPITHELIAL-CELLS; BRAIN; CYTOSKELETON; VESICLES; ORGANIZATION; MITOCHONDRIA; MORPHOLOGY; COMPONENT; MYELIN AB 2',3'-Cyclic nucleotide-3'-phosphodiesterase (CNP) is firmly associated with tubulin from brain tissue and FRTL-5 thyroid cells as demonstrated by copolymerization with microtubules through several warm/cold cycles, the presence of CNIP activity in purified tubulin preparations, and identical behavior during various extraction procedures. CNIP acts as a microtubule-associated protein in promoting microtubule assembly at low mole ratios. This activity resides in the C terminus of the enzyme, which, by itself, promotes microtubule assembly at higher mole ratios. Phosphorylation of CNP interferes with its assembly-promoting activity, as does deletion of the C terminus, which leads to abnormal microtubule distribution in the cell. Submembranous colocalization of the proteins and CNP-dependent microtubule organization suggest that CNP is a membrane-bound microtubule-associated protein that can link tubulin to membranes and may regulate cytoplasmic microtubule distribution. C1 Univ Salerno, Dipartimento Sci Farmaceut, I-84084 Salerno, Italy. Univ Naples Federico II, CNRS, Dipartimento Biol & Patol Cellulare & Mol L Calif, Ctr Studio Endocrinol & Oncol Sperimentale, I-80131 Naples, Italy. NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Bifulco, M (reprint author), Univ Salerno, Dipartimento Sci Farmaceut, I-84084 Salerno, Italy. OI Bifulco, Maurizio/0000-0002-1771-4531 NR 31 TC 103 Z9 103 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 19 PY 2002 VL 99 IS 4 BP 1807 EP 1812 DI 10.1073/pnas.042678799 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524UK UT WOS:000174031100013 PM 11842207 ER PT J AU Kojima, H Gu, H Nomura, S Caldwell, CC Kobata, T Carmeliet, P Semenza, GL Sitkovsky, MV AF Kojima, H Gu, H Nomura, S Caldwell, CC Kobata, T Carmeliet, P Semenza, GL Sitkovsky, MV TI Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1 alpha-deficient chimeric mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CELL DEVELOPMENT; TUMOR ANGIOGENESIS; FACTOR 1-ALPHA; EXPRESSION; DIFFERENTIATION; VASCULARIZATION; PROLIFERATION; HIF-1-ALPHA; EMBRYOS; LACKING AB Immune cells are exposed to low oxygen tensions as they develop and migrate between blood and different tissues, but the mechanisms by which lymphocytes adapt to hypoxia are poorly understood. Studies reported here of hypoxia-inducible factor 1alpha (HIF-1alpha) in lymphocyte development and functions suggest that it has a critical role in regulation of these processes. HIF-1alpha deficiency in Hif1alpha(-/-) Rag2(-/-) chimeric mice results in dramatic and cell lineage-specific defects, which include appearance of abnormal peritoneal B-1-like lymphocytes, with high expression of B220 (CD45) receptor-associated protein tyrosine phosphatase and autoimmunity (accumulation of anti-dsDNA antibodies and rheumatoid factor in serum, deposits of IgG and IgM in kidney and proteinuria) as well as distortions of maturation of B-2 lymphocytes in bone marrow. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. Dokkyo Univ, Sch Med, Inst Med Sci, Div Immunol, Mibu, Tochigi 3210293, Japan. Katholieke Univ Leuven, Ctr Transgene Technol & Gene Therapy, B-3000 Louvain, Belgium. Johns Hopkins Univ, Sch Med, Inst Genet Med, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. RP Sitkovsky, MV (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. OI Caldwell, Charles/0000-0003-1692-4550 NR 26 TC 120 Z9 125 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 FEB 19 PY 2002 VL 99 IS 4 BP 2170 EP 2174 DI 10.1073/pnas.052706699 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524UK UT WOS:000174031100076 PM 11854513 ER PT J AU Pendaries, C Darblade, B Rochaix, P Krust, A Chambon, P Korach, KS Bayard, F Arnal, JF AF Pendaries, C Darblade, B Rochaix, P Krust, A Chambon, P Korach, KS Bayard, F Arnal, JF TI The AF-1 activation-function of ER alpha may be dispensable to mediate the effect of estradiol on endothelial NO production in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN ESTROGEN-RECEPTOR; VASCULAR INJURY RESPONSE; E-DEFICIENT MICE; MESSENGER-RNA; CARDIOVASCULAR-SYSTEM; DEPENDENT RESPONSES; 17-BETA ESTRADIOL; PROMOTER-CONTEXT; CORONARY-ARTERY; BETA AB Two isoforms of estrogen receptor (ER) have been described: ERalpha and ERbeta. The initial gene targeting of ERalpha, consisting in the introduction of a Neo cassette in exon 1 [alphaERKO, hereafter called ERalpha-Neo KO (knockout)], was reported in 1993. More recently, another mouse deficient in ERalpha because of the deletion of exon 2 (ERalphaKO, hereafter called ERalpha-Delta2 KO) was generated. In ovariectomized ERalpha-wild-type mice, estradiol (E-2) increases uterine weight and basal production of endothelial nitric oxide (NO). Both of these effects are abolished in ERalpha-Delta2 KO mice. In contrast, we show here that both of these effects of E2 are partially (uterine weight) or totally (endothelial NO production) preserved in ERalpha-Neo KO. We also confirm the presence of two ERa mRNA splice variants in uterus and aorta from ERalpha-Neo KO mice, One of them encodes a chimeric ERalpha protein (ERalpha55), partially deleted in the A/B domain, that was detected in both uterus and aorta by Western blot analysis. The other ERa mRNA splice variant codes for an isoform deleted for the A/B domain (ERalpha46), which was detected in uterus of ERalpha-Neo KO, and wild-type mice. This protein isoform was not detected in aorta. The identification of these two N-terminal modified isoforms in uterus, and at least one of them in aorta, probably explains the persistence of the E2 effects in ERalphaNeo KO mice. Furthermore, ERa-Neo KO mice may help in the elucidation of the specific functions of full-length ERa (ERalpha66) and ERalpha46, both shown to be physiologically generated in vivo. C1 CHU Rangueil, Inst Louis Bugnard, Physiol Lab, F-31054 Toulouse, France. INSERM, U397, F-31054 Toulouse, France. NIH, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. Univ Strasbourg 1, Coll France, CNRS, INSERM,Inst Genet & Biol Mol & Cellulaire, F-67404 Illkirch Graffenstaden, France. Inst Claudius Regaud, Lab Anatomopathol, F-31300 Toulouse, France. RP Arnal, JF (reprint author), INSERM, U397, F-31054 Toulouse, France. RI Rochaix, Philippe/O-4710-2014; OI Rochaix, Philippe/0000-0001-6238-1599; Korach, Kenneth/0000-0002-7765-418X NR 42 TC 132 Z9 133 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 FEB 19 PY 2002 VL 99 IS 4 BP 2205 EP 2210 DI 10.1073/pnas.042688499 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524UK UT WOS:000174031100082 PM 11854517 ER PT J AU Krishna, MC English, S Yamada, K Yoo, J Murugesan, R Devasahayam, N Cook, JA Golman, K Ardenkjaer-Larsen, JH Subramanian, S Mitchell, JB AF Krishna, MC English, S Yamada, K Yoo, J Murugesan, R Devasahayam, N Cook, JA Golman, K Ardenkjaer-Larsen, JH Subramanian, S Mitchell, JB TI Overhauser enhanced magnetic resonance imaging for tumor oximetry: Coregistration of tumor anatomy and tissue oxygen concentration SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DYNAMIC NUCLEAR-POLARIZATION; ELECTRON-PARAMAGNETIC-RESONANCE; LOW-FIELD; SPECTROSCOPY; PROTEINS; OXYMETRY; HYPOXIA; INVIVO AB An efficient noninvasive method for in vivo imaging of tumor oxygenation by using a low-field magnetic resonance scanner and a paramagnetic contrast agent is described. The methodology is based on Overhauser enhanced magnetic resonance imaging (OMRI), a functional imaging technique. OMRI experiments were performed on tumor-bearing mice (squamous cell carcinoma) by i.v. administration of the contrast agent Oxo63 (a highly derivatized triarylmethyl radical) at nontoxic doses in the range of 2-7 mmol/kg either as a bolus or as a continuous infusion. Spatially resolved pO(2) (oxygen concentration) images from OMRI experiments of tumor-bearing mice exhibited heterogeneous oxygenation profiles and revealed regions of hypoxia in tumors (<10 mmHg; 1 mmHg = 133 Pa). Oxygenation of tumors was enhanced on carbogen (95% O-2/5% CO2) inhalation. The pO(2) measurements from OMRI were found to be in agreement with those obtained by independent polarographic measurements using a pO(2) Eppendorf electrode. This work illustrates that anatomically coregistered pO(2) maps of tumors can be readily obtained by combining the good anatomical resolution of water proton-based MRI, and the superior pO(2) sensitivity of EPR. OMRI affords the opportunity to perform noninvasive and repeated pO(2) measurements of the same animal with useful spatial (approximate to1 mm) and temporal (2 min) resolution, making this method a powerful imaging modality for small animal research to understand tumor physiology and potentially for human applications. C1 NCI, Radiat Biol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Nycomed Innovat AB, MEDEON, SE-20512 Malmo, Sweden. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RI Yamada, Ken-ichi/E-6318-2012; Ardenkjar-Larsen, Jan Henrik/B-5765-2017 OI Ardenkjar-Larsen, Jan Henrik/0000-0001-6167-6926 NR 28 TC 184 Z9 190 U1 4 U2 19 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 19 PY 2002 VL 99 IS 4 BP 2216 EP 2221 DI 10.1073/pnas.042671399 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524UK UT WOS:000174031100084 PM 11854518 ER PT J AU Bjorklund, LM Sanchez-Pernaute, R Chung, SM Andersson, T Chen, IYC McNaught, KS Brownell, AL Jenkins, BG Wahlestedt, C Kim, KS Isacson, O AF Bjorklund, LM Sanchez-Pernaute, R Chung, SM Andersson, T Chen, IYC McNaught, KS Brownell, AL Jenkins, BG Wahlestedt, C Kim, KS Isacson, O TI Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DIRECT NEURAL INDUCTION; PHARMACOLOGICAL MRI; NERVOUS-SYSTEM; IN-VIVO; VENTRAL MESENCEPHALON; SPEMANN ORGANIZER; HUMAN BLASTOCYSTS; PROGENITOR CELLS; XENOPUS ECTODERM; MOUSE NODE AB Although implantation of fetal dopamine (DA) neurons can reduce parkinsonism in patients, current methods are rudimentary, and a reliable donor cell source is lacking. We show that transplanting low doses of undifferentiated mouse embryonic stem (ES) cells into the rat striatum results in a proliferation of ES cells into fully differentiated DA neurons. ES cell-derived DA neurons caused gradual and sustained behavioral restoration of DA-mediated motor asymmetry. Behavioral recovery paralleled in vivo positron emission tomography and functional magnetic resonance imaging data demonstrating DA-mediated hemodynamic changes in the striatum and associated brain circuitry. These results demonstrate that transplanted ES cells can develop spontaneously into DA neurons. Such DA neurons can restore cerebral function and behavior in an animal model of Parkinson's disease. C1 Harvard Univ, McLean Hosp, Sch Med, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA. Harvard Univ, McLean Hosp, Sch Med, Neuroregenerat Labs, Belmont, MA 02478 USA. Harvard Univ, McLean Hosp, Sch Med, Mol Neurobiol Lab, Belmont, MA 02478 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Program Neurosci, Sch Med, Boston, MA 02114 USA. Karolinska Inst, SE-17177 Stockholm, Sweden. RP Bjorklund, LM (reprint author), Harvard Univ, McLean Hosp, Sch Med, Udall Parkinsons Dis Res Ctr Excellence, 115 Mill St, Belmont, MA 02478 USA. RI Wahlestedt, Claes/A-7039-2009 FU NINDS NIH HHS [P50 NS039793, P50 NS39793] NR 63 TC 770 Z9 843 U1 1 U2 78 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 19 PY 2002 VL 99 IS 4 BP 2344 EP 2349 DI 10.1073/pnas.022438099 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524UK UT WOS:000174031100106 PM 11782534 ER PT J AU Chittajallu, R Chen, Y Wang, H Yuan, X Ghiani, CA Heckman, T McBain, CJ Gallo, V AF Chittajallu, R Chen, Y Wang, H Yuan, X Ghiani, CA Heckman, T McBain, CJ Gallo, V TI Regulation of Kv1 subunit expression in oligodendrocyte progenitor cells and their role in G(1)/S phase progression of the cell cycle SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CLONAL PITUITARY-CELLS; K+ CHANNELS; MEMBRANE DEPOLARIZATION; SUBVENTRICULAR ZONE; POTASSIUM CHANNELS; CALCIUM CHANNELS; PRECURSOR CELLS; DIFFERENTIATION; PROLIFERATION; TRANSCRIPTION AB Proliferative oligodendrocyte progenitor cells (OPs) express large, delayed outward-rectifying K+ currents (l(K)), whereas nondividing immature and mature oligodendrocytes display much smaller l(K.) Here, we show that up-regulation Of l(K) occurs in G, phase of the cell cycle in purified cultured OPs and is the result of an RNA synthesis-dependent, selective increase of the K+ channel subunit proteins Kv1.3 and Kv1.5. In oligodendrocyte cells acutely isolated from developing rat brain, a decrease of cyclin D expression is observed as these cells mature along their lineage. This is accompanied by a decrease in Kv1.3 and Kv1.5 subunit expression, suggesting a role for these subunits in the proliferative potential of OPs in situ. l(K) expressed in OPs in subventricular zone and developing white matter in acutely isolated slice preparations were selectively blocked by antagonists of Kv1.3, illustrating the functional presence of this subunit in situ. Interestingly, Kv1.3 block inhibited S-phase entry of both purified OPs in culture and in tissue slice cultures. Thus, we employ both in vitro and in situ experimental approaches to show that (i) RNA-dependent synthesis of Kv1.3 and Kv1.5 subunit proteins occurs in G(1) phase of the OP cell cycle and is responsible for the observed increase in l(K), and (ii) currents through Kv1.3-containing channels play a crucial role in G(1)/S transition of proliferating OPs. C1 NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Gallo, V (reprint author), Childrens Hosp, Childrens Res Inst, Ctr Res Neurosci, Ctr 5, 111 Michigan Ave,NW, Washington, DC 20010 USA. OI Ghiani, Cristina/0000-0002-9867-6185 NR 32 TC 107 Z9 110 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 19 PY 2002 VL 99 IS 4 BP 2350 EP 2355 DI 10.1073/pnas.042698399 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524UK UT WOS:000174031100107 PM 11854528 ER PT J AU Joseph, J Tan, SH Karpova, TS McNally, JG Dasso, M AF Joseph, J Tan, SH Karpova, TS McNally, JG Dasso, M TI SUMO-1 targets RanGAP1 to kinetochores and mitotic spindles SO JOURNAL OF CELL BIOLOGY LA English DT Article DE RanGAP1; SUMO-1; kinetochore; Ran; RanBP2 ID GTPASE-ACTIVATING PROTEIN; NUCLEAR-PORE COMPLEX; RAN-GTPASE; MAMMALIAN-CELLS; TRANSPORT; UBIQUITIN AB RanGAP1 was the first documented substrate for conjugation with the ubiquitin-like protein SUMO-1. However, the functional significance of this conjugation has not been fully clarified. We sought to examine RanGAP1 behavior during mitosis. We found that RanGAP1 associates with mitotic spindles and that it is particularly concentrated at foci near kinetochores. Association with kinetochores appeared soon after nuclear envelope breakdown and persisted until late anaphase, but it was lost coincident with nuclear envelope assembly in telophase. A mutant RanGAP1 protein lacking the capacity to be conjugated to SUMO-1 no longer associated with spindles, indicating that conjugation was essential for RdnGAP1's mitotic localization. RanBP2, a nuclear pore protein that binds SUMO-1-conjugated RanGAP1 during interphase, colocalized with RanGAP1 on spindles, suggesting that a complex between these two proteins may be involved in mitotic targeting of RanGAP1. This report shows for the first time that SUMO-1 conjugation is required for mitotic localization of RanGAP1, and suggests that a major role of SUMO-1 conjugation to RanGAP1 may be the spatial regulation of the Ran pathway during mitosis. C1 Natl Inst Child Hlth & Dev, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. Natl Canc Inst, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Dasso, M (reprint author), Natl Inst Child Hlth & Dev, Lab Gene Regulat & Dev, NIH, Bldg 18T,Room 105,Library DR,MSC 5431, Bethesda, MD 20892 USA. RI Tan, Shyh-Han/I-7037-2013; OI Tan, Shyh-Han/0000-0001-8250-7005; Dasso, Mary/0000-0002-5410-1371 NR 18 TC 192 Z9 197 U1 1 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD FEB 18 PY 2002 VL 156 IS 4 BP 595 EP 602 DI 10.1083/jcb.200110109 PG 8 WC Cell Biology SC Cell Biology GA 566KA UT WOS:000176425900002 PM 11854305 ER PT J AU Petricoin, EF Ardekani, AM Hitt, BA Levine, PJ Fusaro, VA Steinberg, SM Mills, GB Simone, C Fishman, DA Kohn, EC Liotta, LA AF Petricoin, EF Ardekani, AM Hitt, BA Levine, PJ Fusaro, VA Steinberg, SM Mills, GB Simone, C Fishman, DA Kohn, EC Liotta, LA TI Use of proteomic patterns in serum to identify ovarian cancer SO LANCET LA English DT Article AB Background New technologies for the detection of early-stage ovarian cancer are urgently needed. Pathological changes within an organ might be reflected in proteomic patterns in serum. We developed a bioinformatics tool and used it to identify proteomic patterns in serum that distinguish neoplastic from non-neoplastic disease within the ovary. Methods Proteomic spectra were generated by mass spectroscopy (surface-enhanced laser desorption and ionisation). A preliminary "training" set of spectra derived from analysis of serum from 50 unaffected women and 50 patients with ovarian cancer were analysed by an iterative searching algorithm that identified a proteomic pattern that completely discriminated cancer from non-cancer. The discovered pattern was then used to classify an independent set of 116 masked serum samples: 50 from women with ovarian cancer, and 66 from unaffected women or those with non-malignant disorders. Findings The algorithm identified a cluster pattern that, in the training set, completely segregated cancer from non-cancer. The discriminatory pattern correctly identified all 50 ovarian cancer cases in the masked set, including all 18 stage I cases. Of the 66 cases of non-malignant disease, 63 were recognised as not cancer. This result yielded a sensitivity of 100% (95% CI 93-100), specificity of 95% (87-99), and positive predictive, value of 94% (84-99). Interpretation These findings justify a prospective population-based assessment of proteomic pattern technology as a screening tool for all stages of ovarian cancer in high-risk and general populations. C1 US FDA, Natl Inst Hlth Clin Proteom Program, Dept Therapeut Prot, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Correlog Syst Inc, Bethesda, MD USA. Univ Texas, MD Anderson Canc Ctr, Dept Mol Therapeut, Div Canc Med, Houston, TX 77030 USA. Simone Protect Canc Inst, Lawrenceville, NJ USA. Northwestern Univ, Sch Med, Natl Ovarian Canc Early Detect Program, Chicago, IL USA. RP Petricoin, EF (reprint author), Bldg 29A,Room 2B02,8800 Rockville Pike, Bethesda, MD 20892 USA. NR 20 TC 2086 Z9 2284 U1 12 U2 131 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD FEB 16 PY 2002 VL 359 IS 9306 BP 572 EP 577 DI 10.1016/S0140-6736(02)07746-2 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 523FP UT WOS:000173943600011 PM 11867112 ER PT J AU Falloon, J Ait-Khaled, M Thomas, DA Brosgart, CL Eron, JJ Feinberg, J Flanigan, TP Hammer, SM Kraus, PW Murphy, R Torres, R Masur, H AF Falloon, J Ait-Khaled, M Thomas, DA Brosgart, CL Eron, JJ Feinberg, J Flanigan, TP Hammer, SM Kraus, PW Murphy, R Torres, R Masur, H CA CNA2007 Study Team TI HIV-1 genotype and phenotype correlate with virological response to abacavir, amprenavir and efavirenz in treatment-experienced patients SO AIDS LA English DT Article DE resistance; antiretroviral therapy; rescue regimen; predictors ID PROTEASE INHIBITOR THERAPY; ANTIVIRAL ACTIVITY; SALVAGE THERAPY; RESISTANCE; SAQUINAVIR; RITONAVIR; INDINAVIR; INFECTION; FAILURE; REGIMEN AB Objective: To assess the safety and efficacy of three new drugs in patients with antiretroviral failure and to correlate retrospectively baseline factors with virological response. Design and setting: Open-label, 48-week, single-arm, multi-center phase 11 trial conducted at nine US university or government clinics and private practices. Patients and interventions: Patients with HIV-1 RNA greater than or equal to 500 copies/ml despite greater than or equal to 20 weeks of treatment with at least one protease inhibitor received abacavir 300 mg twice a day, amprenavir 1200 mg twice a day and efavirenz 600 mg once a day. Other antiretrovirals were prohibited until week 16 except for substitutions for possible abacavir hypersensitivity. Main outcome measures: HIV RNA at weeks 16 and 48. Results: A total of 101 highly treatment-experienced patients enrolled; 60 were naive to non-nucleoside analog reverse transcriptase inhibitors (NNRTI). HIV RNA < 400 copies/ml was attained in 25 out of 101 (25%) patients at 16 weeks (35% of NNRTI-naive and 10% of -experienced patients) and 23 (23%) patients at 48 weeks (33% of naive and 7% of experienced patients). CD4 cells increased by a median of 15 x 10(6) and 43 x 10(6) cells/l at weeks 16 and 48, respectively. Drug-related rash occurred in 50 out of 99 (51%) of patients, and 17 out of 99 (17%) permanently discontinued one or more drugs as a result. Lower baseline viral load, fewer NNRTI-related mutations, absence of decreased abacavir (&GE; 4-fold) and efavirenz (&GE; 10-fold) susceptibility, and greater number of drugs to which virus was susceptible were associated with virological response at week 16. Conclusions: Abacavir, amprenavir and efavirenz durably reduced HIV RNA and increased CD4 cell counts in a subset of treatment-experienced adults. Baseline viral load and some genotypic and phenotypic markers of resistance correlated with HIV RNA response. (C) 2002 Lippincott Williams & Wilkins. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Glaxo Wellcome, Stevenage, Herts, England. Glaxo Wellcome, Greenford, Middx, England. Glaxo Wellcome Inc, Res Triangle Pk, NC 27709 USA. E Bay AIDS Ctr, Berkeley, CA USA. Univ N Carolina, Chapel Hill, NC USA. Univ Cincinnati, Cincinnati, OH USA. Miriam Hosp, Providence, RI 02906 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Kraus Med Partners, Los Angeles, CA USA. Northwestern Univ, Chicago, IL 60611 USA. St Vincents Hosp, New York, NY USA. RP Falloon, J (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10 Room 11C103,10 Ctr Dr, Bethesda, MD 20892 USA. OI Murphy, Robert/0000-0003-3936-2052 NR 33 TC 31 Z9 31 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB 15 PY 2002 VL 16 IS 3 BP 387 EP 396 DI 10.1097/00002030-200202150-00010 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 523AV UT WOS:000173929900010 PM 11834950 ER PT J AU Longnecker, MP Klebanoff, MA Brock, JW Zhou, HB Gray, KA Needham, LL Wilcox, AJ AF Longnecker, MP Klebanoff, MA Brock, JW Zhou, HB Gray, KA Needham, LL Wilcox, AJ TI Maternal serum level of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene and risk of cryptorchidism, hypospadias, and polythelia among male offspring SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE abnormalities; androgen antagonists; androgens; cryptorchidism; DDE; hypospadias; nipples ID POLYCHLORINATED-BIPHENYLS PCBS; SUPERNUMERARY NIPPLES; ADIPOSE-TISSUE; PLASMA; DDE; DIFFERENTIATION; ANTIANDROGEN; PESTICIDES; FRACTIONS; P,P'-DDE AB 1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) is a metabolite of the insecticide 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT) and is a ubiquitous environmental contaminant. Nearly everyone in the United States has a detectable serum level of DDE. DDE was recently found to inhibit binding of androgen to its receptor and to block androgen action in rodents. Normal development of male genitalia in mammals depends on androgen action. The authors used stored serum samples to examine the relation between maternal DDE levels during pregnancy and adjusted odds of cryptorchidism (n = 219), hypospadias (n = 199), and polythelia (extra nipples) (n = 167) among male offspring, using a nested case-control design with one control group (n = 552). Subjects were selected from the Collaborative Perinatal Project, a US birth cohort study begun in 1959-1966, when DDE levels were much higher than they are at present. Compared with boys whose mother's recovery-adjusted serum DDE level was less than 21.4 mug/liter, boys with maternal levels greater than or equal to 85.6 mug/liter had adjusted odds ratios of 1.3 (95% confidence interval (CI): 0.7, 2.4) for cryptorchidism, 1.2 (95% CI: 0.6, 2.4) for hypospadias, and 1.9 (95% CI: 0.9, 4.0) for polythelia. For cryptorchidism and polythelia, the results were consistent with a modest-to-mode rate association, but in no instance was the estimate very precise. The results were inconclusive. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. NICHHD, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. Univ N Carolina, Dept Biostat, Durham, NC USA. Vet Affairs Med Ctr, Epidemiol Res & Informat Ctr, Durham, NC USA. RP Longnecker, MP (reprint author), NIEHS, Epidemiol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. RI Needham, Larry/E-4930-2011; OI Longnecker, Matthew/0000-0001-6073-5322; Wilcox, Allen/0000-0002-3376-1311 NR 37 TC 118 Z9 123 U1 1 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 FEB 15 PY 2002 VL 155 IS 4 BP 313 EP 322 DI 10.1093/aje/155.4.313 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 522WV UT WOS:000173920700005 PM 11836195 ER PT J AU Orioli, IM Vieira, AR Castilla, EE Ming, JE Muenke, M AF Orioli, IM Vieira, AR Castilla, EE Ming, JE Muenke, M TI Mutational analysis of the Sonic Hedgehog gene in 220 newborns with oral clefts in a South American (ECLAMC) population SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE Sonic Hedgehog; cleft lip; cleft palate ID AGENESIS; HUMANS; MSX1 AB Oral clefts generally have a multifactorial etiology. A number of genes contribute to the formation of the face and palate. Cleft lip and/or palate can occur in pedigrees with autosomal dominant holoprosencephaly due to mutations in Sonic Hedgehog (SHH). In addition, animal models have shown that SHH is involved in face development. We thus examined the human SHH gene in 220 newborn infants with nonsyndromic oral clefts registered by the Estudio Colaborativo Latinoamericano de Malformaciones Congenitas: ECLAMC (Latin American Collaborative Study of Congenital Malformations). We found 15 variant bands in 13 patients with oral clefts, representing five different base changes, all of which were found by sequencing to represent silent polymorphisms. Four occurred in introns. The alteration occurring in an exon, Ser190Ser, may create a consensus sequence for the 3'splice site 6 bp downstream of the original consensus sequence. Thus, we did not identify any clearly disease-causing mutation in SHH in these patients, and conclude that SHH mutations are not a frequent cause of isolated oral clefts in humans. Published 2002 Wiley-Liss, Inc.(dagger) C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. Univ Fed Rio de Janeiro, Latin Amer Collaborat Study Congenital Malformat, Dept Genet, ECLAMC, Rio De Janeiro, Brazil. Inst Oswaldo Cruz, Dept Genet, ECLAMC, BR-20001 Rio De Janeiro, Brazil. CEMIC, ECLAMC, Buenos Aires, DF, Argentina. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr,MSC 1852,Bldg 10,10C101, Bethesda, MD 20892 USA. FU NICHD NIH HHS [HD01218, HD29862] NR 19 TC 16 Z9 17 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD FEB 15 PY 2002 VL 108 IS 1 BP 12 EP 15 DI 10.1002/ajmg.10204 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 515PB UT WOS:000173503500003 PM 11857543 ER PT J AU Yaghmai, R Kashani, AH Geraghty, MT Okoh, J Pomper, M Tangerman, A Wagner, C Stabler, SP Allen, RH Mudd, SH Braverman, N AF Yaghmai, R Kashani, AH Geraghty, MT Okoh, J Pomper, M Tangerman, A Wagner, C Stabler, SP Allen, RH Mudd, SH Braverman, N TI Progressive cerebral edema associated with high methionine levels and betaine therapy in a patient with cystathionine beta-synthase (CBS) deficiency SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE methionine; homocystinuria; betaine; cerebral edema ID AMINO-ACIDS; HOMOCYSTINURIA; METABOLISM; TRANSAMINATION AB Cystathionine beta-synthase (CBS) deficiency, the most common form of homocystinuria, is an autosomal recessive inborn error of homocysteine metabolism. Treatment of B6-nonresponsive patients centers on lowering homocysteine and its disulfide derivatives (tHcy) by adherence to a methionine-restricted diet. However, lifelong dietary control is difficult. Betaine supplementation is used extensively in CBS-deficient patients to lower plasma tHcy. With betaine therapy, methionine levels increase over baseline, but usually remain below 1,500 mumol/L, and these levels have not been associated with adverse affects. We report a child with B6-nonresponsive CBS deficiency and dietary noncompliance whose methionine levels reached 3,000 mumol/L on betaine, and who subsequently developed massive cerebral edema without evidence of thrombosis. We investigated the etiology by determining methionine and betaine metabolites in our patient, and several possible mechanisms for her unusual response to betaine are discussed. We conclude that the cerebral edema was most likely precipitated by the betaine therapy, although the exact mechanism is uncertain. This case cautions physicians to monitor methionine levels in CBS-deficient patients on betaine and to consider betaine as an adjunct, not an alternative, to dietary control. (C) 2002 Wiley-Liss, Inc. C1 Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. Johns Hopkins Univ Hosp, Dept Neuroradiol, Baltimore, MD 21287 USA. Univ Nijmegen Hosp, NL-6500 HB Nijmegen, Netherlands. Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA. Univ Colorado, Hlth Sci Ctr, Dept Biochem, Denver, CO USA. NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Braverman, N (reprint author), Johns Hopkins Med Ctr, CMSC 1004,6000 N Wolfe St, Baltimore, MD 21205 USA. NR 15 TC 28 Z9 31 U1 0 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD FEB 15 PY 2002 VL 108 IS 1 BP 57 EP 63 DI 10.1002/ajmg.10186 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 515PB UT WOS:000173503500011 PM 11857551 ER PT J AU Oz, M Tchugunova, Y Dinc, M Dunn, SMJ AF Oz, M Tchugunova, Y Dinc, M Dunn, SMJ TI Effects of isoflurane on voltage-dependent calcium fluxes in rabbit T-Tubule membranes: Comparison with alcohols SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE calcium channels; volatile anesthetics; stereoisomers; alcohols; skeletal muscle ID SKELETAL-MUSCLE; VOLATILE ANESTHETICS; CA-2+ CHANNELS; SARCOPLASMIC-RETICULUM; GENERAL-ANESTHETICS; CA2+ CHANNELS; HALOTHANE; BINDING; CELLS; INHIBITION AB The effects of racemic (+/-) and (+)- and (-)-stereoisomers of isoflurane on depolarization-induced Ca-45(2+) fluxes mediated by voltage-dependent Ca2+ channels were investigated in transverse tubule membrane vesicles from rabbit skeletal muscle. In the concentration range 0.5 to 2 mM, (+/-)-isoflurane inhibited Ca-45(2+) fluxes and functionally modulated the effects of the Ca2+ channel antagonist nifedipine (1-10 muM). Isoflurane-induced inhibition of Ca-45(2+) fluxes was not significantly affected by pretreatment with either pertussis toxin (5 mug/ml or phorbol 12-myristate 13-acetate (50 nM). Further experiments indicated that there were no significant differences between (+)- and (-)-stereoisomers of isoflurane with respect to the extent of inhibition of Ca-45(2+) fluxes. Radioligand binding studies indicated that racemic and (+)- and (-)-isoflurane were equally effective in displacing the specific binding of ['HIPN 200-110 to transverse tubule membranes. There were no apparent differences between the effects of (+)- and (-)-isoflurane on the characteristics of [H-3]PN 200-110 binding. Although the concentrations of isoflurane for the inhibitions of Ca-45(2+) fluxes and radioligand bindings were similar, the concentrations of n-alcohols required for the inhibition of Ca-45(2+) fluxes were lower than those for the displacement of radioligand. Comparison of the data for the displacement of [H-3]PN 200-110 binding and the inhibition of Ca-45(2+) fluxes by isoflurane and by n-alcohols suggested that both isoflurane and n-alcohols may have more than a single binding site. In conclusion, results indicate that isoflurane, independent of intracellular Ca2+ levels, nonstereospecifically inhibits the function of voltage-dependent Ca2+ channels and this effect is mediated through multiple binding sites. (C) 2002 Elsevier Science (USA). C1 NIDA, Cellular Neurobiol Sect, Baltimore, MD 21224 USA. Oncol Hosp, Dept Pulm Dis, TR-06947 Ankara, Turkey. Univ Alberta, Dept Pharmacol, Edmonton, AB T6G 2H7, Canada. RP Oz, M (reprint author), NIDA, Cellular Neurobiol Sect, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Oz, Murat/E-2148-2012 NR 34 TC 8 Z9 8 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 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD FEB 15 PY 2002 VL 398 IS 2 BP 275 EP 283 DI 10.1006/abbi.2001.2726 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 523WU UT WOS:000173981200017 PM 11831860 ER PT J AU Zheng, CY Baum, BJ AF Zheng, CY Baum, BJ TI Long-term expression after infection by the hybrid vector AdLTR-luc is from integrated transgene SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE gene therapy; integration; adenoretrovirus; hybrid vector; long-term gene expression; extrachromosomal DNA ID CELL-LINE; ADENOVIRAL VECTOR; SALIVARY; DNA; GLAND; SITE AB The novel adenoretroviral vector, AdLTR-luc, infects dividing and nondividing cells, and mediates long-term transgene expression(Zheng, C., Baum, B. J., Iadarola, M. J., and O'Connell, B. C., Nat. Biotech. 18, 176-180, 2000). To determine the source of this expression we examined two epithelial cell lines. One, HSG, permits E1(-) recombinant adenoviral replication, while the other, A5, does not. An HSG clone, that expressed luciferase stably for >6 months, was obtained following infection at similar to0.2 AdLTR-luc particles/cell. Southern and PCR analyses showed that luciferase cDNA present was integrated. A5 cells were infected with AdLTR-luc at similar to1000 particles/cell, and colonies were obtained by limiting dilution. Eight clones showed stable luciferase activity for >9 months. High molecular weight DNA extracts from clones were positive for genomic integration by Southern, PCR, and quantitative PCR analyses. Similar analyses of low molecular weight DNA extracts indicated the absence of intact extrachromosomal vector. These data demonstrate that long-term luciferase expression after infection by AdLTR-luc is derived from the integrated cDNA. C1 NIDCR, GTTB, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), NIDCR, GTTB, NIH, Bldg 10,Room 1N113, Bethesda, MD 20892 USA. NR 20 TC 4 Z9 4 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 FEB 15 PY 2002 VL 291 IS 1 BP 34 EP 40 DI 10.1006/bbrc.2002.6401 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 524HK UT WOS:000174007000006 PM 11829458 ER PT J AU Ly, CD Roche, KW Lee, HK Wenthold, RJ AF Ly, CD Roche, KW Lee, HK Wenthold, RJ TI Identification of rat EMAP, a delta-glutamate receptor binding protein SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE EMAP; WD-repeat; glutamate receptor; delta postsynaptic density ID SUBUNIT; EXPRESSION; INTERACTS; SYNAPSE; MICE AB While most subtypes of glutamate receptors have been studied extensively, less is known about the delta-glutamate receptors, delta1 and delta2. Although neither forms functional channels when expressed in heterologous cells, genetic analyses have demonstrated the physiological significance of delta2. We used the cytosolic C-terminus of the delta2 glutamate receptor subunit in a yeast two-hybrid screen of a rat brain cDNA library to identify delta-glutamate receptor binding proteins. We isolated rat EMAP, the rat homolog of a microtubule-associated protein initially isolated and characterized in echinoderms. Rat EMAP contains 10 WD-repeats, which are domains important for mediating protein-protein interactions in a wide variety of proteins. Rat EMAP binds to delta-glutamate receptor subunits within a 50-amino-acid segment of the delta C-terminus. It is widely expressed in both brain and peripheral tissues, including high expression in brainstem and enrichment in the postsynaptic density. C1 NIDCD, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Wenthold, RJ (reprint author), NIDCD, Neurochem Lab, NIH, Bldg 50,Room 4140, Bethesda, MD 20892 USA. OI Roche, Katherine/0000-0001-7282-6539 NR 15 TC 11 Z9 14 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 FEB 15 PY 2002 VL 291 IS 1 BP 85 EP 90 DI 10.1006/bbrc.2002.6413 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 524HK UT WOS:000174007000014 PM 11829466 ER PT J AU Wagner, B Jakobs, S Habermeyer, M Hippe, F Cho-Chung, YS Eisenbrand, G Marko, D AF Wagner, B Jakobs, S Habermeyer, M Hippe, F Cho-Chung, YS Eisenbrand, G Marko, D TI 7-Benzylamino-6-chloro-2-piperazino-4-pyrrolidino-pteridine, a potent inhibitor of cAMP-specific phosphodiesterase, enhancing nuclear protein binding to the CRE consensus sequence in human tumour cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE cAMP; DC-TA-46; phosphodiesterase; cAMP responsive element; nuclear protein bindings; PKA ID I REGULATORY SUBUNIT; KINASE-A; MOLECULAR-CLONING; NUCLEOTIDE PHOSPHODIESTERASE; GROWTH-INHIBITION; PHOSPHORYLATION; ACTIVATION; ELEMENT; FAMILY; GENE AB The cAMP-specific phosphodiesterase isoenzyme family PDE4 represents the highest cAMP-hydrolysing activity in many human cancer cell lines including the human large cell lung carcinoma cell line LXFL529L. Treatment of LXFL529L cells with the potent PDE4 inhibitor 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidino-pteridine (DC-TA-46) induces dose-dependent growth inhibition. Cells are arrested in the G(1)-phase of the cell cycle and the induction of apoptosis is observed. In this study, we investigated the effect of DC-TA-46 on downstream elements of the cAMP-pathway. DC-TA-46 mediated inhibition of PDE4 activity in LXFL529L cells resulted in an increase of the intracellular cAMP level and significant induction of the activity of protein kinase A (PKA). The regulatory PKA subunit R-la was predominantly expressed in LXFL529L cells. In contrast to effects induced by cAMP analogues like 8-Cl-cAMP, the expression of the regulatory subunits of PKA remained unaffected by DC-TA-46. Treatment of LXFL529L cells with DC-TA-46 enhanced the binding of nuclear proteins to the cAMP-responsive element (CRE) consensus sequence TGACGTCA in a time- and dose-dependent manner, indicating the activation of transcription factors by PKA phosphorylation. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Univ Kaiserslautern, Dept Chem, Div Food Chem & Environm Toxicol, D-67663 Kaiserslautern, Germany. NIH, Tumor Immunol & Biol Lab, Cellular Biochem Sect, Bethesda, MD 20892 USA. RP Marko, D (reprint author), Univ Kaiserslautern, Dept Chem, Div Food Chem & Environm Toxicol, Erwin Schroedinger Str 52, D-67663 Kaiserslautern, Germany. RI Marko, Doris/B-9354-2014 OI Marko, Doris/0000-0001-6568-2944 NR 35 TC 5 Z9 5 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD FEB 15 PY 2002 VL 63 IS 4 BP 659 EP 668 AR PII S0006-2942(01)00893-0 DI 10.1016/S0006-2952(01)00893-0 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 538HY UT WOS:000174810700011 PM 11992633 ER PT J AU Marko, D Merz, KH Kunz, C Muller, A Tarasova, N Eisenbrand, G AF Marko, D Merz, KH Kunz, C Muller, A Tarasova, N Eisenbrand, G TI Intracellular localization of 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidino-pteridine in membrane structures impeding the inhibition of cytosolic cyclic AMP-specific phosphodiesterase SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE phosphodiesterase; cAMP; DC-TA-46; cellular uptakes; endoplasmatic reticulum; confocal microscopy ID CAMP-SPECIFIC PHOSPHODIESTERASE; NUCLEOTIDE PHOSPHODIESTERASE; CGMP; HYDROLYZES; CLONING; GROWTH; FAMILY; PDE11A AB 7-Benzylamino-6-chloro-2-piperazino-4-pyrrolidino-pteridine (DC-TA-46) is a potent inhibitor of the rolipram-sensitive cAMP-specific phosphodiesterase isoenzyme family PDE4. DC-TA-46 inhibits cAMP-hydrolysis of PDE4 isolated from solid tumors of the human large cell lung tumor xenograft LXFL529 in the nanomolar range (IC50 = 16 +/- 5 nM). Tumor cells, however, are growth inhibited only in the lower micromolar range as shown for the human large cell lung carcinoma cell line LXFL529L. To investigate reasons for the discrepancy between IC50 values for target inhibition and inhibition of cell growth, uptake, subcellular distribution and elimination of the compound were measured. DC-TA-46 was rapidly taken up by the cells, predominantly localized in intracellular membranes. Elimination was slow, with 70% of the compound still persisting in the membranes 50 hr after withdrawal. Confocal laser scanning microscopy showed a clear colocalization with a fluorescent marker for the endoplasmatic reticulum (ER). As a result of the subcellular localization, the membrane-bound PDE activity of LXFL529L cells was effectively inhibited by DC-TA-46 (IC50 = 0.06 +/- 0.02 muM). In contrast, inhibition of the cytosolic PDE activity was only achieved at concentrations >1 muM (IC50 = 2.0 +/- 0.5 muM), in the concentration range where also growth inhibition was observed. Thus, the inhibition of the intracellular PDE activity in the different cellular compartments appears to represent an important parameter for the evaluation of the inhibitory properties at least of this class of compounds. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Univ Kaiserslautern, Dept Chem, Div Food Chem & Environm Toxicol, D-67663 Kaiserslautern, Germany. NCI, Mol Aspects Drug Design Sect, Frederick, MD 21701 USA. RP Marko, D (reprint author), Univ Kaiserslautern, Dept Chem, Div Food Chem & Environm Toxicol, Erwin Schroedinger Str 52, D-67663 Kaiserslautern, Germany. RI Marko, Doris/B-9354-2014 OI Marko, Doris/0000-0001-6568-2944 NR 15 TC 5 Z9 5 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD FEB 15 PY 2002 VL 63 IS 4 BP 669 EP 676 AR PII S0006-2952(01)00894-2 DI 10.1016/S0006-2952(01)00894-2 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 538HY UT WOS:000174810700012 PM 11992634 ER PT J AU Bremner, JD Vythilingam, M Vermetten, E Nazeer, A Adil, J Khan, S Staib, LH Charney, DS AF Bremner, JD Vythilingam, M Vermetten, E Nazeer, A Adil, J Khan, S Staib, LH Charney, DS TI Reduced volume of orbitofrontal cortex in major depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE frontal cortex; depression; stress; MRI ID SUBGENUAL PREFRONTAL CORTEX; PHOTON-EMISSION TOMOGRAPHY; CEREBRAL BLOOD-FLOW; BIPOLAR DISORDER; MOOD DISORDERS; FRONTAL-LOBE; AMYGDALA ENLARGEMENT; GERIATRIC DEPRESSION; UNIPOLAR DEPRESSION; GLUCOSE-METABOLISM AB Background: Functional neuroimaging studies have implicated dysfunction of orbitofrontal cortex in the symptoms of depression, and a recent postmortem study of depressed patients found reduced density of neurons and glia in this area. The purpose of this study was to measure volume of orbitofrontal cortex and other frontal cortical subregions in patients with major depression. Methods: Magnetic resonance imaging was used to measure volume of the orbitofrontal cortex and other frontal cortical regions in patients with major depression in remission (n = 15) and comparison subjects (n = 20). Results: Patients with depression had a statistically significant 32% smaller medial orbitofrontal (gyrus rectus) cortical volume, without smaller volumes of other frontal regions including anterior cingulate Brodmann's area 24 (subgenual gyrus), anterior cingulate Brodmann's area 32, subcallosal gyrus (Brodmann's area 25), or whole brain volume. The findings were significant after statistically controlling for brain size. Conclusions: These findings are consistent with smaller orbitofrontal cortical volume in depression. (C) 2002 Society of Biological Psychiatry. C1 NIMH, Mood & Anixety Disorders Res Program, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Diagnost Radiol, New Haven, CT 06510 USA. VAMC, Decatur, GA USA. RP Bremner, JD (reprint author), Emory Univ, Sch Med, Emory Clin Neurosci Res Unit, West Campus,1256,Briarcliff Rd, Atlanta, GA 30306 USA. RI Bremner, James/B-1632-2013; OI Vermetten, Eric/0000-0003-0579-4404; Staib, Lawrence/0000-0002-9516-5136 NR 63 TC 300 Z9 312 U1 6 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2002 VL 51 IS 4 BP 273 EP 279 AR PII S0006-3223(01)01336-1 DI 10.1016/S0006-3223(01)01336-1 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 529BY UT WOS:000174281200001 PM 11958777 ER PT J AU Leverich, GS McElroy, SL Suppes, T Keck, PE Denicoff, KD Nolen, WA Altshuler, LL Rush, AJ Kupka, R Frye, MA Autio, KA Post, RM AF Leverich, GS McElroy, SL Suppes, T Keck, PE Denicoff, KD Nolen, WA Altshuler, LL Rush, AJ Kupka, R Frye, MA Autio, KA Post, RM TI Early physical and sexual abuse associated with an adverse course of bipolar illness SO BIOLOGICAL PSYCHIATRY LA English DT Article DE bipolar; early abuse; course of illness; comorbidity; life-chart ID POSTTRAUMATIC-STRESS-DISORDER; PITUITARY-ADRENAL AXIS; CHILDHOOD ABUSE; RISK-FACTORS; PSYCHIATRIC-INPATIENTS; SUICIDAL-BEHAVIOR; ALCOHOL-PROBLEMS; EMOTIONAL ABUSE; BULIMIA-NERVOSA; PART I AB Background: There is growing awareness of the association between physical and sexual abuse and subsequent development of psychopathology, but little is known, however, about their relationship to the longitudinal course of bipolar disorder. Methods: We evaluated 631 outpatients with bipolar I or II disorder for general demographics, a history of physical or sexual abuse as a child or adolescent, course of illness variables, and prior suicide attempts, as well as SCID-derived Axis I and patient endorsed Axis II comorbidity. Results: Those who endorsed a history of child or adolescent physical or sexual abuse, compared with those who did not, had a history of an earlier onset of bipolar illness, an increased number of Axis I, II, and III comorbid disorders, including drug and alcohol abuse, faster cycling frequencies, a higher rate of suicide attempts, and more psychosocial stressors occurring before the first and most recent affective episode. The retrospectively reported associations of early abuse with a more severe course of illness were validated prospectively. Conclusions: Greater appreciation of the association of early traumatic experiences and an adverse course of bipolar illness should lead to preventive and early intervention approaches that may lessen the associated risk of a poor outcome. (C) 2002 Society of Biological Psychiatry. C1 NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. NIMH, Stanley Fdn Bipolar Treatment Outcome Network, Bethesda, MD 20892 USA. Vet Adm Med Ctr, Los Angeles, CA 91343 USA. Altrecht Inst Mental Hlth Care, Utrecht, Netherlands. Univ Utrecht, Med Ctr, Utrecht, Netherlands. Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX USA. Univ Texas, SW Med Ctr, Dept Psychiat, Bipolar Disorder Clin, Dallas, TX USA. Univ Texas, SW Med Ctr, Dept Psychiat, Res Program, Dallas, TX USA. Univ Cincinnati, Coll Med, Dept Psychiat, Biol Psychiat Program, Cincinnati, OH USA. RP NIMH, Biol Psychiat Branch, Bldg 10,Room 3S 239,10 Ctr Dr,MSC 1272, Bethesda, MD 20892 USA. RI Nolen, Willem/E-9006-2014; OI Rush, Augustus/0000-0003-2004-2382 NR 76 TC 226 Z9 230 U1 3 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2002 VL 51 IS 4 BP 288 EP 297 AR PII S0006-3223(01)01239-2 DI 10.1016/S0006-3223(01)01239-2 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 529BY UT WOS:000174281200003 PM 11958779 ER PT J AU Kupka, RW Nolen, WA Post, RM McElroy, SL Altshuler, LL Denicoff, KD Frye, MA Keck, PE Leverich, GS Rush, AJ Suppes, T Pollio, C Drexhage, HA AF Kupka, RW Nolen, WA Post, RM McElroy, SL Altshuler, LL Denicoff, KD Frye, MA Keck, PE Leverich, GS Rush, AJ Suppes, T Pollio, C Drexhage, HA TI High rate of autoimmune thyroiditis in bipolar disorder: Lack of association with lithium exposure SO BIOLOGICAL PSYCHIATRY LA English DT Article DE bipolar disorder; thyroid antibodies; hypothyroidism; lithium ID MANIC-DEPRESSIVE PATIENTS; ANTITHYROID ANTIBODIES; PREVALENCE; HYPOTHYROIDISM; THERAPY; ABNORMALITIES; DYSFUNCTION; POPULATION; PARAMETERS; DISEASE AB Background: We assessed the prevalence of thyroperoxidase antibodies (TPO-Abs) and thyroid failure in outpatients with bipolar disorder compared with two control groups. Methods: The TPO-Abs of outpatients with DSM-IV bipolar disorder (n = 226), a population control group (n = 252), and psychiatric inpatients of any diagnosis (n = 3190) were measured. Thyroid failure was defined as a raised thyroid stimulating hormone level, previously diagnosed hypothyroidism, or both. Subjects were compared with attention to age, gender, and exposure to lithium. Results: The TPO-Abs were more prevalent in bipolar patients (28%) than population and psychiatric controls (3-18%). The presence of TPO-Abs in bipolar patients was associated with thyroid failure, but not with age, gender, mood state, rapid cycling, or lithium exposure. Thyroid failure was present in 17% of bipolar patients and more prevalent in women. It was associated with lithium exposure, especially in the presence of TPO-Abs, but not with current rapid cycling, although an association may have been masked by thyroid hormone replacement. Conclusions: Thyroid autoimmunity was highly prevalent in this sample of outpatients with bipolar disorder and not associated with lithium treatment. These variables appear to be independent risk factors for the development of hypothyroidism, especially in women with bipolar disorder. (C) 2002 Society of Biological Psychiatry. C1 Altrecht Ctr Mental Hlth Care, NL-3512 PZ Utrecht, Netherlands. Stanley Fdn Data Coordinating Ctr, Bethesda, MD USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Vet Adm Med Ctr, Los Angeles, CA 91343 USA. Univ Calif Los Angeles, Mood Disorders Res Program, Los Angeles, CA USA. Univ Cincinnati, Coll Med, Biol Psychiat Program, Cincinnati, OH USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Erasmus Univ, Dept Immunol, NL-3000 DR Rotterdam, Netherlands. Univ Utrecht, Med Ctr, Utrecht, Netherlands. RP Kupka, RW (reprint author), Altrecht Ctr Mental Hlth Care, Vrouwjuttenhof 18, NL-3512 PZ Utrecht, Netherlands. RI Nolen, Willem/E-9006-2014; OI Rush, Augustus/0000-0003-2004-2382 NR 42 TC 122 Z9 126 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2002 VL 51 IS 4 BP 305 EP 311 AR PII S0006-3223(01)01217-3 DI 10.1016/S0006-3223(01)01217-3 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 529BY UT WOS:000174281200005 PM 11958781 ER PT J AU Coplan, JD Moreau, D Chaput, F Martinez, JM Hoven, CW Mandell, DJ Gorman, JM Pine, DS AF Coplan, JD Moreau, D Chaput, F Martinez, JM Hoven, CW Mandell, DJ Gorman, JM Pine, DS TI Salivary cortisol concentrations before and after carbon-dioxide inhalations in children SO BIOLOGICAL PSYCHIATRY LA English DT Article DE children; anxiety; panic; biological correlates; cortisol; saliva; hypothalamic-pituitary-adrenal ID ANXIETY DISORDERS; PANIC DISORDER; NONHUMAN-PRIMATES; PLASMA-CORTISOL; RESPONSES; ATTACKS; STRESSORS; SECRETION AB Background: Considerable research implicates over-activity of the hypothalamic-pituitary adrenal axis in the pathophysiology of adult mood and anxiety disorders. The current study, evaluates the association between salivary cortisol concentrations and response to carbon-dioxide inhalation in children and adolescents with anxiety disorders, mood disorders, or no psychiatric illness. The central question was whether response to carbon-dioxide inhalation is associated with levels of hypothalamic-pituitary adrenal axis activation. If confirmed, this would relate hypothalamic-pituitary adrenal axis activation in juveniles, as in adults, and response to a well-studied respiratory procedure. Methods: Serial salivary cortisol samples were examined in 98 subjects (ages 9-17 years), including 62 subjects with an anxiety and/or mood disorder and 36 nonpsychiatrically ill comparisons. Samples were obtained upon arrival at the laboratory, following a tilt test, then before and immediately, after a standard 5% carbon dioxide inhalation procedure. Results: Salivary cortisol levels pre-carbon-dioxide inhalation were significantly higher in patients sensitive to the anxiogenic effects of carbon dioxide (n = 20) than in patients who did not respond to carbon dioxide (n = 42) and in healthy subjects, none of whom were sensitive to carbon dioxide (n = 36); cortisol concentrations in the latter two groups were indistinguishable. Salivary cortisol did not increase during carbon-dioxide inhalation, irrespective of diagnostic group or degree of reactivity to the procedure. Conclusions: The current data resemble data from studies of laboratory-induced panic among adult patients. In both groups, activation of the hypothalamic-pituitary adrenal axis is associated with the response to a standardized stressor. Similarly, as in adults, carbon-dioxide inhalation in juveniles does not produce a significant change in hypothalamic-pituitary adrenal axis activation. (C) 2002 Society of Biological Psychiatry. C1 Columbia Univ, New York, NY USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. Suny Downstate Med Ctr, Dept Psychiat, Brooklyn, NY 11203 USA. RP Pine, DS (reprint author), NIMH, Intramural Res Program, 1 Ctr Dr,Bldg 1,Room B310-0135, Bethesda, MD 20892 USA. FU NIMH NIH HHS [MH 43878, MH 01039, MH 01391, MH 16432, MH 41778, MH 46091, MH 50527-01A, MH 58911-01A1] NR 31 TC 25 Z9 25 U1 0 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 FEB 15 PY 2002 VL 51 IS 4 BP 326 EP 333 AR PII S0006-3223(01)01250-1 DI 10.1016/S0006-3223(01)01250-1 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 529BY UT WOS:000174281200008 PM 11958784 ER PT J AU Botteron, KN Raichle, ME Drevets, WC Heath, AC Todd, RD AF Botteron, KN Raichle, ME Drevets, WC Heath, AC Todd, RD TI Volumetric reduction in left subgenual prefrontal cortex in early onset depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE major depression; adolescence; neuroimaging; anterior cingulate cortex; epidemiology ID MOOD DISORDERS AB Background: Subgenual prefrontal cortex (SGPFC) volume reduction has been reported in middle age adults with major depression (MD) or bipolar affective disorder. In this study, the authors test the hypothesis that SGPFC reduction is present in adolescent onset MD, and examine differences in the magnitude of reduction in younger versus older women. Methods: Subgenual prefrontal cortex volume was measured from T1 weighted MR images in (1) 30 young women with early onset MD versus eight age-matched controls, and (2) 18 middle aged women with recurrent MD versus nine age-matched controls. Results: Left SGPFC volume was reduced in adolescent and middle aged females with depression. The magnitude of the difference between depressed and control groups (average 19% difference) was similar in younger and older women. Conclusions: Left subgenual cingulate volume reductions are present in young women with adolescent onset MD. (C) 2002 Society of Biological Psychiatry. C1 Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. NIMH, Bethesda, MD 20892 USA. RP Botteron, KN (reprint author), Washington Univ, Sch Med, Dept Psychiat, 660 S Euclid Ave,Box 8134, St Louis, MO 63110 USA. FU NIAAA NIH HHS [AA 09022]; NIMH NIH HHS [MH 5813] NR 8 TC 230 Z9 239 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2002 VL 51 IS 4 BP 342 EP 344 AR PII S0006-3223(01)01280-X DI 10.1016/S0006-3223(01)01280-X PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 529BY UT WOS:000174281200010 PM 11958786 ER PT J AU Okamoto, M Kato, S Oizumi, K Kinoshita, M Inoue, Y Hoshino, K Akira, S Mckenzie, ANJ Young, HA Hoshino, T AF Okamoto, M Kato, S Oizumi, K Kinoshita, M Inoue, Y Hoshino, K Akira, S Mckenzie, ANJ Young, HA Hoshino, T TI Interleukin 18 (IL-18) in synergy with IL-2 induces lethal lung injury in mice: A potential role for cytokines, chemokines, and natural killer cells in the pathogenesis of interstitial pneumonia SO BLOOD LA English DT Article ID TUMOR-NECROSIS-FACTOR; INDUCED PULMONARY FIBROSIS; INTERFERON-GAMMA PRODUCTION; CD4(+) T-CELLS; RECOMBINANT INTERLEUKIN-2; TH2 CELLS; INFLAMMATORY RESPONSE; MOUSE MODEL; IN-VIVO; EXPRESSION AB Interleukin 18 (IL-18) was discovered as an interferon-gamma (IFN-gamma)-inducing factor and plays important roles in natural killer (NK) cell activation. IL-18 also induces proinflammatory cytokines; chemokines; helper T-cell 2 (T(H)2) cytokines (eg, IL-4, IL-13); and immunoglobulin E (Ig-E) and IgG1 production. The combination of IL-18 plus IL-2 or IL-12 up-regulates IFN-gamma gene expression and NK cytotoxicity and has synergistic antitumor activity in vivo and in vitro. Here it is reported that daily administration of IL-18 with IL-2, but not of IL-18 or IL-2 alone, induces lethal lung injury in normal mice, but not in IL-18 receptor alpha (IL-1 receptor-related protein)-deficient (IL-18 receptor alpha(-/-)) mice. Marked interstitial infiltration of lymphocytes, composed mainly of NK cells, was found in the lungs of IL-18/IL-2-treated mice. Increased cytokine and chemokine levels were observed in the sera and lungs of IL-18/IL-2-treated mice. Administration of IL-18/IL-2 was also lethal to mice treated with a metalloproteinase inhibitor, which inhibited tumor necrosis factor-alpha and Fas-ligand release. While IFN-gamma(-/-) mice were partially resistant to the treatment, IL-4(-/-), IL-13(-/-), IL-4/IL-13(-/-), and Stat6(-/-) mice were sensitive, to IL-18/IL-2, indicating that these genes were not involved in the host response. The lethal effect by IL-18/IL-2 was completely eliminated in severe combined immunodeficient mice pretreated with antiasialo-GM1 antibody and normal mice pretreated with anti-NK1.1 but not with anti-CD4 or anti-CD8, monoclonal antibody. These results suggest that specific cytokines, chemokines, and NK cells are involved in the pathogenesis of interstitial pneumonia. These results suggest that the clinical use of this interleukin may result in unexpected physiological consequences. (C) 2002 by The American Society of Hematology. C1 Kurume Univ, Sch Med, Dept Internal Med 1, Kurume, Fukuoka 8300011, Japan. Kurume Univ, Sch Med, Dept Pathol, Kurume, Fukuoka 8300011, Japan. Nippon Organon, Div Res & Dev, R&D Labs, Osaka, Japan. Osaka Univ, Res Inst Microbial Dis, Dept Host Def, Suita, Osaka 565, Japan. Japan Sci & Technol Corp, CREST, Suita, Osaka, Japan. MRC, Mol Biol Lab, Cambridge CB2 2QH, England. NCI, Expt Immunol Lab, Frederick, MD 21701 USA. RP Hoshino, T (reprint author), Kurume Univ, Sch Med, Dept Internal Med 1, 67 Asahi Machi, Kurume, Fukuoka 8300011, Japan. RI Young, Howard/A-6350-2008; Akira, Shizuo/C-3134-2009; Hoshino, Katsuaki/L-9162-2014 OI Young, Howard/0000-0002-3118-5111; Hoshino, Katsuaki/0000-0003-0493-4815 NR 48 TC 67 Z9 73 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 FEB 15 PY 2002 VL 99 IS 4 BP 1289 EP 1298 DI 10.1182/blood.V99.4.1289 PG 10 WC Hematology SC Hematology GA 520NH UT WOS:000173787600029 PM 11830478 ER PT J AU Decker, T Hipp, S Kreitman, RJ Pastan, I Peschel, C Licht, T AF Decker, T Hipp, S Kreitman, RJ Pastan, I Peschel, C Licht, T TI Sensitization of B-cell chronic lymphocytic leukemia cells to recombinant immunotoxin by immunostimulatory phosphorothioate oligodeoxynucleotides SO BLOOD LA English DT Article ID STABILIZED FV FRAGMENT; PSEUDOMONAS EXOTOXIN; CPG-DNA; BACTERIAL-DNA; IN-VIVO; MONOCLONAL-ANTIBODY; HEMATOLOGIC MALIGNANCIES; IMMUNOGENIC PHENOTYPE; ANTITUMOR-ACTIVITY; CYTOTOXIC ACTIVITY AB A recombinant anti-CD25 immunotoxin, LMB-2, has shown clinical efficacy in hairy cell leukemia and T-cell neoplasms. Its activity in B-cell chronic lymphocytic leukemia (B-CLL) is Inferior but might be Improved if B-CLL cells expressed higher numbers of CD25 binding sites. It was recently reported that DSP30, a phosphorothioate CpG-oligodeoxynucleotide (CpG-ODN) induces immunogenicity of B-CLL cells by up-regulation of CD25 and other antigens. The present study investigated the antitumor activity of LMB-2 in the presence of DSP30. To this end, B-CLL cells from peripheral blood of patients were isolated Immunomagnetically to more than 98% purity. Incubation with DSP30 for 48 hours augmented CD25 expression in 14 of 15 B-CLL samples, as assessed by flow cytometry. DSP30 Increased LMB-2 cytotoxicity dose dependently whereas a control ODN with no CpG motif did not. LMB-2 displayed no antitumor cell activity in the absence of CpG-ODN as determined colorimetrically with an (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy- phenyl)-2-(4-sulfophenyl)-2H-tetrazolium, Inner salt (MTS) assay. In contrast, B-CLL growth was inhibited In 12 of 13 samples with 50% inhibition concentrations (IC50) in the range of LMB-2 plasma levels achieved in clinical studies. Two samples were not evaluable because of spontaneous B-CLL cell death In the presence of DSP30. Control experiments with an Immunotoxin that does not recognize hematopoietic cells, and an anti-CD22 Immunotoxin, confirmed that sensitization to LMB-2 was specifically due to up-regulation of CD25. LMB-2 was much less toxic to normal B and T lymphocytes compared with B-CLL cells. In summary, immunostimulatory CpG-ODNs efficiently sensitize B-CLL cells to a recombinant Immunotoxin by modulation of its target. This new treatment strategy deserves further attention. (C) 2002 by The American Society of Hematology. C1 Tech Univ Munich, Dept Med 3, D-81675 Munich, Germany. NCI, Div Basic Sci, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Decker, T (reprint author), Tech Univ Munich, Dept Med 3, Ismaninger Str 15, D-81675 Munich, Germany. NR 56 TC 35 Z9 37 U1 0 U2 1 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 FEB 15 PY 2002 VL 99 IS 4 BP 1320 EP 1326 PG 7 WC Hematology SC Hematology GA 520NH UT WOS:000173787600033 PM 11830482 ER PT J AU Talvensarri, K Clave, E Douay, C Rabian, C Garderet, L Busson, M Garnier, F Douek, D Gluckman, E Charron, D Toubert, A AF Talvensarri, K Clave, E Douay, C Rabian, C Garderet, L Busson, M Garnier, F Douek, D Gluckman, E Charron, D Toubert, A TI A broad T-cell repertoire diversity and an efficient thymic function indicate a favorable long-term immune reconstitution after cord blood stem cell transplantation SO BLOOD LA English DT Article ID BONE-MARROW TRANSPLANTATION; VERSUS-HOST DISEASE; PROGENITOR CELLS; RECOVERY; RECIPIENTS; CHILDREN; AGE; REGENERATION; PROGRESSION; COMPLEXITY AB Cord blood (CB) is used increasingly as a source of hematopoietic stem cells because of a lower risk of acute and chronic graft-versus-host disease (GVHD). However, there is some concern regarding the ability to adequately reconstitute host immune response due to the immaturity and naivety of CB T cells. This study was designed to evaluate T-cell reconstitution using combined approaches of phenotyping, analysis of alphabeta T-cell receptor (TCR) diversity, and assessment of ex vivo thymic function by measuring TCR rearrangement excision circles (TRECs). Ten patients who underwent CB transplantation for high-risk hematologic disorders were compared to a reference group of 19 age and GVHD-matched patients who underwent transplantation with non-T cell-depleted bone marrow from an HILA-Identical sibling donor. TREC values correlated with the relative number of naive T cells and with TCR repertoire polyclonality. During the first year after transplantation, TCR repertoires were highly abnormal and TREC values low in both groups.Notably, 2 years after transplantation onward TREC values as well as TCR diversity were higher In CB recipients than in recipients of bone marrow transplants. These data Indicate an efficient thymic regeneration pathway from CB lymphoid progenitors despite the low number of cells Infused compared to bone marrow, arguing for a complete clinical Immune recovery after CB transplantation. (C) 2002 by The American Society of Hematology. C1 Hop St Louis, APHP, Serv Hematol Greffe de Moelle, F-75475 Paris 10, France. Inst Univ Hematol, Lab Immunol & Histocompatibil, INSERM U396, Paris, France. NCI, Dept Expt Transplantat & Immunol, NIH, Bethesda, MD 20892 USA. NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Toubert, A (reprint author), Hop St Louis, Lab Immunol & Histocompatibil, Ctr G Hayem, 1 Ave Claude Vellefaux, F-75475 Paris 10, France. NR 38 TC 134 Z9 145 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 FEB 15 PY 2002 VL 99 IS 4 BP 1458 EP 1464 DI 10.1182/blood.V99.4.1458 PG 7 WC Hematology SC Hematology GA 520NH UT WOS:000173787600051 PM 11830500 ER PT J AU McAllister, KA Bennett, LM Houle, CD Ward, T Malphurs, J Collins, NK Cachafeiro, C Haseman, J Goulding, EH Bunch, D Eddy, EM Davis, BJ Wiseman, RW AF McAllister, KA Bennett, LM Houle, CD Ward, T Malphurs, J Collins, NK Cachafeiro, C Haseman, J Goulding, EH Bunch, D Eddy, EM Davis, BJ Wiseman, RW TI Cancer susceptibility of mice with a homozygous deletion in the COOH-terminal domain of the Brca2 gene SO CANCER RESEARCH LA English DT Article ID BREAST-CANCER; DNA-REPAIR; RAD51; MUTATIONS; CELLS; HYPERSENSITIVITY; RADIATION; PROTEINS; HOMOLOGS; REPEATS AB Inherited mutations of the human BRCA2 gene confer increased risks for developing breast, ovarian, and several other cancers. Unlike previously described Brca2 knockout mice that display predominantly embryonic lethal phenotypes, we developed mice with a homozygous germ-line deletion of Brca2 exon 27 that exhibit a moderate decrease in perinatal viability and are fertile. We deleted this Brca2 COOH-terminal domain because it interacts directly with the Rad51 protein, contains a nuclear localization signal, and is required to maintain genomic stability in response to various types of DNA damage. These homozygous Brca2-mutant mice have a significantly increased overall tumor incidence and decreased survival compared with their heterozygous littermates. Virgin female mice homozygous for this Brca2 mutation also display an inhibition of ductal side branching in the mammary gland at 6 months of age. Given their substantial viability and cancer predisposition, these mutant mice will be useful to further define the role of the COOH-terminal Brca2 domain in tumorigenesis both in vivo and in vitro. C1 NIEHS, Lab Womens Hlth, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA 94551 USA. Integrated Lab Syst Inc, Durham, NC 27713 USA. Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. RP McAllister, KA (reprint author), NIEHS, Lab Womens Hlth, NIH, MD C4-06,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 29 TC 69 Z9 69 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2002 VL 62 IS 4 BP 990 EP 994 PG 5 WC Oncology SC Oncology GA 523RP UT WOS:000173969400009 PM 11861370 ER PT J AU Wu, YP Yakar, S Zhao, L Hennighausen, L LeRoith, D AF Wu, YP Yakar, S Zhao, L Hennighausen, L LeRoith, D TI Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis SO CANCER RESEARCH LA English DT Article ID FACTOR EXPRESSION; BREAST-CANCER; IGF-I; PLASMA-LEVELS; ATHYMIC MICE; CARCINOMA; RISK; TUMOR; RECEPTORS; HORMONE AB It has been shown previously. that slight elevations in serum levels of insulin-like growth factor-I (IGF-I) are correlated with an increased risk for developing prostate, breast, colon, and lung cancer. The aim of this study was to determine the role of serum IGF-I levels in the process of stimulating tumor growth and metastasis in a mouse model of colon cancer. Colon 38 adenocarcinoma tissue fragments were orthotopically transplanted by attachment to the surface of the cecum in control and liver-specific IGF-I-dericient (LID) mice in which serum IGF-I levels are 25% of that in control mice. A total of 156 male mice at 5 weeks of age (74 control mice and 82 LID mice) received tumor transplants. Mice were divided randomly into two groups; one group was injected i.p. with recombinant human IGF-I (2 mg/kg) twice daily for 6 weeks, and the other group received saline injections. IGF-I treatment increased the serum levels of IGF-I and IGFBP-3 in both control and LID mice. In the saline-injected group, the incidence of tumor growth on the cecum as well as the frequency of hepatic metastasis was significantly, higher in control mice as compared with LID mice. Both control and LID mice treated with recombinant human IGF-I displayed significantly increased rates of tumor development on the cecum and metastasis to the liver, as compared with saline-injected mice. The number of metastatic nodules in the liver was significantly higher in control mice as compared with LID mice. The expression of vascular epithelial growth factor (VEGF) as well as vessel abundance in the cecum tumors was dependent on the levels of serum IGF-I. This study supports the hypothesis that circulating IGF-I levels play an important role in tumor development and metastasis. C1 NIDDKD, Sect Cellular & Mol Physiol, Cellular Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP LeRoith, D (reprint author), NIDDKD, Clin Endocrinol Branch, NIH, Room 8D12,Bldg 10, Bethesda, MD 20892 USA. NR 35 TC 263 Z9 290 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2002 VL 62 IS 4 BP 1030 EP 1035 PG 6 WC Oncology SC Oncology GA 523RP UT WOS:000173969400017 PM 11861378 ER PT J AU Tan, C Waldmann, TA AF Tan, C Waldmann, TA TI Proteasome inhibitor PS-341, a potential therapeutic agent for adult T-cell leukemia SO CANCER RESEARCH LA English DT Article ID NF-KAPPA-B; VIRUS TYPE-1 TAX; ACTIVATION; PROTEIN; PHOSPHORYLATION; INACTIVATION; DEGRADATION; INDUCTION; PATHWAY; ALPHA AB Nuclear factor kappaB (NF-kappaB) plays a major role in the pathogenesis of human T-cell lymphotrophic virus I-associated malignancy. Proteasome inhibitors provide a rational approach to control constitutively activated NF-kappaB in human T-cell lymphotrophic virus I-infected T cells. We report that the proteasome inhibitor PS-341 decreased NF-kappaB DNA binding activity by preventing degradation of IkappaBalpha. In our murine model of adult T-cell leukemia, PS-341 used alone did not yield prolongation of the survival of tumor-bearing mice. However, when combined with the current clinically approved drug humanized anti-Tac, therapy with PS-341 was associated with a complete remission in a proportion of treated animals, whereas only a partial response was observed in animals treated with humanized anti-Tac alone. C1 NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Waldmann, TA (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bldg 10,Room 4N115,10 Ctr Dr, Bethesda, MD 20892 USA. NR 19 TC 125 Z9 130 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2002 VL 62 IS 4 BP 1083 EP 1086 PG 4 WC Oncology SC Oncology GA 523RP UT WOS:000173969400025 PM 11861386 ER PT J AU Platzer, P Upender, MB Wilson, K Willis, J Lutterbaugh, J Nosrati, A Willson, JKV Mack, D Ried, T Markowitz, S AF Platzer, P Upender, MB Wilson, K Willis, J Lutterbaugh, J Nosrati, A Willson, JKV Mack, D Ried, T Markowitz, S TI Silence of chromosomal amplifications in colon cancer SO CANCER RESEARCH LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; RECEPTOR COACTIVATOR GENE; OLIGONUCLEOTIDE ARRAYS; COLORECTAL-CANCER; OVARIAN-CANCER; BREAST-CANCER; SOLID TUMORS; EXPRESSION; AIB1; CARCINOMAS AB Oncogene activation by gene amplification is a major pathogenetic mechanism in human cancer. Using comparative genomic hybridization, we determined that metastatic human colon cancers commonly acquire numerous extra copies of chromosome arms 7p, 8q, 13q, and 20q. We then examined the consequence of these amplifications on gene expression using DNA microarrays. Of 55,000 transcripts profiled, 2,146 were determined to map to one of the four common colon cancer amplicons and to also be expressed in normal or malignant colon tissues. Of these, only 81 transcripts (3.8%) demonstrated a 2-fold increase over normal expression among cancers bearing the corresponding chromosomal amplification. Chromosomal amplifications are common in colon cancer metastasis, but increased expression of genes within these amplicons is rare. C1 Howard Hughes Med Inst, Cleveland, OH 44106 USA. NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Eos Biotechnol, San Francisco, CA 94080 USA. Univ Hosp Cleveland, Dept Pathol, Cleveland, OH 44106 USA. Case Western Reserve Univ, Ireland Canc Ctr, Dept Med, Cleveland, OH 44106 USA. Case Western Reserve Univ, Ireland Canc Ctr, Ctr Canc, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Res Inst, Cleveland, OH 44106 USA. RP Markowitz, S (reprint author), Howard Hughes Med Inst, Room 200,11001 Cedar Rd, Cleveland, OH 44106 USA. EM sxm10@po.cwru.edu FU NCI NIH HHS [CA88130] NR 24 TC 116 Z9 118 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2002 VL 62 IS 4 BP 1134 EP 1138 PG 5 WC Oncology SC Oncology GA 523RP UT WOS:000173969400033 PM 11861394 ER PT J AU Sargent, LM Senft, JR Lowry, DT Jefferson, AM Tyson, FL Malkinson, AM Coleman, AE Reynolds, SH AF Sargent, LM Senft, JR Lowry, DT Jefferson, AM Tyson, FL Malkinson, AM Coleman, AE Reynolds, SH TI Specific chromosomal aberrations in mouse lung adenocarcinoma cell lines detected by spectral karyotyping: A comparison with human lung adenocarcinoma SO CANCER RESEARCH LA English DT Article ID IN-SITU HYBRIDIZATION; PLASMINOGEN-ACTIVATOR; TUMOR SUSCEPTIBILITY; GENETIC-CONTROL; BREAST-CANCER; MICE; PROGRESSION; ASSIGNMENT; LOCI; EXPRESSION AB Although adenocarcinoma is rapidly, becoming the must common form of lung cancer in the United States, the difficulty, in obtaining lung cancer families and representative samples of the various stages of adenocarcinoma progression has led to intense study. of mouse models. As a powerful approach to delineating molecular changes, we have analyzed 15 early-passage mouse cell lines by spectral karyotyping. Entire copies of chromosomes 1, 2, 6, 12, 15, and 19 were gained, and entire copies of chromosomes 4, 7, 8, and 14 were lost. Significant gains of portions of chromosome 1 (93% of the tumor cell lines analyzed), chromosome 2 (53%), chromosome 6 (73%). chromosome 7 (80%). chromosome 12 (47%). and chromosome 15 (73%) and partial loss of chromosome 4 (87%), chromosome 7 (80%), chromosome 8 (53%), chromosome 10 (33%), and chromosome 14 (33%) were observed. Recurrent translocations included 10:del(10)(A1::C1), t(4;8)(C4;A1), and der (1;12)(C2;C2). The minimal regions of chromosomal alteration, 1G1, 2F1, 4C4, 6D, 7F1, 8B3, and 12C2, contain putative susceptibility genes for mouse lung adenocarcinoma. Chromosomal regions containing susceptibility genes linked to tumor size were frequently amplified, whereas regions with susceptibility loci linked to tumor multiplicity, were deleted. Similar linkage groups are altered in human lung adenocarcinoma, implying that the mouse is a valid genetic model for the study of human lung adenocarcinoma susceptibility. C1 NIOSH, Hlth Effects Lab Div, Toxicol & Mol Biol Branch, Genet Susceptibil Team, Morgantown, WV 26505 USA. NIEHS, Div Extramural Res & Training, Chem Exposures & Mol Biol Branch, Res Triangle Pk, NC 27709 USA. Univ Colorado, Hlth Sci Ctr, Dept Pharmaceut Sci, Denver, CO 80262 USA. NCI, Genet Lab, Bethesda, MD 20892 USA. RP Sargent, LM (reprint author), Ctr Dis Control, NIOSH, 1095 Willowdale Rd,MS-3014, Morgantown, WV 26505 USA. NR 54 TC 20 Z9 21 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 FEB 15 PY 2002 VL 62 IS 4 BP 1152 EP 1157 PG 6 WC Oncology SC Oncology GA 523RP UT WOS:000173969400036 PM 11861397 ER PT J AU Cerignoli, F Guo, XJ Cardinali, B Rinaldi, C Casaletto, J Frati, L Screpanti, I Gudas, LJ Gulino, A Thiele, CJ Giannini, G AF Cerignoli, F Guo, XJ Cardinali, B Rinaldi, C Casaletto, J Frati, L Screpanti, I Gudas, LJ Gulino, A Thiele, CJ Giannini, G TI retSDR1, a short-chain retinol dehydrogenase/reductase, is retinoic acid-inducible and frequently deleted in human neuroblastoma cell lines SO CANCER RESEARCH LA English DT Article ID N-MYC AMPLIFICATION; BREAST-CANCER CELLS; TUMOR-SUPPRESSOR GENES; EMBRYONIC STEM-CELLS; HUMAN NEURO-BLASTOMA; ALL-TRANS; VITAMIN-A; GROWTH ARREST; SHORT ARM; RECEPTOR LIGANDS AB Vitamin A is required for a number of developmental processes and for the homeostatic maintenance of several adult differentiated tissues and organs. In human neuroblastoma (NB) cells as well as some other tumor types, pharmacological doses of retinoids are able to control growth and induce differentiation in vitro and in vivo. In a search for new genes that are regulated by retinoids and that contribute to the biological effects retinoids have on NB cells, we have isolated five differentially expressed transcripts. Here we report on the characterization of one of them (DD83.1) in NB cell lines. DD83.1 is identical to the human retSDR1, a short chain dehydrogenase/reductase that is thought to regenerate retinol from retinal in the visual cycle. Its expression is strongly, but differently, regulated by retinoids in NB cell lines, and it is widely expressed in human tissues, which suggests that it is involved in a more general retinol metabolic pathway. Both the retinoic acid-dependent and the exogenous expression of retSDR1 in SK-N-AS cells induce the accumulation of retinyl esters, which indicates that it is involved in generating storage forms of retinol in tissues exposed to physiological retinol concentrations. We also show that the human retSDR1 gene, which maps on chromosome 1p36.1, is contained in the DNA fragment deleted in Man. NB cell lines bearing MYCN amplification but is conserved in a cell line with a small I p deletion and normal MYCN. Our observations suggest that retSDR1 is a novel regulator of vitamin A metabolism and that its frequent deletion in NB cells bearing MYCN amplification could compromise the sensitivity of those cells to retinol, thereby contributing to cancer development and progression. C1 Univ Roma La Sapienza, Policlin Umberto I, Dept Expt Med & Pathol, I-00161 Rome, Italy. Neuromed Inst, I-86077 Pozzilli, Italy. Univ Aquila, Dept Expt Med, I-67100 Laquila, Italy. Pasteur Inst Cenci Bolognetti Fdn, I-00161 Rome, Italy. CNR, Inst Cell Biol, I-00016 Monterotondo, Italy. Cornell Univ, Weill Med Coll, Dept Pharmacol, New York, NY 10021 USA. NCI, Cellular & Mol Biol Sect, NIH, Bethesda, MD 20892 USA. RP Giannini, G (reprint author), Univ Roma La Sapienza, Policlin Umberto I, Dept Expt Med & Pathol, Viale Regina Elena 324, I-00161 Rome, Italy. RI Giannini, Giuseppe/B-5672-2013; Cardinali, Beatrice/M-8862-2015 OI Giannini, Giuseppe/0000-0003-0299-4056; Cardinali, Beatrice/0000-0002-3333-3384 FU NCI NIH HHS [R01 CA77509] NR 65 TC 54 Z9 56 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2002 VL 62 IS 4 BP 1196 EP 1204 PG 9 WC Oncology SC Oncology GA 523RP UT WOS:000173969400043 PM 11861404 ER PT J AU Rossouw, JE AF Rossouw, JE TI Hormones, genetic factors, and gender differences in cardiovascular disease SO CARDIOVASCULAR RESEARCH LA English DT Review DE gender; gene therapy ID CORONARY HEART-DISEASE; FACTOR-V-LEIDEN; DENSITY LIPOPROTEIN CHOLESTEROL; RANDOMIZED CONTROLLED TRIAL; ACTIVATED PROTEIN-C; POSTMENOPAUSAL WOMEN; REPLACEMENT THERAPY; MYOCARDIAL-INFARCTION; VENOUS THROMBOSIS; ARTERY DISEASE C1 NHLBI, Womens Hlth Initiat, Bethesda, MD 20892 USA. RP Rossouw, JE (reprint author), NHLBI, Womens Hlth Initiat, 1 Rockledge Ctr,Suite 300,6705 Rockledge Dr, Bethesda, MD 20892 USA. NR 72 TC 107 Z9 110 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD FEB 15 PY 2002 VL 53 IS 3 SI SI BP 550 EP 557 AR PII S0008-6363(01)00478-3 DI 10.1016/S0008-6363(01)00478-3 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 541JD UT WOS:000174980700003 PM 11861025 ER PT J AU Cross, HR Murphy, E Koch, WJ Steenbergen, C AF Cross, HR Murphy, E Koch, WJ Steenbergen, C TI Male and female mice overexpressing the beta(2)-adrenergic receptor exhibit differences in ischemia/reperfusion injury: role of nitric oxide SO CARDIOVASCULAR RESEARCH LA English DT Article DE energy metabolism; gender; ischemia; nitric oxide; NMR ID ESTROGEN REPLACEMENT THERAPY; MONOPHOSPHORYL-LIPID-A; TRANSGENIC MICE; MYOCARDIAL-FUNCTION; ISCHEMIC-INJURY; INFARCT SIZE; RAT-HEART; IN-VITRO; SYNTHASE; EXPRESSION AB Objective: Cardiac overexpression of beta(2)-adronergic receptors (beta(2)ARs) in male mice (MTG4) results in increased contractility and increased ischemic injury. Considering recent clinical data indicating that premenopausal women arc protected from cardiovascular injury, we assessed the consequences of beta(2)AR overexpression in females (FTG4). Since protection in females is mediated via estrogen, which activates endothelial and inducible nitric oxide synthases (eNOS and iNOS) we also examined the role of NOS in ischemia/reperfusion injury in male and female TG4 and wild-type (WT) mice. Methods: Hearts from MTG4, FTG4, MWT and FWT mice were isolated and perfused in the Langendorff mode. Hearts were pretreated with either 1 mumol/l of the nonspecific NOS inhibitor, L-NAME, or 100 nmol/l of the specific iNOS inhibitor, 1400W. Control hearts received no treatment. All hearts were subjected to 20 min ischemia and 40 min reperfusion while P-31-NMR spectra were acquired. Results: During ischemia, ATP and pH fell lower in MTG4 hearts than in FTG4 or WT heart,,,. Hearts from MTG4 mice exhibited increased ischemia/reperfusion injury as indicated by lower recoveries of postischemic contractile function, ATP and PCr than WT. Despite contractility being elevated in FTG4 hearts to the same level as MTG4 hearts, ischemia/reperfusion injury was not increased, as indicated by similar postischemic recoveries of contractile function, ATP and PCr in FTG4 hearts compared to WT. ATP and pH fell lower during ischemia in L-NAME-treated FTG4 hearts than in untreated FTG4 hearts, falling as low, as untreated MTG4s. Recoveries of contractile function, ATP and PCr were as low in L-NAME-treated FTG4 hearts as in untreated MTG4 hearts and lower than untreated FTG4 hearts. In contrast, 1400W had no effect on FTG4 hearts, MTG4 hearts were unaffected by L-NAME or 1400W. Conclusions: beta(2)AR overexpression increased ischemia/reperfusion injury in males but not females, thus females were protected from the detrimental effects or PAR overexpression. Protection was abolished by treatment with L-NAME, but not 1400W, implying that protection was mediated by eNOS not iNOS. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Cross, HR (reprint author), Duke Univ, Med Ctr, Dept Pathol, Box 3712, Durham, NC 27710 USA. FU NHLBI NIH HHS [R01 HL039752] NR 27 TC 36 Z9 38 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD FEB 15 PY 2002 VL 53 IS 3 SI SI BP 662 EP 671 AR PII S0008-6363(01)00528-4 DI 10.1016/S0008-6363(01)00528-4 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 541JD UT WOS:000174980700015 PM 11861037 ER PT J AU Wert, SE Dey, CR Blair, PA Kimura, S Whitsett, JA AF Wert, SE Dey, CR Blair, PA Kimura, S Whitsett, JA TI Increased expression of thyroid transcription factor-1 (TTF-1) in respiratory epithelial cells inhibits alveolarization and causes pulmonary inflammation SO DEVELOPMENTAL BIOLOGY LA English DT Article DE mouse lung; morphogenesis; Nkx2.1; TITF-1; T/EBP; surfactant protein B; eosinophils; eotaxin; IL-6; emphysema ID HEPATOCYTE NUCLEAR FACTOR-3; DEVELOPING MOUSE LUNG; SURFACTANT PROTEIN-B; FACTOR-I TTF-1; TRANSGENIC MICE; C GENE; ACTIVATES TRANSCRIPTION; SECRETORY PROTEIN; EOTAXIN; MORPHOGENESIS AB Thyroid transcription factor-1 (TTF-1), a member of the Nkx2 family of homeodomain-containing transcription factors, is expressed in the epithelium of the lung. TTF-1 is a critical regulator of transcription for the surfactant proteins (SP) A, B, and C and is essential for lung morphogenesis. Sites and levels of TTE-1 expression vary during lung morphogenesis and following injury. In order to determine the role of TTF-1 in lung formation, transgenic mice were generated in which TTF-1 was expressed in respiratory epithelial cells of wild-type and Ttf1 null mutant (-/-) mice, using the lung-specific SP-C promoter. The SP-C-Ttf1 transgene did not rescue the severe pulmonary hypoplasia characteristic of the Ttf1 (-/-) mice. Increased expression of TTF-1, however, caused dose-dependent alterations in postnatal lung morphology: of wild-type mice. Modest overexpression of TTF-1 caused type II cell hyperplasia and increased the cellular content of SP-B. In contrast, higher expression levels of TTF-1 disrupted alveolar septation, causing emphysema. In mice with the highest transgene expression, TTF-1 caused severe inflammation, pulmonary fibrosis, respiratory failure, and deaths associated with eosinophil infiltration and increased expression of eotaxin and IL-6. Increased expression of TTF-1 altered alveolarization and caused chronic pulmonary inflammation, demonstrating that precise regulation of TTF-1 is critical for homeostasis in the postnatal lung. (C) 2002 Elsevier Science (USA). C1 Childrens Hosp, Med Ctr, Div Pulm Biol, Cincinnati, OH 45229 USA. NCI, NIH, Lab Metab, Bethesda, MD 20892 USA. RP Whitsett, JA (reprint author), Childrens Hosp, Med Ctr, Div Pulm Biol, Cincinnati, OH 45229 USA. FU NHLBI NIH HHS [HL38859, HL56397] NR 36 TC 56 Z9 56 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD FEB 15 PY 2002 VL 242 IS 2 BP 75 EP 87 DI 10.1006/dbio.2001.0540 PG 13 WC Developmental Biology SC Developmental Biology GA 524CW UT WOS:000173995300001 PM 11820807 ER PT J AU Mrsny, RJ Daugherty, AL McKee, ML FitzGerald, DJ AF Mrsny, RJ Daugherty, AL McKee, ML FitzGerald, DJ TI Bacterial toxins as tools for mucosal vaccination SO DRUG DISCOVERY TODAY LA English DT Review ID HEAT-LABILE ENTEROTOXIN; COMPLEX CLASS-I; AERUGINOSA EXOTOXIN-A; VIRUS-LIKE PARTICLES; T-CELL RESPONSES; ESCHERICHIA-COLI; CHOLERA-TOXIN; PSEUDOMONAS-AERUGINOSA; B-SUBUNIT; INTRANASAL IMMUNIZATION AB Several studies have demonstrated that the biological properties of secreted bacterial toxins could be harnessed for the induction of mucosal and systemic immunity following application at epithelial surfaces. Although the properties and potential application of several of these toxins will be discussed in this review, special focus will be placed on Pseudomonas aeruginosa exotoxin A (PE). A non-toxic form of PE (ntPE) into which antigenic epitopes can be integrated appears to be a particularly promising vaccination tool, which is able to cross the polarized epithelia of the gastrointestinal, respiratory and reproductive tracts and selectively target macrophages and dendritic cells. C1 Cardiff Univ, Welsh Sch Pharm, Ctr Drug Delivery Biol, Cardiff CF10 3XF, S Glam, Wales. NCI, Div Basic Sci, Lab Mol Biol, Biotherapy Sect NIH, Bethesda, MD 20892 USA. RP Mrsny, RJ (reprint author), Cardiff Univ, Welsh Sch Pharm, Ctr Drug Delivery Biol, Redwood Bldg King Edward 7, Cardiff CF10 3XF, S Glam, Wales. NR 79 TC 12 Z9 15 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD FEB 15 PY 2002 VL 7 IS 4 BP 247 EP 258 DI 10.1016/S1359-6446(01)02139-0 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 522TP UT WOS:000173913300009 PM 11839522 ER PT J AU Tufan, AC Daumer, KM DeLise, AM Tuan, RS AF Tufan, AC Daumer, KM DeLise, AM Tuan, RS TI AP-1 transcription factor complex is a target of signals from both WNT-7a and N-cadherin-dependent cell-cell adhesion complex during the regulation of limb mesenchymal chondrogenesis SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE AP-1; c-jun; Erk; Wnt-7a; N-cadherin; limb chondrogenesis ID GLYCOGEN-SYNTHASE KINASE-3; BETA-CATENIN; C-JUN; ACTIVATION; DIFFERENTIATION; TRANSFORMATION; EXPRESSION; PATHWAY; FAMILY; GENES AB Wnt signaling has been implicated in the regulation of limb mesenchymal chondrogenesis. In this study, we have analyzed the molecular mechanism of Wnt-7a inhibition of chondrogenic differentiation by examining the involvement of mitogen-activated protein kinase (MAPK) pathways, i.e., Erk and p38. The combination of Wnt-7a misexpression and Erk inhibition partially recovers Wnt-7a inhibition of chondrogenic differentiation, whereas the combination of Wnt-7a misexpression and p38 inhibition acts in a synergistic chondro-inhibitory fashion. Although Wnt-7a misexpression has no direct effect on Erk signaling, it increases the activity of one of the ultimate targets of the MAPK pathway, c-jun, a major component of the activator protein-1 (AP-1) transcription factor complex. In addition, Wnt-7a misexpression enhances the activity of an AP-1 promoter-luciferase reporter construct by similar to2.3-fold in vitro. Interestingly, misexpression of wild-type N-cadherin in these micromass cultures suppresses the activity of the same AP-1 promoter by similar to40%, whereas misexpression of an extracellular 390-amino-acid N-terminal deletion mutant of N-cadherin has a stimulatory effect on the AP-1 promoter activity by similar to2.6-fold. Thus, our results suggest that at least a part of the chondro-inhibitory effect of Wnt-7a misexpression may involve AP-1 transcription factor stimulation. Furthermore, a very tightly regulated level of AP-1 activity is necessary for the process of limb mesenchymal chondrogenesis, and signals from Wnt-ligands (e.g., Wnt-7a), cell adhesion molecules (e.g., N-cadherin), and MAPK pathways (e.g., Erk and p38) are interactively involved in this regulation. m (C) 2002 Elsevier Science (USA). C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Dept Orthopaed Surg, Philadelphia, PA 19107 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bldg 13,3W17,MSC 5755, Bethesda, MD 20892 USA. FU NIDCR NIH HHS [DE16864] NR 29 TC 38 Z9 40 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 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 15 PY 2002 VL 273 IS 2 BP 197 EP 203 DI 10.1006/excr.2001.5448 PG 7 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 524JL UT WOS:000174009400009 PM 11822875 ER PT J AU Moncman, CL Wang, K AF Moncman, CL Wang, K TI Targeted disruption of nebulette protein expression alters cardiac myofibril assembly and function SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE ischemia; Z-lines; titin; tropomyosin; alpha-actinin ID HUMAN NEBULIN FRAGMENTS; SKELETAL-MUSCLE SARCOMERE; VERTEBRATE Z-DISCS; ALPHA-ACTININ; STUNNED MYOCARDIUM; BINDING-PROPERTIES; NEMALINE MYOPATHY; TERMINAL REGION; THIN-FILAMENTS; N-TERMINUS AB To evaluate nebulette's role in cardiac myofibrils, cardiomyocytes expressing green fluorescent protein (GFP)-nebulette constructs were monitored for their ability to contract and myofilament protein distribution was analyzed. Cells expressing full-length GFP-nebulette appear unaffected and exhibit normal beating frequencies. Expression of the GFP linker and SH3 results in loss of the endogenous nebulette and tropomyosin; however, Z-line and thick filaments are undisturbed. Cells expressing either of these domains have dramatically reduced beating frequencies, consistent with the loss of thin filament proteins. This loss was inhibited by the addition of protease inhibitors during culturing. The GFP repeat domain disrupts both myofibrillogenesis and contraction in spreading cardiomyocytes, whereas introduction of this protein into well-spread cardiomyocytes results in localization at the Z-line and a 50% reduction in beating frequency. Ultimately, these cells form bundles containing the GFP repeat and many myofilament proteins. Interestingly, butanedione monoxime inhibition of contraction inhibited the formation of these bundles. These results show that the GFP-nebulette domains have a dominant-negative effect on the distribution and function of the sarcomeric proteins. Taken together with the observation that nebulette colocalizes with a-actinin in the pre-, nascent, and mature myofibrils, our data demonstrate the importance of this cardiac-specific nebulin isoform in myofibril organization and function. (C) 2002 Elsevier Science (USA). C1 Univ Texas, Dept Chem & Biochem, Austin, TX 78712 USA. NIAMSD, Phys Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wang, K (reprint author), NIAMS, LMB, NIH, B50,Rm 1140, Bethesda, MD 20892 USA. FU NIAMS NIH HHS [AR 43541] NR 58 TC 32 Z9 32 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 15 PY 2002 VL 273 IS 2 BP 204 EP 218 DI 10.1006/excr.2001.5423 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 524JL UT WOS:000174009400010 PM 11822876 ER PT J AU Miyakawa, T Obaru, K Maeda, K Harada, S Mitsuya, H AF Miyakawa, T Obaru, K Maeda, K Harada, S Mitsuya, H TI Identification of amino acid residues critical for LD78 beta, a variant of human macrophage inflammatory protein-1 alpha, binding to CCR5 and inhibition of R5 human immunodeficiency virus type 1 replication SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN TONSILLAR LYMPHOCYTES; CHEMOKINE RECEPTOR CXCR4; NON-ALLELIC VARIANT; HIV-1 ENTRY; MONONUCLEAR PHAGOCYTES; ANTI-HIV-1 ACTIVITY; TUMOR PROMOTER; GP120 BINDING; MIP-1-ALPHA; POTENT AB In an attempt to determine which amino acid(s) of LD78beta, a variant of human macrophage inflammatory protein-1alpha, plays a critical role in the interaction with CCR5, we generated six LD78beta variants with an amino acid substituted to Ala at the NH2 terminus of LD78beta. There was no significant difference in eliciting Ca2+ flux and chemotaxis among the variants with the exception of LD78beta(T9A) showing a substantially reduced activity. The comparative order for human immunodeficiency virus type 1 (HIV-1) replication inhibition was: LD78beta(P8A) > LD78beta(D6A) > LD78beta(WT), LD78beta(L3A) > LD78beta(T7A), LD78beta(P2A) > LD78beta(T9A). In binding inhibition assays of LD78beta variants using 2D7 monoclonal antibody and I-125-labeled macrophage inflammatory protein-la, the comparative order was: LD78beta(P8A), LD78beta(D6A) > LD78beta(WT) > LD78beta(L3A) > LD78beta(T7A) > LD78beta(T9A), LD78beta(P2A). The order for CCR5 down-regulation induction was comparable to that for binding inhibition. The present data suggest that Pro-2, Asp-6, Pro-8, and Thr-9 are critical for LD78beta binding to CCR5 and HIV-1 replication inhibition, and that LD78beta binding to CCR5, regardless of affinity, is sufficient for the initial signal transduction of LD78beta, whereas the greater anti-HIV-1 activity requires the greater magnitude of binding. The data also suggest that LD78beta variants with appropriate amino acid substitution(s) such as LD78beta(D6A) and LD78beta(P8A) may represent effective chemokine-based anti-HIV-1 therapeutics while preserving LD78beta-CCR5 interactions. C1 Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 8600811, Japan. NCI, NIH, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Mitsuya, H (reprint author), Kumamoto Univ, Sch Med, Dept Internal Med 2, 1-1-1 Honjo, Kumamoto 8600811, Japan. NR 41 TC 8 Z9 10 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 FEB 15 PY 2002 VL 277 IS 7 BP 4649 EP 4655 DI 10.1074/jbc.M109198200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 523NX UT WOS:000173962900015 PM 11734558 ER PT J AU Belova, GI Prasad, R Nazimov, IV Wilson, SH Slesarev, AI AF Belova, GI Prasad, R Nazimov, IV Wilson, SH Slesarev, AI TI The domain organization and properties of individual domains of DNA topoisomerase V, a type 1B topoisomerase with DNA repair activities SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POLYMERASE-BETA; HYPERTHERMOPHILIC PROKARYOTE; PHOSPHATE LYASE; CIRCULAR DNA; BINDING; MECHANISM; PROTEIN; ENZYME; RECOMBINATION; TYROSINE AB Topoisomerase V (Topo V) is a type IB (eukaryotic-like) DNA topoisomerase. It was discovered in the hyperthermophilic prokaryote Methanopyrus kandleri and is the only topoisomerase with associated apurinic/apyrimidinic (AP) site-processing activities. The structure of Topo V in the free and DNA-bound states was probed by limited proteolysis at 37 degreesC and 80 degreesC. The Topo V protein is comprised of (i) a 44-kDa NH2-terminal core subdomain, which contains the active site tyrosine residue for topoisomerase activity, (ii) an immediately adjacent 16-kDa subdomain that contains degenerate helix-hairpin-helix (HhH) motifs, (iii) a protease-sensitive 18-kDa HhH "hinge" region, and (iv) a 34-kDa COOH-terminal HhH domain. Three truncated Topo V polypeptides comprising the NH2-terminal 44-kDa and 16-kDa domains (Topo61), the 44-, 16-, and 18-kDa domains (Topo78), and the COOH-terminal 34-kDa domain (Topo34) were cloned, purified, and characterized. Both Topo61 and Topo78 are active topoisomerases, but in contrast to Topo V these enzymes are inhibited by high salt concentrations. Topo34 has strong DNA-binding ability but shows no topoisomerase activity. Finally, we demonstrate that Topo78 and Topo34 possess AP lyase activities that are important in base excision DNA repair. Thus, Topo V has at least two active sites capable of processing AP DNA. The significance of multiple HhH motifs for the Topo V processivity is discussed. C1 Fidel Syst Inc, Gaithersburg, MD 20879 USA. Russian Acad Sci, MM Shemyakin & Yu A Ovchinnikov Inst Bioorgan Che, Moscow 117871, Russia. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Slesarev, AI (reprint author), Fidel Syst Inc, 7960 Cessna Ave, Gaithersburg, MD 20879 USA. FU NHGRI NIH HHS [1R43HG2186-01A1] NR 26 TC 20 Z9 20 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 FEB 15 PY 2002 VL 277 IS 7 BP 4959 EP 4965 DI 10.1074/jbc.M110131200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 523NX UT WOS:000173962900055 PM 11733530 ER PT J AU Shieh, JJ Terzioglu, M Hiraiwa, H Marsh, J Pan, CJ Chen, LY Chou, JY AF Shieh, JJ Terzioglu, M Hiraiwa, H Marsh, J Pan, CJ Chen, LY Chou, JY TI The molecular basis of glycogen storage disease type 1a SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID UBIQUITIN-PROTEASOME PATHWAY; GLUCOSE-6-PHOSPHATASE GENE; MUTATIONS; DEGRADATION; CFTR; LACTACYSTIN; TOPOLOGY; IA; 1B AB Glycogen storage disease type la is caused by a deficiency in glucose-6-phosphatase (G6Pase), a nine-helical endoplasmic reticulum transmembrane protein required for maintenance of glucose homeostasis. To date, 75 G6Pase mutations have been identified, including 48 mutations resulting in single-amino acid substitutions. However, only 19 missense mutations have been functionally characterized. Here, we report the results of structure and function studies of the 48 missense mutations and the DeltaF327 codon deletion mutation, grouped as active site, helical, and nonhelical mutations. The 5 active site mutations and 22 of the 31 helical mutations completely abolished G6Pase activity, but only 5 of the 13 nonhelical mutants were devoid of activity. Whereas the active site and nonhelical mutants supported the synthesis of G6Pase protein in a manner similar to that of the wild-type enzyme, immunoblot analysis showed that the majority (64.5%) of helical mutations destabilized G6Pase. Furthermore, we show that degradation of both wild-type and mutant G6Pase is inhibited by lactacystin, a potent proteasome inhibitor. Taken together, we have generated a data base of residual G6Pase activity retained by G6Pase mutants, established the critical roles of transmembrane helices in the stability and activity of this phosphatase, and shown that G6Pase is a substrate for proteasome-mediated degradation. C1 NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Chou, JY (reprint author), NICHHD, Heritable Disorders Branch, NIH, Bldg 10,Rm 9S241, Bethesda, MD 20892 USA. NR 36 TC 32 Z9 34 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 15 PY 2002 VL 277 IS 7 BP 5047 EP 5053 DI 10.1074/jbc.M110486200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 523NX UT WOS:000173962900066 PM 11739393 ER PT J AU Chong, JM Uren, A Rubin, JS Speicher, DW AF Chong, JM Uren, A Rubin, JS Speicher, DW TI Disulfide bond assignments of secreted frizzled-related protein-1 provide insights about frizzled homology and netrin modules SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID WNT SIGNALING PATHWAY; GLYCOGEN-SYNTHASE KINASE-3-BETA; RECEPTOR TYROSINE KINASES; CYSTEINE-RICH DOMAIN; BETA-CATENIN; NEGATIVE REGULATOR; FUNCTIONAL INTERACTION; SPEMANN ORGANIZER; ENHANCER PROTEIN; XENOPUS EMBRYOS AB Secreted Frizzled-related protein-1 (sFRP-1), a soluble protein that binds to Wnts and modulates Wnt signaling, contains an N-terminal domain homologous to the putative Wnt-binding site of Frizzled (Fz domain) and a C-terminal heparin-binding domain with weak homology to netrin. Both domains are cysteine-rich, having 10 and 6 cysteines in the Fz and heparin-binding domains, respectively. In this study, the disulfide linkages of recombinant sFRP-1 were determined. Numbering sFRP-1 cysteines sequentially from the N terminus, the five disulfide linkages in the Fz domain are 1-5, 2-4, 3-8, 6-10, and 7-9, consistent with the disulfide pattern determined for homologous domains of several other proteins. The disulfide linkages of the heparin-binding domain are 11-14, 12-15, and 13-16. This latter set of assignments provides experimental verification of one of the disulfide patterns proposed for netrin (NTR) modules and thereby supports the prediction that the C-terminal heparin-binding domain of sFRP-1 is an NTR-type domain. Interestingly, two subsets of sFRPs appear to have alternate disulfide linkage patterns compared with sFRP-1, one of which involves the loss of a disulfide due to deletion of a single cysteine from the NTR module, whereas the remaining cysteine may pair with a new cysteine introduced in the Fz domain of the protein. Analysis of glycosylation sites showed that sFRP-1 contains a relatively large carbohydrate moiety on Asn(172) (similar to2.8 kDa), whereas Asn(262), the second potential N-linked glycosylation site, is not modified. No O-linked carbohydrate groups were detected. There was evidence of heterogeneous proteolytic processing at both the N and C termini of the recombinant protein. The predominant N terminus was Ser(31), although minor amounts of the protein with Asp(41) and Phe(50) as the N termini were observed. The major C-terminal processing event was removal of the terminal amino acid (Lys(313)) with only a trace amount of unprocessed protein detected. C1 Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. NCI, Canc Res Ctr, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Speicher, DW (reprint author), Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA. FU NCI NIH HHS [CA10815, CA74294] NR 58 TC 63 Z9 64 U1 0 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 FEB 15 PY 2002 VL 277 IS 7 BP 5134 EP 5144 DI 10.1074/jbc.M108533200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 523NX UT WOS:000173962900077 PM 11741940 ER PT J AU Park, SH Lee, SR Kim, BC Cho, EA Patel, SP Kang, HB Sausville, EA Nakanishi, O Trepel, JB Lee, BI Kim, SJ AF Park, SH Lee, SR Kim, BC Cho, EA Patel, SP Kang, HB Sausville, EA Nakanishi, O Trepel, JB Lee, BI Kim, SJ TI Transcriptional regulation of the transforming growth factor beta type II receptor gene by histone acetyltransferase and deacetylase is mediated by NF-Y in human breast cancer cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CCAAT-BINDING-FACTOR; TGF-BETA; MICROSATELLITE INSTABILITY; CHROMATIN STRUCTURE; DNA-BINDING; IN-VIVO; ACETYLATION; REPRESSION; PROMOTER; ACTIVATION AB Transcriptional repression of the transforming growth factor-beta (TGF-beta) type II receptor (TbetaRII) gene is one of several mechanisms leading to TGF-beta resistance. Previously, we have shown that MS-275, a synthetic inhibitor of histone deacetylase (HDAC), specifically induces the expression of the TbetaRII gene and restores the TGF-beta signaling in human breast cancer cell lines. However, little is known about the mechanism by which inhibition of HDAC activates TbetaRII expression. MS-275 treatment of cells expressing a wild-type TbetaRII promoter/luciferase construct resulted in a 10-fold induction of the promoter activity. DNA transfection and an electrophoretic mobility shift assay showed that the induction of the TbetaRII promoter by MS-275 requires the inverted CCAAT box and its cognate binding protein, NF-Y. In addition, a DNA affinity pull-down assay indicated that the PCAF protein, a transcriptional coactivator with intrinsic histone acetyltransferase (HAT) activity, is specifically recruited to the NF-Y complex in the presence of either MS-275 or trichostatin A. Based on these results, we suggest that treatment with the HDAC inhibitor induces TbetaRII promoter activity by the recruitment of the PCAF protein to the NF-Y complex, interacting with the inverted CCAAT box in the TbetaRII promoter. C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. Natl Canc Ctr, Div Basic Sci, Goyang Si 411764, Gyeongi Do, South Korea. Mitsui Pharmaceut, Chiba 2970017, Japan. RP Kim, SJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. NR 34 TC 67 Z9 70 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 FEB 15 PY 2002 VL 277 IS 7 BP 5168 EP 5174 DI 10.1074/jbc.M106451200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 523NX UT WOS:000173962900081 PM 11744689 ER PT J AU Kasai, T Iwanaga, Y Iha, H Jeang, KT AF Kasai, T Iwanaga, Y Iha, H Jeang, KT TI Prevalent loss of mitotic spindle checkpoint in adult T-cell leukemia confers resistance to microtubule inhibitors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN CANCERS; VIRUS TYPE-1; P53 FUNCTION; LUNG-CANCER; GENES; LYMPHOMA; MUTATIONS; MECHANISMS; APOPTOSIS; SURVIVAL AB Human T-cell leukemia virus type I (HTLV-I) is the causative agent for adult T-cell leukemia (ATL). Molecularly, ATL cells have extensive aneugenic abnormalities that occur, at least in part, from cell cycle dysregulation by the HTLV-I-encoded Tax oncoprotein. Here, we compared six HTLV-I-transformed cells to Jurkat and primary peripheral blood mononuclear cells (PBMC) in their responses to treatment with microtubule inhibitors. We found that both Jurkat and PBMCs arrested efficiently in mitosis when treated with nocodazole. By contrast, all six HTLV-I cells failed to arrest comparably in mitosis, suggesting that ATL cells have a defect in the mitotic spindle assembly checkpoint. Mechanistically, we observed that in HTLV-I Tax-expressing cells human spindle assembly checkpoint factors hsMAD1 and hsMAD2 were mislocated from the nucleus to the cytoplasm. This altered localization of hsMAD1 and hsMAD2 correlated with loss of mitotic checkpoint function and chemoresistance to microtubule inhibitors. C1 NIAID, Mol Microbiol Lab, Mol Virol Sect, NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIAID, Mol Microbiol Lab, Mol Virol Sect, NIH, Bldg 4,Rm 306,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Jeang, Kuan-Teh/A-2424-2008; OI Iha, Hidekatsu/0000-0002-0999-5636 NR 43 TC 94 Z9 97 U1 1 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 FEB 15 PY 2002 VL 277 IS 7 BP 5187 EP 5193 DI 10.1074/jbc.M110295200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 523NX UT WOS:000173962900083 PM 11729202 ER PT J AU Shen, X Sayer, JM Kroth, H Ponten, I O'Donnell, M Woodgate, R Jerina, DM Goodman, MF AF Shen, X Sayer, JM Kroth, H Ponten, I O'Donnell, M Woodgate, R Jerina, DM Goodman, MF TI Efficiency and accuracy of SOS-induced DNA polymerases replicating benzo[a]pyrene-7,8-diol 9,10-epoxide A and G adducts SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ESCHERICHIA-COLI; POL-II; BACTERIOPHAGE-LAMBDA; ADAPTIVE MUTATION; UV MUTAGENESIS; MOUSE HOMOLOGS; RECA PROTEIN; DAMAGE; GENE; PURIFICATION AB Nucleotide incorporation fidelity, mismatch extension, and translesion DNA synthesis efficiencies were determined using SOS-induced Escherichia coli DNA polymerases (pol) II, IV, and V to copy 10R and 10S isomers of trans-opened benzo[a]pyrene-7,8-diol 9,10-epoxide (BaP DE) A and G adducts. A-BaP DE adducts were bypassed by pol V with moderate accuracy and considerably higher efficiency than by pol II or IV. Error-prone pol V copied G-BaP DE-adducted DNA poorly, forming A(.)G-BaP DE-S and -R mismatches over C(.)G-BaP DE-S and -R correct matches by factors of similar to350- and 130-fold, respectively, even favoring G(.)G-BaP DE mismatches over correct matches by factors of 2-4-fold. In contrast, pol IV bypassed G-BaP DE adducts with the highest efficiency and fidelity, making misincorporations with a frequency of 10(-2) to 10(-4) depending on sequence context. G-BaP DE-S-adducted M13 DNA yielded 4-fold fewer plaques when transfected into SOS-induced DeltadinB (pol IV-deficient) mutant cells compared with the isogenic wild-type E. coli strain, consistent with the in vitro data showing that pol IV was most effective by far at copying the G-BaP DE-S adduct. SOS polymerases are adept at copying a variety of lesions, but the relative contribution of each SOS polymerase to copying damaged DNA appears to be determined by the lesion's identity. C1 Univ So Calif, Hedco Mol Biol Lab, Dept Biol Sci & Chem, Los Angeles, CA 90089 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, Chem Carcinogenesis Lab, Frederick, MD 21702 USA. Rockefeller Univ, New York, NY 10021 USA. Howard Hughes Med Inst, New York, NY 10021 USA. RP Goodman, MF (reprint author), Univ So Calif, Dept Biol Sci, SHS Rm 172,Univ Pk, Los Angeles, CA 90089 USA. FU NIGMS NIH HHS [GM21422, GM38839, GM42554] NR 58 TC 84 Z9 85 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 FEB 15 PY 2002 VL 277 IS 7 BP 5265 EP 5274 DI 10.1074/jbc.M109575200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 523NX UT WOS:000173962900092 PM 11734560 ER PT J AU Liang, WH Burnett, CB Rowland, JH Meropol, NJ Eggert, L Hwang, YT Silliman, RA Weeks, JC Mandelblatt, JS AF Liang, WH Burnett, CB Rowland, JH Meropol, NJ Eggert, L Hwang, YT Silliman, RA Weeks, JC Mandelblatt, JS TI Communication between physicians and older women with localized breast cancer: Implications for treatment and patient satisfaction SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RADIATION-THERAPY; CONSERVING SURGERY; DECISION-MAKING; AGE-DIFFERENCES; CARE; INFORMATION; MASTECTOMY; LUMPECTOMY; PREFERENCES; ATTITUDES AB Purpose: To identify factors associated with patient-physician communication and to examine the impact of communication on patients' perception of having a treatment choice, actual treatment received, and satisfaction with care among older breast cancer patients. Materials and Methods: Data were collected from 613 pairs of surgeons and their older (greater than or equal to 67 years) patients diagnosed with localized breast cancer. Measures of patients' self-reported communication included physician- and patient-initiated communication and the number of treatment options discussed. Logistic regression analyses were conducted to examine the relationships between communication and outcomes. Results: Patients who reported that their surgeons mentioned more treatment options were 2.21 times (95% confidence interval [CI], 1.62 to 3.01) more likely to report being given a treatment choice, and 1.33 times (95% CI, 1.02 to 1.73) more likely to get breast-conserving surgery with radiation than other types of treatment. Surgeons who were trained in surgical oncology, or who treated a high volume of breast cancer patients (greater than or equal to 75% of practice), were more likely to initiate communication with patients (odds ratio [OR] = 1.62; 95% CI, 1.02 to 2.56; and OR = 1.68; 95% CI, 1.01 to 2.76, respectively). A high degree of physician-initiated communication, in turn, was associated with patients' perception of having a treatment choice (OR = 2.46; 95% CI, 1.29 to 4.70), and satisfaction with breast cancer care (OR = 2.13; 95% CI, 1.17 to 3.85) in the 3 to 6 months after surgery. Conclusion: Greater patient-physician communication was associated with a sense of choice, actual treatment, and satisfaction with care. Technical information and caring components of communication impacted outcomes differently. Thus, the quality of cancer care for older breast cancer patients may be improved through interventions that improve communication within the physician-patient dyad. (C) 2002 by American Society of Clinical Oncology. C1 Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Med, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Sch Nursing, Washington, DC 20007 USA. NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. Fox Chase Canc Ctr, Div Med Sci, Philadelphia, PA 19111 USA. Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. Boston Univ, Med Ctr, Boston, MA USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Oncol, Boston, MA 02115 USA. RP Liang, WH (reprint author), Georgetown Univ, Med Ctr, Dept Oncol, 2233 Wisconsin Ave NW,Ste 440, Washington, DC 20007 USA. FU AHRQ HHS [HS08395] NR 44 TC 113 Z9 113 U1 1 U2 5 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 FEB 15 PY 2002 VL 20 IS 4 BP 1008 EP 1016 DI 10.1200/JCO.20.4.1008 PG 9 WC Oncology SC Oncology GA 522GZ UT WOS:000173889100021 PM 11844824 ER PT J AU Riemenschneider, WK Sidell, BD AF Riemenschneider, WK Sidell, BD TI Cold acclimation induces proliferation of sarcoplasmic reticulum without increase in Ca2+-ATPase activity in white axial muscle of striped bass (Morone saxatilis) SO JOURNAL OF EXPERIMENTAL ZOOLOGY LA English DT Article ID THERMAL-ACCLIMATION; TEMPERATURE-ACCLIMATION; MYOFIBRILLAR ATPASE; ANTARCTIC FISHES; SKELETAL-MUSCLE; CARP; DIFFUSION; ULTRASTRUCTURE; THAPSIGARGIN; CA-2+-ATPASE AB The effects of acclimation of striped bass to cold (5degreesC) and warm (25degreesC) temperatures upon ultrastructural features of white axial skeletal muscle are quantified. Surface density of sarcoplasmic reticulum (SR) increased by almost 30%, and SR volume density increased by about 20% during cold acclimation. Proliferation of SR suggests an increase in available SR surface for re-sequestration of Ca2+ and a decrease in diffusion path length for Ca2+ during cold acclimation. Average cross-sectional areas and cross-sectional perimeters of myofibrils situated in the center of muscle fibers decreased during cold acclimation by approximately 20% and 11%, respectively. Additionally, average major and minor axes of ellipses fit to central myofibrillar cross-sections decreased by approximately 12% and 8%, respectively, during cold acclimation. These measurements define a decrease in average myofibrillar diameter and suggest a decrease in diffusion path length for Ca2+, to and from myofibrillar activation sites. Measurements of peripheral myofibrils that had elongated profiles in cross-sections indicate that maximum profile length of these myofibrils decreases by about 17%. Peripheral myofibrils may break up into smaller myofibrils with more rounded cross-sectional profiles during cold acclimation. SR Ca2+-ATPase of white axial muscle was also measured in unfractionated homogenates and in crude SR-enriched subcellular fractions from cold-and warm-acclimated striped bass. No difference in SR Ca2+-ATPase activity per g wet weight was observed between cold- and warm-acclimated animals. Lack of increase in SR Ca2+-ATPase per g wet weight, despite a significant proliferation of SR, probably results in a decrease in average Ca2+-ATPase pump density within the SR membrane during cold acclimation. Thus, compensation for decreased diffusion coefficient of Ca2+ during cold acclimation appears due to the combined effects of proliferation of SR surface density and a decrease in average myofibrillar diameter. (C) 2002 Wiley-Liss, Inc. C1 Univ Maine, Sch Marine Sci, Orono, ME 04469 USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. RP Sidell, BD (reprint author), Univ Maine, Sch Marine Sci, 5751 Murray Hall,Rm 316, Orono, ME 04469 USA. NR 31 TC 4 Z9 4 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 0022-104X J9 J EXP ZOOL JI J. Exp. Zool. PD FEB 15 PY 2002 VL 292 IS 3 BP 231 EP 240 DI 10.1002/jez.10041 PG 10 WC Zoology SC Zoology GA 520FB UT WOS:000173769000003 PM 11857457 ER PT J AU Verthelyi, D Kenney, RT Seder, RA Gam, AA Friedag, B Klinman, DM AF Verthelyi, D Kenney, RT Seder, RA Gam, AA Friedag, B Klinman, DM TI CpG oligodeoxynucleotides as vaccine adjuvants in primates SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BACTERIAL-DNA; CUTANEOUS LEISHMANIASIS; IMMUNOSTIMULATORY DNA; IMMUNE-RESPONSES; B-CELL; MOTIFS; ACTIVATION; TRIGGER; INTERLEUKIN-12; ENHANCER AB Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs act as immune adjuvants in mice, boosting the humoral and cellular response to coadministered Ags. CpG ODN that stimulate human PBMC are only weakly active in mice. Thus, alternative animal models are needed to monitor the activity and safety of "human" CpG ODN in vivo. This work demonstrates that rhesus macaques recognize and respond to the same CpG motifs that trigger human immune cells. Coadministering CpG ODN with heat-killed Leishmania vaccine provided significantly increased protection of macaques against cutaneous Leishmania infection. These findings indicate that rhesus macaques provide a useful model for studying the in vivo activity of human CpG motifs, and that ODN expressing these motifs act as strong immune adjuvants. C1 US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Bacterial Parasit & Allergen Prod, Bethesda, MD 20892 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Klinman, DM (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bldg 29 A,Room 3 D 10, Bethesda, MD 20892 USA. NR 38 TC 132 Z9 141 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2002 VL 168 IS 4 BP 1659 EP 1663 PG 5 WC Immunology SC Immunology GA 520FU UT WOS:000173771000021 PM 11823494 ER PT J AU Shimozato, O Ortaldo, JR Komschlies, KL Young, HA AF Shimozato, O Ortaldo, JR Komschlies, KL Young, HA TI Impaired NK cell development in an IFN-gamma transgenic mouse: Aberrantly expressed IFN-gamma enhances hematopoietic stem cell apoptosis and affects NK cell differentiation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; MURINE BONE-MARROW; INTERFERON-GAMMA; PROGENITOR CELLS; FLT3 LIGAND; IN-VIVO; T-CELLS; B-CELLS; MICE; PROLIFERATION AB Aberrant expression of IFN-gamma has been demonstrated to cause a wide variety of alterations in cell function and development. Previously we reported that constitutive expression of IFN-gamma in bone marrow (BNI) and thymus results in a total absence of B cells and a substantial decrease in the number of hematopoietic progenitor cells. In this study, we demonstrate a severe deficiency of NK1.1(+)CD3(-) cells in this transgenic mouse model. Compared with normal control littermates, we found a pronounced reduction of NK cells in IFN-gamma transgenic mouse spleen and liver despite maintenance of normal function. In addition, we observed a reduced number of BNI cells in the IFN-gamma transgenic mouse despite normal expression of hematopoietic growth factors in the BM. Interestingly, these cells were less responsive to stem cell factor (SCF) despite e-kit expression on hematopoietic stern cells (HSCs). We observed that addition of exogenous IFN-gamma inhibited proliferation of HSCs and differentiation of NK precursors from HSCs in normal mice in response to SCF, IL-7,fins-like tyrosine kinase 3 ligand, and IL-15. Furthermore, we found that HSCs express the IFN-gammaRalpha subunit and undergo apoptosis in response to exogenous IFN-gamma. Thus, we have demonstrated the occurrence of a severe deficiency of NK cells and lower numbers of BNI cells in an IFN-gamma transgenic mouse model. Furthermore, because exogenous IFN-gamma affects the responsiveness to hematopoietic growth factors such as SCF in vitro, our results indicate that chronic expression of IFN-gamma in vivo leads to widespread immune system defects, including alterations in NK cell differentiation. C1 NCI, Expt Immunol Lab, Canc Res Ctr, Frederick, MD 21702 USA. NCI, Sci Applicat Int Corp Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. RP Young, HA (reprint author), NCI, Expt Immunol Lab, Canc Res Ctr, Bldg 560,Room 31-93, Frederick, MD 21702 USA. RI Young, Howard/A-6350-2008 OI Young, Howard/0000-0002-3118-5111 FU NCI NIH HHS [N01-CO-12400] NR 44 TC 17 Z9 17 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2002 VL 168 IS 4 BP 1746 EP 1752 PG 7 WC Immunology SC Immunology GA 520FU UT WOS:000173771000033 PM 11823506 ER PT J AU Santra, S Schmitz, JE Kuroda, MJ Lifton, MA Nickerson, CE Lord, CI Pal, R Franchini, G Letvin, NL AF Santra, S Schmitz, JE Kuroda, MJ Lifton, MA Nickerson, CE Lord, CI Pal, R Franchini, G Letvin, NL TI Recombinant canarypox vaccine-elicited CTL specific for dominant and subdominant simian immunodeficiency virus epitopes in rhesus monkeys SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; IMMUNE-RESPONSES; CELL RESPONSES; SERONEGATIVE ADULTS; INFECTION; VIREMIA; COMPLEX; HIV-1; AIDS; QUANTITATION AB Since virus-specific CTL play a central role in containing HIV replication, a candidate AIDS vaccine should generate virus-specific CTL responses. In this study, the ability of a recombinant canarypox virus expressing SIV Gag-Pol-Env (ALVAC/SIV gag-pol-env) was assessed for its ability to elicit both dominant and subdominant epitope-specific CTL responses in rhesus monkeys. Following a series of five immunizations, memory CTL responses specific for a dominant Gag epitope could be demonstrated in the peripheral blood of vaccinated monkeys. Memory CTL responses to a subdominant Pol epitope were undetectable in these animals. Following challenge with SIVmac251, the experimentally vaccinated animals developed high frequency CTL responses specific for the dominant Gag epitope that emerged in temporal association with the early containment of viral replication. Interestingly, the experimentally vaccinated, but not the control vaccinated animals, developed CTL responses to the subdominant Pol epitope that were detectable only after containment of early viremia. Thus, recombinant canarypox vaccination elicited low frequency, but durable memory CTL populations. The temporal association of the emergence of the dominant epitope-specific response with early viral containment following challenge suggests that this immune response played a role in the accelerated clearing of early viremia in these animals. The later emerging CTL response specific for the subdominant epitope may contribute to the control of viral replication in the setting of chronic infection. C1 Harvard Univ, Beth Israel Deaconess Med Ctr,Med Sch, Dept Med, Div Viral Pathogenesis, Boston, MA 02215 USA. Basic Res Lab, NCI, Bethesda, MD 20892 USA. Adv Biosci Labs, Kensington, MD 20895 USA. RP Letvin, NL (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr,Med Sch, Dept Med, Div Viral Pathogenesis, RE113 POB 15732, Boston, MA 02215 USA. FU NIAID NIH HHS [AI-26507, AI-85343, U01 AI026507, P01 AI026507] NR 40 TC 32 Z9 33 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2002 VL 168 IS 4 BP 1847 EP 1853 PG 7 WC Immunology SC Immunology GA 520FU UT WOS:000173771000045 PM 11823518 ER PT J AU Roberts, CW Roberts, F Lyons, RE Kirisits, MJ Mui, EJ Finnerty, J Johnson, JJ Ferguson, DJP Coggins, JR Krell, T Coombs, GH Milhous, WK Kyle, DE Tzipori, S Barnwell, J Dame, JB Carlton, J McLeod, R AF Roberts, CW Roberts, F Lyons, RE Kirisits, MJ Mui, EJ Finnerty, J Johnson, JJ Ferguson, DJP Coggins, JR Krell, T Coombs, GH Milhous, WK Kyle, DE Tzipori, S Barnwell, J Dame, JB Carlton, J McLeod, R TI The shikimate pathway and its branches in apicomplexan parasites SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Symposium on Insights on Infection and Immunity CY JAN 19, 2001 CL STANFORD UNIV MED CTR, FAIRCHILD AUDITORIUM, PALO ALTO, CALIFORNIA HO STANFORD UNIV MED CTR, FAIRCHILD AUDITORIUM ID 3-DEOXY-D-ARABINO-HEPTULOSONATE 7-PHOSPHATE SYNTHASE; ESCHERICHIA-COLI K-12; 5-ENOLPYRUVYLSHIKIMATE 3-PHOSPHATE SYNTHASE; SACCHAROMYCES-CEREVISIAE; PLASMODIUM-FALCIPARUM; CHORISMATE SYNTHASE; HERBICIDE GLYPHOSATE; TOXOPLASMA-GONDII; EUGLENA-GRACILIS; EPSP SYNTHASE AB The shikimate pathway is essential for production of a plethora of aromatic compounds in plants, bacteria, and fungi. Seven enzymes of the shikimate pathway catalyze sequential conversion of erythrose 4-phosphate and phosphoenol pyruvate to chorismate. Chorismate is then used as a substrate for other pathways that culminate in production of folates, ubiquinone, napthoquinones, and the aromatic amino acids tryptophan, phenylalanine, and tyrosine. The shikimate pathway is absent from animals and present in the apicomplexan parasites Toxoplasma gondii, Plasmodium falciparum, and Cryptosporidium parvum. Inhibition of the pathway by glyphosate is effective in controlling growth of these parasites. These findings emphasize the potential benefits of developing additional effective inhibitors of the shikimate pathway. Such inhibitors may function as broad-spectrum antimicrobial agents that are effective against bacterial and fungal pathogens and apicomplexan parasites. C1 Univ Chicago, Ctr Visual Sci, Dept Ophthalmol, Chicago, IL 60637 USA. Univ Strathclyde, Dept Immunol, Glasgow, Lanark, Scotland. Victoria Infirm, Dept Pathol, Glasgow G42 9TY, Lanark, Scotland. Univ Glasgow, Inst Biomed & Life Sci, Div Biochem & Mol Biol, Glasgow, Lanark, Scotland. Univ Oxford, John Radcliffe Hosp, Nuffield Dept Pathol, Oxford OX3 9DU, England. Univ Chicago, Dept Visual Sci, Chicago, IL 60637 USA. Univ Chicago, Dept Med, Chicago, IL 60637 USA. Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. Univ Chicago, Comm Genet, Chicago, IL 60637 USA. Univ Chicago, Comm Immunol, Chicago, IL 60637 USA. Michael Reese Hosp, Dept Med, Chicago, IL USA. Boston Univ, Dept Biol, Boston, MA 02215 USA. Tufts Univ, Sch Vet Med, Boston, MA 02111 USA. Walter Reed Army Inst Res, Div Expt Therapeut, Washington, DC USA. NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Dept Parasit Dis, Chamblee, GA USA. Univ Florida, Sch Vet Med, Gainesville, FL USA. RP McLeod, R (reprint author), Univ Chicago, Ctr Visual Sci, Dept Ophthalmol, AMBH S206,5841 S Maryland, Chicago, IL 60637 USA. RI Roberts, Craig/B-8016-2008; Lyons, Russell/A-7051-2011; Russell, Lyons/H-7942-2013 OI Roberts, Craig/0000-0002-0653-835X; Russell, Lyons/0000-0002-0795-7994 FU NIAID NIH HHS [AI-44328] NR 105 TC 80 Z9 85 U1 1 U2 8 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 FEB 15 PY 2002 VL 185 SU 1 BP S25 EP S36 DI 10.1086/338004 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 517FP UT WOS:000173600700005 PM 11865437 ER PT J AU Hampel, H Teipel, SJ Bayer, W Alexander, GE Schwarz, R Schapiro, MB Rapoport, SI Moller, HJ AF Hampel, H Teipel, SJ Bayer, W Alexander, GE Schwarz, R Schapiro, MB Rapoport, SI Moller, HJ TI Age transformation of combined hippocampus and amygdala volume improves diagnostic accuracy in Alzheimer's disease SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Alzheimer's disease; diagnosis; hippocampus; magnetic resonance imaging; discriminant analysis; ROC analysis; age-transformation ID TEMPORAL-LOBE; ATROPHY; MRI; DEMENTIA AB Objective: The specificity of magnetic resonance imaging (MRI)-based hippocampal measurements in detecting Alzheimer's disease (AD) pathology is reduced by an age-related reduction of the hippocampus volume. We propose an adjustment for this age effect to increase the diagnostic accuracy of hippocampal volumes in AD. Method: Using an orthogonal rotational transformation of the coordinate system, values of MRI-determined volumes of hippocampus-amygdala formation (HAF) were transformed according to the age effect in 27 AD patients and 28 age- and sex-matched healthy control subjects. Results: The age transformation increased the diagnostic accuracy of HAF volumes in the study sample and in an independent sample from the literature. The age-transformed HAF volume predicted AD in a subject with mild cognitive impairment (MCI) with later biopsy-confirmed AD. Conclusion: Age transformation may provide an easily applicable method to increase the clinical diagnostic accuracy of hippocampal measurements by considering the effect of aging on hippocampus volume. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Munich, Dept Psychiat, Mem Clin, Dementia Res & Neuroimaging Sect, D-80336 Munich, Germany. Arizona State Univ, Arizona Alzheimers Res Ctr, Tempe, AZ 85287 USA. Arizona State Univ, Dept Psychol, Tempe, AZ 85287 USA. Childrens Hosp, Med Ctr, Dept Pediat Neurol, Cincinnati, OH 45229 USA. NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Hampel, H (reprint author), Univ Munich, Dept Psychiat, Mem Clin, Dementia Res & Neuroimaging Sect, Nussbaumstr 7, D-80336 Munich, Germany. NR 17 TC 31 Z9 36 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD FEB 15 PY 2002 VL 194 IS 1 BP 15 EP 19 DI 10.1016/S0022-510X(01)00669-4 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 519UM UT WOS:000173743900004 PM 11809161 ER PT J AU Breslin, MB Zhu, M Notkins, AL Lan, MS AF Breslin, MB Zhu, M Notkins, AL Lan, MS TI Neuroendocrine differentiation factor, IA-1, is a transcriptional repressor and contains a specific DNA-binding domain: identification of consensus IA-1 binding sequence SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ZINC-FINGER PROTEIN; BETA-CELLS; ISLET DEVELOPMENT; MICE LACKING; ALPHA-CELLS; PANCREAS; GENE; NEUROGENIN3; EXPRESSION; AGENESIS AB A novel cDNA, insulinoma-associated antigen-1 (IA-1), containing five zinc-finger DNA-binding motifs, was isolated from a human insulinoma subtraction library. IA-1 expression is restricted to fetal but not adult pancreatic and brain tissues as well as tumors of neuroendocrine origin. Using various GAL4 DNA binding domain (DBD)/1A-1 fusion protein constructs, we demonstrated that IA-1 functions as a transcriptional repressor and that the region between amino acids 168 and 263 contains the majority of the repressor activity. Using a selected and amplified random oligonucleotide binding assay and bacterially expressed GST-IA-1DBD fusion protein (257-510 a.a.), we identified the consensus IA-1 binding sequence, T-G/(C)(T)/(C)(T)/(T)(T)/(A)GGGG(G)/C-T(G)/(A). Further experiments showed that zinc-fingers 2 and 3 of IA-1 are sufficient to demonstrate transcriptional activity using an IA-1 consensus site containing a reporter construct. A database search with the consensus IA-1 binding sequence revealed target sites in a number of pancreas- and brain-specific genes consistent with its restricted expression pattern. The most significant matches were for the 5'-flanking regions of IA-1 and NeuroD/beta2 genes. Co-transfection of cells with either the full-length IA-1 or hEgr-1AD/IA-1DBD construct and IA-1 or NeuroD/beta2 promoter/CAT construct modulated CAT activity. These findings suggest that the IA-1 protein may be auto-regulated and play a role in pancreas and neuronal development, specifically in the regulation of the NeuroD/beta2 gene. C1 Louisiana State Univ, Hlth Sci Ctr, Dept Pediat, Childrens Hosp,Res Inst Children, New Orleans, LA 70112 USA. Louisiana State Univ, Hlth Sci Ctr, Dept Genet, Childrens Hosp,Res Inst Children, New Orleans, LA 70112 USA. Natl Inst Dent & Craniofacial Res, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Lan, MS (reprint author), Childrens Hosp, Res Inst Children, Res & Educ Bldg,Room 2211,200 Henry Clay Ave, New Orleans, LA 70118 USA. NR 36 TC 48 Z9 50 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB 15 PY 2002 VL 30 IS 4 BP 1038 EP 1045 DI 10.1093/nar/30.4.1038 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 524TU UT WOS:000174029600021 PM 11842116 ER PT J AU Sham, YY Ma, BY Tsai, CJ Nussinov, R AF Sham, YY Ma, BY Tsai, CJ Nussinov, R TI Thermal unfolding molecular dynamics simulation of Escherichia coli dihydrofolate reductase: Thermal stability of protein domains and unfolding pathway SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE protein folding; protein stability; dihydrofolate reductase; folding pathway; temperature-induced unfolding simulation ID SUBSTRATE BINDING; TRANSITION-STATE; FOLDING UNITS; ENERGY; MODEL; INTERMEDIATE; SPECTROSCOPY; RECOGNITION; MECHANISM; CATALYSIS AB Temperature-induced unfolding of Escherichia coli dihydrofolate reductase was carried out by using molecular dynamic simulations. The simulations show that the unfolding generally involves an initial end-to-end collapse of the adenine binding domain into partially extended loops, followed by a gradual breakdown of the remaining beta-sheet core structure. The core, which consists of beta-strands 5-7, was observed to be the most resistant to thermal unfolding. This region, which is made up of part of the N-terminus domain and part of the large domain of the E. coli dihydrofolate reductase, may constitute the nucleation site for protein folding and may be important for the eventual formation of both domains. The unfolding of different domains at different stages of the unfolding process suggests that protein domains vary in stability and that the rate at which they unfold can affect the overall outcome of the unfolding pathway. This observation is compared with the recently proposed hierarchical folding model. Finally, the results of the simulation were found to be consistent with a previous experimental study (Frieden, Proc Natl Acad Sci USA 1990;87:4413-4416) which showed that the folding process of E. coli dihydrofolate reductase involves sequential formation of the substrate-binding sites. (C) 2002 Wiley-Liss, Inc. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Dept Human Genet, Sackler Inst Mol Med, Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, Bldg 469,Rm 151, Frederick, MD 21702 USA. RI Sham, Yuk/A-6472-2011; Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU NCI NIH HHS [N01-CO-56000] NR 48 TC 32 Z9 34 U1 1 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-3585 J9 PROTEINS JI Proteins PD FEB 15 PY 2002 VL 46 IS 3 BP 308 EP 320 DI 10.1002/prot.10040 PG 13 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 518CE UT WOS:000173648400008 PM 11835506 ER PT J AU Willis, MW Ketter, TA Kimbrell, TA George, MS Herscovitch, P Danielson, AL Benson, BE Post, RM AF Willis, MW Ketter, TA Kimbrell, TA George, MS Herscovitch, P Danielson, AL Benson, BE Post, RM TI Age, sex and laterality effects on cerebral glucose metabolism in healthy adults SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE positron emission tomography (PET); normal aging; sex differences; laterality; asymmetry ID POSITRON EMISSION TOMOGRAPHY; GENDER DIFFERENCES; NORMAL MALES; BRAIN; RATES; PET; FDG; HYPOMETABOLISM; VOLUNTEERS; DISORDERS AB Normal cerebral glucose metabolism (CMRglc) was assessed with positron emission tomography in 66 healthy adults (28 women, 38 men; mean age 39, range 20-69 years) to determine effects of age, sex and laterality on CMRglc using statistical parametric mapping. Significant age-related decreases in global metabolism (gCMRglc) were noted in the entire sample and in both sexes, as well as widespread and bilateral decreases in cortical absolute regional metabolism (rCMRglc) and more focal anterior paralimbic normalized rCMRglc. However, significant positive correlations of age with normalized rCMRglc were observed in cerebellum, thalamus and occipital areas. Although the declines in gCMRglc and rCMRglc with age did not significantly differ between sexes, men compared with women had significantly lower gCMRglc and widespread decreased cortical and subcortical absolute rCMRglc. In the entire sample, and similarly in both sexes, left greater than right asymmetry was observed in medial frontal gyrus, posterior thalamus, lingual gyrus, cuneus and superior cingulate. The opposite laterality appeared in mesio-anterior cerebellum, and lateral frontal and temporal regions. Few regions showed significant interactions of metabolic laterality with either age or sex. These findings contribute toward a convergence in the literature, and the regression models of CMRglc vs. age serve as a normative database to which patients may be compared. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Univ Arkansas Med Sci, Little Rock, AR 72205 USA. Med Univ S Carolina, Charleston, SC 29425 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Willis, MW (reprint author), NIMH, Biol Psychiat Branch, 10 Ctr Dr MSC-1272, Bethesda, MD 20892 USA. NR 45 TC 76 Z9 80 U1 1 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD FEB 15 PY 2002 VL 114 IS 1 BP 23 EP 37 AR PII S0925-4927(01)00126-3 DI 10.1016/S0925-4927(01)00126-3 PG 15 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 530GE UT WOS:000174349300003 PM 11864807 ER PT J AU Ramakrishna, G Perella, C Birely, L Diwan, BA Fornwald, LW Anderson, LM AF Ramakrishna, G Perella, C Birely, L Diwan, BA Fornwald, LW Anderson, LM TI Decrease in K-ras p21 and increase in Raf1 and activated Erk 1 and 2 in murine lung tumors initiated by N-nitrosodimethylamine and promoted by 2,3,7,8-tetrachlorodibenzo-p-dioxin SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE lung tumor; tumor promotion; K-ras; raf; erk; N-nitrosodimethylamine; TCDD; macrophage; PCNA ID EPIDERMAL GROWTH-FACTOR; PROTEIN-PHOSPHORYLATION PATHWAY; ALVEOLAR MACROPHAGES; EPITHELIAL-CELLS; FACTOR RECEPTOR; AH-RECEPTOR; TRANSFORMING GROWTH-FACTOR-BETA-1; CANCER CELLS; CELLULAR SRC; II RECEPTOR AB Recent evidence suggests that K-ras protooncogene protein p21 may have a tumor-suppressive role in the context of development of lung adenocarcinoma. Levels of K-ras p21, raf-1, mitogen-activated protein kinases Erk 1 and 2, the phosphorylated-activated forms of Erk 1 and 2 (Erk 1P and 2P), and proliferating cell nuclear antigen (PCNA) were measured by immoblotting in mouse lung tumors (5 to 9 mm in size) caused by N-nitrosodimethylamine (NDMA) and in control lungs. In tumors compared with normal lung, cell membrane-associated K-ras p21 was significantly decreased and cytosolic K-ras p21 increased. Total, membrane, and cytosolic raf-1 and Erk 1P and 2P were increased in tumors compared with normal lung. A single dose of 5 nmol/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) given after NDMA resulted in a significant 2.4-fold increase in tumor multiplicity. A significantly greater decrease in membrane-associated K-ras p21 and increase in total and membrane associated raf-1 occurred in the NDMA/TCDD tumors compared with the NDMA- only tumors. PCNA levels increased in tumors, a finding confirmed by immunohistochemistry, and correlated with tumor size after NDMA/TCDD treatment but not after NDMA only. The increase in raf-1 in the tumors was confirmed by immunohistochemistry, which also revealed an increase in raf-1-positive alveolar macrophages specifically associating with tumors from the earliest stages. These results suggest a possible tumor-suppressive function for K-ras p21 in lung and a positive role for raf-1 and Erk 1/2 in lung tumorigenesis. TCDD may promote tumors by contributing to downregulation of K-ras and stimulation of raf-1. (C) 2002 Elsevier Science (USA). C1 NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. SAIC Frederick Inc, Frederick, MD 21702 USA. RP Anderson, LM (reprint author), NCI, Comparat Carcinogenesis Lab, Bldg 538, Frederick, MD 21702 USA. NR 54 TC 25 Z9 26 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD FEB 15 PY 2002 VL 179 IS 1 BP 21 EP 34 DI 10.1006/taap.2001.9344 PG 14 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 532LX UT WOS:000174477700003 PM 11884234 ER PT J AU Raviv, Y Viard, M Bess, J Blumenthal, R AF Raviv, Y Viard, M Bess, J Blumenthal, R TI Quantitative measurement of fusion of HIV-1 and SIV with cultured cells using photosensitized labeling SO VIROLOGY LA English DT Article DE HIV; SIV; viral entry; membrane fusion; fluorescence; photolabeling; gp120; gp41; gp32 ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENVELOPE GLYCOPROTEIN; BIOLOGICAL-MEMBRANES; INFLUENZA HEMAGGLUTININ; CONFORMATIONAL-CHANGES; SYNTHETIC PEPTIDE; 6-HELIX BUNDLE; GP41; PROTEINS; ENTRY AB The fusion of HIV and SIV with biological membranes was studied by photosensitized activation of a hydrophobic probe, [(125)I]iodonaphthylazide ([(125)I]INA), by a fluorescent lipid which is situated in the target membrane. Photosensitized labeling of viral envelope-resident proteins occurs only upon their insertion into target membranes. Photosensitized labeling as a result of HIV-1 Env-mediated cell fusion showed the same kinetics as aqueous dye transfer. We have for the first time measured kinetics of HIV and SIV virus-cell fusion. HIV-1(MN) virions were about 10X less fusion active than SIVmne virions. SIV inactivated by aldrithiol-2 retained fusion activity similar to that seen with untreated virus. The relatively slow time course of SIV-cell fusion (t(1/2) = 19 min) indicates that the fusion events are stochastic. This feature provides a basis for understanding the mode of action of HIV/SIV entry inhibitors that target transition states. (C) 2002 Elsevier Science (USA). C1 NCI, Canc Res Ctr, Lab Expt & Computat Biol, Frederick, MD 21702 USA. Intramural Res Support Program, Ft Detrick, MD 21702 USA. SAIC, Aids Vaccine Program, Ft Detrick, MD 21702 USA. RP Blumenthal, R (reprint author), NCI, Canc Res Ctr, Lab Expt & Computat Biol, POB B,Bldg 469,Room 216A,Miller Dr, Frederick, MD 21702 USA. EM blumen@helix.nih.gov RI Bess, Jr., Julian/B-5343-2012 FU NCI NIH HHS [N01-CO-56000] NR 43 TC 29 Z9 29 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB 15 PY 2002 VL 293 IS 2 BP 243 EP 251 DI 10.1006/viro.2001.1237 PG 9 WC Virology SC Virology GA 530UV UT WOS:000174378100006 PM 11886244 ER PT J AU Poon, DTK Chertova, EN Ott, DE AF Poon, DTK Chertova, EN Ott, DE TI Human immunodeficiency virus type 1 preferentially encapsidates genomic RNAs that encode Pr55(Gag): Functional linkage between translation and RNA packaging SO VIROLOGY LA English DT Article ID NUCLEOCAPSID PROTEIN; IN-VIVO; SIGNAL; GAG; MYRISTOYLATION; RECOGNITION; INFECTIVITY; VECTORS; MUTANT; DOMAIN AB Full-length retroviral RNA serves as both messenger and genomic RNA. Therefore, an unspliced RNA could play both roles: viral mRNA could be bound in cis by the same Gag polyprotein that it produced, becoming a packaged genomic RNA. To test this possibility we used in vivo packaging experiments which coexpressed wild-type NL4-3 RNA and NL4-3-based mutant RNA that, ideally, could not translate Gag. However, mutating the gag initiator produced a mutant (pNLX) that expressed a truncated Gag, Gag*, initiated at methionine 10 in the CA region (142 of Pr55(Gag)). Gag* can be rescued into virions by Gag and, as it contains the NC domain, could package RNA in cis. To eliminate NC and the CA dimerization domain, a nonsense mutation in CA at residue 99 was introduced into pNLX to produce pNLXX, which expresses an RNA that should only be packaged in trans. Cotransfection packaging experiments revealed that wild-type genomic RNA was packaged at an 8-fold greater level than NLXX RNA given equal expression of both RNAs. Experiments that varied the relative amounts of these RNAs in the cell found that the wild-type RNA was encapsidated with a packaging preference (i,e., the relative amount of this RNA in virions versus cells) of 6- to 13-fold over the NLXX RNA, showing that the NLXX RNA did not efficiently compete with NL4-3 RNA, These data suggest that the wild-type RNA's ability to express Pr55(Gag) and, by inference, actively translate Gag confers an advantage in packaging over the nearly identical NLXX RNA. In contrast, the NLX RNA competed with wild-type RNA at a 1-to-3 preference. This ratio is similar to the amounts of Gag* rescued by Gag, suggesting that the presence of Gag* assists in the encapsidation of NLX RNA. Together, our data link translation and particle formation to the packaging of viral RNA and support a model of cis packaging where nascent Gag proteins encapsidate their cognate RNA. (C) 2002 Elsevier Science (USA). C1 NCI, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21702 USA. RP Ott, DE (reprint author), NCI, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO56000] NR 40 TC 44 Z9 44 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB 15 PY 2002 VL 293 IS 2 BP 368 EP 378 DI 10.1006/viro.2001.1283 PG 11 WC Virology SC Virology GA 530UV UT WOS:000174378100019 PM 11886257 ER PT J AU Rabow, AA Shoemaker, RH Sausville, EA Covell, DG AF Rabow, AA Shoemaker, RH Sausville, EA Covell, DG TI Mining the National Cancer Institute's tumor-screening database: Identification of compounds with similar cellular activities SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Review ID PROTEIN-KINASE-C; GENE-EXPRESSION DATA; ANTICANCER DRUG SCREEN; SELF-ORGANIZING MAPS; DOWN-REGULATION; MOLECULAR PHARMACOLOGY; ELLIPTICINE ANALOGS; EPITHELIAL-CELLS; CLUSTER-ANALYSIS; HIGH-THROUGHPUT AB In an effort to enhance access to information available in the National Cancer Institute's (NCI) anticancer drug-screening database, a new suite of Internet accessible (http://spheroid.ncifcrf.gov) computational tools has been assembled for self-organizing map-based (SOM) cluster analysis and data visualization. A range of analysis questions were initially addressed to evaluate improvements in SOM cluster quality based on the data-conditioning procedures of Z-score normalization, capping, and treatment of missing data as well as completeness of drug cell-screening data. These studies established a foundation for SOM cluster analysis of the complete set of NCIs publicly available antitumor drug-screening data. This analysis identified relationships between chemotypes of screened agents and their effect on four major classes of cellular activities: mitosis, nucleic acid synthesis, membrane transport and integrity, and phosphatase- and kinase-mediated cell cycle regulation. Validations of these cellular activities, obtained from literature sources, found (i) strong evidence supporting within cluster memberships and shared cellular activity, (ii) indications of compound selectivity between various types of cellular activity, and (iii) strengths and weaknesses of the NCI's antitumor drug screen data for assigning compounds to these classes of cellular activity. Subsequent analyses of averaged responses within these tumor panel types find a strong dependence on chemotype for coherence among cellular response patterns. The advantages of a global analysis of the complete screening data set are discussed. C1 NCI, Sci Applicat Int Corp, NIH, DCTD, Frederick, MD 21702 USA. NCI, Dev Therapeut Program, NIH, DCTD, Frederick, MD 21702 USA. RP Rabow, AA (reprint author), NCI, Sci Applicat Int Corp, NIH, DCTD, Frederick, MD 21702 USA. NR 113 TC 98 Z9 104 U1 2 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD FEB 14 PY 2002 VL 45 IS 4 BP 818 EP 840 DI 10.1021/jm010385b PG 23 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 523YN UT WOS:000173985300008 PM 11831894 ER PT J AU Rong, SB Enyedy, IJ Qiao, LX Zhao, LY Ma, DW Pearce, LL Lorenzo, PS Stone, JC Blumberg, PM Wang, SM Kozikowski, AP AF Rong, SB Enyedy, IJ Qiao, LX Zhao, LY Ma, DW Pearce, LL Lorenzo, PS Stone, JC Blumberg, PM Wang, SM Kozikowski, AP TI Structural basis of RasGRP binding to high-affinity PKC ligands SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; GTPASE-ACTIVATING PROTEIN; SITE-DIRECTED MUTAGENESIS; PHORBOL ESTER RECEPTORS; CYSTEINE-RICH DOMAIN; CAENORHABDITIS-ELEGANS; TUMOR PROMOTERS; ENERGY FUNCTION; INDOLACTAM-V; N-CHIMAERIN AB The Ras guanyl releasing protein RasGRP belongs to the CDC25 class of guanyl nucleotide exchange factors that regulate Ras-related GTPases. These GTPases serve as switches for the propagation and divergence of signaling pathways. One interesting feature of RasGRP is the presence of a C-terminal C1 domain, which has high homology to the PKC C1 domain and binds to diacylglycerol (DAG) and phorbol esters. RasGRP thus represents a novel, non-kinase phorbol ester receptor. In this paper, we investigate the binding of indolactam(V) (ILV), 7-(n-octyl)-ILV, 8-(1-decynyl)benzolactam(V) (benzolactam), and 7-methoxy-8-(1-decynyl)benzolactam(V) (methoxylated benzolactam) to RasGRP through both experimental binding assays and molecular modeling studies. The binding affinities of these lactams to RasGRP are within the nanomolar range. Homology modeling was used to model the structure of the RasGRP C1 domain (C1-RasGRP), which was subsequently used to model the structures of C1-RasGRP in complex with these ligands and phorbol 13-acetate using a computational docking method. The structural model of C1-RasGRP exhibits a folding pattern that is nearly identical to that of C1b-PKCdelta and is comprised of three antiparallel-strand beta-sheets capped against a C-terminal alpha-helix. Two loops A and B comprising residues 8-12 and 21-27 form a binding pocket that has some positive charge character. The ligands phorbol 13-acetate, benzolactam, and ILV are recognized by C1-RasGRP through a number of hydrogen bonds with loops A and B. In the models of C1-RasGRP in complex with phorbol 13-acetate, benzolactam, and ILV, common hydrogen bonds are formed with two residues Thr12 and Leu21, whereas other hydrogen bond interactions are unique for each ligand. Furthermore, our modeling results suggest that the shallower insertion of ligands into the binding pocket of C1-RasGRP compared to C1b-PKCdelta may be due to the presence of Phe rather than Leu at position 20 in C1-RasGRP. Taken together, our experimental and modeling studies provide us with a better understanding of the structural basis of the binding of PKC ligands to the novel phorbol ester receptor RasGRP. C1 Georgetown Univ, Med Ctr, Dept Neurol, Drug Discovery Program, Washington, DC 20007 USA. NCI, Mol Mech Tumor Promot Sect, Bethesda, MD 20892 USA. Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Bioorgan & Nat Chem 123, Shanghai 200032, Peoples R China. Univ Alberta, Dept Biochem, Edmonton, AB T6G 2H7, Canada. RP Kozikowski, AP (reprint author), Georgetown Univ, Med Ctr, Dept Neurol, Drug Discovery Program, Washington, DC 20007 USA. RI Wang, Shaomeng/E-9686-2010 FU NCI NIH HHS [CA 79601] NR 60 TC 20 Z9 20 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD FEB 14 PY 2002 VL 45 IS 4 BP 853 EP 860 DI 10.1021/jm010422z PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 523YN UT WOS:000173985300010 PM 11831896 ER PT J AU Fisahn, A Yamada, M Duttaroy, A Gan, JW Deng, CX McBain, CJ Wess, J AF Fisahn, A Yamada, M Duttaroy, A Gan, JW Deng, CX McBain, CJ Wess, J TI Muscarinic induction of hippocampal gamma oscillations requires coupling of the M1 receptor to two mixed cation currents SO NEURON LA English DT Article ID HYPERPOLARIZATION-ACTIVATED CURRENTS; VOLTAGE-CLAMP ANALYSIS; CURRENT I-H; CHOLINERGIC INNERVATION; NETWORK OSCILLATIONS; ALZHEIMERS-DISEASE; RAT HIPPOCAMPUS; KNOCKOUT MICE; NEURONS; CELLS AB Oscillatory network activity at gamma frequencies is assumed to be of major importance in cortical information processing. Whereas the synaptic mechanisms of gamma oscillations have been studied in detail, the ionic currents involved at the cellular level remain to be elucidated. Here we show that in vitro gamma oscillations induced by muscarine require activation of M1 receptors on hippocampal CA3 pyramidal neurons and are absent in M1 receptor-deficient mice. M1 receptor activation depolarizes pyramidal neurons by increasing the mixed Na+/K+ current I-h and the Ca2+-dependent nonspecific cation current I-cat, but not by modulation of I-M. Our data provide important insight into the molecular basis of gamma oscillations by unequivocally establishing a novel role for muscarinic modulation Of I-h and I-cat in rhythmic network activity. C1 NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Biochem & Metab Lab, NIH, Bethesda, MD 20892 USA. RP McBain, CJ (reprint author), NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 47 TC 156 Z9 160 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD FEB 14 PY 2002 VL 33 IS 4 BP 615 EP 624 DI 10.1016/S0896-6273(02)00587-1 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 522RQ UT WOS:000173911100013 PM 11856534 ER PT J AU Shinefield, H Black, S Fattom, A Horwith, G Rasgon, S Ordonez, J Yeoh, H Law, D Robbins, JB Schneerson, R Muenz, L Naso, R AF Shinefield, H Black, S Fattom, A Horwith, G Rasgon, S Ordonez, J Yeoh, H Law, D Robbins, JB Schneerson, R Muenz, L Naso, R TI Use of a Staphylococcus aureus conjugate vaccine in patients receiving hemodialysis. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RECOMBINANT EXOPROTEIN-A; CAPSULAR POLYSACCHARIDES; ANTIBODIES; INFECTIONS; IMMUNOGENICITY; BACTEREMIA; TYPE-5; MICE AB Background: In patients with decreased resistance to infection, Staphylococcus aureus is a major cause of bacteremia and its complications. The capsular polysaccharides are essential for the pathogenesis of and immunity to S. aureus infection and are targets for vaccines. Methods: In a double-blind trial involving patients with end-stage renal disease who were receiving hemodialysis, we evaluated the safety, immunogenicity, and efficacy of a vaccine with S. aureus type 5 and 8 capsular polysaccharides conjugated to nontoxic recombinant Pseudomonas aeruginosa exotoxin A. Between April 1998 and August 1999, 1804 adult patients at 73 hemodialysis centers were randomly assigned to receive a single intramuscular injection of either vaccine or saline. IgG antibodies to S. aureus type 5 and 8 capsular polysaccharides were measured for up to two years, and episodes of S. aureus bacteremia were recorded. Efficacy was estimated by comparing the incidence of S. aureus bacteremia in the patients who received the vaccine with the incidence in the control patients. Results: Reactions to the vaccine were generally mild to moderate, and most resolved within two days. The capsular polysaccharides elicited an antibody response of at least 80 microg per milliliter (the estimated minimal level conferring protection) in 80 percent of patients for type 5 and in 75 percent of patients for type 8. The efficacy during weeks 3 to 54 was only 26 percent (P=0.23). However, between weeks 3 and 40 after vaccination, S. aureus bacteremia developed in 11 of 892 patients in the vaccine group who could be evaluated for bacteremia, as compared with 26 of 906 patients in the control group (estimate of efficacy, 57 percent; 95 percent confidence interval, 10 to 81 percent; nominal P=0.02). Conclusions: In patients receiving hemodialysis, a conjugate vaccine can confer partial immunity against S. aureus bacteremia for approximately 40 weeks, after which protection wanes as antibody levels decrease. (N Engl J Med 2002;346:491-6.) Copyright (C) 2002 Massachusetts Medical Society. C1 Kaiser Permanente Vaccine Study Ctr, Oakland, CA 94612 USA. Nabi, Rockville, MD USA. So Calif Kaiser Permanente, Los Angeles, CA USA. NICHHD, Bethesda, MD 20892 USA. Larry Muenz & Associates, Rockville, MD USA. Total Renal Res, Minneapolis, MN USA. RP Shinefield, H (reprint author), Kaiser Permanente Vaccine Study Ctr, 1 Kaiser Plaza,16th Fl, Oakland, CA 94612 USA. NR 29 TC 281 Z9 291 U1 0 U2 13 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 FEB 14 PY 2002 VL 346 IS 7 BP 491 EP 496 DI 10.1056/NEJMoa011297 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 521AE UT WOS:000173815300005 PM 11844850 ER PT J AU Vortmeyer, A Huang, SC Pack, SD Koch, CA Lubensky, IA Oldfield, EH Zhuang, ZP AF Vortmeyer, A Huang, SC Pack, SD Koch, CA Lubensky, IA Oldfield, EH Zhuang, ZP TI Somatic point mutation of the wild-type allele detected in tumors of patients with VHL germline deletion SO ONCOGENE LA English DT Article DE VHL disease; VHL gene; mutation; deletion ID VONHIPPEL-LINDAU DISEASE; SUPPRESSOR GENE; CARCINOMA AB The majority of patients with Von Hippel-Lindau (VHL) disease are affected by a VHL germline mutation involving one copy of the VHL gene. Loss of heterozygosity of the second VHL allele can be consistently demonstrated in tumor tissue from these patients, suggesting that allelic deletion is a very early or even initiating event for tumorigenesis. Approximately 20% of VHL disease patients, however, exhibit germline deletion of one entire copy or at least a substantial part of the VHL gene. To investigate the nature of the 'second genetic hit' in this patient population, we analysed two renal cell carcinomas and one CNS hemangioblastoma from three unrelated patients for genetic changes of the second copy of the VHL gene. All three tumors showed retention of one VHL allele by FISH. Single-strand conformation polymorphism and mutation analysis of microdissected tumor DNA revealed somatic point mutations of the wild-type VHL copies in each of the three tumors. The results indicate that the 'two hit model' is equally applicable to patients with VHL germline mutation and VHL germline deletion. In contrast to tumors from patients with VHL germline mutation, however, point mutations of the wild-type allele can be detected in tumors from patients with VHL germline deletion. C1 NINCDS, Surg Neurol Branch, Mol Pathogenesis Unit, Bethesda, MD 20892 USA. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Zhuang, ZP (reprint author), NINCDS, Surg Neurol Branch, Mol Pathogenesis Unit, Bldg 10,Room 5D37, Bethesda, MD 20892 USA. RI Koch, Christian/A-4699-2008; Pack, Svetlana/C-2020-2014; OI Koch, Christian/0000-0003-3127-5739; Koch, Christian/0000-0003-0678-1242 NR 11 TC 32 Z9 33 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 14 PY 2002 VL 21 IS 8 BP 1167 EP 1170 DI 10.1038/sj.onc.1205121 PG 4 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 519ME UT WOS:000173729400004 PM 11850836 ER PT J AU Aouacheria, A Ory, S Schmitt, JR Rigal, D Jurdic, P Gillet, G AF Aouacheria, A Ory, S Schmitt, JR Rigal, D Jurdic, P Gillet, G TI p60(v-src) and serum control cell shape and apoptosis via distinct pathways in quail neuroretina cells SO ONCOGENE LA English DT Article DE v-src; cytoskeleton; apoptosis; MAP kinases; G-proteins; retina ID ROUS-SARCOMA VIRUS; PP60C-SRC PROTEIN-KINASE; FAMILY TYROSINE KINASES; FOCAL ADHESION KINASE; V-SRC; SUBSTRATUM ADHESIONS; SIGNALING PATHWAYS; RAT FIBROBLASTS; TRANSFORMATION; ACTIVATION AB We made use of QNR cells transformed by a thermosensitive (tsNY68) strain of the Rous sarcoma virus (RSV) to compare the effect of p60(v-src) and serum in cultured nerve cells. In this system, both p60(v-src) heat inactivation and serum removal resulted in growth arrest in G1. In both cases, growth arrest was reversible since cell proliferation was rapidly re-induced following respectively p60v-src renaturation or serum re-addition. However, cells did not fully recover their ability to grow in soft agar, suggesting that, in contrast to the cell cycle machinery, the transforming capacities of these cells have been irreversibly altered. We found that p60(v-src) kinase activity prevented detachment from the substratum and cell death following serum removal. Thermal inactivation of p60(v-src) at restrictive temperature (41.5degreesC), but not serum removal, resulted in dramatic morphological changes, which occured 4 h after temperature shift up to 41.5degreesC. Later on, typical features of apoptotic cells could be observed. Cell death was greatly reduced by the caspase-3 inhibitor ZVAD.FMK, but not by the caspase-1 inhibitor Ac-YVAD.CHO. Together, these results suggested that p60(v-src) and serum factors act on distinct pathways, at least in part. In an attempt to identify the signalling pathways involved in the cell response to p60(v-src) down regulation, we found that Erk and Rac were rapidly inactivated following temperature shift up to 41.5degreesC. Thus, the combined effects of p60(v-src) and serum factors on the cytoskeleton dynamics and the apoptosis machinery are essential for full neoplastic transformation of neuroretina cells. C1 Univ Lyon 1, CNRS, UMR 5086, Inst Biol & Chim Prot, F-69367 Lyon 07, France. Ecole Normale Super Lyon, UMR 5665, Biol Cellulaire & Mol Lab, CNRS, F-69364 Lyon, France. Etab Transfus Sanguine, F-69007 Lyon, France. RP Gillet, G (reprint author), NCI, Regulat Cell Growth Lab, Frederick, MD 21702 USA. RI Ory, Stephane/E-9947-2010; gillet, germain/A-9095-2013 OI Ory, Stephane/0000-0003-4359-1157; NR 66 TC 9 Z9 9 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 14 PY 2002 VL 21 IS 8 BP 1171 EP 1186 DI 10.1038/sj.onc.1205170 PG 16 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 519ME UT WOS:000173729400005 PM 11850837 ER PT J AU Drake, KD Schuette, D Chepelinsky, AB Crabbe, MJC AF Drake, KD Schuette, D Chepelinsky, AB Crabbe, MJC TI Heterologous expression and topography of the main intrinsic protein (MIP) from rat lens SO FEBS LETTERS LA English DT Article DE confocal microscopy; cataract; lens; antibody ID ALPHA-B-CRYSTALLIN; ESCHERICHIA-COLI; WATER; FACILITATOR; AQUAPORIN-1; MUTATIONS; MEMBRANE; STRESS; FORMS; CELL AB Wild type rat lens main intrinsic protein (MIP) and MIP mutated (17731, F75L) to resemble the glycerol facilitator of Escherichia coli in the region of the NPA1 box were used to investigate the topology of MIP in the membrane of Spodoptera frugiperda (Sf21) cells using the baculovirus expression system and expression in mouse erythroid leukaemia cells (MEL C88). Differential fixation for staining was used, with paraformaldehyde for externally exposed antigenic sites, and acetone for both externally and internally exposed protein antigenic sites. Immunofluorescence using antibodies to synthetic MIP peptides showed that wild type MIP had a six transmembrane topography. The N- and C-termini were intracellular in both expression systems, and both NPA boxes were found to be extracellular. These results show that residues around the NPA1 box can influence the folding of the MIP in the membrane, and provide structural evidence for the poor water transport properties of MIP, as the NPA boxes lie outside the plane of the membrane. (C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. C1 Univ Reading, Sch Anim & Microbial Sci, Div Cell & Mol Biol, Reading RG6 6AJ, Berks, England. NEI, NIH, Bethesda, MD 20892 USA. RP Crabbe, MJC (reprint author), Univ Reading, Sch Anim & Microbial Sci, Div Cell & Mol Biol, POB 228, Reading RG6 6AJ, Berks, England. NR 32 TC 4 Z9 4 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD FEB 13 PY 2002 VL 512 IS 1-3 BP 191 EP 198 AR PII S0014-5793(02)02256-1 DI 10.1016/S0014-5793(02)02256-1 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 525QF UT WOS:000174081900038 PM 11852078 ER PT J AU Drake, KD Schuette, D Chepelinsky, AB Jacob, TJ Crabbe, MJC AF Drake, KD Schuette, D Chepelinsky, AB Jacob, TJ Crabbe, MJC TI pH-dependent channel activity of heterologously-expressed main intrinsic protein (MIP) from rat lens SO FEBS LETTERS LA English DT Article DE baculovirus; mouse erythroid leukaemia cell; lens; patch clamping; cataract; eye ID ALPHA-B-CRYSTALLIN; ESCHERICHIA-COLI; XENOPUS OOCYTES; FROG LENS; MEMBRANE; WATER; FACILITATOR; MUTATIONS; STRESS; CELL AB Wild-type rat lens main intrinsic protein (MIP) Was heterologously expressed in the membrane of Spodoptera frugiperda (Sf21) cells using the baculovirus expression system and in mouse erythroid leukaemia cells (MEL C88). Both MEL and Sf21 cell lines expressing wild-type MIP were investigated for the conductance of ions using a whole cell patch clamp technique. An increase in conductance was seen in both expression systems, particularly on lowering the pH to 6.3. In Sf21 cells, addition of antibodies to the NPA1 box resulted in a reduction of current flow. These results suggest that MIP has pH-dependent ion channel activity, which involves the NPA1 box domain. (C) 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies. C1 Univ Reading, Sch Anim & Microbial Sci, Div Cell & Mol Biol, Reading RG6 6AJ, Berks, England. NEI, NIH, Bethesda, MD USA. Univ Cardiff, Sch Biosci, Cardiff, S Glam, Wales. RP Crabbe, MJC (reprint author), Univ Reading, Sch Anim & Microbial Sci, Div Cell & Mol Biol, POB 228, Reading RG6 6AJ, Berks, England. NR 28 TC 11 Z9 11 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD FEB 13 PY 2002 VL 512 IS 1-3 BP 199 EP 204 AR PII S0014-5793(02)02284-6 DI 10.1016/S0014-5793(02)02284-6 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 525QF UT WOS:000174081900039 PM 11852079 ER PT J AU Molazowski, S AF Molazowski, S TI Drug-related hyperglycemia SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIDDKD, Bethesda, MD 20892 USA. RP Molazowski, S (reprint author), NIDDKD, Bethesda, MD 20892 USA. NR 5 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 13 PY 2002 VL 287 IS 6 BP 714 EP 715 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 520XR UT WOS:000173809500019 PM 11851529 ER PT J AU Turner, CF Rogers, SM Miller, HG Miller, WC Gribble, JN Chromy, JR Leone, PA Quinn, TC Zenilman, JM AF Turner, CF Rogers, SM Miller, HG Miller, WC Gribble, JN Chromy, JR Leone, PA Quinn, TC Zenilman, JM TI Untreated gonococcal and chlamydial infection in a probability sample of adults SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID SEXUALLY-TRANSMITTED DISEASES; LIGASE CHAIN-REACTION; TRACHOMATIS INFECTION; NEISSERIA-GONORRHOEAE; DIAGNOSIS; URINE; MEN; WOMEN; PREVALENCE; BEHAVIOR AB Context The prevalence and distribution of gonococcal and chlamydial infections in the general population are poorly understood. Development of nucleic acid amplification tests, such as the ligase chain reaction assay, provides new opportunities to estimate the prevalence of untreated infections in the population. Objective To estimate the overall prevalence of untreated gonococcal and chlamydial infections and to describe patterns of infection within specific demographic subgroups of the young adult population in Baltimore, Md. Design and Setting Cross-sectional behavioral survey based on a probability sample of Baltimore households with collection of urine specimens between January 1997 and September 1998. Participants A total of 728 adults aged 18 to 35 years completed the interview portion of the study, and 579 of these respondents also provided a urine specimen adequate for testing. Main Outcome Measure Prevalence of untreated infection, as measured by the percentage of specimens testing positive for gonococcal and chlamydial infection by ligase chain reaction, weighted to reflect variations in probabilities of sample selection from the population. Alternate estimates of the prevalence of recent treated infection were derived from clinically diagnosed cases reported to the Baltimore City Health Department and by diagnoses reported by participants in the survey. Results An estimated 5.3% (SE, 1.4%) of the population aged 18 to 35 years has an untreated gonococcal infection, and 3.0% (SE, 0.8%) is estimated to have an untreated chlamydial infection. While 7.9% (SE, 1.6%) of the population is estimated to have either an untreated gonococcal or chlamydial infection, estimated prevalence is substantially higher among black women (15.0%; SE, 3.7%). Few participants with untreated infections reported dysuria or discharge during the 6 months preceding testing. The estimated number of untreated gonococcal infections in the population (9241; SE, 2441) substantially exceeds both the number of such infections diagnosed among Baltimore adults aged 18 to 35 years and reported to the Baltimore City Health Department during 1998 (4566), and the estimated number of diagnoses derived using participants' reports for the 12 months prior to the survey (4708 [SE, 1918] to 5231 [SE, 2092]). The estimated number of untreated chlamydial infections (5231; SE, 1395) is also greater than the number of cases reported to the health department in 1998 (3664) but is slightly less than the estimated number of diagnoses derived using participants' reports of chlamydial infections diagnosed during the 12 months prior to the survey (5580 [SE, 1918] to 6975 [SE, 2441]). Conclusion In 1997-1998, the estimated number of undiagnosed gonococcal and chlamydial infections prevalent in the population of Baltimore adults aged 18 to 35 years approached or exceeded the number of infections that were diagnosed and treated annually. C1 Res Triangle Inst, Program Hlth & Behav Measurement, Washington, DC 20036 USA. CUNY Queens Coll, Flushing, NY 11367 USA. CUNY, Grad Ctr, Flushing, NY USA. Res Triangle Inst, Div Stat Res, Res Triangle Pk, NC 27709 USA. Res Triangle Inst, Res Comp Div, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Med, Div Infect Dis, Chapel Hill, NC USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. NIAID, Bethesda, MD 20892 USA. RP Turner, CF (reprint author), Res Triangle Inst, Program Hlth & Behav Measurement, 1615 M St NW, Washington, DC 20036 USA. RI Quinn, Thomas/A-2494-2010; Miller, William/H-4800-2014 OI Miller, William/0000-0002-1934-7827 FU NCRR NIH HHS [RR00046]; NIAID NIH HHS [K24-AI01633, U19-AI38533]; NICHD NIH HHS [R01-HD31067] NR 30 TC 146 Z9 151 U1 2 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 13 PY 2002 VL 287 IS 6 BP 726 EP 733 DI 10.1001/jama.287.6.726 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 520XR UT WOS:000173809500029 PM 11851539 ER PT J AU Hager-Braun, C Tomer, KB AF Hager-Braun, C Tomer, KB TI Characterization of the tertiary structure of soluble CD4 bound to glycosylated full-length HIVgp120 by chemical modification of arginine residues and mass spectrometric analysis SO BIOCHEMISTRY LA English DT Article ID ENVELOPE GLYCOPROTEIN GP120; PROTEIN SURFACE-TOPOLOGY; CONFORMATIONAL-CHANGES; BINDING-SITE; NUCLEOTIDE-SEQUENCE; VIRUS; RETROVIRUS; RECEPTOR; PEPTIDE; AIDS AB The initial step of infection of blood cells with the human immunodeficiency virus, HIV, is the formation of a complex of the viral envelope protein gp120 and its human receptor CD4. We have examined structural features of recombinant soluble CD4 (sCD4) by chemical modification of arginine residues with hydroxyphenylglyoxal and subsequent analysis by matrix-assisted laser desorption/ionization and electrospray ionization mass spectrometry. As R58, R59, R131, R134, R219, R240, R293, and R329 could be derivatized free in solution, these arginine residues were exposed on the surface of the protein. In the noncovalent complex of sCD4 with HIV(SF2)gp120, only R58, R131, R 134, R219, R240, R293, and R329 were accessible for the derivatizing agent. R59 was shielded from hydroxyphenylglyoxal and was, therefore, considered to be part of the interaction site with gp120. This indicates that the carbohydrate moieties and the flexible variable loops of the glycosylated full-length gp120 from HIV strain SF2 do not induce a reorganization of CD4 in its binding to gp120 and, therefore, do not appear to significantly affect the structural orientation of the primary receptor in complex with the HIV envelope protein as compared to the binding observed in the crystal structure of CD4 with truncated deglycosylated gp120. C1 Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Tomer, KB (reprint author), Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RI Tomer, Kenneth/E-8018-2013 NR 37 TC 25 Z9 27 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 12 PY 2002 VL 41 IS 6 BP 1759 EP 1766 DI 10.1021/bi011626k PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 520NF UT WOS:000173787400008 PM 11827520 ER PT J AU Jhee, KH Niks, D McPhie, P Dunn, MF Miles, EW AF Jhee, KH Niks, D McPhie, P Dunn, MF Miles, EW TI Yeast cystathionine beta-synthase reacts with L-allothreonine, a non-natural substrate, and L-homocysteine to form a new amino acid, 3-methyl-L-cystathionine SO BIOCHEMISTRY LA English DT Article ID O-ACETYLSERINE SULFHYDRYLASE; ENZYMATIC-SYNTHESIS; SALMONELLA-TYPHIMURIUM; TRYPTOPHAN-SYNTHETASE; REACTION-MECHANISM; INTERMEDIATE; HEME; TRANSSULFURATION; STEREOCHEMISTRY; ENZYMES AB Our studies of the reaction mechanism of cystathionine P-synthase from yeast (Saccharomyces cerevisiae) are facilitated by the spectroscopic properties of the pyridoxal phosphate coenzyme. The enzyme catalyzes the reaction Of L-serine with L-homocysteine to form L-cystathionine through a series of pyridoxal phosphate intermediates. In this work, we explore the substrate specificity of the enzyme by use of substrate analogues combined with kinetic measurements under pre-steady-state conditions and with circular dichroism and fluorescence spectroscopy under steady-state conditions. Our results show that L-allothreonine, but not L-threonine, serves as an effective substrate. L-Allothreonine reacts with the pyridoxal phosphate cofactor to form a stable 3-methyl an-aminoacrylate intermediate that absorbs maximally at 446 run. The rapid-scanning stopped-flow results show that the binding Of L-allothreonine as the external aldimine is faster than formation of the 3-methyl aminoacrylate intermediate. The 3-methyl aminoacrylate intermediate reacts with L-homocysteine to form a new amino acid, 3-methyl-L-cystathionine, which was characterized by nuclear magnetic resonance spectroscopy. This new amino acid may be a useful analogue of L-Cystathionine. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. Univ Calif Riverside, Dept Biochem, Riverside, CA 92521 USA. RP Miles, EW (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [GM55749] NR 44 TC 9 Z9 9 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 12 PY 2002 VL 41 IS 6 BP 1828 EP 1835 DI 10.1021/bi011756t PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 520NF UT WOS:000173787400015 PM 11827527 ER PT J AU Remeta, DP Krumbiegel, M Minetti, CASA Puri, A Ginsburg, A Blumenthal, R AF Remeta, DP Krumbiegel, M Minetti, CASA Puri, A Ginsburg, A Blumenthal, R TI Acid-induced changes in thermal stability and fusion activity of influenza hemagglutinin SO BIOCHEMISTRY LA English DT Article ID MEDIATED MEMBRANE-FUSION; VIRUS HEMAGGLUTININ; LOW-PH; CONFORMATIONAL CHANGE; SCANNING CALORIMETRY; ELECTRON-MICROSCOPY; CIRCULAR-DICHROISM; FUSOGENIC ACTIVITY; ESCHERICHIA-COLI; SURFACE-DENSITY AB The conformational and thermal stability of full-length hemagglutinin (HA) of influenza virus (strain X31) has been investigated using a combination of differential scanning calorimetry (DSC), analytical ultracentrifugation, fluorescence, and circular dichroism (CD) spectroscopy as a function of pH. HA sediments as a rosette comprised of 5-6 trimers (31-35 S) over the pH range of 7.4-5.4. The DSC profile of HA in the native state at pH 7.4 is characterized by a single cooperative endotherm with a transition temperature (T-m) of 66 degreesC and unfolding enthalpy (DeltaH(ca1)) of 800 kcal(.)(mol of trimer)(-1). Upon acidification to pH 5.4, there is a significant decrease in the transition temperature (from 66 to 45 degreesC), unfolding enthalpy [from 800 to 260 kcal(.)(mol of trimer)(-1)], and DeltaH(ca1)/DeltaH(vH) ratio (from 3.0 to similar to1.3). Whereas the far- and near-UV ellipticities are maintained over this pH range, there is an acid-induced increase in surface hydrophobicity and decrease in intrinsic tryptophanyl fluorescence. The major contribution to the DSC endotherm arises from unfolding HA1 domains. The relationship between acid-induced changes in thermal stability and the fusion activity of HA has been examined by evaluating the kinetics and extent of fusion of influenza virus with erythrocytes over the temperature and pH range of the DSC measurements. Surprisingly, X31 influenza virus retains its fusion activity at acidic pH and temperatures significantly below the unfolding transition of HA. This finding is consistent with the notion that the fusion activity of influenza virus may involve structural changes of only a small fraction of HA molecules. C1 NCI, FCRDC, NIH, Lab Expt & Computat Biol, Frederick, MD 21702 USA. NHLBI, Biochem Lab, Sect Prot Chem, NIH, Bethesda, MD 20892 USA. RP Blumenthal, R (reprint author), NCI, FCRDC, NIH, Lab Expt & Computat Biol, Bldg 469,Room 216A,Room 211, Frederick, MD 21702 USA. RI Minetti, Conceicao/B-5077-2009 OI Minetti, Conceicao/0000-0002-9682-2898 NR 54 TC 30 Z9 31 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 12 PY 2002 VL 41 IS 6 BP 2044 EP 2054 DI 10.1021/bi015614a PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 520NF UT WOS:000173787400040 PM 11827552 ER PT J AU Nabel, EG AF Nabel, EG TI Stem cells combined with gene transfer for therapeutic vasculogenesis - Magic bullets? SO CIRCULATION LA English DT Editorial Material DE editorials; angiogenesis; cells; endothelium; gene therapy ID ENDOTHELIAL PROGENITOR CELLS; NEOVASCULARIZATION C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Nabel, EG (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 10,8C103,10 Ctr Dr, Bethesda, MD 20892 USA. NR 13 TC 16 Z9 17 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 FEB 12 PY 2002 VL 105 IS 6 BP 672 EP 674 DI 10.1161/hc0602.104892 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 522YM UT WOS:000173924600012 PM 11839618 ER PT J AU Okin, PM Devereux, RB Fabsitz, RR Lee, ET Galloway, JM Howard, BV AF Okin, PM Devereux, RB Fabsitz, RR Lee, ET Galloway, JM Howard, BV TI Principal component analysis of the T wave and prediction of cardiovascular mortality in American Indians - The Strong Heart Study SO CIRCULATION LA English DT Article DE electrocardiography; epidemiology; mortality; prognosis ID HUMAN VENTRICULAR REPOLARIZATION; CORONARY-ARTERY DISEASE; LONG-QT SYNDROME; ST-T; DISPERSION; ELECTROCARDIOGRAMS; HETEROGENEITY; POTENTIALS; ALGORITHMS; MORPHOLOGY AB Background-Increased QT interval dispersion (QTd) is a proposed ECG marker of vulnerability to ventricular arrhythmias and of cardiovascular (CV) mortality. However, principal component analysis (PCA) of the T-wave vector loop may more accurately represent repolarization abnormalities than QTd. Methods and Results-Predictive values of QTd and PCA were assessed in 1839 American Indian participants in the first Strong Heart Study examination. T-wave loop morphology was quantified by the ratio of the second to first eigenvalues of the T-wave vector by PCA (PCA ratio); QTd was quantified as the difference between maximum and minimum QT intervals. After 3.7 +/- 0.9 years mean follow-up, there were 55 CV deaths. In univariate analyses, an increased PCA ratio predicted CV mortality in women (chi(2)=7.8, P=0.0053) and men (chi(2)=9.5, P=0.0021). In contrast, increased QTd was a significant predictor of CV mortality in women (chi(2)=30.6, P<0.0001) but not in men (chi(2)=2.0, P=NS). In multivariate Cox analyses controlling for risk factors and rate-corrected QT interval, the PCA ratio remained a significant predictor of CV mortality in women (chi(2)=4.0, P=0.043) and men (chi(2)=6.4, P=0.011); QTd was a significant predictor in women only (chi(2)=11.0, P=0.0009). PCA ratios >90th percentile (32% in women and 24.6% in men) identified women with a 3.68-fold increased risk of CV mortality (95% CI, 1.54 to 8.83) and men with a 2.77-fold increased risk (95% CI, 1.18 to 6.49). Conclusions-Abnormalities of repolarization measured by PCA of the T-wave loop predict CV death in men and women, supporting use of PCA for quantifying repolarization abnormalities. C1 Cornell Med Ctr, Dept Med, Div Cardiol, New York, NY 10021 USA. NHLBI, Bethesda, MD 20892 USA. Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Oklahoma City, OK USA. Univ Arizona, Tucson, AZ USA. Medlant Res Inst, Washington, DC USA. RP Okin, PM (reprint author), Cornell Med Ctr, Dept Med, Div Cardiol, 525 E 68th St, New York, NY 10021 USA. EM pokin@med.cornell.edu FU NHLBI NIH HHS [U01-HL-41652, U01-HL-41654, U01-HL-41642] NR 35 TC 67 Z9 69 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 12 PY 2002 VL 105 IS 6 BP 714 EP 719 DI 10.1161/hc0602.103585 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 522YM UT WOS:000173924600021 PM 11839627 ER PT J AU Hayashi, K Nakanishi, Y Bastow, KF Cragg, G Nozaki, H Lee, KH AF Hayashi, K Nakanishi, Y Bastow, KF Cragg, G Nozaki, H Lee, KH TI Antitumor agents. Part 212: Bucidarasins A-C, three new cytotoxic clerodane diterpenes from Bucida buceras SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID CASEARIA-CORYMBOSA; ZUELANIA-GUIDONIA; STEM BARK AB As part of a study on antitumor agents from rainforest plants, four new clerodane diterpenes, bucidarasins A-D (1-4), were isolated from Bucida buceras. Their structures were elucidated from detailed 2D NMR analyses. Compounds 1 3 showed potent cytotoxicity against human tumor cell lines with IC50 values of 0.5-1.9 muM. The potency was retained in drug resistant lines. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Univ N Carolina, Sch Pharm, Nat Prod Lab, Chapel Hill, NC 27599 USA. NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. Okayama Univ Sci, Dept Biochem, Okayama 7000005, Japan. RP Lee, KH (reprint author), Univ N Carolina, Sch Pharm, Nat Prod Lab, Chapel Hill, NC 27599 USA. OI Hayashi, Ken-ichiro/0000-0002-9812-2801 FU NCI NIH HHS [CA-17625] NR 13 TC 22 Z9 22 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 11 PY 2002 VL 12 IS 3 BP 345 EP 348 AR PII S0960-894X(01)00742-9 DI 10.1016/S0960-894X(01)00742-9 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 526TJ UT WOS:000174145500020 PM 11814793 ER PT J AU Maeda, DY Williams, W Kim, WE Thatcher, LN Bowen, WD Coop, A AF Maeda, DY Williams, W Kim, WE Thatcher, LN Bowen, WD Coop, A TI N-arylalkylpiperidines as high-affinity sigma-1 and sigma-2 receptor ligands: Phenylpropylamines as potential leads for selective sigma-2 agents SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID ANTIPSYCHOTIC-DRUGS; BINDING; MODULATION; APOPTOSIS; RELEASE; DESIGN AB To delineate the differences between the structural requirements necessary for recognition at sigma-1 and sigma-2 receptors, a range of phenethyl- and phenylpropylpiperidines were evaluated in binding assays. Phenethylpiperidines were found to favor sigma-1 receptors, whereas phenylpropylpiperidines tend to favor sigma-2 receptors. It appears that phenylpropylamine is a potential pharmacophore for selective sigma-2 ligands. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. NIDDK, Med Chem Lab, Bethesda, MD 20892 USA. RP Coop, A (reprint author), Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, 20 N Pine St, Baltimore, MD 21201 USA. NR 30 TC 25 Z9 29 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 11 PY 2002 VL 12 IS 3 BP 497 EP 500 AR PII S09060-894X(01)00788-0 DI 10.1016/S0960-894X(01)00788-0 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 526TJ UT WOS:000174145500054 PM 11814827 ER PT J AU Luhrs, H Hock, R Schauber, J Weihrauch, M Harrer, M Melcher, R Scheppach, W Bustin, M Menzel, T AF Luhrs, H Hock, R Schauber, J Weihrauch, M Harrer, M Melcher, R Scheppach, W Bustin, M Menzel, T TI Modulation of HMG-N2 binding to chromatin by butyrate-induced acetylation in human colon adenocarcinoma cells SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE butyrate; colon cancer; high mobility group protein N2; hyperacetylation; prevention ID CHROMOSOMAL PROTEIN HMG-17; MOBILITY GROUP PROTEIN-14; CHAIN FATTY-ACIDS; HISTONE DEACETYLASE; SODIUM-BUTYRATE; TRANSCRIPTIONAL REPRESSION; DNA-DAMAGE; CANCER; NUCLEOSOMES; PHOSPHORYLATION AB Butyrate, a short chain fatty acid (SCFA), is generated by anaerobic fermentation of undigested carbohydrates within the colon. Butyrate enhances acetylation of core histones, a process directly linked to the formation of active chromatin and gene expression. However, additional chromatin components also contribute to the formation of transcriptionally active chromatin. The high mobility group protein N2 (HMG-N2), a nonhistone protein, is involved in chromatin structure modulation. We examined the effects of butyrate on HMG-N2 expression, hyperacetylation and chromatin binding. HT29 human adenocarcinoma cells were incubated with butyrate. Levels of HMG-N2 mRNA and of total or acetylated HMG-N2 protein were analyzed. Protein dynamics were investigated with transfected cells expressing HMG-N2-EGFP fusion proteins. Treatment of HT29 cells with butyrate led to significant hyperacetylation of HMG-N2. Levels of HMG-N2 protein remained unchanged. Northern blot analysis revealed a significant reduction in HMG-N2 mRNA levels after treatment with butyrate. Analysis of HMG-N2-EGFP transfected HT29 cells demonstrated that butyrate treatment changes the binding properties of HMG-N2-EGFP to chromatin. In addition, butyrate treatment resulted in solubilization of endogenous acetylated HMG-N2 into the supernatant of permeabilized cells. We demonstrate that butyrate treatment is associated with hyperacetylation of HMG-N2 protein in HT29 cells. The modulation of this nonhistone chromatin protein resulted in altered binding properties to chromatin. This may represent an additional step in changing chromatin structure and composition with subsequent consequences for transcription and gene expression. Modulation of nonhistone chromatin proteins, like the ubiquitous HMG-N2 proteins, may be partly responsible for the wide range of butyrate-associated effects. (C) 2002 Wiley-Liss, Inc. C1 Univ Wurzburg, Dept Med, Div Gastroenterol, D-97080 Wurzburg, Germany. Univ Wurzburg, Dept Cell & Dev Biol, Wurzburg, Germany. NCI, DBS, LMC, Prot Sect,NIH, Bethesda, MD USA. RP Luhrs, H (reprint author), Univ Wurzburg, Dept Med, Div Gastroenterol, J Schneider Str 2, D-97080 Wurzburg, Germany. RI Bustin, Michael/G-6155-2015 NR 48 TC 17 Z9 17 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 10 PY 2002 VL 97 IS 5 BP 567 EP 573 DI 10.1002/ijc.10098 PG 7 WC Oncology SC Oncology GA 513EG UT WOS:000173364500003 PM 11807779 ER PT J AU Engels, EA Frisch, M Goedert, JJ Biggar, RJ Miller, RW AF Engels, EA Frisch, M Goedert, JJ Biggar, RJ Miller, RW TI Merkel cell carcinoma and HIV infection SO LANCET LA English DT Article AB Merkel cell carcinoma (MCC) is a rare skin cancer that occurs more frequently after organ transplantation or B-cell malignancy, conditions of suppressed or disordered immunity. To assess further whether immune suppression increases MCC risk, we studied its occurrence in a cohort of 309 365 individuals with acquired immunodeficiency syndrome (AIDS) by using linked AIDS and cancer registries. We identified six cases of MCC, corresponding to a relative risk of 13.4 (95% CI 4.9-29.1) compared with the general population. These results suggest that immune suppression induced by the human immunodeficiency virus increases MCC risk. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. Statens Serum Inst, Danish Epidemiol Sci Ctr, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. RP Engels, EA (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. RI Frisch, Morten/E-9206-2016 OI Frisch, Morten/0000-0002-3864-8860 NR 4 TC 226 Z9 228 U1 2 U2 7 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD FEB 9 PY 2002 VL 359 IS 9305 BP 497 EP 498 DI 10.1016/S0140-6736(02)07668-7 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 520ML UT WOS:000173785600017 PM 11853800 ER PT J AU Daws, LC Callaghan, PD Moron, JA Kahlig, KM Shippenberg, TS Javitch, JA Galli, A AF Daws, LC Callaghan, PD Moron, JA Kahlig, KM Shippenberg, TS Javitch, JA Galli, A TI Cocaine increases dopamine uptake and cell surface expression of dopamine transporters SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE cocaine; dopamine transporter; trafficking; uptake; biotinylation; chronoamperometry; striatum; nucleus accumbens ID RAT NUCLEUS-ACCUMBENS; EXTRACELLULAR DOPAMINE; STRIATUM; CLEARANCE; MECHANISM; DIFFUSION; RECEPTOR AB In HEK 293 cells expressing the human dopamine transporter (DAT), a 10-min incubation with 10 muM cocaine followed by extensive washing resulted in a 30% increase in [H-3]dopamine (DA) uptake as well as an increase in cell surface DAT in biotinylation experiments. Consistent with this novel regulation, [H-3]DA uptake into synaptosomes prepared from the nucleus accumbens of rats sacrificed 30 min after a single cocaine injection (30 mg/kg) was significantly increased compared to controls (56% increase in V-max, no change in K-m). In addition, DA clearance in the striatum of anesthetized rats was increased after local application of a low (3 pmol) but not high (65 pmol) dose of cocaine presumably as a result of mobilization of DAT to the cell surface. Cocaine-induced increases in cell surface expression of DAT and associated changes in DA clearance represent a novel mechanism that may play a role in its addictive properties. (C) 2002 Elsevier Science (USA). C1 Univ Texas, Hlth Sci Ctr, Dept Pharmacol, San Antonio, TX 78229 USA. NIDA IRP, Integrat Neurosci Sect, Baltimore, MD 21224 USA. Columbia Univ Coll Phys & Surg, Ctr Mol Recognit, New York, NY 10032 USA. RP Galli, A (reprint author), Univ Texas, Hlth Sci Ctr, Dept Pharmacol, 7703 Floyd Curl Dr,MC 7764, San Antonio, TX 78229 USA. FU NIDA NIH HHS [DA11495, DA13975]; NIMH NIH HHS [MH57324] NR 24 TC 112 Z9 114 U1 2 U2 4 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 FEB 8 PY 2002 VL 290 IS 5 BP 1545 EP 1550 DI 10.1006/bbrc.2002.6384 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 520LT UT WOS:000173783900028 PM 11820798 ER PT J AU Song, LS Guia, A Muth, JN Rubio, M Wang, SQ Xiao, RP Josephson, IR Lakatta, EG Schwartz, A Cheng, HP AF Song, LS Guia, A Muth, JN Rubio, M Wang, SQ Xiao, RP Josephson, IR Lakatta, EG Schwartz, A Cheng, HP TI Ca2+ signaling in cardiac myocytes overexpressing the alpha(1) subunit of L-type Ca2+ channel SO CIRCULATION RESEARCH LA English DT Article DE L-type Ca2+ channels; excitation-contraction coupling; Ca2+ sparks; Ca2+ homeostasis; cardiac hypertrophy ID RAT VENTRICULAR MYOCYTES; CALCIUM SPARKS; LOCAL-CONTROL; RYANODINE RECEPTORS; HEART-MUSCLE; CONTRACTION; RELEASE; INACTIVATION; HYPERTROPHY; FAILURE AB Voltage-gated L-type Ca2+ channels (LCCs) provide Ca2+ ingress into cardiac myocytes and play a key role in intracellular Ca2+ homeostasis and excitation-contraction coupling. We investigated the effects of a constitutive increase of LCC density on Ca2+ signaling in ventricular myocytes from 4-month-old transgenic (Tg) mice overexpressing the a, subunit of LCC in the heart. At this age, cells were somewhat hypertrophic as reflected by a 20% increase in cell capacitance relative to those from nontransgenic (Ntg) littermates. Whole cell I-Ca density in Tg myocytes was elevated by 48% at 0 mV compared with the Ntg group. Single-channel analysis detected an increase in LCC density with similar conductance and gating properties. Although the overexpressed LCCs triggered an augmented SR Ca2+ release, the "gain" function of EC coupling was uncompromised, and SR Ca2+ content, diastolic cytosolic Ca2+, and unitary properties of Ca2+ sparks were unchanged. Importantly, the enhanced I-Ca entry and SR Ca2+ release were associated with an upregulation of the Na+-Ca2+ exchange activity (indexed by the half decay time of caffeine-elicited Ca2+ transient) by 27% and SR Ca2+ recycling by approximate to35%. Western analysis detected a 53% increase in the Na+-Ca2+ exchanger expression but no change in the abundance of ryanodine receptor (RyR), SERCA2, and phospholamban. Analysis of I-Ca kinetics suggested that SR Ca2+ release-dependent inactivation of LCCs remains intact in Tg cells. Thus, in spite of the modest cardiac hypertrophy, the overexpressed LCCs form functional coupling with RyRs, preserving both orthograde and retrograde Ca2+ signaling between LCCs and RyRs. These results also suggest that a modest but sustained increase in Ca2+ influx triggers a coordinated remodeling of Ca2+ handling to maintain Ca2+ homeostasis. C1 NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. Univ Cincinnati, Inst Mol Pharmacol & Biophys, Cincinnati, OH USA. RP Cheng, HP (reprint author), NIA, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Song, Long-Sheng/D-5899-2012 FU NHLBI NIH HHS [T32 HL 07382, P01 HL22619] NR 31 TC 38 Z9 42 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD FEB 8 PY 2002 VL 90 IS 2 BP 174 EP 181 DI 10.1161/hh0202.103230 PG 8 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 521CT UT WOS:000173821800012 PM 11834710 ER PT J AU Liao, P Wang, SQ Wang, S Zheng, M Zheng, M Zhang, SJ Cheng, H Wang, Y Xiao, RP AF Liao, P Wang, SQ Wang, S Zheng, M Zheng, M Zhang, SJ Cheng, H Wang, Y Xiao, RP TI p38 mitogen-activated protein kinase mediates a negative inotropic effect in cardiac myocytes SO CIRCULATION RESEARCH LA English DT Article DE p38 mitogen-activated protein kinase; cardiac contractility; excitation-contraction coupling; troponin I; intracellular pH ID N-TERMINAL KINASES; STRESS-RESPONSE; PERFUSED HEART; MAP KINASES; RAT HEARTS; INHIBITION; PATHWAY; PHOSPHORYLATION; HYPERTROPHY; APOPTOSIS AB p38 Mitogen-activated protein kinase (MAPK) is one of the most ancient signaling molecules and is involved in multiple cellular processes, including cell proliferation, cell growth, and cell death. In the heart, enhanced activation of p38 MAPK is associated with ischemia/reperfusion injury and the onset of heart failure. In the present study, we investigated the function of p38 MAPK in regulating cardiac contractility and its underlying mechanisms. In cultured adult rat cardiomyocytes, activation of p38 MAPK by adenoviral gene transfer of an activated mutant of its upstream kinase, MKK3bE, led to a significant reduction in baseline contractility, compared with uninfected cells or those infected with a control adenoviral vector (Adv-beta-galactosidase). The inhibitory effect of MKK3bE on contractility was largely prevented by coexpressing a dominant-negative mutant of p38 MAPK or treating cells with a p38 MAPK inhibitor, SB203580. Conversely, inhibition of endogenous p38 MAPK activity by SB203580 rapidly and reversibly enhanced cell contractility in a dose-dependent manner, without altering L-type Ca2+ currents or Ca-i(2+) transients. MKK3bE-induced p38 activation had no significant effect on pH;, whereas SB203580 had a minor effect to elevate pH,. Furthermore, activation of p38 MAPK was unable to increase troponin I phosphorylation. Thus, we conclude that the negative inotropic effect of p38 MAPK is mediated by decreasing myofilament response to Ca2+, rather than by altering Ca-i(2+) homeostasis and that the reduced myofilament Ca2+ sensitivity is unlikely attributable to troponin I phosphorylation or alterations in pH(i). These findings reveal a novel function of p38 MAPK and shed a new light on our understanding of the coincidence of p38 MAPK activation and the onset of heart failure. C1 NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. Peking Univ, Coll Life Sci, Hlth Sci Ctr, Beijing, Peoples R China. RP Xiao, RP (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Wang, Yibin/0000-0003-0852-0767 FU NHLBI NIH HHS [R01 HL062311] NR 37 TC 120 Z9 124 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD FEB 8 PY 2002 VL 90 IS 2 BP 190 EP 196 DI 10.1161/hh0202.104220 PG 7 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 521CT UT WOS:000173821800014 PM 11834712 ER PT J AU Buchholz, DR Hayes, TB AF Buchholz, DR Hayes, TB TI Evolutionary patterns of diversity in spadefoot toad metamorphosis (Anura : Pelobatidae) SO COPEIA LA English DT Article ID AMPHIBIAN METAMORPHOSIS; SCAPHIOPUS-COUCHII; PLASTICITY; FROGS AB The larvae of spadefoot toads exhibit extreme developmental/endocrinological diversity. For example, New World spadefoot toads (Scaphiopus and Spea) have the shortest larval periods known among anurans, and the tadpoles of Old World spade-foot taxa (Pelobates) are among the largest known. To analyze the patterns of this diversity in an evolutionary context, we generated comparable larval growth and development data from 10 of the 11 taxa of spadefoot toads and from one taxon of parsley frog (Pelodytes), the nearest spadefoot toad relative. We found dramatic differences in growth and development among taxa, which indicated that taxon-specific physiology, rather than phenotypic plasticity, underlies larval period diversity. For all eight response variables (development rate, three growth rates, time to forelimb emergence, time to tail resorption, mass at tail resorption, and body length at tail resorption), taxa within genera were similar to each other and were different from taxa in other genera. Larvae of Scaphiopus were small with short larval periods, larvae of Spea were large with short larval periods, larvae of Pelobates were large with long larval periods, and larvae of Pelodytes were small with long larval periods. Even though taxa within the same genus live in different environments, larval growth and development correlated with phylogenetic groupings rather than breeding habitat. Mapping larval data onto a molecular phylogeny indicated that short larval periods, as well as rapid embryonic development and high temperature tolerance, originated within the spadefoot toad family. C1 NICHHD, LME, NIH, Bethesda, MD 20892 USA. Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. RP Buchholz, DR (reprint author), NICHHD, LME, NIH, Bldg 18T,Room 106,18 Lib Dr,MSC 5431, Bethesda, MD 20892 USA. EM dbuchholz@nih.gov NR 35 TC 33 Z9 34 U1 1 U2 6 PU AMER SOC ICHTHYOLOGISTS & HERPETOLOGISTS PI MIAMI PA MAUREEN DONNELLY, SECRETARY FLORIDA INT UNIV BIOLOGICAL SCIENCES, 11200 SW 8TH STREET, MIAMI, FL 33199 USA SN 0045-8511 EI 1938-5110 J9 COPEIA JI Copeia PD FEB 8 PY 2002 IS 1 BP 180 EP 189 DI 10.1643/0045-8511(2002)002[0180:EPODIS]2.0.CO;2 PG 10 WC Zoology SC Zoology GA 520ZJ UT WOS:000173813400022 ER PT J AU Zolotukhin, AS Tan, W Bear, J Smulevitch, S Felber, BK AF Zolotukhin, AS Tan, W Bear, J Smulevitch, S Felber, BK TI U2AF Participates in the binding of TAP (NXF1) to mRNA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MESSENGER-RNA EXPORT; CONSTITUTIVE TRANSPORT ELEMENT; RIBONUCLEOPROTEIN AUXILIARY FACTOR; NUCLEAR-PORE COMPLEX; VIRUS TYPE-1 REV; SPLICING FACTOR; POLY(A)(+) RNA; BIOCHEMICAL-CHARACTERIZATION; RAE1 GENE; PROTEIN AB TAP/NXF1 is a conserved mRNA export receptor serving as a link between messenger ribonucleoproteins (mRNPs) and the nuclear pore complex. The mechanism by which TAP recognizes its export substrate is unclear. We show here that TAP is added to spliced mRNP in human cells. We identified a distinct region of TAP that targets it to mRNP. Using yeast two-hybrid screens and in vitro binding studies, we found that this, region coincides with a direct binding site for U2AF35, the small subunit of the splicing factor U2AF. This interaction is evolutionarily conserved across metazoa, indicating its significance. We further found in human cells that the exogenously expressed large U2AF subunit, U2AF65, accumulates in spliced mRNP, leading to the recruitment of U2AF35 and TAP. Similarly to TAP, U2AF65 stimulated directly the nuclear export and expression,of an mRNA that is otherwise retained in the nucleus. Together with our finding that U2AF is continuously exported from the nucleus, these data suggest that U2AF participates in nuclear export, by facilitating TAP's addition to its mRNA substrates. C1 NCI, Human Retrovirus Pathogenesis Sect, Basic Res Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Felber, BK (reprint author), NCI, Human Retrovirus Pathogenesis Sect, Basic Res Lab, Ctr Canc Res,NIH, Bldg 535,Rm 110, Frederick, MD 21702 USA. FU NCI NIH HHS [CA33572] NR 57 TC 51 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 FEB 8 PY 2002 VL 277 IS 6 BP 3935 EP 3942 DI 10.1074/jbc.M107598200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 520ZP UT WOS:000173813900020 PM 11724776 ER PT J AU Yang, XY Wang, LH Mihalic, K Xiao, WH Chen, TS Li, P Wahl, LM Farrar, WL AF Yang, XY Wang, LH Mihalic, K Xiao, WH Chen, TS Li, P Wahl, LM Farrar, WL TI Interleukin (IL-4) indirectly suppresses IL-2 production by human T lymphocytes via peroxisome proliferator-activated receptor gamma activated by macrophage-derived 12/15-lipoxygenase ligands SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PPAR-GAMMA; HUMAN MONOCYTES; TRANSCRIPTIONAL REPRESSION; INFLAMMATORY CYTOKINES; UP-REGULATION; OXIDIZED LDL; EXPRESSION; CELLS; GENE; PATHWAYS AB The respective development of either T helper type 1 (Th1) or Th2 cells is believed to be mediated by the effects of cytokines acting directly on Th precursors (Thp). We have generated evidence for an indirect monocyte-dependent immunoregulatory pathway. Recently, interleukin (IL) 4 has been shown to produce "new" potential peroxisome proliferator-activated receptor gamma (PPARgamma) ligands by inducing macrophage 12/ 15-lipoxygenase (12/15-LO). We have shown previously that the activated PPARgamma is a profound inhibitor of IL-2 transcription in human T lymphocytes. It is hypothetically possible that IL-4 might indirectly affect IL-2 production by Thp cells via macrophage-derived PPARgamma ligands. Using human monocytes and T lymphocytes from same donors, we have found that monocyte 12/15-LO products mediate the indirect inhibitory effect of IL-4 on anti-CD3- or phytohemagglutinin/ phorbol 12-myristate 13-acetate-stimulated IL-2 production by T lymphocytes. We further analyzed which major 12/15-LO metabolites contributed to the above inhibition. 13-Hydroxyoctadecadienoic acid (13-HODE), a 12/15-LO product, markedly blocked IL-2 production by human blood T lymphocytes, but not Jurkat T cells. Moreover, the IL-4-conditioned macrophage medium contained a sufficient amount of 13-HODE and anti-13-HODE antibody indeed neutralized the inhibitory effects of the IL-4-conditional medium on T-cell IL-2 production. Using human: T lymphocytes and the PPARgamma-transfected Jurkat T cells, we demonstrated the specific inhibition by 13-HODE of the transcription factors NFAT (nuclear factor of activated T cells) and nuclear factor kappaB, the IL-2 promoter reporter, and IL-2 production. However, 15-hydroxytetraenoic acid had little inhibitory effect. The potency of such inhibitory effects correlates well with the capability of the above metabolic lipids to activate PPARgamma. These data provide a mechanism whereby IL-4 may indirectly affect Thp function via PPARgamma activated by macrophage products of the 12/15-LO pathway. C1 NCI, Cytokine Mol Mechanisms Sect, Immunogenet Mol Lab, NIH, Frederick, MD 21702 USA. Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. NIDR, Immunopathol Sect, NIH, Bethesda, MD 20892 USA. RP Farrar, WL (reprint author), NCI, Cytokine Mol Mechanisms Sect, Immunogenet Mol Lab, NIH, POB B,Bldg 560,Rm 31-76, Frederick, MD 21702 USA. RI Chen, Taosheng/I-6351-2013; Xiao, Weihua/N-2775-2013 OI Xiao, Weihua/0000-0001-9102-6326 FU NCI NIH HHS [N01-CO-56000] NR 55 TC 57 Z9 60 U1 1 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 FEB 8 PY 2002 VL 277 IS 6 BP 3973 EP 3978 DI 10.1074/jbc.M105619200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 520ZP UT WOS:000173813900025 PM 11726648 ER PT J AU Cabral, WA Fertala, A Green, LK Korkko, J Forlino, A Marini, JC AF Cabral, WA Fertala, A Green, LK Korkko, J Forlino, A Marini, JC TI Procollagen with skipping of alpha 1(I) Exon 41 has lower binding affinity for alpha 1(I) C-telopeptide, impaired in vitro fibrillogenesis, and altered fibril morphology SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PRO-ALPHA-1(I) COLLAGEN GENE; TRIPLE HELICAL STRUCTURE; OSTEOGENESIS IMPERFECTA; I COLLAGEN; N-PROTEINASE; POINTED TIPS; COL1A1 GENE; INVITRO; CLEAVAGE; SEQUENCES AB Previous in vitro data on type I collagen self-assembly into fibrils suggested that the amino acid 776-796 region of the alpha1(I) chain is crucial for fibril formation because it serves as the recognition site for the telopeptide of a docking collagen monomer. We used a natural collagen mutation with a deletion of amino acids,766-801 to confirm the importance of this region for collagen fibril formation. The proband has type III osteogenesis imperfecta and is heterozygous for a COL1A1 IVS 41 A(+4) --> C substitution. The intronic mutation causes splicing of exon 41, confirmed by sequencing of normal and shorter reverse transcriptase-PCR products. Reverse transcriptase-PCR using RNA from proband dermal fibroblasts and clonal cell lines showed the mutant cDNA was about 15% of total alpha1(I) cDNA. The mutant transcript is translated; structurally abnormal a chains are demonstrated in the cell layer of proband fibroblasts by SDS-urea-PAGE. The proportion of mutant chains in the secreted procollagen was determined to be 10% toy resistance to digestion with MMP-1, since chains lacking exon 41 are missing the vertebral collagenase cleavage site. Secreted proband collagen was used for analysis of kinetics of binding of alpha1(I) C-telopeptide using an optical biosensor. Telopeptide had slower association and faster dissociation from proband than from normal collagen. Purified proband pC-collagen was used to study fibril formation. The presence of the mutant molecules decreases the rate of fibril formation. The fibrils formed in the presence of 10-15% mutant molecules have strikingly increased length compared with normal collagen, but are well organized, as demonstrated by D-periodicity. These results suggest that some collagen molecules containing the mutant chain are incorporated into fibrils and that the absence of the telopeptide binding region from even a small portion of the monomers interferes with fibril growth. Both abnormal fibrils and slower remodeling may contribute to the severe phenotype. C1 NICHHD, Heritable Disorders Branch, Sect Connect Tissue Disorders, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA. Allegheny Univ Hlth Sci, Ctr Gene Therapy, Philadelphia, PA 19102 USA. RP Marini, JC (reprint author), NICHHD, Heritable Disorders Branch, Sect Connect Tissue Disorders, NIH, Bldg 10,Rm 9S241,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Forlino, Antonella/H-5385-2015 OI Forlino, Antonella/0000-0002-6385-1182 NR 39 TC 16 Z9 16 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 FEB 8 PY 2002 VL 277 IS 6 BP 4215 EP 4222 DI 10.1074/jbc.M109048200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 520ZP UT WOS:000173813900058 PM 11706004 ER PT J AU Cristillo, AD Bierer, BE AF Cristillo, AD Bierer, BE TI Identification of novel targets of immunosuppressive agents by cDNA-based microarray analysis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID T-CELL PROLIFERATION; SIGNAL-TRANSDUCTION; CYCLOSPORINE-A; TYROSINE PHOSPHORYLATION; PHOSPHOLIPASE C-GAMMA-1; TRANSCRIPTION FACTORS; PROTEIN PHOSPHATASE; GENE-EXPRESSION; STAT PROTEINS; GROWTH-FACTOR AB The immunosuppressive agents cyclosporin A (C A) and tacrolimus (FK506) bind to unrelated intracellular immunophilin receptors, cyclophilin (CyP) and FK506-binding protein (FKBP), respectively. The complexes of CsA.CyP and of FK506-FKBP both bind to and inhibit the activity of the calcium/calmodulin-dependent serine/ threonine phosphatase calcineurin. We used cDNA microarray analysis to characterize early human peripheral blood T cell transcriptional responses following antigen receptor stimulation in the absence or presence of CsA or FK506, hoping to identify novel targets dependent upon calcineurin or immunophilins or, perhaps, specific targets of either CyP or FKBP inhibitable by one drug alone. The array data failed to identify genes uniquely sensitive to only one drug, suggesting that transcriptionally regulated, immunophilin-dependent but calcineurin-independent targets fell below the limits of detection in this system. In contrast, transcript profiling identified and mRNA and protein analysis confirmed novel as well as known genes reproducibly induced or inhibited by both immunosuppressive agents. In this context, we show that transcriptional activation of Stat5a and repression of the cytokine interleukin-16 are regulated by T cell receptor engagement and dependent upon drug-immunophilin complexes and, presumably, calcineurin activity. C1 NHLBI, Lab Lymphocyte Biol, NIH, Bethesda, MD 20892 USA. RP Bierer, BE (reprint author), NHLBI, Lab Lymphocyte Biol, NIH, Bldg 10,Rm 6C208,10 Ctr Dr, Bethesda, MD 20892 USA. NR 76 TC 34 Z9 35 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 FEB 8 PY 2002 VL 277 IS 6 BP 4465 EP 4476 DI 10.1074/jbc.M108598200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 520ZP UT WOS:000173813900089 PM 11694517 ER PT J AU Oka, H Suzuki, M Harada, KI Iwaya, M Fujii, K Goto, T Ito, Y Matsumoto, H Ito, Y AF Oka, H Suzuki, M Harada, KI Iwaya, M Fujii, K Goto, T Ito, Y Matsumoto, H Ito, Y TI Purification of Food Color Red No. 106 (acid red) using pH-zone-refining counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE counter-current chromatography; preparative chromatography; Food Color Red No. 106; acid red; dyes ID PERFORMANCE LIQUID-CHROMATOGRAPHY; UNSULFONATED AROMATIC-AMINES; C YELLOW NO-6; COAL-TAR DYES; SUBSIDIARY COLORS; SEPARATION; DIAZOTIZATION AB pH-Zone-refining counter-current chromatography was successfully applied to the separation of the main components of Food Color Red No. 106 (R-106, acid red, Color Index No. 45100). A 300-mg quantity of sample was separated using the following two-phase solvent system: n-butanol-water, 40 mM sulfuric acid in organic stationary phase and 30 mM ammonia in aqueous mobile phase. The obtained fractions were analyzed by high-performance liquid chromatography and fast atom bombardment mass spectrometry. The separation yielded 261.9 mg of main component of acid red with purity of 99.9%. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Aichi Prefectural Inst Publ Hlth, Kita Ku, Nagoya, Aichi 4628576, Japan. Meijo Univ, Fac Pharm, Tempa Ku, Nagoya, Aichi 4688503, Japan. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Oka, H (reprint author), Aichi Prefectural Inst Publ Hlth, Kita Ku, Nagoya, Aichi 4628576, Japan. NR 23 TC 38 Z9 38 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD FEB 8 PY 2002 VL 946 IS 1-2 BP 157 EP 162 DI 10.1016/S0021-9673(01)01548-5 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 521CF UT WOS:000173820700015 PM 11873964 ER PT J AU Muellbacher, W Ziemann, U Wissel, J Dang, N Kofler, M Facchini, S Boroojerdi, B Poewe, W Hallett, M AF Muellbacher, W Ziemann, U Wissel, J Dang, N Kofler, M Facchini, S Boroojerdi, B Poewe, W Hallett, M TI Early consolidation in human primary motor cortex SO NATURE LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; POSITRON EMISSION TOMOGRAPHY; LONG-TERM POTENTIATION; HORIZONTAL CONNECTIONS; DEPRESSION; PLASTICITY; IMPLICIT; MONKEYS; MEMORY; SAFETY AB Behavioural studies indicate that a newly acquired motor skill is rapidly consolidated from an initially unstable state to a more stable state(1), whereas neuroimaging studies demonstrate that the brain engages new regions for performance of the task as a result of this consolidation(2). However, it is not known where a new skill is retained and processed before it is firmly consolidated. Some early aspects of motor skill acquisition involve the primary motor cortex (M1)(3), but the nature of that involvement is unclear. We tested the possibility that the human M1 is essential to early motor consolidation. We monitored changes in elementary motor behaviour while subjects practised fast finger movements that rapidly improved in movement acceleration and muscle force generation. Here we show that low-frequency, repetitive transcranial magnetic stimulation of M1 but not other brain areas specifically disrupted the retention of the behavioural improvement, but did not affect basal motor behaviour, task performance, motor learning by subsequent practice, or recall of the newly acquired motor skill. These findings indicate that the human M1 is specifically engaged during the early stage of motor consolidation. C1 NINCDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Innsbruck Hosp, Dept Neurol, A-6020 Innsbruck, Austria. RP Hallett, M (reprint author), NINCDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Rm 5N226,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. OI Kofler, Markus/0000-0002-2962-0903 NR 23 TC 408 Z9 410 U1 5 U2 48 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 7 PY 2002 VL 415 IS 6872 BP 640 EP 644 DI 10.1038/nature712 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 519DC UT WOS:000173709100046 PM 11807497 ER PT J AU Miller, LH Baruch, DI Marsh, K Doumbo, OK AF Miller, LH Baruch, DI Marsh, K Doumbo, OK TI The pathogenic basis of malaria SO NATURE LA English DT Review ID FALCIPARUM-INFECTED ERYTHROCYTES; CHONDROITIN SULFATE-A; INTERCELLULAR-ADHESION MOLECULE-1; APICAL MEMBRANE ANTIGEN-1; RED-CELL SURFACE; PLASMODIUM-FALCIPARUM; ENDOTHELIAL-CELLS; CEREBRAL MALARIA; GLYCOSYLPHOSPHATIDYLINOSITOL TOXIN; VARIANT ANTIGEN AB Malaria is today a disease of poverty and underdeveloped countries. In Africa, mortality remains high because there is limited access to treatment in the villages. We should follow in Pasteur's footsteps by using basic research to develop better tools for the control and cure of malaria. Insight into the complexity of malaria pathogenesis is vital for understanding the disease and will provide a major step towards controlling it. Those of us who work on pathogenesis must widen our approach and think in terms of new tools such as vaccines to reduce disease. The inability of many countries to fund expensive campaigns and antimalarial treatment requires these tools to be highly effective and affordable. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Ctr Geog Med Res Coast, KEMRI Wellcome Trust Collaborat Programme, Kilifi, Kenya. Malaria Res & Training Ctr, Bamako, Mali. RP Miller, LH (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NR 82 TC 866 Z9 890 U1 43 U2 338 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 7 PY 2002 VL 415 IS 6872 BP 673 EP 679 DI 10.1038/415673a PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 519DC UT WOS:000173709100056 PM 11832955 ER PT J AU Richie, TL Saul, A AF Richie, TL Saul, A TI Progress and challenges for malaria vaccines SO NATURE LA English DT Review ID PLASMODIUM-FALCIPARUM MALARIA; HUMORAL IMMUNE-RESPONSES; PROTECTIVE EFFICACY; DNA VACCINATION; STAGE MALARIA; AOTUS MONKEYS; VIRUS ANKARA; PLASMID DNA; IN-VIVO; IMMUNOGENICITY AB Malaria causes much physical and economic hardship in tropical regions, particularly in communities where medical care is rudimentary. Should a vaccine be developed, it is the residents of these areas that stand to benefit the most. But the vaccine, which has been promised to be 'just round the corner' for many years, remains elusive. It is important to ask why this is so, when effective vaccines exist for many other infectious diseases. What are the reasons for the slow rate of progress, and what has been learned from the first clinical trials of candidate malaria vaccines? What are the remaining challenges, and what strategies can be pursued to address them? C1 Naval Med Res Ctr, Malaria Program, Silver Spring, MD 20910 USA. NIAID, Malaria Vaccine Dev Unit, NIH, Rockville, MD USA. RP Richie, TL (reprint author), Naval Med Res Ctr, Malaria Program, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. RI Richie, Thomas/A-8028-2011; Saul, Allan/I-6968-2013 OI Saul, Allan/0000-0003-0665-4091 NR 87 TC 218 Z9 227 U1 6 U2 24 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 7 PY 2002 VL 415 IS 6872 BP 694 EP 701 DI 10.1038/415694a PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 519DC UT WOS:000173709100059 PM 11832958 ER PT J AU Recio, JA Merlino, G AF Recio, JA Merlino, G TI Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1 SO ONCOGENE LA English DT Article DE melanoma; HGF/SF; p38; ATF-2; c-Met ID FACTOR SCATTER FACTOR; SIGNAL-TRANSDUCTION PATHWAY; PAPILLARY RENAL CARCINOMAS; ELEMENT-BINDING PROTEIN; FOCAL ADHESION KINASE; BREAST-CANCER CELLS; TYROSINE KINASE; C-MET; LEUCINE ZIPPER; SOMATIC MUTATIONS AB Members of the mitogen-activated protein kinase (MAPK) superfamily, including p38 kinase and SAPK/JNK, play a central role in mediating cellular response to environmental stress. growth factors and cytokines. Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional cytokine capable of eliciting mitogenic, motogenic and morphogenetic activities in responsive cells, and has been implicated in tumor development and metastasis. Binding of HGF/SF to its tyrosine kinase receptor c-Met stimulates multiple signal transduction pathways, leading to the activation of numerous transcription factors. We here report that HGF/SF can induce cyclin D1 expression in mouse melanoma cells. and that this up-regulation is mediated in part by the activating transcription factor-2 (ATF-2). HGF/SF-mediated phosphorylation of ATF-2 was reduced in the presence of either the p38 kinase-specific inhibitor SB203580, a dominant negative p38 mutant, the SAPK/JNK inhibitor JNK-interacting protein-1 (JIP-1), or the phosphatidylinositol 3-kinase (PI3K)-specific inhibitor LY294002. Activation of p38 kinase by HGF/SF was partially blocked by the PI3K-specific inhibitor as well. The upstream kinases for p38, MKK3/6, did not become activated following HGF/SF exposure, and ATF-2 activation was undiminished by transient transfection of a dominant negative MKK6 mutant. However, transcriptional up-regulation of cyclin D1 by HGF/SF was partially inhibited by the p38 kinase-specific inhibitor, and cyclin D1 protein induction was partially blocked by a dominant negative ATF-2 mutant. Notably, the p38 kinase-specific inhibitor was able to block melanoma cell proliferation but not motility. We conclude that the ATF-2 transcription factor becomes activated by HGF/SF through p38 MAPK and SAPK/JNK. Moreover, the p38-ATF-2 pathway can help mediate proliferation signals in tumor cells through transcriptional activation of key cell cycle regulators. C1 NCI, Mol Biol Lab, Mol Genet Sect, NIH, Bethesda, MD 20892 USA. RP Merlino, G (reprint author), NCI, Mol Biol Lab, Mol Genet Sect, NIH, Bldg 37,Room 5002,MSC 4264, Bethesda, MD 20892 USA. EM gmerlino@helix.nih.gov NR 70 TC 105 Z9 114 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 7 PY 2002 VL 21 IS 7 BP 1000 EP 1008 DI 10.1038/sj.onc.1205150 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 516WQ UT WOS:000173580100003 PM 11850817 ER PT J AU Rong, R He, Q Liu, Y Sheikh, MS Huang, Y AF Rong, R He, Q Liu, Y Sheikh, MS Huang, Y TI TC21 mediates transformation and cell survival via activation of phosphatidylinositol 3-kinase/Akt and NF-kappa B signaling pathway SO ONCOGENE LA English DT Article DE TC21; PI3-K; Akt; transformation; cell survival; NF-kappa B ID PROTEIN-KINASE-B; PHOSPHOINOSITIDE 3-KINASE; RAS; AKT; GENE; EXPRESSION; APOPTOSIS; CASCADE; INDUCTION; STRESS AB The signaling pathways of TC21-mediated transformation and cell survival are not well-established. In this study, we have investigated the role of PI3-K/Akt signaling pathway in oncogenic-TC21-mediated transformation and cell survival. We found that oncogenic-TC21 stimulated the PI3-K activity. This was associated with the activation of Akt, a key, component of PI3-K signaling pathway. We also found that TC21 interacted and formed complex with PI3-K. Mutations in the GTP-binding region of TC21, which enhanced GTP-binding potential of this protein, also stimulated its association with PI3-K, suggesting that PI3-K may preferentially interact with the GTP-bound form. Suppression of PI3-K and Akt by specific inhibitors LY294002 and Wortmannin reversed TC21-induced transformation. Likewise, inhibition of PI3-K activity by the PI3-K phosphotase PTEN reduced TC21-mediated focus formation in NIH3T3 cells. Investigation of TC21's effect on cell survival revealed that mutant-TC21 expressing cells were more resistant to etoposide- and cisplatin-induced cell death, and this was associated with the activation of anti-apoptotic protein NF-kappaB, a downstream target of Akt. Treatment of PI3-K inhibitor LY294002 significantly suppressed TC21-mediated NF-kappaB activation. In conclusion, we have identified PI3-K as an effector of TC21 and demonstrated that the PI3-K/Akt signaling pathway plays important roles in TC21-mediated transformation and cell survival. C1 SUNY Upstate Med Univ, Dept Pharmacol, Syracuse, NY 13210 USA. NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. RP Huang, Y (reprint author), SUNY Upstate Med Univ, Dept Pharmacol, 750 E Adams St, Syracuse, NY 13210 USA. RI Liu, Yusen/E-3527-2011 NR 59 TC 36 Z9 38 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 7 PY 2002 VL 21 IS 7 BP 1062 EP 1070 DI 10.1038/sj.onc.1205154 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 516WQ UT WOS:000173580100009 PM 11850823 ER PT J AU Clinton, JM Chansky, HA Odell, DD Zielinska-Kwiatkowska, A Hickstein, DD Yang, L AF Clinton, JM Chansky, HA Odell, DD Zielinska-Kwiatkowska, A Hickstein, DD Yang, L TI Characterization and expression of the human gene encoding two translocation liposarcoma protein-associated serine-arginine (TASR) proteins SO GENE LA English DT Article DE U12-type intron; retroposition; alternative splicing; RNA-binding protein ID SPLICE SITES; RNA; TRANSCRIPTION; SPECIFICITY; RETROPOSONS; SEQUENCES; INTERACTS; INTRONS; FAMILY AB Translocation liposarcoma protein (TLS)-associated serine-arginine (TASR)-1 and -2 are two newly identified serine-arginine splicing factors. Our recent studies suggest that disruption of TASR-mediated pre-mRNA splicing is involved in the pathogenesis of human leukemia and sarcomas. The mRNA transcripts for TASR-1 and -2 share an identical sequence at the 5' untranslated region (5' UTR) and in part of the coding region; however the other regions of the transcripts diverge from each other and it was not clear whether the differences resulted from alternative splicing or transcription from two distinct genes. Here we describe the assignment of both TASR cDNAs to the same 16 kb DNA segment located on chromosome 1. Despite the presence of at least three retroposed products of TASR-1 mRNA in the human genome, only the 16 kb structural TASR gene on chromosome 1 is actively transcribed. In addition, multiple polyadenylation sites and a rare U12-type intron were found within the TASR gene. Transcription initiation site of the TASR gene was determined by primer extension; analysis of the TASR promoter revealed that it lacks the TATA box but contains a GC-rich sequence. When cloned into a luciferase reporter and transfected into human cells, the TASR promoter construct generated luciferase activity that was at least 2000 fold greater than the promoterless plasmid. Northern blot analysis showed that at least five different TASR-1 and -2 transcripts are expressed in a broad range of human tissues. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Washington, Sch Med, Dept Orthoped & Sports Med, Seattle, WA 98108 USA. VA Puget Sound Hlth Care Syst, Med Res Serv, Seattle, WA 98108 USA. NCI, Dept Expt Transplantat & Immunol, Bethesda, MD 20892 USA. RP Yang, L (reprint author), Univ Washington, Sch Med, Dept Orthoped & Sports Med, 1660 S Columbian Way GMR 151, Seattle, WA 98108 USA. NR 21 TC 8 Z9 10 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD FEB 6 PY 2002 VL 284 IS 1-2 BP 141 EP 147 AR PII S0378-1119(02)00382-7 DI 10.1016/S0378-1119(02)00382-7 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 534QN UT WOS:000174598100014 PM 11891055 ER PT J AU Makalowska, I Sood, R Faruque, MU Hu, P Robbins, CM Eddings, EM Mestre, JD Baxevanis, AD Carpten, JD AF Makalowska, I Sood, R Faruque, MU Hu, P Robbins, CM Eddings, EM Mestre, JD Baxevanis, AD Carpten, JD TI Identification of six novel genes by experimental validation of GeneMachine predicted genes SO GENE LA English DT Article DE chromosome 1; sequence annotation ID PROTEIN-CODING REGIONS; PROSTATE-CANCER; DISCRIMINANT-ANALYSIS; DNA-SEQUENCES; HUMAN GENOME; PROGRAMS; SEARCH; LOCUS AB In silico gene identification from finished and unfinished human genome sequence has become critically important in many projects seeking to gain insights into the gene content of genomic regions implicated in diseases. To establish limitations and criteria for in silico gene identification, and to identify novel genes of potential relevance to human prostate cancer and melanoma, 3 Mb of chromosome 1 sequence have been analyzed using GeneMachine. This program is a software suite comprising of sequence similarity programs and four gene identification programs. A total of 49 potential transcripts were selected and 37 of them were selected for experimental validation. We verified 16 of the predicted genes by experimental analysis. The comparison of the predicted transcripts with their cloned forms helped to refine predicted gene models as well as to identify splice variants for several of them. Although sequences matching with ten of our verified genes have been recently deposited in the GenBank, six of them remain novel, Our studies support the feasibility of identifying novel genes from regions of interest using draft human genome sequence. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Natl Inst Hlth, Natl Human Genome Res Inst, Genome Technol Branch, Bethesda, MD USA. Natl Inst Hlth, Natl Human Genome Res Inst, Canc Genet Branch, Bethesda, MD USA. RP Makalowska, I (reprint author), Penn State Univ, Life Sci Consortium, 506 Wartik Lab, University Pk, PA 16802 USA. EM izabelam@psu.edu NR 28 TC 3 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD FEB 6 PY 2002 VL 284 IS 1-2 BP 203 EP 213 AR PII S0378-1119(01)00897-6 DI 10.1016/S0378-1119(01)00897-6 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 534QN UT WOS:000174598100020 PM 11891061 ER PT J AU Leshner, AI AF Leshner, AI TI What should the public be told about the risks of ecstasy? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIH, Washington, DC 20032 USA. RP Leshner, AI (reprint author), NIH, Washington, DC 20032 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 6 PY 2002 VL 287 IS 5 BP 585 EP 585 DI 10.1001/jama.287.5.585 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 518UR UT WOS:000173686700016 PM 11829686 ER PT J AU Travis, LB Gospodarowicz, M Curtis, RE Clarke, EA Andersson, M Glimelius, B Joensuu, T Lynch, CF van Leeuwen, FE Holowaty, E Storm, H Glimelius, I Pukkala, E Stovall, M Fraumeni, JF Boice, JD Gilbert, E AF Travis, LB Gospodarowicz, M Curtis, RE Clarke, EA Andersson, M Glimelius, B Joensuu, T Lynch, CF van Leeuwen, FE Holowaty, E Storm, H Glimelius, I Pukkala, E Stovall, M Fraumeni, JF Boice, JD Gilbert, E TI Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID 2ND CANCERS; RISK; LEUKEMIA; THERAPY; DNA; SMOKING; REPAIR; METHYLATION; SURVIVORS; EXPOSURE AB Background: Lung cancer is a frequent cause of death in patients cured of Hodgkin's disease, but the contributions of chemotherapy, radiotherapy, and smoking are not well described. We quantified the risk of treatment-associated lung cancer, taking into account tobacco use. Methods: Within a population-based cohort of 19 046 Hodgkin's disease patients (diagnosed from 1965 through 1994), a case-control study of lung cancer was conducted. The cumulative amount of cytotoxic drugs, the radiation dose to the specific location in the lung where cancer developed, and tobacco use were compared for 222 patients who developed lung cancer and for 444 matched control patients. All statistical tests were two-sided. Results: Treatment with alkylating agents without radiotherapy was associated with increased lung cancer risk (relative risk [RR] = 4.2; 95% confidence interval [CI] = 2.1 to 8.8), as was radiation dose of 5 Gy or more without alkylating agents (RR = 5.9; 95% CI = 2.7 to 13.5). Risk increased with both increasing number of cycles of alkylating agents and increasing radiation dose (P for trend <.001). Among patients treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), risk increased with cumulative amounts of mechlorethamine and procarbazine (P<.001) when evaluated separately. Statistically significantly elevated risks of lung cancer were apparent within 1-4 years after treatment with alkylating agents, whereas excess risk after radiotherapy began 5 years after treatment and persisted for more than 20 years. Risk after treatment with alkylating agents and radiotherapy together was as expected if individual excess risks were summed. Tobacco use increased lung cancer risk more than 20-fold; risks from smoking appeared to multiply risks from treatment. Conclusions: Past treatments with alkylating agents and radiation therapy for Hodgkin's disease were associated with an increased risk of lung cancer in a dose-dependent and additive fashion. The precise risk estimates, however, should be interpreted cautiously, given the possible residual and enhancing effects of tobacco. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. Canc Care Ontario, Toronto, ON, Canada. Danish Canc Soc, Copenhagen, Denmark. Uppsala Univ, Stockholm, Sweden. Univ Helsinki, Cent Hosp, Helsinki, Finland. Univ Iowa, Iowa City, IA USA. Netherlands Canc Inst, Amsterdam, Netherlands. Finnish Canc Registry, FIN-00170 Helsinki, Finland. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Int Epidemiol Inst, Rockville, MD USA. Vanderbilt Univ, Dept Med, Nashville, TN USA. Vanderbilt Ingram Canc Ctr, Dept Med, Nashville, TN USA. RP Travis, LB (reprint author), NIH, EPS 7086, Bethesda, MD 20892 USA. OI Glimelius, Ingrid/0000-0001-6158-3041 NR 54 TC 284 Z9 289 U1 0 U2 4 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 FEB 6 PY 2002 VL 94 IS 3 BP 182 EP 192 PG 11 WC Oncology SC Oncology GA 517KC UT WOS:000173608800009 PM 11830608 ER PT J AU Walsh, CR Larson, MG Evans, JC Djousse, L Ellison, RC Vasan, RS Levy, D AF Walsh, CR Larson, MG Evans, JC Djousse, L Ellison, RC Vasan, RS Levy, D TI Alcohol consumption and risk for congestive heart failure in the Framingham Heart Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID IDIOPATHIC DILATED CARDIOMYOPATHY; CIGARETTE-SMOKING; NATURAL-HISTORY; BLOOD-PRESSURE; MORTALITY; POPULATION; DISEASE; WOMEN; MEN; DYSFUNCTION AB Background: Although excessive alcohol consumption can promote cardiomyopathy, little is known about the association between alcohol consumption and risk for congestive heart failure in the community. Objective: To determine the relation between alcohol consumption and risk for congestive heart failure in the community. Design: Community-based, prospective observational study. Setting: Framingham, Massachusetts. Participants: Participants in the Framingham Heart Study who were free of congestive heart failure and coronary heart disease. Measurements: Self-reported alcohol consumption; sex-specific rates of congestive heart failure per 1000 person-years of follow-up by level of alcohol consumption. Results: In men, 99 cases of congestive heart failure occurred during 26 035 person-years of follow-up. In women, 120 cases of congestive heart failure occurred during 35 563 person-years of follow-up. After adjustment for multiple confounders, risk for congestive heart failure was lower among men at all levels of alcohol consumption compared with men who consumed less than 1 drink/wk. The hazard ratio for congestive heart failure was lowest among men who consumed 8 to 14 drinks/wk (0.41 [95% CI, 0.21 to 0.81]) compared with those who consumed less than 1 drink/wk. In women, the age-adjusted hazard ratio for congestive heart failure was lowest among those who consumed 3 to 7 drinks/wk (0.49 [CI, 0.25 to 0.96]) compared with those who consumed less than 1 drink/wk. However, after adjustment for multiple predictors of congestive heart failure, this association was no longer statistically significant. Conclusions: In the community, alcohol consumption is not associated with increased risk for congestive heart failure, even among heavy drinkers (greater than or equal to15 drinks/wk in men and greater than or equal to8 drinks/wk in women). To the contrary, when consumed in moderation, alcohol appears to protect against congestive heart failure. C1 NHLBI, Framingham Heart Study, NIH, Framingham, MA 01702 USA. Boston Univ, Sch Med, Massachusetts Gen Hosp, Beth Israel Deaconess Med Ctr, Boston, MA 02118 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, NIH, 5 Thurber St, Framingham, MA 01702 USA. RI Djousse, Luc/F-5033-2017; OI Djousse, Luc/0000-0002-9902-3047; Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [N01-HC-38038, 1K24 HL04334]; NIAMS NIH HHS [AR/AG 41398] NR 47 TC 109 Z9 112 U1 0 U2 12 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 FEB 5 PY 2002 VL 136 IS 3 BP 181 EP 191 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 517YD UT WOS:000173637400001 PM 11827493 ER PT J AU Laco, GS Collins, JR Luke, BT Kroth, H Sayer, JM Jerina, DM Pommier, Y AF Laco, GS Collins, JR Luke, BT Kroth, H Sayer, JM Jerina, DM Pommier, Y TI Human topoisomerase I inhibition: Docking camptothecin and derivatives into a structure-based active site model SO BIOCHEMISTRY LA English DT Article ID DNA CLEAVABLE COMPLEXES; DIOL EPOXIDE ADDUCTS; DOUBLE-STRAND BREAKS; REPLICATION FORKS; CARBOXYLATE FORMS; CRYSTAL-STRUCTURE; CYTO-TOXICITY; RESISTANT; LACTONE; CELLS AB Human topoisomerase I (top 1) is an important target for anti-cancer drugs, which include camptothecin (CPT) and its derivatives. To elucidate top 1 inhibition in vitro, we made a series of duplex DNA substrates containing a deoxyadenosine stereospecifically modified by a covalent adduct of benzo[a]pyrene (BaP) diol epoxide [Pommier, Y., et al. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 10739-10744]. The known orientation of the hydrocarbon adduct in the DNA duplex relative to the top 1 cleavage site, in combination with a top 1/DNA crystal structure [Redinbo, M. R., et al. (1998) Science 279, 1504-1513], was used to construct a structure-based model to explain the in vitro top 1 inhibition results obtained with adducted DNA duplexes. Here we experimentally determined that the lactone form of CPT was stabilized by an irreversible top 1/DNA covalent complex. We removed the BaP moiety from the DNA in the published model, and docked the lactone forms of CPT and derivatives into the top 1/DNA active site cavity. The docked ligands were minimized, and interaction energy scores between the ligands and the top 1/DNA complex were determined. CPT docks perpendicular to the DNA backbone, projects outward 7 from the major groove, and makes a network of potential H-bonds with the active site DNA and top 1 residues, including Arg364, Lys532, and Asn722. The results are consistent with the known structureactivity relationships of CPT and derivatives. In addition, the model proposed a novel top 1/N352A "resistance" mutation for 10-OH derivatives of CPT. The in vitro biochemical characterization of the top 1/N352A mutant supported the model. C1 NCI, Div Basic Sci, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NCI, Frederick SAIC, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Pommier, Y (reprint author), NCI, Div Basic Sci, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CO-56000] NR 65 TC 65 Z9 70 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 5 PY 2002 VL 41 IS 5 BP 1428 EP 1435 DI 10.1021/bi011774a PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 517LP UT WOS:000173612300002 PM 11814334 ER PT J AU Schron, EB Exner, DV Yao, Q Jenkins, LS Steinberg, JS Cook, JR Kutalek, SP Friedman, PL Bubien, RS Page, RL Powell, J AF Schron, EB Exner, DV Yao, Q Jenkins, LS Steinberg, JS Cook, JR Kutalek, SP Friedman, PL Bubien, RS Page, RL Powell, J CA AVID Investigators TI Quality of life in the antiarrhythmics versus Implantable Defibrillators trial - Impact of therapy and influence of adverse symptoms and defibrillator shocks SO CIRCULATION LA English DT Article DE quality of life; antiarrhythmia agents; heart arrest; tachyarrhythmias; defibrillation ID INTERNAL CARDIOVERTER-DEFIBRILLATOR; OF-LIFE; MEDICAL OUTCOMES; ARRHYTHMIAS; INDEX; SF-36 AB Background-Implantable cardioverter defibrillator (ICD) use reduces mortality in patients with serious ventricular arrhythmias compared with antiarrhythmic drug (AAD) use. However, the relative impact of these therapies on self-perceived quality of life (QoL) is unknown. Methods and Results-Three self-administered instruments were used to measure generic and disease-specific QoL in Antiarrhythmics Versus Implantable Defibrillators trial participants. Generalized linear models were used to assess the relationships between self-perceived QoL and treatment (AAD versus ICD) and adverse symptoms and ICD shocks. To minimize the impact of missing data, only patients surviving 1 year were included in the primary analyses. Baseline characteristics among QoL participants (n=905) and nonparticipants (n=111) were similar, but participants who survived 1 year (n=800) were healthier at baseline than nonsurvivors (n=105). Of the 800 patients in the primary analysis, characteristics of those randomized to AAD (n=384) versus ICD (n=416) were similar. Overall, ICD and AAD use were associated with similar alterations in QoL. The development of sporadic shocks and adverse symptoms were each associated with reduced physical functioning and mental well-being and increased concerns among ICD recipients, whereas development of adverse symptoms was associated with reduced physical functioning and increased concerns among AAD recipients. Conclusions-ICD and AAD therapy are associated with similar alterations in self-perceived QoL over 1-year follow-up. Adverse symptoms were associated with reduced self-perceived QoL in both groups, and sporadic shocks were associated with reduced QoL in ICD recipients. C1 NHLBI, Clin Trials Grp, Bethesda, MD 20892 USA. Univ Calgary, Calgary, AB T2N 1N4, Canada. Univ Washington, Seattle, WA 98195 USA. Univ Maryland, Baltimore, MD 21201 USA. St Lukes Hosp, New York, NY USA. Baystate Med Ctr, Springfield, MA USA. MCP Hahnemann Univ Hosp, Philadelphia, PA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Alabama, Birmingham, AL USA. UT Southwestern, Dallas, TX USA. Seattle Univ, Seattle, WA 98122 USA. RP Exner, DV (reprint author), 3330 Hosp Dr NW,Room G208, Calgary, AB T2N 4N1, Canada. RI Page, Richard/L-5501-2014 OI Page, Richard/0000-0001-5603-1330 FU NHLBI NIH HHS [N01 HC-25117] NR 35 TC 347 Z9 352 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 5 PY 2002 VL 105 IS 5 BP 589 EP 594 DI 10.1161/hc0502.103330 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 519PV UT WOS:000173735400025 PM 11827924 ER PT J AU Cumming, B AF Cumming, B TI Stereopsis: Where depth is seen SO CURRENT BIOLOGY LA English DT Editorial Material ID AREA MT; PERCEPTION; NEURONS AB Disparity-selective cells appear to occur in all parts of the visual cortex, but a recent fMRI study finds that some cortical areas are more strongly associated with disparity than others. More sophisticated tests of binocular function may be needed to identify the properties of single neurons that support this specialization. C1 NEI, Lab Sensorimotor Res, NIH, Bethesda, MD 20892 USA. RP Cumming, B (reprint author), NEI, Lab Sensorimotor Res, NIH, Bldg 49 Rm 2A50, Bethesda, MD 20892 USA. NR 18 TC 6 Z9 6 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD FEB 5 PY 2002 VL 12 IS 3 BP R93 EP R95 DI 10.1016/S0960-9822(02)00669-3 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 520FG UT WOS:000173769900008 PM 11839288 ER PT J AU Phillips, LR Jorden, JL Rivera, MI Upadhyay, K Wolfe, TL Stinson, SF AF Phillips, LR Jorden, JL Rivera, MI Upadhyay, K Wolfe, TL Stinson, SF TI Identification of the major metabolite of 2,5-bis(5-hydroxymethyl-2-thienyl)furan (NSC 652287), an antitumor agent, in the S9 subcellular fraction of dog liver cells SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE 2,5-bis(5-hydroxymethyl-2-thienyl)furan; NSC 652287 AB alpha-Terthienyl (1) is a trithiophene found widely distributed in plants. Other naturally occurring trithiophenes axe less widely distributed, but nonetheless exhibit potent antiviral and cytotoxic activities. A synthetic analog of 1, 2,5-bis(5-hydroxymethyl-2-thienyl)furan (2, NSC 652287) has recently been shown to possess exceptional activity and selectivity against several cell lines of the National Cancer Institute (NCI) anticancer drug screen.. When incubated with the S9 subcellular fraction of dog liver cells, the concentration of 2 was observed to decline as a function of time, with a concomitant increase in a significant, time-dependent concentration of an unknown entity. The results of electron-ionization mass spectrometric analysis of the metabolite indicate an increase in 14 amu over that of 2, leading to suspicions that either an oxidation or a methylation had occurred. Results of differential derivatization and accurate mass analysis allow us to propose that metabolism of 2 involves the biotransformation of one of the two hydroxymethyl groups of 2 into a carboxylic acid functionality. This is further supported by separate experiments involving chemical oxidation and S9 incubation of 5-[5-[5-hydroxymethyl-2-thienyl]-2-furanyl]-2-thiophenecarboxaldehyde comparing the mass spectra and gas chromatographic retention times of the resulting products to those of the identified metabolite of 2 show all to be the same. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NCI, Biol Testing Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD 21701 USA. NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. RP Phillips, LR (reprint author), NCI, Biol Testing Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Bldg 1052,Room 121, Frederick, MD 21701 USA. FU NCI NIH HHS [N01-CO-56000] NR 12 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD FEB 5 PY 2002 VL 767 IS 1 BP 27 EP 33 DI 10.1016/S0378-4347(01)00530-8 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 517YA UT WOS:000173637000004 PM 11863292 ER PT J AU Minnick, DT Liu, LX Grindley, NDF Kunkel, TA Joyce, CM AF Minnick, DT Liu, LX Grindley, NDF Kunkel, TA Joyce, CM TI Discrimination against purine-pyrimidine mispairs in the polymerase active site of DNA polymerase I: A structural explanation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MISMATCHED BASE-PAIRS; ESCHERICHIA-COLI; KLENOW FRAGMENT; REPLICATION FIDELITY; CRYSTAL-STRUCTURES; SPECIFICITY; MUTAGENESIS; RESOLUTION; SUBSTRATE; COMPLEXES AB We previously identified five derivatives of Klenow fragment DNA polymerase that have lower fidelity because of amino acid substitutions in the polymerase active site. One of these has alanine substituted for the invariant Glu-710, whose side chain interacts with the deoxyribose of the incoming dNTP. Here we show that the E710A enzyme has reduced fidelity for five of the 12 possible mismatches. All but one of these involve misinsertion of pyrimidines, including two transition mismatches A-dCTP and G-dTTP. In contrast, E710A polymerase error rates for the reciprocal C-dATP and T-dGTP transition mismatches were similar to those of the wild-type enzyme. The kinetics of formation of correct base pairs and transition mismatches by the wild-type and E710A polymerases, combined with information on the structure of the DNA polymerase active site and the asymmetry of wobble base pairs, provides a plausible explanation for the differential effects of the E710A mutation on fidelity. The data suggest that the Glu-710 side chain plays a pivotal role in excluding wobble base pairs between template pyrimidines and purine triphosphates by steric clash. Moreover, this same side chain enhances the stability of incoming correct dNTPs, such that loss of this interaction on removal of the side chain leads to lower selectivity against mismatches involving incoming pyrimidines. C1 Yale Univ, Dept Mol Biophys & Biochem, Bass Ctr Mol & Struct Biol, New Haven, CT 06520 USA. NIEHS, Genet Mol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Joyce, CM (reprint author), Yale Univ, Dept Mol Biophys & Biochem, Bass Ctr Mol & Struct Biol, 266 Whitney Ave,POB 208114, New Haven, CT 06520 USA. FU NIGMS NIH HHS [GM-28550, R01 GM028550] NR 42 TC 37 Z9 37 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 FEB 5 PY 2002 VL 99 IS 3 BP 1194 EP 1199 DI 10.1073/pnas.032457899 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 519YF UT WOS:000173752500020 PM 11830658 ER PT J AU Leikina, E Mertts, MV Kuznetsova, N Leikin, S AF Leikina, E Mertts, MV Kuznetsova, N Leikin, S TI Type I collagen is thermally unstable at body temperature SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MOLECULAR CHAPERONE; PROCOLLAGEN; STABILITY; HSP47; FIBRILLOGENESIS; STABILIZATION; CLEAVAGE; FIBRILS; FIBERS; HELIX AB Measured by ultra-slow scanning calorimetry and isothermal circular dichroism, human lung collagen monomers denature at 37degreesC within a couple of days. Their unfolding rate decreases exponentially at lower temperature, but complete unfolding is observed even below 36degreesC. Refolding of full-length, native collagen triple helices does occur, but only below 30degreesC. Thus, contrary to the widely held belief, the energetically preferred conformation of the main protein of bone and skin in physiological solution is a random coil rather than a triple helix. These observations suggest that once secreted from cells collagen helices would begin to unfold. We argue that initial microunfolding of their least stable domains would trigger self-assembly of fibers where the helices are protected from complete unfolding. Our data support an earlier hypothesis that in fibers collagen helices may melt and refold locally when needed, giving fibers their strength and elasticity. Apparently, Nature adjusts collagen hydroxyproline content to ensure that the melting temperature of triple helical monomers is several degrees below rather than above body temperature. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Leikin, S (reprint author), NICHHD, NIH, 12A,Room 2041,12 S Dr MSC 5626, Bethesda, MD 20892 USA. RI Leikin, Sergey/A-5518-2008 OI Leikin, Sergey/0000-0001-7095-0739 NR 27 TC 283 Z9 290 U1 2 U2 34 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 5 PY 2002 VL 99 IS 3 BP 1314 EP 1318 DI 10.1073/pnas.032307099 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 519YF UT WOS:000173752500041 PM 11805290 ER PT J AU Resnati, M Pallavicini, I Wang, JM Oppenheim, J Serhan, CN Romano, M Blasi, F AF Resnati, M Pallavicini, I Wang, JM Oppenheim, J Serhan, CN Romano, M Blasi, F TI The fibrinolytic receptor for urokinase activates the G protein-coupled chemotactic receptor FPRL1/LXA4R SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PLASMINOGEN-ACTIVATOR; CELL-ADHESION; DEFICIENT MICE; MIGRATION; A(4); IDENTIFICATION; INFECTION; INVASION; CLEAVAGE; GROWTH AB The function of urokinase and its receptor is essential for cell migration in pathological conditions, as shown by the analysis of knockout mice phenotypes. How a protease of a fibrinolytic pathway can induce migration is not understood and no link between this protease and migration-promoting G protein-coupled receptors has been described. We now show that FPRL1/LXA4R, a G protein-coupled receptor for a number of polypeptides and for the endogenous lipoxin A4 (LXA4), is the link between urokinase-type plasminogen activator (uPA) and migration as it directly interacts with an activated, soluble, cleaved form of uPA receptor (uPAR) (D2D3(88-274)) to induce chemotaxis, In this article we show that (i) both uPAR and FPRL1/LXA4R are necessary for the chemotactic activity of uPA whereas FPRL1/LXA4R is sufficient to mediate D2D3(88-274)-induced cell migration. (R) Inhibition or desensitization of FPRL1/LXA4R by antibodies or specific ligands specifically prevents chemotaxis induced by D2D388-274 in THP-1 cells and human peripheral blood monocytes. (M) Desensitization of FPRL1/ LXA4R prevents the activation of tyrosine kinase Hck induced by D2D3(88-274). (iv) D2D3(88-274) directly binds to FPRL1/LXA4R and is competed by two specific FPRL1/LXA4R agonists, the synthetic MMK-1 peptide and a stable analog of LXA4. Thus, a naturally produced cleaved form of uPAR is a unique endogenous chemotactic agonist for FPRL1/LXA4R receptor and its activity can be antagonized by specific ligands. These results provide the first direct link, to our knowledge, between the fibrinolytic machinery and the inflammatory response, demonstrating that uPA-derived peptide fragments can activate a specific chemotactic receptor. C1 San Raffaele Sci Inst, DIBIT, Dept Cell Biol & Funct Genom, Mol Genet Unit, I-20132 Milan, Italy. Univ Vita Salute San Raffaele, I-20132 Milan, Italy. NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Frederick, MD 21702 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med,Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. Univ Messina, Dept Human Pathol, I-98125 Messina, Italy. RP Blasi, F (reprint author), San Raffaele Sci Inst, DIBIT, Dept Cell Biol & Funct Genom, Mol Genet Unit, Via Olgettina 58, I-20132 Milan, Italy. OI ROMANO, Mario/0000-0001-8512-1458 FU NIGMS NIH HHS [R37 GM038765, GM 38765, R01 GM038765] NR 32 TC 257 Z9 270 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 5 PY 2002 VL 99 IS 3 BP 1359 EP 1364 DI 10.1073/pnas.022652999 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 519YF UT WOS:000173752500049 PM 11818541 ER PT J AU Kovalchuk, AL Kim, JS Park, SS Coleman, AE Ward, JM Morse, HC Kishimoto, T Potter, M Janz, S AF Kovalchuk, AL Kim, JS Park, SS Coleman, AE Ward, JM Morse, HC Kishimoto, T Potter, M Janz, S TI IL-6 transgenic mouse model for extraosseous plasmacytoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID C-MYC; CHROMOSOMAL TRANSLOCATIONS; MURINE PLASMACYTOMAS; BALB/C MICE; INTERLEUKIN-6; ACTIVATION; CELLS; OVEREXPRESSION; RECOMBINATIONS; INDUCTION AB Plasma cell neoplasms in humans comprise plasma cell myeloma, otherwise known as multiple myeloma, Ig deposition and heavy chain diseases, and plasmacytoma (PCT). A subset of PCT, designated extramedullary PCT, is distinguished from multiple myeloma and solitary PCT of bone by its distribution among various tissue sites but not the bone marrow. Extramedullary (extraosseus) PCT are rare spontaneous neoplasms of mice but are readily induced in a susceptible strain, BALB/c, by treatment with pristane. The tumors develop in peritoneal granulomas and are characterized by Myc-activating T(12;15) chromosomal translocations and, most frequently, by secretion of IgA. A uniting feature of human and mouse plasma cell neoplasms is the critical role played by IL-6, a B cell growth, differentiation, and survival factor. To directly test the contribution of IL-6 to PCT development, we generated BALB/c mice carrying a widely expressed IL-6 transgene. All mice exhibited lymphoproliferation and plasmacytosis. By 18 months of age, over half developed readily transplantable PCT in lymph nodes, Peyer's patches, and sometimes spleen. These neoplasms also had T(12;15) translocations, but remarkably, none expressed IgA. Unexpectedly, approximate to30% of the mice developed follicular and diffuse large cell B cell lymphomas that often coexisted with PCT. These findings provide a unique model of extramedullary PCT for studies on pathogenesis and treatment and suggest a previously unappreciated role for IL-6 in the genesis of germinal center-derived lymphomas. C1 NCI, Genet Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. Korea Res Inst Biosci & Biotechnol, Taejon 305333, South Korea. NCI, Vet & Tumor Pathol Sect, NIH, Ft Detrick, MD 21702 USA. Osaka Univ, Sch Med, Inst Mol & Cellular Biol, Osaka 565, Japan. RP Janz, S (reprint author), NCI, Genet Lab, Canc Res Ctr, NIH, Bldg 37,Room 2B10, Bethesda, MD 20892 USA. RI Kishimoto, Tadamitsu/C-8470-2009; OI Morse, Herbert/0000-0002-9331-3705 NR 43 TC 92 Z9 93 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 5 PY 2002 VL 99 IS 3 BP 1509 EP 1514 DI 10.1073/pnas.022643999 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 519YF UT WOS:000173752500075 PM 11805288 ER PT J AU Wu, L Bashirova, AA Martin, TD Villamide, L Mehlhop, E Chertov, AO Unutmaz, D Pope, M Carrington, M KewalRamani, VN AF Wu, L Bashirova, AA Martin, TD Villamide, L Mehlhop, E Chertov, AO Unutmaz, D Pope, M Carrington, M KewalRamani, VN TI Rhesus macaque dendritic cells efficiently transmit primate lentiviruses independently of DC-SIGN SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; C-TYPE LECTIN; T-CELLS; LYMPHOID-TISSUE; INFECTION; REPLICATION; HIV-1; SUSCEPTIBILITY; BLOOD; SIV AB Here, we describe the isolation and characterization of the rhesus macaque homolog for human DC-SIGN, a dendritic cell-specific C-type lectin. mac-DC-SIGN is 92% identical to hu-DC-SIGN. mac-DC-SIGN preserves the virus transmission function of hu-DC-SIGN, capturing and efficiently transducing simian and human immunodeficiency virus to target CD4(+) T cells. Surprisingly, however, mac-DC-SIGN plays no discernable role in the ability of rhesus macaque dendritic cells to capture and transmit primate lentiviruses. Expression and neutralization analyses suggest that this process is DC-SIGN independent in macaque, although the participation of other lectin molecules cannot be ruled out. The ability of primate lentiviruses to effectively use human and rhesus dendritic cells in virus transmission without the cells becoming directly infected suggests that these viruses have taken advantage of a conserved dendritic cell mechanism in which DC-SIGN family molecules are significant contributors but not the only participants. C1 Natl Canc Inst, HIV Drug Resistance Program, Ft Detrick, MD 21702 USA. Natl Canc Inst, Lab Genom Divers, Ft Detrick, MD 21702 USA. Natl Canc Inst, Basic Res Program, Sci Applicat Int Corp Frederick, Ft Detrick, MD 21702 USA. Populat Council, Ctr Biomed Res, New York, NY 10021 USA. Vanderbilt Univ, Sch Med, Nashville, TN 37232 USA. RP KewalRamani, VN (reprint author), Natl Canc Inst, HIV Drug Resistance Program, Ft Detrick, MD 21702 USA. RI Wu, Li/E-4330-2011 OI Wu, Li/0000-0002-5468-2487 FU NCI NIH HHS [N01CO12400, N01-CO-12400]; NIAID NIH HHS [R37 AI040877, AI40877, R01 AI040877] NR 44 TC 74 Z9 78 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 5 PY 2002 VL 99 IS 3 BP 1568 EP 1573 DI 10.1073/pnas.032654399 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 519YF UT WOS:000173752500085 PM 11818554 ER PT J AU Dobolyi, A Ueda, H Uchida, H Palkovits, M Usdin, TB AF Dobolyi, A Ueda, H Uchida, H Palkovits, M Usdin, TB TI Anatomical and physiological evidence for involvement of tuberoinfundibular peptide of 39 residues in nociception SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HORMONE-RELATED PEPTIDE; RAT SPINAL-CORD; PARATHYROID-HORMONE; PTH2 RECEPTOR; NOCICEPTIN/ORPHANIN FQ; PROTEIN; MICE; PAIN; AGONIST; MODULATION AB The parathyroid hormone 2 (PTH2) receptor's anatomical distribution suggests that, among other functions, it may be involved in modulation of nociception. We localized PTH2 receptor protein to spinal cord lamina 11 and showed that it is synthesized by subpopulations of primary sensory neurons and intrinsic spinal cord dorsal horn neurons. Tuberoinfundibular peptide of 39 residues (TIP39) selectively activates the PTH2 receptor. Intraplantar microinjection of TIP39 caused a paw-withdrawal response and intrathecal injection caused scratching, biting, and licking, a nocifensive response. Intrathecal administration of a TIP39 antibody decreased sensitivity in tail-flick and paw-pressure assays. Intrathecal administration of TIP39 potentiated responses in these assays. We determined the sequence of TIP39's precursor and found that mRNA encoding TIP39 and TIP39-like immuno reactivity is concentrated in two brainstem areas, the subparafascicular area and the caudal paralemniscal nucleus. Cells in these areas project to the superficial dorsal horn of the spinal cord. Our data suggest that TIP39 released from supraspinal fibers potentiates aspects of nociception within the spinal cord. C1 NIMH, Genet Lab, Bethesda, MD 20892 USA. Nagasaki Univ, Sch Pharmaceut Sci, Dept Mol Pharmacol & Neurosci, Nagasaki 8528521, Japan. RP Usdin, TB (reprint author), NIMH, Genet Lab, Bethesda, MD 20892 USA. RI Dobolyi, Arpad/B-9089-2008; Palkovits, Miklos/F-2707-2013; OI Palkovits, Miklos/0000-0003-0578-0387 NR 40 TC 49 Z9 53 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 FEB 5 PY 2002 VL 99 IS 3 BP 1651 EP 1656 DI 10.1073/pnas.042416199 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 519YF UT WOS:000173752500099 PM 11818570 ER PT J AU Afione, S Kotin, R AF Afione, S Kotin, R TI Gene transfer on target SO CHEMISTRY & INDUSTRY LA English DT Article ID RECOMBINANT ADENOASSOCIATED VIRUS; RETINAL DEGENERATION; THERAPY; EXPRESSION C1 NHLBI, Lab Biochem Genet, NIH, Field Recombinant Viral Vectors, Bethesda, MD 20892 USA. RP Afione, S (reprint author), NHLBI, Lab Biochem Genet, NIH, Field Recombinant Viral Vectors, Bldg 10, Bethesda, MD 20892 USA. RI kotin, robert/B-8954-2008 NR 22 TC 0 Z9 0 U1 0 U2 2 PU SOC CHEMICAL INDUSTRY PI LONDON PA 14 BELGRAVE SQUARE, LONDON SW1X 8PS, ENGLAND SN 0009-3068 J9 CHEM IND-LONDON JI Chem. Ind. PD FEB 4 PY 2002 IS 3 BP 16 EP 18 PG 3 WC Chemistry, Applied SC Chemistry GA 519VJ UT WOS:000173745900017 ER PT J AU Li, Q Li, T Wu, JG AF Li, Q Li, T Wu, JG TI Water solubilization capacity and conductance behaviors of AOT and NaDEHP systems in the presence of additives SO COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS LA English DT Article DE water solubilization capacity; conductivity; additives; AOT; NaDEHP; percolation ID SODIUM BIS(2-ETHYLHEXYL) PHOSPHATE; IN-OIL MICROEMULSIONS; MIXED REVERSE MICELLES; N-HEPTANE; NONIONIC SURFACTANTS; AEROSOL OT; FT-IR; PERCOLATION; DYNAMICS; SULFOSUCCINATE AB The influences of two typical additives, long-chain organic molecule (bis(2-ethylhexyl) phosphoric acid (HDEHP)) and inorganic electrolyte (sodium chloride), on the water solubilization capacity of sodium bis(2-ethylhexyl) sulfosuccinate (AOT) and sodium bis(2-ethylhexyl) phosphate (NaDEHP) in n-heptane solutions have been investigated. The presence or optimal content of HDEHP remarkably enhances the water solubilization capability of the NaDEHP system, while it decreases the solubilization capacity of the AOT system. The addition of low concentration of NaCl solution in the AOT microemulsions tends to enhance its solubilization capacity. The conductance behaviors of the AOT system have also been investigated, focusing on the influences of the HDEHP content, NaCl concentration, and temperature. For the water/AOT/n-heptane reverse micelles/microemulsions, with increasing water content, no percolation phenomena can be observed in the presence of HDEHP; whereas the percolation conductance occurs with the addition of NaCl solutions and the onset water content increases with an increase of the NaCl concentration. With an increase of temperature, the percolation conductance also occurs in the AOT system in the presence of HDEHP and the onset temperature for the percolation conductance decreases with increasing HDEHP content. The influences of the variables on the water solubilization capacity and conductance behaviors could be understood from their effects on the rigidity of the oil/water interface and the attractive interactions of the surfactant aggregates. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Peking Univ, Coll Chem & Mol Engn, Beijing 100871, Peoples R China. RP Li, T (reprint author), NIH, Bldg 10,Rm 10D08,10 Ctr Dr, Bethesda, MD 20892 USA. NR 33 TC 31 Z9 31 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0927-7757 J9 COLLOID SURFACE A JI Colloid Surf. A-Physicochem. Eng. Asp. PD FEB 4 PY 2002 VL 197 IS 1-3 BP 101 EP 109 DI 10.1016/S0927-7757(01)00861-5 PG 9 WC Chemistry, Physical SC Chemistry GA 509NU UT WOS:000173154500011 ER PT J AU Hotary, KB Yana, I Sabeh, F Li, XY Holmbeck, K Birkedal-Hansen, H Allen, ED Hiraoka, N Weiss, SJ AF Hotary, KB Yana, I Sabeh, F Li, XY Holmbeck, K Birkedal-Hansen, H Allen, ED Hiraoka, N Weiss, SJ TI Matrix metalloproteinases (MMPs) regulate fibrin-invasive activity via MT1-MMP-dependent and -independent processes SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE matrix metalloproteinases; MT-MMP; fibrin; proteolysis; invasion ID SMOOTH-MUSCLE CELLS; GROWTH-FACTOR RECEPTOR; I COLLAGEN MATRIX; KERATINOCYTE MIGRATION; EXTRACELLULAR-MATRIX; TISSUE LOCALIZATION; PLASMINOGEN GENE; PROGELATINASE-A; PLASMA CLOTS; GELATINASE-A AB Cross-linked fibrin is deposited in tissues surrounding wounds, inflammatory sites, or tumors and serves not only as a supporting substratum for trafficking cells, but also as a structural barrier to invasion. While the plasminogen activator-plasminogen axis provides cells with a powerful fibrinolytic system, plasminogen-deleted animals use alternate proteolytic processes that allow fibrin invasion to proceed normally. Using fibroblasts recovered from wild-type or gene-deleted mice, invasion of three-dimensional fibrin gels proceeded in a matrix metalloproteinase (MMP)-dependent fashion. Consistent with earlier studies supporting a singular role for the membrane-anchored MMP, MT1-MMP, in fibrin-invasive events, fibroblasts from MT1-MMP-null mice displayed an early defect in invasion. However, MT1-MMP-deleted fibroblasts circumvented this early deficiency and exhibited compensatory fibrin-invasive activity. The MT1-MMP-independent process was sensitive to MMP inhibitors that target membrane-anchored MMPs, and further studies identified MT2-MMP and MT3-MMP, but not MT4-MMP, as alternate pro-invasive factors. Given the widespread distribution of MT1-, 2-, and 3-MMP in normal and neoplastic cells, these data identify a subset of membrane-anchored MMPs that operate in an autonomous fashion to drive fibrin-invasive activity. C1 Univ Michigan, Comprehens Canc Ctr, Ann Arbor, MI 48109 USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Weiss, SJ (reprint author), 5220 MSRB 3 1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. FU NCI NIH HHS [CA71699, CA88308, R01 CA071699, R01 CA088308] NR 70 TC 151 Z9 158 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD FEB 4 PY 2002 VL 195 IS 3 BP 295 EP 308 DI 10.1084/jem.20010815 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 560YY UT WOS:000176110000003 PM 11828004 ER PT J AU McConnell, R Berhane, K Gilliland, F London, SJ Islam, T Gauderman, WJ Avol, E Margolis, HG Peters, JM AF McConnell, R Berhane, K Gilliland, F London, SJ Islam, T Gauderman, WJ Avol, E Margolis, HG Peters, JM TI Asthma in exercising children exposed to ozone: a cohort study SO LANCET LA English DT Article ID SOUTHERN CALIFORNIA CHILDREN; AIR-POLLUTION; BRONCHIAL RESPONSIVENESS; CHILDHOOD ASTHMA; SCHOOL CHILDREN; PREVALENCE; POLLUTANTS; ASSOCIATION; SYMPTOMS; TAIWAN AB Background Little is known about the effect of exposure to air pollution during exercise or time spent outdoors on the development of asthma. We investigated the relation between newly-diagnosed asthma and team sports in a cohort of children exposed to different concentrations and mixtures of air pollutants. Methods 3535 children with no history of asthma were recruited from schools in 12 communities in southern California and were followed up for up to 5 years. 265 children reported a new diagnosis of asthma during follow-up. We assessed risk of asthma in children playing team sports at study entry in six communities with high daytime ozone concentrations, six with lower concentrations, and in communities with high or low concentrations of nitrogen dioxide, particulate matter, and inorganic-acid vapour. Findings In communities with high ozone concentrations, the relative risk of developing asthma in children playing three or more sports was 3.3 (95% CI 1.9-5.8), compared with children playing no sports. Sports had no effect in areas of low ozone concentration (0.8, 0.4-1.6). Time spent outside was associated with a higher incidence of asthma in areas of high ozone (1.4, 1.0-2.1), but not in areas of low ozone. Exposure to pollutants other than ozone did not alter the effect of team sports. Interpretation Incidence of new diagnoses of asthma is associated with heavy exercise in communities with high concentrations of ozone, thus, air pollution and outdoor exercise could contribute to the development of asthma in children. C1 Univ So Calif, Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Calif Air Resources Board, Sacramento, CA USA. RP McConnell, R (reprint author), Univ So Calif, Sch Med, Dept Prevent Med, 1540 Alcazar St,CHP 236, Los Angeles, CA 90089 USA. OI London, Stephanie/0000-0003-4911-5290 FU NHLBI NIH HHS [1R01HL61768]; NIEHS NIH HHS [1PO1ES0939581-02, 5P30ES07048-05] NR 32 TC 386 Z9 396 U1 3 U2 51 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD FEB 2 PY 2002 VL 359 IS 9304 BP 386 EP 391 DI 10.1016/S0140-6736(02)07597-9 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 518UP UT WOS:000173686500008 PM 11844508 ER PT J AU Esser, L De Brabander, JK AF Esser, L De Brabander, JK TI 2-[(7R,9S,10R,12E)-4,9-Dihydroxy-10-methyl-5-oxo-7,8,9,10,11,14-hexahydr o-5H-6-oxa-benzocyclo-dodecen-7-yl]ethyl octanoate SO ACTA CRYSTALLOGRAPHICA SECTION E-STRUCTURE REPORTS ONLINE LA English DT Article ID SALICYLIHALAMIDE AB The structure of the title compound, C26H38O6, is described. Two molecules of the title compound are related by a twofold non-crystallographic symmetry operation. There is an extensive hydrogen-bonding network, as well as van der Waals interactions between alkyl groups. C1 NCI, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA. RP Esser, L (reprint author), NCI, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. NR 8 TC 1 Z9 1 U1 0 U2 3 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1600-5368 J9 ACTA CRYSTALLOGR E JI Acta Crystallogr. Sect. E.-Struct Rep. Online PD FEB PY 2002 VL 58 BP o142 EP o144 DI 10.1107/S1600536802000466 PN 2 PG 3 WC Crystallography SC Crystallography GA 525UB UT WOS:000174089800038 ER PT J AU Esser, L Otwinowski, Z Kim, H AF Esser, L Otwinowski, Z Kim, H TI 2,5-Dibromo-6-isopropyl-3-methyl-p-benzoquinone SO ACTA CRYSTALLOGRAPHICA SECTION E-STRUCTURE REPORTS ONLINE LA English DT Article ID BC1 COMPLEX; PROTEIN AB The title compound, C10H10Br2O2, is a well known inhibitor of respiratory and photosynthetic processes. The methyl groups of the isopropyl group assume approximately equal distances from the ring plane and maximum distances from the neighboring Br atom, possibly to avoid unfavourable steric interactions. C1 NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dallas, TX 75390 USA. Seoul Natl Univ, Seoul 151742, South Korea. RP Esser, L (reprint author), NIH, 37 Convent Dr,Bldg 37,Rm 1B22, Bethesda, MD 20892 USA. RI Otwinowski, Zbyszek/F-3665-2011 NR 12 TC 1 Z9 1 U1 0 U2 4 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1600-5368 J9 ACTA CRYSTALLOGR E JI Acta Crystallogr. Sect. E.-Struct Rep. Online PD FEB PY 2002 VL 58 BP o170 EP o171 DI 10.1107/S1600536801021353 PN 2 PG 2 WC Crystallography SC Crystallography GA 525UB UT WOS:000174089800049 ER PT J AU Perl, HI Hilton, ME AF Perl, HI Hilton, ME TI Ask the right questions and make good use of the answers: A response to Humphreys & Tucker SO ADDICTION LA English DT Editorial Material ID HEALTH-SERVICES RESEARCH; BRIEF PHYSICIAN ADVICE; ALCOHOL; TRIAL C1 NIAAA, Hlth Serv Res Branch, Bethesda, MD 20892 USA. RP Perl, HI (reprint author), NIAAA, Hlth Serv Res Branch, 6000 Execut Blvd,Suite 505,MSC 7003, Bethesda, MD 20892 USA. NR 13 TC 2 Z9 2 U1 1 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD FEB PY 2002 VL 97 IS 2 BP 134 EP 136 DI 10.1046/j.1360-0443.2002.0005c.x PG 3 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 518DN UT WOS:000173651500004 PM 11860381 ER PT J AU Launer, LJ AF Launer, LJ TI Demonstrating the case that AD is a vascular disease: epidemiologic evidence SO AGEING RESEARCH REVIEWS LA English DT Review DE Alzheimer's disease; vascular disease; epidemiology; risk factors ID APOLIPOPROTEIN-E GENOTYPE; MIDLIFE BLOOD-PRESSURE; WHITE-MATTER LESIONS; ALZHEIMERS-DISEASE; COGNITIVE FUNCTION; DIABETES-MELLITUS; INSULIN-RESISTANCE; RISK-FACTORS; ELDERLY PEOPLE; APOE GENOTYPE AB Alzheimer's disease (AD) is the most frequent type of dementia in old age. The pathology of AD is not well understood. One hypothesis states that AD has a vascular basis. This hypothesis is controversial because AD has traditionally been studied and treated as a separate disease from vascular dementia. This article reviews the epidemiologic evidence supporting an association between AD and two major vascular risk factors-blood pressure and diabetes. Both methodologic and biologic explanations for these associations are discussed. Published by Elsevier Science Ireland Ltd. C1 NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Neuroepidemiol Sect, Bethesda, MD 20892 USA. RP Launer, LJ (reprint author), NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Neuroepidemiol Sect, 7201 Wisconsin Ave,Gateway Bldg,Suite 3C-309, Bethesda, MD 20892 USA. NR 101 TC 158 Z9 163 U1 0 U2 2 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 FEB PY 2002 VL 1 IS 1 BP 61 EP 77 AR PII S0047-6374(02)00364-5 DI 10.1016/S0047-6374(01)00364-5 PG 17 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 603AM UT WOS:000178536700006 PM 12039449 ER PT J AU Mattson, MP Kruman, II Duan, W AF Mattson, MP Kruman, II Duan, W TI Folic acid and homocysteine in age-related disease SO AGEING RESEARCH REVIEWS LA English DT Review DE DNA repair; folate deficiency; homocysteine ID CYSTATHIONINE BETA-SYNTHASE; ENDOTHELIAL-CELL INJURY; NEURAL-TUBE DEFECTS; NESTED CASE-CONTROL; METHYLENETETRAHYDROFOLATE REDUCTASE; PARKINSONS-DISEASE; PLASMA HOMOCYSTEINE; ALZHEIMERS-DISEASE; FOLATE-DEFICIENCY; DNA-DAMAGE AB It has been known for decades that babies born to women that have a dietary deficiency in folic acid (folate) are at increased risk for birth defects, and that the nervous system is particularly susceptible to such defects. Folate deficiency in adults can increase risk of coronary artery disease, stroke, several types of cancer, and possibly Alzheimer's and Parkinson's diseases. Recent findings have begun to reveal the cellular and molecular mechanisms whereby folate counteracts age-related disease. An increase in homocysteine levels is a major consequence of folate deficiency that may have adverse effects on multiple organ systems during aging. Humans with inherited defects in enzymes involved in homocysteine metabolism, including cystathionine beta-synthase and 5, 10-methylenetetrahydrofolate reductase, exhibit features of accelerated aging and a marked propensity for several age-related diseases. Homocysteine enhances accumulation of DNA damage by inducing a methyl donor deficiency state and impairing DNA repair. In mitotic cells such DNA damage can lead to cancer, while in postmitotic cells such as neurons it promotes cell death. The emerging data strongly suggest that elevated homocysteine levels increase the risk of multiple age-related diseases, and point to dietary supplementation with folate as a primary means of normalizing homocysteine levels and increasing healthspan. Published by Elsevier Science Ireland Ltd. C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 97 TC 78 Z9 80 U1 2 U2 10 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 FEB PY 2002 VL 1 IS 1 BP 95 EP 111 AR PII S0047-6374(01)00365-7 DI 10.1016/S0047-6374(01)00365-7 PG 17 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 603AM UT WOS:000178536700008 PM 12039451 ER PT J AU Ferrucci, L Russo, CR Lauretani, F Bandinelli, S Guralnik, JM AF Ferrucci, L Russo, CR Lauretani, F Bandinelli, S Guralnik, JM TI A role for sarcopenia in late-life osteoporosis SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Editorial Material DE mechanostat; osteopenia; osteoporosis; postmenopausal women; sarcopenia; vibration exercise ID BONE-MINERAL DENSITY; POSTMENOPAUSAL WOMEN; RANDOMIZED TRIALS; EXERCISE; MUSCLE; MASS; PREMENOPAUSAL; METAANALYSIS; FRACTURES; STRENGTH C1 IOT, Lab Clin Epidemiol, Dept Geriatr, INRCA, I-50125 Florence, Italy. Univ Florence, Unit Gerontol & Geriatr Med, I-50121 Florence, Italy. NIA, Epidemiol Demog & Biometry Dept, Bethesda, MD 20892 USA. RP Ferrucci, L (reprint author), IOT, Lab Clin Epidemiol, Dept Geriatr, INRCA, Viale Michelangelo 41, I-50125 Florence, Italy. RI Lauretani, Fulvio/K-5115-2016 OI Lauretani, Fulvio/0000-0002-5287-9972 NR 28 TC 21 Z9 23 U1 1 U2 4 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1594-0667 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD FEB PY 2002 VL 14 IS 1 BP 1 EP 4 PG 4 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 560UY UT WOS:000176100800001 PM 12027146 ER PT J AU McBride, WJ Le, AD Noronha, A AF McBride, WJ Le, AD Noronha, A TI Central nervous system mechanisms in alcohol relapse SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE alcohol relapse; animal models; alcohol addiction; alcohol deprivation effect ID SEEKING BEHAVIOR; C57BL/6 MICE; ETHANOL-CONSUMPTION; PLACE-PREFERENCE; DEPRIVATION; NALTREXONE; RAT; ACAMPROSATE; DISCRIMINATION; REINSTATEMENT AB Background: Alcohol relapse is a major problem in the treatment of alcohol abuse and alcoholism. Understanding the long-term neuronal alterations that promote relapse of alcohol drinking is critical for the development of pharmacotherapies to treat alcoholism and alcohol abuse. The major objectives of this workshop were to present recent findings, by using rodent models, on behavioral and neurobiological factors that may underlie alcohol relapse and the results of clinical and pharmacological treatment strategies for preventing relapse. Methods: Prolonged ethanol drinking and repeated periods of alcohol deprivation were studied in nonselected rats and in rats selectively bred for high alcohol preference (P rat). The expression of a robust alcohol deprivation effect (ADE) was used as a model for alcohol relapse in rodents. Operant techniques were used to examine responding for ethanol after deprivation in both rats and C57BL/6J mice. Environmental cues and stress were used to assess their effects on reinstatement of alcohol responding. Microdialysis and [14C]-2-deoxyglucose techniques were used to examine neuronal alterations associated with alcohol relapse. Results: Prolonged free-choice ethanol drinking followed by deprivation produced an ADE in both stock and P rats. These rats demonstrated loss of control on reinstatement after chronic drinking and after prolonged deprivation. Acamprosate and naltrexone effectively reduced the ADE in stock rats. Stress reinstated operant responding for alcohol, and rats trained to associate a cue with ethanol presentation increased responding on the ethanol-associated lever in the absence of ethanol. After repeated deprivations, P rats shifted their preference toward drinking higher concentrations of ethanol, which increased the magnitude and duration of the ADE. Stock rats also shifted their preference toward solutions with higher ethanol concentrations and demonstrated a loss of control after prolonged ethanol drinking and deprivation. Long-lasting alterations in neuronal activity, serotonin-3 receptor function, and dopamine neurotransmission within the mesolimbic system were evident after chronic drinking that followed a prolonged deprivation period. Conclusions: The ADE is a useful model for studying alcohol relapse in both rats and mice. The potential validity of this model is supported by the findings that acamprosate and naltrexone are effective in preventing the ADE in rodents, and both compounds have gained recognition for their therapeutic effects in clinical populations. Genetics, stress, and environmental cues are all important factors that influence alcohol relapse. Long-term alterations in neuronal activity within the mesolimbic system, which possibly involve dopamine and serotonin, may underlie alcohol relapse. C1 Indiana Univ, Sch Med, Inst Psychiat Res, Dept Psychiat, Indianapolis, IN 46202 USA. Addict Res Fdn, Biobehav Res Dept, Toronto, ON M5S 2S1, Canada. NIAAA, Rockville, MD 20852 USA. RP McBride, WJ (reprint author), Indiana Univ, Sch Med, Inst Psychiat Res, Dept Psychiat, Indianapolis, IN 46202 USA. NR 28 TC 53 Z9 53 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD FEB PY 2002 VL 26 IS 2 BP 280 EP 286 DI 10.1097/00000374-200202000-00017 PG 7 WC Substance Abuse SC Substance Abuse GA 524UF UT WOS:000174030700017 PM 11964569 ER PT J AU Enoch, MA Goldman, D AF Enoch, MA Goldman, D TI Problem drinking and alcoholism: Diagnosis and treatment SO AMERICAN FAMILY PHYSICIAN LA English DT Article ID PLACEBO-CONTROLLED TRIAL; PRIMARY-CARE; SCREENING INSTRUMENTS; UNITED-STATES; DEPENDENCE; ABUSE; DRINKERS; DISULFIRAM; DISORDERS; SETTINGS AB Alcoholism is one of the most common psychiatric disorders with a prevalence of 8 to 14 percent. This heritable disease is frequently accompanied by other substance abuse disorders (particularly nicotine), anxiety and mood disorders, and antisocial personality disorder. Although associated with considerable morbidity and mortality; alcoholism often goes unrecognized in a clinical or primary health care setting. Several brief screening instruments are available to quickly identify problem drinking, often a pre-alcoholism condition. Problem drinking can be successfully treated with brief intervention by primary care physicians. Alcohol addiction is a lifelong disease with a relapsing, remitting course. Because of the potentially serious implications of the diagnosis, assessment for alcoholism should be detailed. Alcoholism is treated by a variety of psychosocial methods with or without newly developed pharmacotherapies that improve relapse rates. Screening for problem drinking and alcoholism needs to become an integral part of the routine health screening questionnaire for adolescents and all adults, particularly women of child-bearing age, because of the risk of fetal alcohol syndrome. Copyright (C) 2002 American Academy of Family Physicians. C1 NIAAA, DICBR, LNG, NIH, Bethesda, MD 20892 USA. RP Enoch, MA (reprint author), NIAAA, DICBR, LNG, NIH, 12420 Parklawn Dr,Pk Bldg 5,Rm 451,MSC 8110, Bethesda, MD 20892 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 35 TC 34 Z9 34 U1 8 U2 11 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 FEB 1 PY 2002 VL 65 IS 3 BP 441 EP 448 PG 8 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 521JZ UT WOS:000173838000009 PM 11858627 ER PT J AU Campia, U Choucair, WK Bryant, MB Quyyumi, AA Cardillo, C Panza, JA AF Campia, U Choucair, WK Bryant, MB Quyyumi, AA Cardillo, C Panza, JA TI Role of cyclooxygenase products in the regulation of vascular tone and in the endothelial vasodilator function of normal, hypertensive, and hypercholesterolemic humans SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID DEPENDENT CONTRACTIONS; CARDIOVASCULAR-DISEASE; HUMAN FOREARM; NITRIC-OXIDE; ACETYLCHOLINE; ASPIRIN; RAT; AORTA; DYSFUNCTION; RELAXATION AB A defective vascular activity of endothelial vasoactive substances is observed in essential hypertension and hypercholesterolemia, and is believed to participate in the vascular abnormalities characteristic of these conditions. The present study aimed to determine the role of cyclooxygenase (COX) products in the maintenance of vascular tone and in the endothelium-mediated vasodilation of healthy subjects, and to investigate their contribution to the endothelial dysfunction of essential hypertensive and hypercholesterolemic patients. The effects of intra-arterial aspirin (acetylsalicylic acid [ASA], 1, 3, and 10 mg/min) were assessed on basal forearm blood flow (strain gauge plethysmography) and on responses to acetylcholine (7.5, 15 and 30 mug/min) and sodium nitroprusside (0.8, 1.6 and 3.2 mug/min) in 24 normal, 23 hypertensive, and 24 hypercholesterolemic subjects. Basal forearm blood flow was not different among the 3 groups (p = 0.95). ASA resulted in a significant reduction of forearm blood flow from baseline in normal (p = 0.003), hypertensive (p = 0.001), and hypercholesterolemic subjects (p = 0.001), without any difference among the 3 groups (p = 0.90). ASA significantly improved the effect of acetylcholine in normal (p = 0.008), hypertensive (p = 0.008), and hypercholesterolemic subjects (p = 0.022), without significant difference among the 3 groups (p = 0.46). ASA did not significantly modify the vasodilator effect of sodium nitroprusside in any of the 3 groups. These findings suggest that in humans, vasoclilator prostanoids actively contribute to the maintenance of basal vascular tone, whereas vasoconstrictor products of COX activity limit endothelium-dependent vasodilation. COX products do not appear to play a major role in the endothelial dysfunction of hypertensive or hypercholesterolemic patients. (C) 2002 by Excerpta Medica, Inc. C1 NIH, Cardiol Branch, Bethesda, MD 20892 USA. RP Panza, JA (reprint author), Washington Hosp Ctr, 110 Irving St NW,Suite 2A 74, Washington, DC 20010 USA. NR 30 TC 22 Z9 22 U1 0 U2 2 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 FEB 1 PY 2002 VL 89 IS 3 BP 286 EP 290 DI 10.1016/S0002-9149(01)02229-9 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 517RZ UT WOS:000173624800007 PM 11809430 ER PT J AU Glynn, NW Kriska, AM Barton, BA Kronsberg, SS Daniels, SR Schreiber, GB Obarzanek, E AF Glynn, NW Kriska, AM Barton, BA Kronsberg, SS Daniels, SR Schreiber, GB Obarzanek, E TI The longitudinal relationship between physical activity and changes in adiposity during adolescence. SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Meeting Abstract C1 Univ Pittsburgh, Pittsburgh, PA USA. Maryland Med Res Inst, Baltimore, MD USA. Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. Westat Corp, Rockville, MD USA. NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD FEB PY 2002 VL 75 IS 2 SU S MA 8 BP 341S EP 341S PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 516FU UT WOS:000173542600009 ER PT J AU McDuffie, J Uwaifo, G Sebring, N Fallon, E Hubbard, V Yanovski, J AF McDuffie, J Uwaifo, G Sebring, N Fallon, E Hubbard, V Yanovski, J TI A pilot study of the efficacy of orlistat in overweight adolescents. SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Meeting Abstract C1 NICHHD, Unit Growth & Obes, NIH, Bethesda, MD USA. NIH, Drug Informat Serv, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Nutr, Bethesda, MD 20892 USA. NIDDK, Div Nutr Res Coordinat, NIH, Bethesda, MD 20892 USA. RI Uwaifo, Gabriel/M-2361-2016 OI Uwaifo, Gabriel/0000-0002-6962-9304 NR 0 TC 0 Z9 0 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 FEB PY 2002 VL 75 IS 2 SU S MA 114 BP 374S EP 374S PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 516FU UT WOS:000173542600113 ER PT J AU Raman, A Schoeller, D Subar, A Troiano, R Schatzkin, A Bingham, S Harris, T Bauer, D Everhart, J AF Raman, A Schoeller, D Subar, A Troiano, R Schatzkin, A Bingham, S Harris, T Bauer, D Everhart, J TI Water turnover and total body water in 546 adults. SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Meeting Abstract C1 Univ Wisconsin, Madison, WI USA. NCI, Bethesda, MD 20892 USA. Univ Cambridge, Cambridge, England. NIA, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIDDKD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 FEB PY 2002 VL 75 IS 2 SU S MA P162 BP 389S EP 389S PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 516FU UT WOS:000173542600160 ER PT J AU Ferruggiaro, EB Costello, R AF Ferruggiaro, EB Costello, R TI The International Bibliographic Information on Dietary Supplements (IBIDS) database: How to access and search effectively. SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Meeting Abstract C1 Natl Agr Lib, Food & Nutr Informat Ctr, Beltsville, MD USA. NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD FEB PY 2002 VL 75 IS 2 SU S MA P194 BP 399S EP 399S PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 516FU UT WOS:000173542600192 ER PT J AU Elberg, J Goldhar, L Chin, J Fallon, E Parikh, S Yanovski, JA AF Elberg, J Goldhar, L Chin, J Fallon, E Parikh, S Yanovski, JA TI Air displacement plethysmography accurately estimates changes of body fatness in African-American and Caucasian children. SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Meeting Abstract C1 NIH, Unit Growth & Obesity, Bethesda, MD USA. NR 0 TC 0 Z9 0 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 FEB PY 2002 VL 75 IS 2 SU S MA 208 BP 403S EP 404S PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 516FU UT WOS:000173542600206 ER PT J AU Del Parigi, A Chen, KW Salbe, A Hill, JO Wing, RR Reiman, EM Tataranni, A AF Del Parigi, A Chen, KW Salbe, A Hill, JO Wing, RR Reiman, EM Tataranni, A TI Neuronal response to a meal in the dorsal hippocampus: A marker of increased risk for obesity? SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Meeting Abstract C1 Natl Inst Hlth, Phoenix, AZ USA. Good Samaritan Hosp, Phoenix, AZ USA. Univ Colorado, Denver, CO 80202 USA. Brown Univ, Providence, RI 02912 USA. NR 0 TC 0 Z9 0 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 FEB PY 2002 VL 75 IS 2 SU S MA 240 BP 413S EP 414S PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 516FU UT WOS:000173542600238 ER PT J AU Hoebel, BG Colantuoni, C Schwenker, J McCarthy, J Ladenheim, B Cadet, JL Schwartz, G Moran, T Rada, P AF Hoebel, BG Colantuoni, C Schwenker, J McCarthy, J Ladenheim, B Cadet, JL Schwartz, G Moran, T Rada, P TI Sugar dependence: Neural and behavioral signs of sensitization and withdrawal. SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Meeting Abstract C1 Princeton Univ, Princeton, NJ 08544 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. NIDA, Bethesda, MD 20892 USA. Cornel Hosp, White Plains, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD FEB PY 2002 VL 75 IS 2 SU S MA 241 BP 414S EP 414S PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 516FU UT WOS:000173542600239 ER PT J AU Earthman, CP Reid, PM Harper, IT Ravussin, E Howell, WR AF Earthman, CP Reid, PM Harper, IT Ravussin, E Howell, WR TI Clinical assessment of body cell mass repletion by bioimpedance spectroscopy in HIV-infected individuals after oxandrolone and nutritional therapy. SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Meeting Abstract C1 Virginia Tech, Blacksburg, VA USA. Univ Arizona, Tucson, AZ USA. NIDDK, CDNS, NIH, Phoenix, AZ USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. NR 0 TC 0 Z9 0 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 FEB PY 2002 VL 75 IS 2 SU S MA P280 BP 426S EP 426S PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 516FU UT WOS:000173542600278 ER PT J AU Sherman, ME Solomon, D Schiffman, M AF Sherman, ME Solomon, D Schiffman, M TI Qualification of ASCUS - The authors' reply SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Letter C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. NCI, Div Canc Prevent, Rockville, MD USA. RP Sherman, ME (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD FEB PY 2002 VL 117 IS 2 BP 335 EP 336 PG 2 WC Pathology SC Pathology GA 518HK UT WOS:000173661600027 ER PT J AU Harris, PR Weber, HC Wilcox, CM Jensen, RT Smith, PD AF Harris, PR Weber, HC Wilcox, CM Jensen, RT Smith, PD TI Cytokine gene profile in gastric mucosa in Helicobacter pylori infection and Zollinger-Ellison syndrome SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID EPIDERMAL GROWTH-FACTOR; NECROSIS-FACTOR-ALPHA; MESSENGER-RNA; CAPILLARY ELECTROPHORESIS; SURFACE-PROTEINS; MACROPHAGES; LIPOPOLYSACCHARIDE; ACTIVATION; EXPRESSION; DISEASE AB OBJECTIVE: Helicobacter pylori-associated inflammation is mediated, in part, by inflammatory cytokines. In contrast, the mucosal disease associated with Zollinger-Ellison syndrome (ZES) is acid driven, and the role of cytokines is not known. The aim of this study was to elucidate the role of cytokines in these two diseases, as we quantitated proinflammatory cytokine messenger RNA (mRNA) levels in the gastric mucosa from patients with H. pylori infection and ZES. METHODS: The study population included 11 patients with H. pylori infection, 12 with ZES, 17 with both H. pylori infection and ZES, and three control subjects with neither. Using a competitive polymerase chain reaction for interleukin (IL)-1beta, IL-6, IL-8, and tumor necrosis factor-alpha, the polymerase chain reaction products in gastric biopsies were quantitated by capillary electrophoresis and laser-induced fluorescence. RESULTS: The levels of IL-1beta, IL-6, IL-8, and tumor necrosis factor-alpha mRNA in gastric tissue of patients with H. pylori infection only and ZES only exceeded the levels in the control gastric tissue (p < 0.05 to p < 0.005). Unexpectedly, the number of molecules of IL-1beta and IL-8 mRNA in gastric tissue from ZES patients exceeded the levels in gastric tissue from patients with H. pylori only (p < 0.05). The local levels of cytokine mRNA in patients with both diseases exceeded the levels in patients with H. pylori only (IL-6, p < 0.05; IL-8, p < 0.05) and ZES only (IL-6, p < 0.05; tumor necrosis factor-alpha, p < 0.05). CONCLUSIONS: Levels of proinflammatory cytokine mRNA are increased in acid-driven as well as infection-driven,gastric inflammation, and the presence of both disease processes appears to have an additive effect on local cytokine message expression. Inflammatory cytokines may mediate both infection- and acid-driven gastric inflammation. (Am J Gastroenterol 2002;97:312-318. (C) 2002 by Am. Coll. of Gastroenterology). C1 Univ Alabama, Div Gastroenterol & Hepatol, Birmingham, AL 35294 USA. Vet Affairs Med Ctr, Birmingham, AL USA. Boston Univ, Sch Med, Gastroenterol Sect, Boston, MA 02118 USA. NIDDK, Digest Dis Branch, NIH, Bethesda, MD USA. RP Smith, PD (reprint author), Univ Alabama, Div Gastroenterol & Hepatol, ZRB 633,703 S 19th St, Birmingham, AL 35294 USA. FU NIDDK NIH HHS [DK54495] NR 40 TC 7 Z9 8 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD FEB PY 2002 VL 97 IS 2 BP 312 EP 318 AR PII S0002-9270(01)04025-4 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 522DL UT WOS:000173880400015 PM 11866267 ER PT J AU Taylor, JG Tang, DL Foster, CB Serjeant, GR Rodgers, GP Chanock, SJ AF Taylor, JG Tang, DL Foster, CB Serjeant, GR Rodgers, GP Chanock, SJ TI Patterns of low-affinity immunoglobulin receptor polymorphisms in stroke and homozygous sickle cell disease SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article DE sickle cell anemia; cerebrovascular accident/stroke; F-c gamma receptors; genetic susceptibility to disease; population genetics ID FACTOR-V-LEIDEN; FC-GAMMA-RIIIA; RISK-FACTORS; METHYLENETETRAHYDROFOLATE REDUCTASE; LIGAND-BINDING; ANEMIA; IGG; ERYTHROCYTES; PHAGOCYTOSIS; ENDOTHELIUM AB Symptomatic stroke is a major complication of homozygous sickle cell (SS) disease, with a prevalence of approximately 10%. An elevated peripheral leukocyte count has been identified as a risk factor for hemorrhagic stroke in adults with SS disease. It has been observed that sickle cells coated with immunoglobulin have increased adherence to endothelial cells or phagocytes, possibly via binding to the low-affinity F(c)gamma receptors. Common polymorphisms have been described in three low-anity receptors: FCGR2A, FCGR3A, and FCGR3B; each has been shown to alter biological function, and each has also been associated with disease susceptibility. On the basis of this information, we evaluated common genetic variants of the low-anity F(c)gamma receptors for an association with symptomatic stroke in SS disease in a pilot case-control study of 51 Jamaican adult SS disease stroke cases and 51 SS disease-matched controls. Comparison of allelic distributions between cases and controls at 3 loci, FCGR2A (P = 0.39), FCGR3A (P = 0.67), FCGR3B (P = 0.35), failed to demonstrate a significant association. In a separate analysis, the FCGR2A/FCGR3A two-locus combination does not appear to segregate randomly (P-COR = 0.0053), suggesting that these two loci could be linked in this population. We conclude that polymorphisms of the low-anity F(c)gamma receptors are not associated with stroke In SS disease. Published 2002 Wiley-Liss, Inc.(dagger) C1 NCI, Pediat Oncol Branch, NIH, Gaithersburg, MD 20877 USA. Natl Inst Diabet Digest & Kidney Dis, NIH, Bethesda, MD USA. Univ W Indies, MRC Labs, Kingston, Jamaica. RP Chanock, SJ (reprint author), NCI, Pediat Oncol Branch, NIH, 8717 Grovemont Circle, Gaithersburg, MD 20877 USA. OI Taylor, James/0000-0002-4421-1809 NR 39 TC 10 Z9 10 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 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD FEB PY 2002 VL 69 IS 2 BP 109 EP 114 DI 10.1002/ajh.10048 PG 6 WC Hematology SC Hematology GA 516XD UT WOS:000173581300004 PM 11835346 ER PT J AU Shen, L Pichel, JG Mayeli, T Sariola, H Lu, B Westphal, H AF Shen, L Pichel, JG Mayeli, T Sariola, H Lu, B Westphal, H TI Gdnf haploinsufficiency causes Hirschsprung-like intestinal obstruction and early-onset lethality in mice SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ENTERIC NERVOUS-SYSTEM; SACRAL NEURAL CREST; ENDOTHELIN-B RECEPTOR; NEUROTROPHIC FACTOR; RET PROTOONCOGENE; TYROSINE KINASE; HUMAN-DISEASE; LACKING GDNF; GERMLINE MUTATIONS; MOUSE MODELS AB Hirschsprung disease (HSCR) is a common congenital disorder that results in intestinal obstruction and lethality, as a result of defective innervation of the gastrointestinal (GI) tract. Despite its congenital origin, the molecular etiology of HSCR remains elusive for >70% of patients. Although mutations in the c-RET receptor gene are frequently detected in patients with HSCR, mutations in the gene encoding its ligand (glial cell line-derived neurotrophic factor [GDNF]), are rarely found. In an effort to establish a possible link between human HSCR and mutations affecting the Gdnf locus, we studied a large population of mice heterozygous for a Gdnf null mutation. This Gdnf(+/-) mutant cohort recapitulates complex features characteristic of HSCR, including dominant inheritance, incomplete penetrance, and variable severity of symptoms. The lack of one functioning Gdnf allele causes a spectrum of defects in gastrointestinal motility and predisposes the mutant mice to HSCR-like phenotypes. As many as one in five Gdnf(+/-) mutant mice die shortly after birth. Using a transgenic marking strategy, we identified hypoganglionosis of the gastrointestinal tract as a developmental defect that renders the mutant mice susceptible to clinical symptoms of HSCR. Our findings offer a plausible way to link an array of seemingly disparate features characteristic of a complex disease to a much more narrowly defined genetic cause. These findings may have general implications for the genetic analysis of cause and effect in complex human diseases. C1 NICHHD, Lab Mol Genet & Dev, NIH, Bethesda, MD 20814 USA. Hosp Merida, Unidad Invest, Merida, Spain. Univ Helsinki, Inst Biotechnol, Helsinki, Finland. RP Westphal, H (reprint author), NICHHD, Lab Mol Genet & Dev, NIH, Bldg 6B,Room 413, Bethesda, MD 20814 USA. RI Lu, Bai/A-4018-2012 NR 48 TC 44 Z9 44 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB PY 2002 VL 70 IS 2 BP 435 EP 447 DI 10.1086/338712 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 511FQ UT WOS:000173254300015 PM 11774071 ER PT J AU Kan, S Elankko, N Johnson, D Cornejo-Roldan, L Cook, J Reich, EW Tomkins, S Verloes, A Twigg, SRF Rannan-Eliya, S McDonald-McGinn, DM Zackai, EH Wall, SA Muenke, M Wilkie, AOM AF Kan, S Elankko, N Johnson, D Cornejo-Roldan, L Cook, J Reich, EW Tomkins, S Verloes, A Twigg, SRF Rannan-Eliya, S McDonald-McGinn, DM Zackai, EH Wall, SA Muenke, M Wilkie, AOM TI Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ANTLEY-BIXLER-SYNDROME; AUTOSOMAL-DOMINANT CRANIOSYNOSTOSIS; KINASE DOMAIN MUTATIONS; CROUZON-SYNDROME; PFEIFFER-SYNDROME; TYROSINE KINASE; APERT-SYNDROME; FGFR2 GENE; CORONAL CRANIOSYNOSTOSIS; ACTIVATING MUTATIONS AB It has been known for several years that heterozygous mutations of three members of the fibroblast growth-factor-receptor family of signal-transduction molecules-namely, FGFR1, FGFR2, and FGFR3-contribute significantly to disorders of bone patterning and growth. FGFR3 mutations, which predominantly cause short-limbed bone dysplasia, occur in all three major regions (i.e., extracellular, transmembrane, and intracellular) of the protein. By contrast, most mutations described in FGFR2 localize to just two exons (IIIa and IIIc), encoding the IgIII domain in the extracellular region, resulting in syndromic craniosynostosis including Apert, Crouzon, or Pfeiffer syndromes. Interpretation of this apparent clustering of mutations in FGFR2 has been hampered by the absence of any complete FGFR2-mutation screen. We have now undertaken such a screen in 259 patients with craniosynostosis in whom mutations in other genes (e. g., FGFR1, FGFR3, and TWIST) had been excluded; part of this screen was a cohort-based study, enabling unbiased estimates of the mutation distribution to be obtained. Although the majority (61/62 in the cohort sample) of FGFR2 mutations localized to the IIIa and IIIc exons, we identified mutations in seven additional exons-including six distinct mutations of the tyrosine kinase region and a single mutation of the IgII domain. The majority of patients with atypical mutations had diagnoses of Pfeiffer syndrome or Crouzon syndrome. Overall, FGFR2 mutations were present in 9.8% of patients with craniosynostosis who were included in a prospectively ascertained sample, but no mutations were found in association with isolated fusion of the metopic or sagittal sutures. We conclude that the spectrum of FGFR2 mutations causing craniosynostosis is wider than previously recognized but that, nevertheless, the IgIIIa/IIIc region represents a genuine mutation hotspot. C1 John Radcliffe Hosp, Weatherall Inst Mol Med, Oxford OX3 9DS, England. Radcliffe Infirm, Oxford Craniofacial Unit, Oxford OX2 6HE, England. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Sheffield Childrens Hosp, N Trent Clin Genet Serv, Sheffield, S Yorkshire, England. NYU, Sch Med, New York, NY USA. Univ Wales Hosp, Med Genet Serv Wales, Cardiff CF4 4XW, S Glam, Wales. Hop Robert Debre, Clin Genet Unit, F-75019 Paris, France. Childrens Hosp Philadelphia, Clin Genet Ctr, Philadelphia, PA 19104 USA. RP Wilkie, AOM (reprint author), John Radcliffe Hosp, Weatherall Inst Mol Med, Oxford OX3 9DS, England. OI , Alain/0000-0003-4819-0264 NR 82 TC 149 Z9 161 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB PY 2002 VL 70 IS 2 BP 472 EP 486 DI 10.1086/338758 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 511FQ UT WOS:000173254300018 PM 11781872 ER PT J AU Walsh, CR Larson, MG Vasan, RS Levy, D AF Walsh, CR Larson, MG Vasan, RS Levy, D TI Serum potassium is not associated with blood pressure tracking in the Framingham Heart Study SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article; Proceedings Paper CT American-Heart-Association Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 02, 2001 CL SAN ANTONIO, TEXAS SP Amer Heart Assoc DE hypertension; potassium; prospective studies; blood pressure ID MODERATE SODIUM RESTRICTION; ESSENTIAL-HYPERTENSION; SUPPLEMENTATION; ALDOSTERONISM; HYPERKALEMIA; MAGNESIUM; LINKAGE; MEN AB Background: Abnormal potassium homeostasis accompanies many secondary forms of hypertension as well as uncommon inherited, monogenic forms of hypertension. We hypothesized that serum potassium may be associated with longitudinal tracking of blood pressure (BP) and development of hypertension. Methods: A total of 2358 participants (1292 women, 1066 men) in the Framingham Heart Study who were free of hypertension, were not taking drugs affecting potassium homeostasis, and had serum potassium measured in 1979 to 1983 were followed for longitudinal tracking of BP and development of hypertension at examination 4 years later. Progression of BP stage was defined as an increment of one or more BP category, as defined by the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI), between baseline and follow-up examinations. Results: At baseline, there were no differences in systolic or diastolic BP across serum potassium quartiles. Over 4 years of follow up, 37%, (457 women, 412 men) of subjects progressed by one or more JNC-VI BP category. In a logistic regression model adjusting for multiple confounders, serum potassium quartile was not associated with risk of BP progression. During follow-up, 14% (162 women, 175 men) of subjects progressed to hypertension. After adjustment for multiple confounders, there was no significant association between serum potassium quartile and risk for progression to hypertension, Conclusions: In our community-based study sample, serum potassium was not associated with current BP, longitudinal BP tracking, or progression to hypertension. Am J Hypertens 2002 15:130-136 (C) 2002 American Journal of Hypertension, Ltd. C1 NHLBI, Framingham Heart Study, NIH, Framingham, MA 01702 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div, Boston, MA USA. Boston Univ, Sch Med, Evans Dept Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med, Boston, MA 02215 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, NIH, 5 Thurber St, Framingham, MA 01702 USA. OI Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [1K24 HL04334] NR 31 TC 9 Z9 9 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD FEB PY 2002 VL 15 IS 2 BP 130 EP 136 AR PII S0895-7061(01)02293-2 DI 10.1016/S0895-7061(01)02293-2 PN 1 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 522JH UT WOS:000173892500006 PM 11863248 ER PT J AU Hauptmann, M Pohlabeln, H Lubin, JH Jockel, KH Ahrens, W Bruske-Hohlfeld, I Wichmann, HE AF Hauptmann, M Pohlabeln, H Lubin, JH Jockel, KH Ahrens, W Bruske-Hohlfeld, I Wichmann, HE TI The exposure-time-response relationship between occupational asbestos exposure and lung cancer in two German case-control studies SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE case-control; lung cancer; asbestos; exposure-time-response; spline; time since exposure ID RISK; LATENCY; DISEASE AB Background Numerous studies have been carried out to evaluate the association between lung cancer and occupational asbestos exposure. However, the effects of timing of exposure have not been analyzed thoroughly. Methods Two German case-control studies with data on occupational asbestos exposure histories have been pooled. Duration of work in potentially asbestos exposed jobs and two derived weighted exposure measures are analyzed together with time since last exposure. A spline function is used to model the effect of time since exposure. Results The odds ratios (OR) and corresponding 95% confidence intervals were 1.8 (1.2, 2.7) and 2.4 (1.7, 3.4) for subjects having worked for 3 to 7 years and 8 or more years, respectively, in a job with potential asbestos exposure compared to never-exposed. Based on an evaluation of tune since last exposure, the OR decreased significantly to about one-half after more than 20 years since exposure ceased. Using a spline function, applied to workers' complete exposure histories, the effect of an increment of exposure is greatest 10-15 years after that exposure was received. Conclusions In contrast to previous indications, the risk of lung cancer increases soon after asbestos exposure, with its maximum effect from 10 to 15 years after the exposure was received. Am. J. Ind. Med. 41:89-97, 2002. Published 2002 Wiley-Liss, Incdagger. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Bremen Inst Prevent Res & Social Med, Bremen, Germany. Univ Essen Gesamthsch, Inst Med Informat, Essen, Germany. GSF Natl Res Ctr Environm & Hlth, Inst Epidemiol, Neuherberg, Germany. RP Hauptmann, M (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Bethesda, MD 20892 USA. RI Bruske, Irene/N-3125-2013 NR 19 TC 27 Z9 29 U1 3 U2 8 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD FEB PY 2002 VL 41 IS 2 BP 89 EP 97 DI 10.1002/ajim.10020 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 513WN UT WOS:000173403700002 PM 11813213 ER PT J AU Rocco, MV Paranandi, L Burrowes, JD Cockram, DB Dwyer, JT Kusek, JW Leung, J Makoff, R Maroni, B Poole, D AF Rocco, MV Paranandi, L Burrowes, JD Cockram, DB Dwyer, JT Kusek, JW Leung, J Makoff, R Maroni, B Poole, D CA HEMO Study Grp TI Nutritional status in the HEMO study cohort at baseline SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE nutrition; energy intake; protein intake; serum albumin; protein catabolic rate; clinical trial ID PROTEIN CATABOLIC RATE; MAINTENANCE HEMODIALYSIS-PATIENTS; DIALYSIS PATIENTS; ALBUMIN CONCENTRATION; PERITONEAL-DIALYSIS; UREMIC PATIENTS; MORTALITY; PREDICTORS; RISK; REQUIREMENTS AB The nutritional status of the first 1,000 patients randomized into the Hemodialysis (HEMO) Study was analyzed at baseline when they received their typical dialysis dose (equilibrated Kt/V = 1.30 +/- 0.22) and dialysis membrane. This is the largest study to date of the nutritional status of chronic hemodialysis patients. The mean (+/-SD) values for these parameters included a serum albumin level of 3.65 +/- 0.38 g/dL, a dietary energy intake of 22.9 +/- 8.4 kcal/kg/day, a dietary protein intake of 0.93 +/- 0.36 g/kg/day, and a double pool normalized protein catabolic rate (enPCR) of 1.00 +/- 0.25 g/kg/day. The percentage of patients below HEMO Study nutritional standards of care included 29% of patients with a serum albumin level less than 3.5 g/dL, 76% of patients with a dietary energy intake less than 28 kcal/kg/day, 61% of patients with a dietary,protein intake less than 1.0 g/kg/day, and 52% of patients with an enPCR of less than 1.0 g/kg/day. There was a strong correlation between dietary,protein intake and dietary energy intake (r = 0.74, P < 0.0001). Significant correlations were also evident between serum albumin and double pool PCR and between dietary protein intake and double-pool PCR. Kt/V and membrane flux were not predictive of baseline dietary protein intake, dietary energy intake, or serum albumin level. Thus, a majority of patients in the HEMO Study had protein and energy intake levels and enPCR levels that were below National Kidney Foundation Kidney Dialysis Outcome Quality Improvement (NKF-K/DOQI) guidelines. (C) 2002 by the National Kidney Foundation, Inc. C1 Wake Forest Univ, Sch Med, Dept Internal Med, Winston Salem, NC 27109 USA. Piedmont Dialysis Ctr, Winston Salem, NC USA. Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. Abbott Labs, Ross Prod Div, Med & Regulatory Affairs, Columbus, OH USA. Beth Israel Med Ctr, New York, NY 10003 USA. Tufts Univ, Sch Med & Nutr, Dept Med, Boston, MA 02111 USA. Tufts Univ, Sch Med & Nutr, Dept Community Hlth, Boston, MA 02111 USA. Tufts Univ New England Med Ctr, Frances Stern Nutr Ctr, Boston, MA 02111 USA. NIDDK, NIH, Div Kidney Urol & Hematol Dis, Bethesda, MD USA. Amgen Inc, Thousand Oaks, CA 91320 USA. R&D Labs Inc, Marina Del Rey, CA USA. RP Rocco, MV (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med Nephrol, Med Ctr Blvd, Winston Salem, NC 27157 USA. OI Dwyer, Johanna/0000-0002-0783-1769 FU NIDDK NIH HHS [5 U01 DK49271] NR 51 TC 66 Z9 76 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 FEB PY 2002 VL 39 IS 2 BP 245 EP 256 DI 10.1053/ajkd.2002.30543 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 520VD UT WOS:000173801800004 PM 11840364 ER PT J AU Biesecker, LG AF Biesecker, LG TI The end of the beginning of chromosome ends SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Editorial Material ID UNEXPLAINED MENTAL-RETARDATION; REARRANGEMENTS; TELOMERES; CHILDREN C1 NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, Genet Dis Res Branch, NIH, Room 4A80,49 Covent Dr, Bethesda, MD 20892 USA. NR 22 TC 76 Z9 79 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 FEB 1 PY 2002 VL 107 IS 4 BP 263 EP 266 DI 10.1002/ajmg.10160 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 512YD UT WOS:000173350400001 PM 11840481 ER PT J AU Gillespie, JW Best, CJM Bichsel, VE Cole, KA Greenhut, SF Hewitt, SM Ahram, M Gathright, YB Merino, MJ Strausberg, RL Epstein, JI Hamilton, SR Gannot, G Baibakova, GV Calvert, VS Flaig, MJ Chuaqui, RF Herring, JC Pfeifer, J Petricoin, EF Linehan, WM Duray, PH Bova, GS Emmert-Buck, MR AF Gillespie, JW Best, CJM Bichsel, VE Cole, KA Greenhut, SF Hewitt, SM Ahram, M Gathright, YB Merino, MJ Strausberg, RL Epstein, JI Hamilton, SR Gannot, G Baibakova, GV Calvert, VS Flaig, MJ Chuaqui, RF Herring, JC Pfeifer, J Petricoin, EF Linehan, WM Duray, PH Bova, GS Emmert-Buck, MR TI Evaluation of non-formalin tissue fixation for molecular profiling studies SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID PARAFFIN-EMBEDDED TISSUE; POLYMERASE CHAIN-REACTION; GENE-EXPRESSION PATTERNS; HOUSEKEEPING GENE; RNA; AMPLIFICATION; CANCER; OPTIMIZATION; SPECIMENS; ETHANOL AB Using a general strategy for evaluating clinical tissue specimens, we found that 70% ethanol fixation and paraffin embedding is a useful method for molecular profiling studies. Human prostate and kidney were used as test tissues. The protein content of the samples was analyzed by one-dimensional gel electrophoresis, immunoblot, two-dimensional gel electrophoresis, and layered expression scanning. In each case, the fixed and embedded tissues produced results similar to that obtained from snap-frozen specimens, although the protein quantity was somewhat decreased. Recovery of mRNA was reduced in both quantity and quality in the ethanol-fixed samples, but was superior to that obtained from formalin-fixed samples and sufficient to perform reverse transcription polymerase chain reactions. Recovery of DNA from ethanol-fixed specimens was superior to formalin-fixed samples as determined by one-dimensional gel electrophoresis and polymerase chain reaction. In conclusion, specimens fixed in 70% ethanol and embedded in paraffin produce good histology and permit recovery of DNA, mRNA, and proteins sufficient for several downstream molecular analyses. Complete protocols and additional discussion of relevant issues are available on an accompanying website (http://cgap-mf.nih.gov/). C1 NCI, Pathol Lab, Pathogenet Unit, Bethesda, MD 20892 USA. NCI, Sci Applicat Int Corp, Frederick, MD 21701 USA. US FDA, Ctr Biolog & Res, Bethesda, MD 20014 USA. NCI, Off Director, CGAP, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. Ctr Prostate Dis Res, Rockville, MD USA. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Emmert-Buck, MR (reprint author), NCI, Pathol Lab, Pathogenet Unit, Rm 2A33,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Cole, Kristina/M-3922-2015; OI Hewitt, Stephen/0000-0001-8283-1788 NR 31 TC 175 Z9 196 U1 2 U2 10 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD FEB PY 2002 VL 160 IS 2 BP 449 EP 457 DI 10.1016/S0002-9440(10)64864-X PG 9 WC Pathology SC Pathology GA 519NZ UT WOS:000173733500009 PM 11839565 ER PT J AU Le Poole, IC Riker, AI Quevedo, ME Stennett, LS Wang, E Marincola, FM Kast, WM Robinson, JK Nickoloff, BJ AF Le Poole, IC Riker, AI Quevedo, ME Stennett, LS Wang, E Marincola, FM Kast, WM Robinson, JK Nickoloff, BJ TI Interferon-gamma reduces melanosomal antigen expression and recognition of melanoma cells by cytotoxic T cells SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID DENDRITIC CELLS; METASTATIC MELANOMA; MALIGNANT-MELANOMA; GENE-EXPRESSION; PROGRESSION; LINE; DIFFERENTIATION; IDENTIFICATION; IMMUNOTHERAPY; MELANOCYTES AB In malignant melanoma, tumor-infiltrating lymphocytes are frequently reactive with melanosomal antigens. Achieving complete remissions by peptide therapy is frequently hampered by metastases evading immune recognition. The tumor microenvironment seems to favor reduced expression of target antigens by melanoma cells. Among candidate factors, interferon-gamma (rFN-gamma) (10(2) to 10(3) U/ml) suppressed expression of antigens MART-1, TRP-1, and gp100 by M14 melanoma cells as shown by immunohistology and fluorescence-activated cell sorting analysis, reducing MART-1 expression by >65%. Northern blot analysis revealed that reduced expression was regulated at the transcriptional level, demonstrating a 79% reduction in MART-1 transcript abundance after 32 hours of IFN-gamma treatment. To evaluate consequences of IFN-gamma exposure for immune recognition, MART-1-responsive T cells were reacted with pretreated HLA-matched melanoma cells. Cytotoxicity was reduced up to 78% by IFN-gamma pretreatment, and was restored by addition of MART-1 peptide AAGIGILTV for 2 hours. Examination of melanoma lesions by quantitative reverse transcriptase-polymerase chain reaction revealed up to 188-fold more abundant IFN-gamma transcripts when compared to control skin. Laser capture microdissection and immunohistology localized most IFN-gamma-producing T cells to the tumor stroma. Reduced MART-1 expression was frequently observed in adjacent tumor cells. Consequently, IFN-gamma may enhance inflammatory responses yet hamper effective recognition of melanoma cells. C1 Loyola Univ, Med Ctr, Canc Immunol Program, Maywood, IL 60153 USA. Cardinal Bernardin Canc Ctr, Dept Pathol, Skin Oncol Res Program, Maywood, IL USA. NIH, Surg Branch, Bethesda, MD 20892 USA. RP Le Poole, IC (reprint author), Loyola Univ, Med Ctr, Canc Immunol Program, Bldg 112,Rm 303,2160 S 1st Ave, Maywood, IL 60153 USA. RI Riker, Adam/A-6065-2011 FU NCI NIH HHS [P01 CA059327, R01 CA/AI 78399, P01 CA 59327]; NIAID NIH HHS [R01 AI078399] NR 37 TC 34 Z9 35 U1 0 U2 2 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD FEB PY 2002 VL 160 IS 2 BP 521 EP 528 DI 10.1016/S0002-9440(10)64871-7 PG 8 WC Pathology SC Pathology GA 519NZ UT WOS:000173733500016 PM 11839572 ER PT J AU Pickle, LW Su, YC AF Pickle, LW Su, YC TI Within-state geographic patterns of health insurance coverage and health risk factors in the United States SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article DE epidemiology; health surveys; maps; small-area analysis; statistics; nonparametric ID TELEPHONE COVERAGE; INTERVIEW-SURVEY; SMOKING; MORTALITY; CARE AB Background: A number of health risk, factors have been associated with the incidence and mortality of common diseases. Although knowing risk factor patterns at a small-area level would be useful for ecologic analyses and prevention program planning, risk factor data are generally published only at the state or regional level in the United States. This study presents maps of within-state patterns of several such factors. Methods: Responses to Behavioral Risk Factor Surveillance System (BRFSS) questions about smoking, obesity, health insurance, and mammography use were aggregated for 1992-1998 by county. These data were then geographically smoothed by adjusting each county's proportional response based oil the responses of its neighboring counties. Results: The maps show risk factor patterns consistent with published state-level maps, but also identify within-state variations masked by aggregation to the larger geographic units. Conclusions: The risk factor maps presented should permit a better understanding of localized patterns of health risk behaviors and access to health care as well as help to target intervention activities in the U.S. areas that most need them. C1 NCI, Stat Res & Applicat Branch, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Pickle, LW (reprint author), NCI, Stat Res & Applicat Branch, Surveillance Res Program, Div Canc Control & Populat Sci, 6116 Execut Blvd,Suite 504, Bethesda, MD 20892 USA. NR 34 TC 27 Z9 27 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD FEB PY 2002 VL 22 IS 2 BP 75 EP 83 AR PII S0749-3797(01)00402-0 DI 10.1016/S0749-3797(01)00402-0 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 529VR UT WOS:000174322100001 PM 11818175 ER PT J AU Hohmann, AA Shear, MK AF Hohmann, AA Shear, MK TI Community-based intervention research: Coping with the "noise" of real life in study design SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Review ID MENTAL-HEALTH-SERVICES; OUTCOMES; CARE AB The ultimate goal of clinical intervention research is to find a way to improve the care and lives of people suffering from specific psychiatric symptoms, illnesses, and/or disabilities. This article provides to clinical researchers a set of issues to consider and steps to follow in making the transition to more public-health-oriented, community-based research. Traditional, academically based, randomized clinical trials test an intervention against a placebo or alternate treatment control condition, focusing on a single, specific main outcome. Community-based intervention trials also test a treatment intervention but in the context of the community environment. These trials, in order to provide meaningful information for community clinical practice, must take into account many factors that are controlled or are not considered in traditional clinical trials. Investigators need to be clear about the goal of community-based interventions; they need to determine the social and cultural norms, expectations, and conflicts of the community and of the setting, and they need to work collaboratively with experts in both qualitative and quantitative design. C1 NIMH, Serv Res & Clin Epidemiol Branch, Div Serv & Intervent Res, Bethesda, MD 20892 USA. Univ Pittsburgh, Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA 15213 USA. RP Hohmann, AA (reprint author), NIMH, Serv Res & Clin Epidemiol Branch, Div Serv & Intervent Res, 6001 Execut Blvd,Rm 7135,MSC 9631, Bethesda, MD 20892 USA. NR 16 TC 142 Z9 142 U1 1 U2 10 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD FEB PY 2002 VL 159 IS 2 BP 201 EP 207 DI 10.1176/appi.ajp.159.2.201 PG 7 WC Psychiatry SC Psychiatry GA 519LJ UT WOS:000173727500004 PM 11823259 ER PT J AU Fee, E Brown, TM Lear, WJ Lazarus, J Theerman, P AF Fee, E Brown, TM Lear, WJ Lazarus, J Theerman, P TI The March on Washington, 1963 SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article C1 NIH, Natl Lib Med, Hist Med Div, Bethesda, MD 20892 USA. Univ Rochester, Dept Hist, Rochester, NY USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY USA. RP Fee, E (reprint author), Bldg 38,Room 1E21,8600 Rockville Pike, Bethesda, MD 20894 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD FEB PY 2002 VL 92 IS 2 BP 195 EP 195 DI 10.2105/AJPH.92.2.195 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 516MX UT WOS:000173558000014 PM 11818289 ER PT J AU Rowland, AS Umbach, DM Stallone, L Naftel, AJ Bohlig, EM Sandler, DP AF Rowland, AS Umbach, DM Stallone, L Naftel, AJ Bohlig, EM Sandler, DP TI Prevalence of medication treatment for attention deficit-hyperactivity disorder among elementary school children in Johnston county, North Carolina SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID PSYCHOTROPIC MEDICATIONS; STIMULANT TREATMENT; PUBLIC-SCHOOLS; ADHD; PERSPECTIVE; SERVICES; MARYLAND AB Objectives. This study estimated the prevalence of medication treatment for attention deficit-hyperactivity disorder (ADHD) among elementary school children in a North Carolina county. Methods. Parents of 7333 children in grades 1 through 5 in 17 public elementary schools were asked whether their child had ever been given a diagnosis of ADHD by a psychologist or physician and whether their child was currently taking medication to treat ADHD. Parents of 6099 children (83%) responded. Results. By parental report, 607 children (10%) had been given an ADHD diagnosis and 434 (7%) were receiving ADHD medication treatment. Seventy-one % of the diagnosed children were receiving medication. Treatment rates varied by sex, race/ethnicity, and grade. Conclusions. If treatment patterns observed in this study are representative, the public health impact of ADHD may be underestimated. (Am J Public Health. 2002;92:231-234). C1 NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. CODA Westat Inc, Durham, NC USA. Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC USA. RP Rowland, AS (reprint author), Univ New Mexico, Hlth Sci Ctr, Dept Family & Community Med, 2400 Tucker NE, Albuquerque, NM 87131 USA. OI Sandler, Dale/0000-0002-6776-0018 NR 21 TC 100 Z9 102 U1 1 U2 5 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD FEB PY 2002 VL 92 IS 2 BP 231 EP 234 DI 10.2105/AJPH.92.2.231 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 516MX UT WOS:000173558000022 PM 11818297 ER PT J AU Cho, HY Jedlicka, AE Reddy, SP Kensler, TW Yamamoto, M Zhang, LY Kleeberger, SR AF Cho, HY Jedlicka, AE Reddy, SP Kensler, TW Yamamoto, M Zhang, LY Kleeberger, SR TI Role of NRF2 in protection against hyperoxic lung injury in mice SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article ID ANTIOXIDANT-RESPONSIVE ELEMENTS; GLUTATHIONE S-TRANSFERASES; PULMONARY OXYGEN-TOXICITY; ENZYME GENE-EXPRESSION; HEME OXYGENASE-1; TRANSCRIPTION FACTOR; SUPEROXIDE-DISMUTASE; MEDIATED EXPRESSION; EPITHELIAL-CELLS; INDUCTION AB NRF2 is a transcription factor important in the protection against carcinogenesis and oxidative stress through antioxidant response element (ARE)-mediated transcriptional activation of several phase 2 detoxifying and antioxidant enzymes. This study was designed to determine the role of NRF2 in the pathogenesis of hyperoxic lung injury by comparing pulmonary responses to 95-98% oxygen between mice with site-directed mutation of the gene for NRF2 (Nrf2(-/-)) and wildtype mice (Nrf2(+/+)). Pulmonary hyperpermeability, macrophage inflammation, and epithelial injury in Nrf2(-/-) mice were 7.6-fold, 47%, and 43% greater, respectively, compared with Nrf2(+/+) mice after 72 h hyperoxia exposure. Hyperoxia markedly elevated the expression of NRF2 mRNA and DNA-binding activity of NRF2 in the lungs of Nrf2(+/+) mice. mRNA expression for ARE-responsive lung antioxidant and phase 2 enzymes was evaluated in both genotypes of mice to identify potential downstream molecular mechanisms of NRF2 in hyperoxic lung responses. Hyperoxia-induced mRNA levels of NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione-S-transferase (GST)-Ya and -Yc subunits, UDP glycosyl transferase (UGT), glutathione peroxidase-2 (GPx2), and heme oxygenase-1 (HO-1) were significantly lower in Nrf2(-/-) mice compared with Ntf2(+/+) mice. Consistent with differential mRNA expression, NQO1 and total GST activities were significantly lower in Nrf2(-/-) mice compared with Nrf2(+/+) mice after hyperoxia. Results demonstrated that NRF2 has a significant protective role against pulmonary hyperoxic injury in mice, possibly through transcriptional activation of lung antioxidant defense enzymes. C1 Johns Hopkins Univ, Bloomberg Sch Hyg & Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. Univ Tsukuba, Inst Basic Med Sci, Tsukuba, Ibaraki 305, Japan. Univ Tsukuba, Ctr Tsukuba Adv Res Alliance, Tsukuba, Ibaraki 305, Japan. RP Kleeberger, SR (reprint author), NIEHS, Pulm Pathobiol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Yamamoto, Masayuki/A-4873-2010; Kensler, Thomas/D-8686-2014 OI Kensler, Thomas/0000-0002-6676-261X FU NCI NIH HHS [CA-44530]; NHLBI NIH HHS [HL-57142, HL-58122, HL-66109]; NIEHS NIH HHS [ES-08319, ES-09606] NR 42 TC 423 Z9 443 U1 2 U2 19 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 FEB PY 2002 VL 26 IS 2 BP 175 EP 182 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 519GH UT WOS:000173716700005 PM 11804867 ER PT J AU Premkumar, A Chow, C Bhandarkar, P Wright, V Koshy, N Taylor, S Arioglu, E AF Premkumar, A Chow, C Bhandarkar, P Wright, V Koshy, N Taylor, S Arioglu, E TI Lipoatrophic-lipodystrophic syndromes: The spectrum of findings on MR imaging SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article C1 NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Premkumar, A (reprint author), NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bldg 10,Rm 1C660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. OI Oral, Elif/0000-0002-9171-1144 NR 8 TC 8 Z9 8 U1 2 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD FEB PY 2002 VL 178 IS 2 BP 311 EP 318 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 515GF UT WOS:000173486500007 PM 11804885 ER PT J AU Coulam, CH Chan, FP Li, KCP AF Coulam, CH Chan, FP Li, KCP TI Can a multiphasic contrast-enhanced three-dimensional fast spoiled gradient-recalled echo sequence be sufficient for liver MR imaging? SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article ID TURBO SPIN-ECHO; HEPATOCELLULAR-CARCINOMA; HASTE SEQUENCES; ANGIOGRAPHY; CT; SUPPRESSION; LESIONS AB OBJECTIVE. The purpose of this study was to determine the accuracy of a multiphasic gadolinium-enhanced three-dimensional (31)) fast spoiled gradient-recalled echo sequence alone in the detection and characterization of local liver lesions compared with a comprehensive liver evaluation using multiphasic gadolinium-enhanced 3D fast spoiled gradient-recalled echo, T1-weighted, and fat-suppressed fast spin-echo T2-weighted sequences. MATERIALS AND METHODS. A retrospective review of abdominal MR imaging examinations in 61 patients was performed. All MR examinations included unenhanced spin-echo T1-weighted, unenhanced fat-suppressed fast spin-echo T2-weighted, and multiphasic gadolinium-enhanced 31) fast spoiled gradient-recalled echo sequences obtained during successive breath-holds. The liver was evaluated for focal lesions first with the 31) spoiled gradient-recalled echo sequences and then, during a separate sitting, with the T1- and T2-weighted sequences. The usefulness of each sequence in the detection and characterization of lesions was recorded. The cold standard for lesion detection and characterization was all three imaging sequences reviewed together. RESULTS. A total of 114 focal liver lesions were identified, 54 of which were simple cysts. The 31) spoiled gradient-recalled echo sequence alone detected 92 (81%) of the 114 lesions, and the T1- and T2-weighted sequences detected 95 (83%) of the 114 lesions. Of the 60 lesions that were not simple cysts, the 3D spoiled gradient-recalled echo sequence alone detected 58 (97%), and T1- and T2-weighted sequences detected 51 (85%). In 2470 of the patients with lesions, the T1- and T2-weighted sequences were found to be helpful for the characterization of lesions. CONCLUSION. A multiphasic contrast-enhanced 3D fast spoiled gradient-recalled echo sequence alone detects most of the clinically relevant focal liver lesions. Additional liver examination using both unenhanced T1- and T2-weighted sequences is helpful for lesion characterization but increases the detection rate only minimally. C1 Stanford Univ, Dept Radiol, Sch Med, Stanford, CA 94305 USA. RP Li, KCP (reprint author), NIH, Bldg 10,Room 1C660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. FU NCI NIH HHS [T32-CA90695] NR 18 TC 15 Z9 15 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD FEB PY 2002 VL 178 IS 2 BP 335 EP 341 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 515GF UT WOS:000173486500010 PM 11804888 ER PT J AU Diallo, TO Spiegel, A Diouf, A Lochouarn, L Kaslow, DC Tall, A Perraut, R Garraud, O AF Diallo, TO Spiegel, A Diouf, A Lochouarn, L Kaslow, DC Tall, A Perraut, R Garraud, O TI Short report: Differential evolution of immunoglobulin G1/G3 antibody responses to Plasmodium falciparum MSP1(19) over time in malaria-immune adult Senegalese patients SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID PROTECTIVE IMMUNITY; TRANSMISSION; ANTIGEN AB This study examined the evolution of immunoglobulin (Ig) G1 and IgG3 antibodies against the asexual stage Plasmodium falciparum protein, MSP1(19) before and after a heavy malaria transmission period in clinically immune Senegalese subjects living under different epidemiological conditions. Plasma was tested for antibodies to a yeast-produced, recombinant PfMSP1(19) antigen (the Q-KNG allelic variant) that has previously been demonstrated to react with IgG1, IgG3, or both in the majority of these people. Anti-P. falciparum antibodies of the IgG1 and IgG3 subclasses, previously reported to be associated with protection, were shown to evolve independently one from another after the transmission period in both settings. These results suggest differential regulation of MSP1(19)-specific IgG1 and IgG3. The precise role of these antibody isotypes in maintaining malaria immunity remains to be determined. C1 Inst Pasteur, Unite Immunol, Dakar, Senegal. ORSTOM, IRD, Lab Zool Med, Dakar, Senegal. NIAID, Malaria Vaccine Sect, NIH, Bethesda, MD 20892 USA. RP Fac Med St Etienne, GIMAP Immunol, 15 Rue Ambroise Pare, F-42023 St Etienne, France. EM Olivier.Garraud@univ-st-etienne.fr NR 12 TC 15 Z9 17 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD FEB PY 2002 VL 66 IS 2 BP 137 EP 139 PG 3 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 571KY UT WOS:000176717600006 PM 12135282 ER PT J AU Fay, MP AF Fay, MP TI Measuring a binary response's range of influence in logistic regression SO AMERICAN STATISTICIAN LA English DT Article DE diagnostic; generalized linear model; leverage ID DIAGNOSTICS; MODELS AB This article proposes a conceptually simple class of diagnostics to determine the potential of a single binary response to affect the outcome of a logistic regression. We simply rerun the regression once for each observation after changing the response and calculate how much the statistics of interest have changed. We show how statistics of this type may be helpful in checking the robustness of a logistic regression and study their relationship to earlier proposed diagnostics. C1 NCI, Bethesda, MD 20892 USA. RP Fay, MP (reprint author), NCI, 6116 Execut Blvd,Suite 504,MSC 8317, Bethesda, MD 20892 USA. RI Fay, Michael/A-2974-2008; OI Fay, Michael P./0000-0002-8643-9625 NR 15 TC 4 Z9 4 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0003-1305 J9 AM STAT JI Am. Stat. PD FEB PY 2002 VL 56 IS 1 BP 5 EP 9 DI 10.1198/000313002753631303 PG 5 WC Statistics & Probability SC Mathematics GA 519EW UT WOS:000173712800002 ER PT J AU Fay, MP Follmann, DA AF Fay, MP Follmann, DA TI Designing Monte Carlo implementations of permutation or bootstrap hypothesis tests SO AMERICAN STATISTICIAN LA English DT Article DE computation; resample size; resampling; sequential design; simulation ID P-VALUES AB This article considers hypothesis testing using resampling or Monte Carlo methods, such as a bootstrap or a permutation procedure, and explores designs for resampling that minimize the expected number of resamples after meeting two constraints. First, we bound the size of the test at the nominal level. Second, we bound the resampling risk, which we define as the expected value of the probability of reaching an accept/reject decision different from complete enumeration. This second bound holds over a postulated set of distributions for the p value, where each distribution is associated with a probability model of the data. In relation to these constraints, we examine the fixed resample size design and two sequential resampling designs, a simple curtailed sampling design, and a new, more complicated design with smaller expected resampling size. C1 NCI, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Fay, MP (reprint author), NCI, Execut Blvd,Suite 504,MSC 8317, Bethesda, MD 20892 USA. RI Fay, Michael/A-2974-2008; OI Fay, Michael P./0000-0002-8643-9625 NR 12 TC 11 Z9 11 U1 2 U2 3 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0003-1305 J9 AM STAT JI Am. Stat. PD FEB PY 2002 VL 56 IS 1 BP 63 EP 70 DI 10.1198/000313002753631385 PG 8 WC Statistics & Probability SC Mathematics GA 519EW UT WOS:000173712800010 ER PT J AU Fitzhugh, AL Anadu, NO Waterhouse, DJ Hrabie, JA Saavedra, JE Keefer, LK AF Fitzhugh, AL Anadu, NO Waterhouse, DJ Hrabie, JA Saavedra, JE Keefer, LK TI Qualitative thin-layer and high-performance liquid chromatographic analysis of 1-substituted diazen-1-ium-1,2-diolates on aminopropyl-bonded silica gel SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE diazeniumdiolate; nitrosamine; HPLC; TLC; nitric oxide donor; aminopropyl-bonded silica gel ID NITRIC-OXIDE DONORS; CEREBRAL VASOSPASM; REVERSAL AB High-performance liquid (HPLC) and thin-layer (TLC) chromatographic methods for the detection and quantification of diazeniumdiolates are described. The HPLC determinations were made using a Rocket Platinum NH2 column (7 x 53 mm, 100-Angstrom pore size, 3-mum particle size), under isocratic conditions with mixtures of acetonitrile, methanol, and water containing 0.1% diethylamine (v/v), at a flow rate of 2.5 ml/min, a column temperature of 22degreesC, and UV detection at 250 nm. The TLC determinations were similarly made using Merck NH2 F-254S precoated glass plates (similar to2 x 5 cm, 5-mum particle size, 0.2-mm layer thickness) with mixtures of acetonitrile, methanol, and water containing 0.1% diethylamine (v/v). Preexisting traces of carcinogenic nitrosamines were detected in some samples of diazeniumdiolates. The methods provide a more efficient means of characterizing the purity of diazeniumdiolate samples prepared for use in biomedical applications than older procedures which rely on differential absorbance measurements at 250 and 350 nm, respectively. (C) 2002 Elsevier Science. C1 NCI, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. NCI, Analyt Chem Lab, SAIC Frederick, Frederick, MD 21702 USA. NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Fitzhugh, AL (reprint author), NCI, Intramural Res Support Program, SAIC Frederick, POB B, Frederick, MD 21702 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01-CO-56000] NR 14 TC 0 Z9 0 U1 0 U2 4 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 FEB 1 PY 2002 VL 301 IS 1 BP 97 EP 102 DI 10.1006/abio.2001.5312 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 518HG UT WOS:000173661300013 PM 11811972 ER PT J AU Njorku, DB Greenberg, RS Bourdi, M Borkowf, CB Dake, EM Martin, JL Pohl, LR AF Njorku, DB Greenberg, RS Bourdi, M Borkowf, CB Dake, EM Martin, JL Pohl, LR TI Autoantibodies associated with volatile anesthetic hepatitis found in the sera of a large cohort of pediatric anesthesiologists SO ANESTHESIA AND ANALGESIA LA English DT Article; Proceedings Paper CT 73rd Clinical and Scientific Congress of the International-Anesthesiology-Research-Society CY MAR 13, 1999 CL LOS ANGELES, CA SP Int Anesthesiol Res Soc ID HALOTHANE HEPATITIS; OCCUPATIONAL EXPOSURE; CYTOCHROME-P450 2E1; PROTEIN; AUTOANTIGEN; INJURY AB Anesthetic-induced hepatitis is thought to have an immune-mediated basis, in part because many patients who develop hepatitis have serum autoantibodies that react with specific hepatic proteins. The present study shows that pediatric anesthesiologists also have these serum autoantibodies. Moreover, levels of these autoantibodies are higher than those of general anesthesiologists. We collected sera from 105 pediatric and 53 general anesthesiologists (including 3 nurse anesthetists), 20 halothane hepatitis patients, and 20 control individuals who were never exposed to inhaled anesthetics. Serum cytochrome P450 2E1 (P450 2E1) and 58-kd hepatic endoplasmic reticulum protein (ERp58) autoantibodies were measured by enzyme-linked immunosorbent assays. Positive values were 2 SD above median control values. Two multiple regression models were constructed. Pediatric anesthesiologists, like halothane hepatitis patients, had higher serum autoantibody levels of ERp58 and P450 2E1 than general anesthesiologists and controls, which was possibly because of their increased occupational exposures to anesthetics. Female anesthesiologists had higher levels of ERp58 autoantibodies than male anesthesiologists, whereas female pediatric anesthesiologists had higher levels of P450 2E1 autoantibodies than all other anesthesiologists. One female pediatric anesthesiologist had symptoms of hepatic injury. Because most anesthesiologists; do not develop volatile anesthetic-induced hepatic injury, the findings suggest that pathogenic ERp58 and P450 2E1 autoantibodies may not directly cause volatile anesthetic hepatitis. Female anesthesiologists have high levels of these autoantibodies; however, the majority of these individuals do not develop hepatitis, suggesting that autoantibodies may not have a pathological role in volatile anesthetic-induced hepatitis. C1 Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Pediat, Baltimore, MD 21205 USA. NIH, NHLBI, Mol & Cellular Toxicol Sect Lab Mol Immunol, Bethesda, MD 20892 USA. NIH, NHLBI, Div Epidemiol & Clin Applicat, Off Biostat Res, Bethesda, MD 20892 USA. RP Njorku, DB (reprint author), Johns Hopkins Univ Hosp, Dept Anesthesiol & Crit Care Med, Blalock 906A,600 N Wolfe St, Baltimore, MD 21287 USA. EM dnjoku@jhmi.edu 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 0003-2999 EI 1526-7598 J9 ANESTH ANALG JI Anesth. Analg. PD FEB PY 2002 VL 94 IS 2 BP 243 EP 249 PG 7 WC Anesthesiology SC Anesthesiology GA 515PT UT WOS:000173505100003 ER PT J AU Hanley, KA Stamps, JA AF Hanley, KA Stamps, JA TI Does corticosterone mediate bidirectional interactions between social behaviour and blood parasites in the juvenile black iguana, Ctenosaura similis? SO ANIMAL BEHAVIOUR LA English DT Article ID MICE MUS-MUSCULUS; HOME-RANGE SIZE; BABESIA-MICROTI; MALE LIZARDS; AGGRESSIVE-BEHAVIOR; HORMONAL RESPONSES; UROSAURUS-ORNATUS; GREEN IGUANAS; STRESS; SUSCEPTIBILITY AB Complex bidirectional interactions between host social behaviour and infectious organisms (parasites) can be mediated by alterations in host glucocorticoid 'stress' hormones. As a result, an animal's social behaviour may affect its susceptibility to parasitism, and its infection status may influence its social behaviour. Our field study of behaviour, hormones and parasites in free-living juvenile male black iguanas revealed a pattern of significantly lower levels of the primary reptilian glucocorticoid, corticosterone (B), in lizards infected with either ticks or blood parasites than in uninfected lizards. To clarify both the mechanisms underpinning this association and the interaction of social behaviour with B and parasites, we conducted an experimental study in which lizards were stocked singly in field enclosures in one of the following four treatments: (1) unmanipulated; (2) implanted with B; (3) implanted with saline; and (4) exposed to a conspecific intruder. We sampled B and blood parasite levels periodically over the course of 4 weeks for each treatment. Lizards that were infected with blood parasites on the day of capture showed a significant increase in B after captivity in the enclosures, whereas uninfected lizards showed no such response. Lizards that were exposed to conspecific intruders showed a significant increase in B relative to controls, and residents that engaged in low levels of aggression showed significantly higher levels of B than residents that engaged in high levels of aggression. However, none of the experimental treatments affected the likelihood of acquiring a new blood parasite infection. (C) 2002 The Association for the Study ofAnimal Behaviour. C1 Univ Calif Davis, Sect Evolut & Ecol, Davis, CA 95616 USA. RP Hanley, KA (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 7,7 Ctr Dr, Bethesda, MD 20892 USA. NR 43 TC 15 Z9 15 U1 0 U2 15 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0003-3472 J9 ANIM BEHAV JI Anim. Behav. PD FEB PY 2002 VL 63 BP 311 EP 322 DI 10.1006/anbe.2001.1874 PN 2 PG 12 WC Behavioral Sciences; Zoology SC Behavioral Sciences; Zoology GA 532YN UT WOS:000174502800014 ER PT J AU Weed, DL Mink, PJ AF Weed, DL Mink, PJ TI Roles and responsibilities of epidemiologists SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE advocacy; epidemiology; ethics; science; policy ID PUBLIC-HEALTH POLICY; PSYCHIATRIC EPIDEMIOLOGY; ACADEMIC EPIDEMIOLOGY; FUTURE; PREVENTION; SCIENCE; DISEASE; PROSECUTION; CHALLENGES; PARADIGMS AB Two distinct views of the roles and responsibilities of epidemiologists have emerged in a decades-tong debate: one keeps professional practice constrained to science; the other adds active participation in public health policymaking. In defense of the narrower view are several claims: that epidemiologists lack expertise in policymaking; that advocating policy adversely affects scientific objectivity; that the limits of epidemiologic science work against translating results into policy; and that participation in policy can bring on personal attacks. In this study, each claim is addressed. Epidemiologists already participate fully in educational, research funding, and editorial policymaking and thereby have an experiential foundation in some of the basics of policymaking. Policymaking can enhance scientific objectivity because it requires not only the use but more importantly the improvement of empirical methods. Finally, the comforts of professional life are not the primary yardsticks of our responsibilities. Arguments in favor of active involvement in public health policymaking are presented. Epidemiologists have been mixing science and policymaking for a long time and there is a strong sense that the benefits of public stewardship outweigh the risks. The American College of Epidemiology's Ethics Guidelines support this view. Active participation in public heath policymaking will, however, require curriculum changes in graduate training programs. With additional training and a broader recognition that public health policymaking is an appropriate professional pursuit, epidemiologists can look to a bright and challenging future in the science and practice of public health. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NCI, Div Canc Prevent, Off Prevent Oncol, Bethesda, MD 20892 USA. RP Weed, DL (reprint author), NCI, Div Canc Prevent, Off Prevent Oncol, 6120 Execut Blvd,Suite T-41, Bethesda, MD 20892 USA. NR 81 TC 22 Z9 24 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD FEB PY 2002 VL 12 IS 2 BP 67 EP 72 AR PII S1047-2797(01)00302-7 DI 10.1016/S1047-2797(01)00302-7 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 527TT UT WOS:000174204200001 PM 11880212 ER PT J AU Welty, TK Rhoades, DA Yeh, F Lee, ET Cowan, LD Fabsitz, RR Robbins, DC Devereux, RB Henderson, JA Howard, BV AF Welty, TK Rhoades, DA Yeh, F Lee, ET Cowan, LD Fabsitz, RR Robbins, DC Devereux, RB Henderson, JA Howard, BV TI Changes in cardiovascular disease risk factors among American Indians: The Strong Heart Study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE cardiovascular diseases; cholesterol; diabetes; hypertension; North American Indians; obesity; risk factors; smoking; alcohol ID IMPAIRED GLUCOSE-TOLERANCE; AGED 45-74 YEARS; PHYSICAL-ACTIVITY; US ADULTS; WOMEN; PREVALENCE; OVERWEIGHT; MORTALITY; ALCOHOL; EPIDEMIOLOGY AB PURPOSE: This study describes changes in cardiovascular disease (CVD) risk factors in older American Indians over a 4-year period. METHODS: The Strong Heart Study, a longitudinal population-based study of CVD and CVD risk factors among American Indians aged 45-74 years, measured CVD risk factors among 3633 members of 13 tribes in three geographic areas during examinations in 1989 to 1991 and 1993 to 1995. RESULTS: Changes in mean low-density lipoprotein (LDL) cholesterol and the prevalence of elevated LDL cholesterol were inconsistent. Mean high- density lipoprotein (HDL) cholesterol decreased, and the prevalence of tow HDL cholesterol increased throughout. Mean systolic blood pressure and hypertension rates increased in nearly all center-sex groups, and hypertension awareness and treatment improved. Smoking rates decreased but remained higher than national rates except among Arizona women. Mean weight and percentage body fat decreased in nearly all center-sex groups but the prevalence of obesity did not change significantly in any group. Diabetes and albuminuria prevalence rates increased throughout the study population. The prevalence of alcohol use decreased, but binge drinking remained common in those who continued to drink. CONCLUSIONS: Improvements in management and prevention of hypertension, diabetes, renal disease, and obesity, and programs to further reduce smoking and alcohol abuse, are urgently needed. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, Oklahoma City, OK 73190 USA. Aberdeen Area Tribal Chairmens Hlth Board, Rapid City, SD USA. Univ Oklahoma, Hlth Sci Ctr, Native Elder Res Ctr, Oklahoma City, OK 73190 USA. NHLBI, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. Medstar Res Inst, Washington, DC USA. Cornell Univ, New York Hosp, Med Ctr, New York, NY 10021 USA. RP Lee, ET (reprint author), Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, POB 26901, Oklahoma City, OK 73190 USA. FU NHLBI NIH HHS [U01 HL041652, U01-HL41642, U01-HL41652, U01-HL41654] NR 42 TC 55 Z9 55 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD FEB PY 2002 VL 12 IS 2 BP 97 EP 106 AR PII S1047-2797(01)00270-8 DI 10.1016/S1047-2797(01)00270-8 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 527TT UT WOS:000174204200006 PM 11880217 ER PT J AU Wang, WY Hu, DS Lee, ET Fabsitz, RR Welty, TK Robbins, DC Yeh, JL Howard, BV AF Wang, WY Hu, DS Lee, ET Fabsitz, RR Welty, TK Robbins, DC Yeh, JL Howard, BV TI Lipoprotein(a) in American Indians is low and not independently associated with cardiovascular disease: The Strong Heart Study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE lipoprotein(a); American Indians; cardiovascular disease; Cox regression model; the Strong Heart Study ID CORONARY-ARTERY DISEASE; DEPENDENT DIABETES-MELLITUS; AGED 45-74 YEARS; RISK-FACTORS; LP(A) LIPOPROTEIN; ELEVATED LIPOPROTEIN(A); SERUM LIPOPROTEIN(A); FIBRINOLYTIC-ACTIVITY; PLASMA-LIPOPROTEIN; NIDDM PATIENTS AB PURPOSE: To evaluate the distribution of lipoprotein(a) (Lp(a)) and assess its association to cardiovascular disease (CVD) in American Indians. METHODS: Lp(a) was measured in 3991 American Indians (aged 45-74 years with no prior history of CVD at baseline) from 13 communities in Arizona, Oklahoma, and South/North Dakota. They were followed prospectively from 1989 to 1997 for CVD. The distribution of Lp(a) was examined by center, sex, and diabetic status. Spearman correlation coefficients and Cox regression models were used to evaluate the association of Lp(a) to CVD. RESULTS: A total of 388 participants subsequently developed CVD. Median Lp(a) concentration in American Indians was 3.0 mg/dl. This was almost half of that in whites and one sixth in blacks from the CARDIA study measured by the same method. Nondiabetic participants had significantly higher Lp(a) levels than diabetic participants for both genders. Lp(a) levels were higher in women than in men for nondiabetic participants, but there was no gender difference for diabetic participants. Correlation analysis showed Lp(a) was significantly negatively correlated with the degree of Indian heritage, insulin, triglycerides (TO), fasting plasma glucose (FPG), and 2-hour plasma glucose (2hPG), and positively with low-density lipoproteins (LDL), apoprotein B (apoB), and fibrinogen (FIB). In Cox regression models, adjusting for other risk factors, Lp(a) was no longer a significant predictor of CVD in either diabetic or nondiabetic participants. CONCLUSIONS: The lower concentration of Lp(a) in American Indians and the high correlation with Indian heritage confirm the concept that Lp(a) concentration is in large part genetically deter-mined. Lp(a) concentration is not an independent predictor of CVD among American Indians; it is higher in those who develop CVD because of its positive correlation with LDL, apoB, and FIB. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, Oklahoma City, OK 73190 USA. Henan Med Univ, Coll Publ Hlth, Zhengzhou, Peoples R China. MedStar Res Inst, Washington, DC USA. NHLBI, NIH, Bethesda, MD 20892 USA. Aberdeen Area Tribal Chairmens Hlth Board, Aberdeen, SD USA. RP Wang, WY (reprint author), Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, POB 26901, Oklahoma City, OK 73190 USA. NR 54 TC 33 Z9 33 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD FEB PY 2002 VL 12 IS 2 BP 107 EP 114 AR PII S1047-2797(01)00273-3 DI 10.1016/S1047-2797(01)00273-3 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 527TT UT WOS:000174204200007 PM 11880218 ER PT J AU Abbott, KC Hypolite, IO Hshieh, P Cruess, D Taylor, AJ Agodoa, LY AF Abbott, KC Hypolite, IO Hshieh, P Cruess, D Taylor, AJ Agodoa, LY TI Hospitalized congestive heart failure after renal transplantation in the United States SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE congestive heart failure; hospitalization; renal transplant; African American; black; male; diabetes mellitus; complications; duration of dialysis; rejection; delayed graft function; USRDS ID RISK-FACTORS; HEMODIALYSIS-PATIENTS; RACIAL-DIFFERENCES; MORTALITY; DISEASE; HYPERTENSION; RACE; ASSOCIATION; SURVIVAL; DIALYSIS AB PURPOSE: African Americans have increased risk for congestive heart failure (CHF) compared to Caucasians in the general population, but the risk of CHF in African American renal transplant recipients has not been studied in a national renal transplant population. METHODS: Therefore, 33,479 renal transplant recipients in the United States Renal Data System (USRDS) from I July, 1994 to 30 June, 1997 were analyzed in an historical cohort study of the incidence, associated factors, and mortality of hospitalizations with a primary discharge diagnosis of CHF [international Classification of Diseases-9 (ICD9) Code 428.x]. RESULTS: African American renal transplant recipients had increased age-adjusted risk of hospitalizations for congestive heart failure compared to African Americans in the general population [rate ratio 4.60, 95% confidence interval (CI) 4.59-4.62]. In logistic regression analysis, African American recipients had increased risk of congestive heart failure after renal transplantation, independent of other factors. Among other significant factors associated with congestive heart failure, the strongest were graft loss and allograft rejection. No maintenance immunosuppressive medications were associated with CHF. In Cox regression analysis patients hospitalized for CHF had increased all-cause mortality compared with all other recipients (hazard ratio 3.69, 95% Cl, 2.23-6.10), but African American recipients with CHF were not at significantly increased risk of mortality compared to Caucasian recipients with CHF. CONCLUSIONS: African Americans recipients were at high risk for CHF after transplant independent of other factors. The reasons for this increased risk should be the subject of further study. All potential transplant recipients should receive particular attention for the diagnosis and prevention of CHF in the transplant evaluation process, which includes preservation of allograft function. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. Walter Reed Army Med Ctr, Serv Cardiol, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NIDDK, Off Minor Hlth Res Coordinat, NIH, Bethesda, MD 20892 USA. RP Abbott, KC (reprint author), Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. OI Abbott, Kevin/0000-0003-2111-7112 NR 38 TC 24 Z9 24 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD FEB PY 2002 VL 12 IS 2 BP 115 EP 122 AR PII S1047-2797(01)00272-1 DI 10.1016/S1047-2797(01)00272-1 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 527TT UT WOS:000174204200008 PM 11880219 ER PT J AU Mattay, VS Tessitore, A Callicott, JH Bertolino, A Goldberg, TE Chase, TN Hyde, TM Weinberger, DR AF Mattay, VS Tessitore, A Callicott, JH Bertolino, A Goldberg, TE Chase, TN Hyde, TM Weinberger, DR TI Dopaminergic modulation of cortical function in patients with Parkinson's disease SO ANNALS OF NEUROLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; MONKEY PREFRONTAL CORTEX; AUTOMATED IMAGE REGISTRATION; SUPPLEMENTARY MOTOR AREA; DELAYED-RESPONSE TASK; WORKING-MEMORY; NEURONAL-ACTIVITY; BASAL GANGLIA; COGNITIVE ACTIVATION; PYRAMIDAL NEURONS AB Patients with idiopathic Parkinson's disease suffer not only from classic motor symptoms, but from deficits in cognitive function, primarily those subserved by the prefrontal cortex as well. The aim of the current study was to investigate the modulatory effects of dopaminergic therapy on neural systems subserving working memory and motor function in patients with Parkinson's disease. Ten patients with stage I and II Parkinson's disease were studied with functional magnetic resonance imaging, during a relatively hypodopaminergic state (ie, 12 hours after a last dose of dopamimetic treatment), and again during a dopamine-replete state. Functional magnetic resonance imaging was performed under three conditions: a working memory task, a cued sensorimotor task and rest. Consistent with prior data, the cortical motor regions activated during the motor task showed greater activation during the dopamine-replete state; however, the cortical regions subserving working memory displayed greater activation during the hypodopaminergic state. Interestingly, the increase in cortical activation during the working memory task in the hypodopaminergic state positively correlated with errors in task performance, and the increased activation in the cortical motor regions during the dopamine-replete state was positively correlated with improvement in motor function. These results support evidence from basic research that dopamine modulates cortical networks subserving working memory and motor function via two distinct mechanisms: nigrostriatal projections facilitate motor function indirectly via thalamic projections to motor cortices, whereas the mesocortical dopaminergic system facilitates working memory function via direct inputs to prefrontal cortex. The results are also consistent with evidence that the hypodopaminergic state is associated with decreased efficiency of prefrontal cortical information processing and that dopaminergic therapy improves the physiological efficiency of this region. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20982 USA. NINCDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Mattay, VS (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bldg 10,Ctr Dr,Room 4S-235, Bethesda, MD 20982 USA. RI Callicott, Joseph/C-9102-2009; Bertolino, Alessandro/O-6352-2016 OI Callicott, Joseph/0000-0003-1298-3334; Bertolino, Alessandro/0000-0002-1251-1380 NR 64 TC 259 Z9 265 U1 2 U2 9 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD FEB PY 2002 VL 51 IS 2 BP 156 EP 164 DI 10.1002/ana.10078 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 517XR UT WOS:000173636200004 PM 11835371 ER PT J AU Fisher, PG Tontiplaphol, A Pearlman, EM Duffner, PK Hyder, DJ Stolle, CA Vortmeyer, AO Zhuang, ZP AF Fisher, PG Tontiplaphol, A Pearlman, EM Duffner, PK Hyder, DJ Stolle, CA Vortmeyer, AO Zhuang, ZP TI Childhood cerebellar hemangioblastoma does not predict germline or somatic mutations in the von Hippel-Landau tumor suppressor gene SO ANNALS OF NEUROLOGY LA English DT Article; Proceedings Paper CT 37th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 12-15, 2001 CL SAN FRANCISCO, CALIFORNIA SP Amer Soc Clin Oncol ID VONHIPPEL-LINDAU DISEASE; CENTRAL-NERVOUS-SYSTEM; RENAL-CELL CARCINOMA AB Tumor suppressor gene "knockout" models would predict that children who present with hemangioblastoma are likely to harbor germline mutation of the von Hippel-Lindau gene. We screened 6 pediatric patients with cerebellar hemangioblastoma for germline or somatic mutations of the von Hippel-Landau gene. Two had prior clinical manifestations of von Hippel-Landau disease and, as expected, had germline von Hippel-Landau gene mutations. Four children with solitary hemangioblastoma did not have a detectable germline deletion, rearrangement, or point mutation in their von Hippel-Landau gene, and tumor specimens in 3 of these 4 showed no somatic von Hippel-Landau allelic loss. Solitary cerebellar hemangioblastoma in children does not predict a germline, or somatic mutation in the von Hippel-Landau tumor suppressor gene. The tumorigenesis of hemangioblastoma in younger patients may differ from that in adults, and may involve a molecular process unrelated to the von Hippel-Lindau tumor suppressor pathway. C1 Stanford Univ, Med Ctr, Dept Neurol, Sch Med, Stanford, CA 94305 USA. Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. SUNY Buffalo, Dept Neurol, Buffalo, NY 14260 USA. Univ So Calif, Sch Med, Dept Neurol, Los Angeles, CA USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. RP Fisher, PG (reprint author), Stanford Univ, Med Ctr, Dept Neurol, Sch Med, Room A343,300 Pasteur Dr, Stanford, CA 94305 USA. FU PHS HHS [K12 1692-05] NR 17 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 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD FEB PY 2002 VL 51 IS 2 BP 257 EP 260 DI 10.1002/ana.10107 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 517XR UT WOS:000173636200017 PM 11835384 ER PT J AU Thambi, P Sausville, EA AF Thambi, P Sausville, EA TI STI571 (imatinib mesylate): the tale of a targeted therapy SO ANTI-CANCER DRUGS LA English DT Review DE imatinib mesylate; STI571; targeted therapy ID TYROSINE KINASE INHIBITOR; BCR-ABL; IN-VIVO; ALPHA-1-ACID GLYCOPROTEIN; LEUKEMIA-CELLS; GROWTH; CGP-57148; PROTEIN AB ST1571 (imatinib mesylate) is an example of the successful development of a targeted agent. Its target is the constitutively active tyrosine kinase (p210(bcr-abl)) In a hematologic neoplasm, chronic myelogenous leukemia (CML). The results in early clinical trials were remarkable and led to rapid approval by the Food and Drug Administration for clinical use of the ST1571 in CML. This article reviews the pre-clinical and clinical development of this agent and also discusses some of the prevailing theories to explain the emerging problem of resistance. Future directions for this drug, possibly directed at other targets, are also discussed. [(C) 2002 Lippincott Williams Wilkins]. C1 Natl Canc Inst, Dev Therapeut Program, Rockville, MD 20852 USA. RP Thambi, P (reprint author), Natl Canc Inst, Dev Therapeut Program, 6130 Execut Blvd,EPN Room 8014, Rockville, MD 20852 USA. NR 28 TC 8 Z9 10 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD FEB PY 2002 VL 13 IS 2 BP 111 EP 114 DI 10.1097/00001813-200202000-00001 PG 4 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 525UR UT WOS:000174092900001 PM 11901302 ER PT J AU Davis, DA Read-Connole, E Pearson, K Fales, HM Newcomb, FM Moskovitz, J Yarchoan, R AF Davis, DA Read-Connole, E Pearson, K Fales, HM Newcomb, FM Moskovitz, J Yarchoan, R TI Oxidative modifications of kynostatin-272, a potent human immunodeficiency virus type 1 protease inhibitor: Potential mechanism for altered activity in monocytes/macrophages SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID MONOCYTE-DERIVED MACROPHAGES; HIV-1 PROTEASE; ANTIRETROVIRAL THERAPY; HTLV-III; INFECTION; METABOLISM; STRESS; CELLS; ALLOPHENYLNORSTATINE; PHARMACOKINETICS AB Previous studies have indicated that human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) are less active at blocking viral replication in HIV-1 infected peripheral blood monocytes/macrophages (M/M) than in HIV-1-infected T cells. We explored the hypothesis that oxidative modification and/or metabolism of the PIs in M/M might account for this reduced potency. We first tested the susceptibility of several PIs (kynostatin-272 [KNI-272], saquinavir, indinavir, ritonavir, or JE-2147) to oxidation after exposure to hydrogen peroxide (H2O2): only KNI-272 was highly susceptible to oxidation. Treatment of KNI-272 with low millimolar concentrations of H2O2 resulted in mono-oxidation of the sulfur in the S-methyl cysteine (methioalanine) moiety, as determined by reversed-phase high-performance liquid chromatography and mass spectrometry (RP-HPLC/MS). Higher concentrations of H2O2 led to an additional oxidation of the sulfur in the thioproline moiety of KNI-272. None of the PIs were metabolized or oxidized when added to T cells and cultured for up to 12 days. However, when KNI-272 was added to M/M, the concentration of the original KNI-272 steadily, decreased with a corresponding increase in the production of three KNI-272 metabolites as identified by RP-HPLC/MS. The structures of these metabolites were different from those produced by H2O2 treatment. The two major products of M/M metabolism of KNI-272 were identified as isomeric forms of KNI-272 oxidized solely on the thioproline ring. Both metabolites had reduced capacities to inhibit HIV-1 protease activity when tested in a standard HIV-1 protease assay. These studies demonstrate that antiviral compounds can be susceptible to oxidative modification in M/M and that this can affect their antiviral potency. C1 NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Davis, DA (reprint author), NCI, HIV & AIDS Malignancy Branch, NIH, Bldg 10,Rm 10S255,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 39 TC 4 Z9 5 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD FEB PY 2002 VL 46 IS 2 BP 402 EP 408 DI 10.1128/AAC.46.2.402-408.2002 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 514FK UT WOS:000173427900021 PM 11796349 ER PT J AU Sedelnikova, OA Karamychev, VN Panyutin, IG Neumann, RD AF Sedelnikova, OA Karamychev, VN Panyutin, IG Neumann, RD TI Sequence-specific gene cleavage in intact mammalian cells by I-125-labeled triplex-forming oligonucleotides conjugated with nuclear localization signal peptide SO ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT LA English DT Article ID AUGER-ELECTRON EMITTERS; COVALENT MODIFICATION; STRAND BREAKS; DNA; I-125; DECAY; RADIOTHERAPY; EXPRESSION; BINDING AB Triplex-forming oligonucleotides (TFO) are designed to bind sequence specifically to their DNA targets without a significant disturbance of the double helix. They have been proposed to deliver DNA-reactive agents to specific DNA sequences for gene targeting applications. We suggested the use of I-125-labeled TFO for delivery of the energy of radioiodine decay to specific genes. This approach is called antigene radiotherapy. Here we demonstrate the ability of I-125-labeled TFO to produce sequence-specific breaks within a target in the human mdr1 gene in cultured cells. TFO and TFO conjugated with a nuclear localization signal peptide (NLS) were delivered into cells using cationic liposomes. This was done either alone or in the presence of an excess of a "ballast" oligonucleotide with an unrelated sequence. In all cases, nuclear localization of TFO and survival of the cells after treatment has been confirmed. Breaks in the gene target were analyzed by restriction enzyme digestion of the DNA recovered from the TFO-treated cells followed by Southern hybridization with DNA probes flanking the target sequence. We have found that TFO/NLS conjugates cleave the target in a concentration-dependent manner regardless of the presence of the "ballast" oligonucleotide. In contrast, TFO without NLS cleaved the target only in the presence of an excess of the "ballast." We hypothesize that TFO and TFO/NLS are delivered into the nucleus by different pathways. These results provide a new insight into the mechanism of intracellular transport of oligonucleotides and open new avenues for improvement of the efficacy of antigene therapies. C1 NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Panyutin, IG (reprint author), NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bldg 10-1C401, Bethesda, MD 20892 USA. NR 30 TC 27 Z9 29 U1 0 U2 5 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1087-2906 J9 ANTISENSE NUCLEIC A JI Antisense Nucleic Acid Drug Dev. PD FEB PY 2002 VL 12 IS 1 BP 43 EP 49 DI 10.1089/108729002753670256 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 545KG UT WOS:000175215800005 PM 12022689 ER PT J AU Kawajiri, H Hsi, LC Kamitani, H Ikawa, H Geller, M Ward, T Eling, TE Glasgow, WC AF Kawajiri, H Hsi, LC Kamitani, H Ikawa, H Geller, M Ward, T Eling, TE Glasgow, WC TI Arachidonic and linoleic acid metabolism in mouse intestinal tissue: Evidence for novel lipoxygenase activity SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE mouse intestine; linoleic acid; arachidonic acid; lipoxygenase; cyclooxygenase ID GENE CHROMOSOMAL ASSIGNMENT; HUMAN COLORECTAL-CANCER; LOW-DENSITY-LIPOPROTEIN; HUMAN COLON-CANCER; EPITHELIAL-CELLS; PPAR-GAMMA; 13-HODE DEHYDROGENASE; FUNCTIONAL EXPRESSION; MOLECULAR-CLONING; CDNA CLONING AB Previous studies in our laboratory revealed a high expression of 15-lipoxygenase-1 in human colorectal carcinomas, suggesting the importance of lipoxygenase in colorectal tumor development. In this report, we have investigated the metabolism of arachidonic and linoleic acid by intestinal tissues of Min mice, an animal model for intestinal neoplasia. The polyp and normal tissues from Min mice intestine were homogenized, incubated with arachidonic or linoleic acid, and analyzed by reverse-, straight-, and chiral-phase HPLC. Arachidonic acid was converted to prostaglandins E-2 and F-2alpha. Little 12- or 15-hydroxyeicosatetraenoic acid was detected. Cyclooxygenase (COX)-2 was detected in polyps and the adjacent normal tissues by Western immunoblotting, but neither COX-1 nor leukocyte-type 12-lipoxygenase, the murine ortholog to human 15-lipoxygenase-1, was detected. These tissue homogenates converted linoleic, acid to an equal mixture of 9(S)- and 13(S)-hydroxyoctadecadienoic acid (HODE). Inhibition of lipoxygenase activity with nordihydroguaiaretic acid blocked HODEs formation, but the COX inhibitor indomethacin did not. Degenerative-nested PCR analyses using primers encoded by highly conserved sequences in lipoxygenases detected 5-lipoxygenase, leukocyte-type 12-lipoxygenase, platelet-type 12-lipoxygenase, 8-lipoxygenase, and epider-mis-type lipoxygenase-3 in mouse intestinal tissue. All of these PCR products represent known lipoxygenase that are not reported to utilize linoleic acid preferentially as substrate and do not metabolize linoleic acid to an equal mixture of 9(S)- and 13(S)-HODE. This somewhat unique profile of linoleate product formation in Min mice intestinal tissue suggests the presence of an uncharacterized and potentially novel lipoxygenase(s) that may play a role in intestinal epithelial cell differentiation and tumor development. (C) 2002 Elsevier Science. C1 NIEHS, Eicosanoid Biochem Sect, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. Mercer Univ, Sch Med, Div Basic Med Sci, Macon, GA 31207 USA. RP Eling, TE (reprint author), NIEHS, Eicosanoid Biochem Sect, Mol Carcinogenesis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 44 TC 11 Z9 12 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD FEB 1 PY 2002 VL 398 IS 1 BP 51 EP 60 DI 10.1006/abbi.2001.2685 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 518HD UT WOS:000173661000007 PM 11811948 ER PT J AU Pine, DS AF Pine, DS TI Respiration in children at risk for panic disorder - In reply SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Letter ID EARLY-ADULTHOOD; SMOKING; ANXIETY C1 NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Pine, DS (reprint author), NIMH, Mood & Anxiety Disorders Program, 15K North Dr,Room 110, Bethesda, MD 20892 USA. NR 5 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD FEB PY 2002 VL 59 IS 2 BP 186 EP 186 PG 1 WC Psychiatry SC Psychiatry GA 519YX UT WOS:000173754000013 ER PT J AU Teipel, SJ Bayer, W Alexander, GE Zebuhr, Y Teichberg, D Kulic, L Schapiro, MB Moller, HJ Rapoport, SI Hampel, H AF Teipel, SJ Bayer, W Alexander, GE Zebuhr, Y Teichberg, D Kulic, L Schapiro, MB Moller, HJ Rapoport, SI Hampel, H TI Progression of corpus callosum atrophy in Alzheimer disease SO ARCHIVES OF NEUROLOGY LA English DT Article ID WHITE-MATTER PATHOLOGY; METABOLISM; INDICATOR AB Background: Atrophy of the corpus callosum in the absence of primary white matter degeneration reflects loss of intracortical projecting neocortical pyramidal neurons in Alzheimer disease (AD). Objectives: To determine individual rates of atrophy progression of the corpus callosum in patients with AD and to correlate rates of atrophy progression with clinical disease severity and subcortical disease. Methods: Magnetic resonance imaging-derived measurements of corpus callosum size were studied longitudinally in 21 patients clinically diagnosed as having AD (mean observation time, 17.0 +/- 8.5 months) and 10 age-and sex-matched healthy controls (mean observation time, 24.1 +/- 6.8 months). Results: Corpus callosum size was significantly reduced in AD patients at baseline. Annual rates of atrophy of total corpus callosum, splenium, and rostrum were significantly larger in AD patients (-7.7%, -12.1%, and -7.3%, respectively) than in controls (-0.9%, -1.5%, and 0.6%, respectively). Rates of atrophy of the corpus callosum splenium were correlated with progression of dementia severity in AD patients (p = 0.52, P<.02). The load of subcortical lesions at baseline (P<.05) predicted rate of anterior corpus callosum atrophy in healthy controls. Rates of atrophy of corpus callosum areas were independent of white matter hyperintensity load in patients with AD. Conclusions: Measurement of corpus callosum size allows in vivo mapping of neocortical neurodegeneration in AD over a wide range of clinical dementia seventies and may be used as a surrogate marker for evaluation of drug efficacy. C1 Univ Munich, Dept Psychiat, Dementia & Neuroimaging Sect, Dept Psychiat, D-80336 Munich, Germany. Childrens Hosp, Med Ctr, Dept Pediat Neurol, Cincinnati, OH 45229 USA. NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. Arizona State Univ, Dept Psychol, Tempe, AZ 85287 USA. Arizona State Univ, Arizona Alzheimers Res Ctr, Tempe, AZ 85287 USA. RP Teipel, SJ (reprint author), Univ Munich, Dept Psychiat, Dementia & Neuroimaging Sect, Dept Psychiat, Nussbaumstr 7, D-80336 Munich, Germany. NR 27 TC 91 Z9 93 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD FEB PY 2002 VL 59 IS 2 BP 243 EP 248 DI 10.1001/archneur.59.2.243 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 520UN UT WOS:000173799900009 PM 11843695 ER PT J AU Kaiser-Kupfer, MI Caruso, RC Valle, D AF Kaiser-Kupfer, MI Caruso, RC Valle, D TI Gyrate atrophy of the choroid and retina - Further experience with long-term reduction of ornithine levels in children SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID MOUSE MODEL; DEGENERATION; VITAMIN-B6; TRIAL AB Objective: To determine whether the long-term reduction of plasma ornithine levels by way of an arginine-restricted diet in patients with gyrate atrophy will slow the progression of this chorioretinal degeneration. Design: Natural history study of 2 pairs of siblings with gyrate atrophy treated with an arginine-restricted diet. Main Outcome Measures: Fundus photography and electrophysical and psychophysical retinal function tests. Results: After 16 to 17 years of receiving an arginine-restricted diet, the younger sibling in each pair, who was prescribed the diet at an earlier age than the older sibling, demonstrated a slower progression of lesions compared with the older sibling. Conclusions: If started at an early age, long-term substantial reduction of plasma ornithine levels may appreciably slow the progression of the chorioretinal lesions and, to a lesser extent, the progressive loss of retinal function in patients with gyrate atrophy. C1 NEI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. RP Kaiser-Kupfer, MI (reprint author), NEI, NIH, 10 Ctr Dr MSC 1860,Bldg 10,Room 10N226, Bethesda, MD 20892 USA. FU NCRR NIH HHS [RR-0052] NR 21 TC 17 Z9 17 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD FEB PY 2002 VL 120 IS 2 BP 146 EP 153 PG 8 WC Ophthalmology SC Ophthalmology GA 520LZ UT WOS:000173784500004 PM 11831916 ER PT J AU Buggage, RR Smith, JA Shen, D Chan, CC AF Buggage, RR Smith, JA Shen, D Chan, CC TI Conjunctival papillomas caused by human papillomavirus type 33 SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID LESIONS; WOMEN; DNA C1 NEI, NIH, Bethesda, MD 20892 USA. RP Buggage, RR (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10,Room 10N112, Bethesda, MD 20892 USA. NR 10 TC 9 Z9 10 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD FEB PY 2002 VL 120 IS 2 BP 202 EP 204 PG 3 WC Ophthalmology SC Ophthalmology GA 520LZ UT WOS:000173784500014 PM 11831924 ER PT J AU Aszalos, A AF Aszalos, A TI Specific cell-signal targets for cancer chemotherapy SO ARCHIVES OF PHARMACAL RESEARCH LA English DT Review DE chemotherapy; tyrosine kinases; signal times duction; leukemia; epidermal growth factor ID TYROSINE KINASE INHIBITOR; IN-VIVO; TELOMERASE ACTIVITY; SOMATOSTATIN ANALOGS; LEUKEMIA-CELLS; BUTYRIC-ACID; GROWTH; PROTEIN; BRYOSTATIN-1; CARCINOMA AB Attempts to develop drugs, specific for cancer cells, are dealt here according to the intended cell-target. While many target specific drugs were developed, they reach only moderate successes in clinics for reasons, such as, delivery problem, lack of in vivo efficacy or toxicity. However, recent efforts focusing on the diversity of tyrosine kinases, participating in cell-signal transduction, brought fruit. The firs such drug, Givec, approved by the USFDA recently, is used in clinics with great success to threat CML. The drug inhibits tyrosin kinase of bcr-abl, c-abl and v-abl. Work is progressing on other tyrosin kinase inhibitors and on other type of specific cancer cell signal protein inhibitors, These efforts are hoped to yield better cures for cancer in the near future. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Aszalos, A (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 79 TC 0 Z9 0 U1 0 U2 0 PU PHARMACEUTICAL SOCIETY KOREA PI SEOUL PA 1489-3 SUHCHO-DONG, SUHCHO-KU, SEOUL 137-071, SOUTH KOREA SN 0253-6269 J9 ARCH PHARM RES JI Arch. Pharm. Res. PD FEB PY 2002 VL 25 IS 1 BP 1 EP 10 DI 10.1007/BF02975254 PG 10 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 525DA UT WOS:000174052400001 PM 11885686 ER PT J AU Harley, JB Trent, J Kastner, DL AF Harley, JB Trent, J Kastner, DL CA Conference Participants TI American College of Rheumatology Basic Research Conference: Genetics and Genomics in Rheumatic Disease SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article C1 Univ Oklahoma, Hlth Sci Ctr, Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. NIH, Bethesda, MD 20892 USA. RP Harley, JB (reprint author), Univ Oklahoma, Hlth Sci Ctr, Oklahoma Med Res Fdn, 825 NE 13th St, Oklahoma City, OK 73104 USA. NR 0 TC 2 Z9 2 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 FEB PY 2002 VL 47 IS 1 BP 93 EP 98 DI 10.1002/art1.10242 PG 6 WC Rheumatology SC Rheumatology GA 520VU UT WOS:000173803700015 PM 11932884 ER PT J AU Makale, M Solomon, J Patronas, NJ Danek, A Butman, JA Grafman, J AF Makale, M Solomon, J Patronas, NJ Danek, A Butman, JA Grafman, J TI Quantification of brain lesions using interactive automated software SO BEHAVIOR RESEARCH METHODS INSTRUMENTS & COMPUTERS LA English DT Article ID SPATIAL NORMALIZATION; IMAGES; SEGMENTATION; ATLAS AB We developed an interactive program, Analysis of Brain Lesions (ABLe) so that researchers studying the effects of brain lesions on cognition could have a user-friendly tool that could quantitatively characterize such lesions. The program was prepared in Tcl/Tk and will run on any UNIX or PC LINUX platform with the MEDx medical imaging software package. The ABLe is almost completely automated and determines the brain lesion size as well as which cytoarchitectonic brain regions (Brodmann areas) are contained within the boundaries of the lesion. Lesion data from multiple subjects can be grouped together and the degree of lesion overlap displayed. All images are analyzed and displayed within standard Talairach coordinate space, and the precision of the match between the ABLe Brodmann area graphics and the subject/patient brain is easily confirmed. The program is the first easy-to-use software that contains these specific features and is available for interested researchers with a background in lesion analysis. C1 NINCDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. HM Jackson Fdn, Bethesda, MD USA. Sensor Syst Inc, Sterling, VA USA. RP Grafman, J (reprint author), NINCDS, Cognit Neurosci Sect, NIH, Bldg 10,Room 5C205,MSC 1440, Bethesda, MD 20892 USA. RI Butman, John/A-2694-2008; Danek, Adrian/G-7339-2011; OI Danek, Adrian/0000-0001-8857-5383; Grafman, Jordan H./0000-0001-8645-4457; Butman, John/0000-0002-1547-9195 NR 23 TC 65 Z9 65 U1 0 U2 1 PU PSYCHONOMIC SOC INC PI AUSTIN PA 1710 FORTVIEW RD, AUSTIN, TX 78704 USA SN 0743-3808 J9 BEHAV RES METH INS C JI Behav. Res. Methods Instr. Comput. PD FEB PY 2002 VL 34 IS 1 BP 6 EP 18 DI 10.3758/BF03195419 PG 13 WC Psychology, Mathematical; Psychology, Experimental SC Psychology GA 545NE UT WOS:000175223200002 PM 12060992 ER PT J AU Blair, RJR Perschardt, KS AF Blair, RJR Perschardt, KS TI Empathy: A unitary circuit or a set of dissociable neuro-cognitive systems? SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material ID FACIAL EXPRESSIONS AB We question whether empathy is mediated by a unitary circuit. We argue that recent neuroimaging data indicate dissociable neural responses for different facial expressions as well as for representing others' mental states (Theory of Mind, TOM). We also argue that the general empathy disorder considered characteristic of autism and psychopathy is not general but specific for each disorder. C1 NIMH, Mood & Anxiety Program, Bethesda, MD 20892 USA. UCL, Inst Cognit Neurosci, London WC1H 3AR, England. RP Blair, RJR (reprint author), NIMH, Mood & Anxiety Program, Bethesda, MD 20892 USA. EM blairJ@intra.nimh.nih.gov NR 6 TC 0 Z9 0 U1 3 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD FEB PY 2002 VL 25 IS 1 BP 27 EP + PG 15 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 692XQ UT WOS:000183685900009 ER PT J AU Zahn-Waxler, C AF Zahn-Waxler, C TI Caregiving, emotion, and concern for others SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material AB Few individuals are constitutionally incapable of showing concern for others at an early age, and malleability is possible. Individual variations will be best understood through study of the representational prerequisites of empathy in close conjunction with caregiving environments and affective underpinnings. C1 NIMH, Sect Dev Psychopathol, MSC, Bethesda, MD 20892 USA. RP Zahn-Waxler, C (reprint author), NIMH, Sect Dev Psychopathol, MSC, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 1 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD FEB PY 2002 VL 25 IS 1 BP 48 EP + PG 15 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 692XQ UT WOS:000183685900032 ER PT J AU Crombag, HS Shaham, Y AF Crombag, HS Shaham, Y TI Renewal of drug seeking by contextual cues after prolonged extinction in rats SO BEHAVIORAL NEUROSCIENCE LA English DT Article ID NUCLEUS-ACCUMBENS; STIMULI; RELAPSE; HEROIN; REINSTATEMENT; BEHAVIOR; COCAINE; MODEL; ABUSE; SENSITIZATION AB Contextual stimuli associated with drug exposure can modulate various effects of drugs, but little is known about their role in relapse to drug seeking. Using a renewal procedure, the authors report that drug-associated contextual stimuli play a critical role in relapse to drug-seeking previously maintained by a heroin-cocaine mixture (speedball). Rats were trained to self-administer speedball, after which drug-reinforced behavior was extinguished over 20 days in the self-administration context or in a different context. On the test day, rats exposed to the drug-associated context, after extinction in a different context, reliably renewed drug seeking. The authors suggest that the renewal procedure can be used to study mechanisms underlying relapse to drug seeking elicited by drug-associated contextual stimuli. C1 NIDA, Behav Neurosci Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Shaham, Y (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI shaham, yavin/G-1306-2014 NR 36 TC 197 Z9 200 U1 2 U2 10 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD FEB PY 2002 VL 116 IS 1 BP 169 EP 173 DI 10.1037//0735-7044.116.1.169 PG 5 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 515MA UT WOS:000173498600017 PM 11895178 ER PT J AU Park, JW Jung, Y Lee, SJ Jin, DJ Lee, Y AF Park, JW Jung, Y Lee, SJ Jin, DJ Lee, Y TI Alteration of stringent response of the Escherichia coli rnpB promoter by mutations in the-35 region SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Escherichia coli; promoter; stringent control; transcription; -35 region ID RNA-POLYMERASE; FIS PROMOTER; BASE SUBSTITUTIONS; DNA-SEQUENCES; M1 RNA; EXPRESSION; TRANSCRIPTION; SELECTIVITY; COMPONENT; VECTORS AB It is well known that the GC-rich discriminator region between the -10 region and the transcription start site is important for the stringent control of the transcription. However, the discriminator activity is influenced by flanking regions, in particular in conjunction with the promoter -35 and -10 sequences. In this study, we changed the sequence in the -35 region of the rnpB P-1 promoter to see how such changes affect the stringent control. The sequence variation in the -35 region changed the stringent signal. The change to the consensus TTGACA sequence caused the most prominent relieving effect on stringent repression of the rnpB transcription. The spacing between the -35 and -10 regions is also significant because the relieving effect of the TTGACA was offset by the change of the spacing from 17 to 16 bp. The nucleotide just upstream of the -35 region contributes toward generating stringent signals as well. (C) 2002 Elsevier Science (USA). C1 Korea Adv Inst Sci & Technol, Dept Chem, Taejon 305701, South Korea. Korea Adv Inst Sci & Technol, Ctr Mol Design & Synth, Taejon 305701, South Korea. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Lee, Y (reprint author), Korea Adv Inst Sci & Technol, Dept Chem, Taejon 305701, South Korea. RI Lee, Younghoon/C-1991-2011; Jung, Yongwon/G-7634-2012 NR 27 TC 14 Z9 14 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 1 PY 2002 VL 290 IS 4 BP 1183 EP 1187 DI 10.1006/bbrc.2001.6331 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 518XK UT WOS:000173693200006 PM 11811987 ER PT J AU Chen, X Mellon, RD Yang, L Dong, HF Oppenheim, JJ Howard, OMZ AF Chen, X Mellon, RD Yang, L Dong, HF Oppenheim, JJ Howard, OMZ TI Regulatory effects of deoxycholic acid, a component of the anti-inflammatory traditional Chinese medicine Niuhuang, on human leukocyte response to chemoattractants SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE deoxycholic acid (DCA); human leukocyte; chemokine/chemoattractant; chemotaxis; calcium mobilization; ligand-receptor binding ID METHIONYL-LEUCYL-PHENYLALANINE; BILE-ACIDS; CHEMOKINE RECEPTORS; CHEMOTACTIC PEPTIDES; HUMAN-NEUTROPHILS; BINDING; FMLP; RADIOIMMUNOASSAY; PROLIFERATION; METABOLISM AB Niuhuang is a commonly used Chinese traditional medicine with immunoregulatory and anti-inflammatory properties. Deoxycholic acid (DCA) is a major active constituent of Niuhuang. The reaction of human leukocytes to chemoattractants is an important part of the host immune response and also plays a crucial role in the development of inflammation. We, therefore, investigated the in vitro effects of DCA on human monocyte and neutrophil responses to classic chemoattractants [fMet-Leu-Phe (fMLP), complement fraction 5a (C5a)], CC chemokine [monocyte chemoattractant protein-1 (MCP-1/CCL2)], and/or CXC chemokines [stromal cell-derived factor-1 (SDF-1alpha/ CXCL12), interleukin-8 (IL-8/CXCL8)]. The results showed that DCA significantly inhibited fMLP-induced monocyte and neutrophil chemotaxis and calcium mobilization, and also blocked the binding of [H-3]fMLP and anti-formyl peptide receptor (FPR) monoclonal antibodies (mAb) to the cells The inhibitory effects of DCA on calcium mobilization and anti-FPR-mAb binding to the receptor could be abrogated by washing DCA out of the cell suspension, suggesting that DCA blocked fMLP receptors via a steric hindrance mechanism, not via receptor internalization, DCA had no significant inhibitory effects on MCP-1-, SDF-1alpha-, or C5a-induced monocyte function, or C5a- or IL-8-induced neutrophil function. Taken together, our experimental results suggest that blockade of fMLP receptors may contribute to the anti-inflammatory effects of traditional medicine containing DCA. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Frederick, MD 21702 USA. NCI, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. RP Howard, OMZ (reprint author), NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Bldg 560,Rm 31-19, Frederick, MD 21702 USA. RI Howard, O M Zack/B-6117-2012; Chen, Xin/I-6601-2015 OI Howard, O M Zack/0000-0002-0505-7052; Chen, Xin/0000-0002-2628-4027 FU NCCIH NIH HHS [Y2-AT-9002]; PHS HHS [N01-C0-5600] NR 51 TC 19 Z9 23 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD FEB 1 PY 2002 VL 63 IS 3 BP 533 EP 541 AR PII S0006-2952(01)00917-0 DI 10.1016/S0006-2952(01)00917-0 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 533AH UT WOS:000174506900020 PM 11853704 ER PT J AU Teng, CT AF Teng, CT TI Lactoferrin gene expression and regulation: an overview SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Article; Proceedings Paper CT 5th International Conference on Lactoferrin Structure, Function , and Applications CY MAY 04-09, 2001 CL BANFF, CANADA DE lactoferrin; gene promoter; transcription factor; estrogen; xenoestrogen ID LINKED IMMUNOSORBENT-ASSAY; IRON-BINDING PROPERTIES; EPIDERMAL GROWTH-FACTOR; HUMAN SALIVARY-GLANDS; AMINO-ACID-SEQUENCE; BOVINE LACTOFERRIN; ESTROGEN-RECEPTOR; MESSENGER-RNA; PORCINE LACTOFERRIN; REPRODUCTIVE-TRACT AB Lactoferrin is highly conserved among human, mouse, bovine, and porcine species. The numbers of amino acids encoded by 15 of the 17 exons in these species are identical, and in 12 locations, they have identical codon interruptions at the intron-exon splice junctions. However, lactoferrin expression is both ubiquitous and species, tissue, and cell-type specific. It is differentially regulated through multiple signaling pathways such as steroid hormone, growth factor, and kinase cascade pathways. Comparing the lactoferrin gene promoters from different species, common and different characteristics are observed. The human, mouse, bovine, porcine, and bubaline (African antelope) promoters all contain a noncanonical TATA box with an adjacent Sp1 site. Both human and mouse have multiple steroid hormone response elements, while none are found in the other species studied, suggesting that the lactoferrin gene is differentially regulated among different species by steroid hormones. Several transcription factors have been identified that are crucial for the expression of the lactoferrin gene during differentiation of the myeloid cells and in estrogen and epidermal growth factor regulation. This article provides an overview on lactoferrin expression and regulation in different species. C1 NIEHS, Reprod & Dev Toxicol Lab, Gene Regulat Sect, NIH, Res Triangle Pk, NC 27709 USA. RP Teng, CT (reprint author), NIEHS, Reprod & Dev Toxicol Lab, Gene Regulat Sect, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 111 TC 84 Z9 94 U1 1 U2 5 PU NATL RESEARCH COUNCIL CANADA PI OTTAWA PA RESEARCH JOURNALS, MONTREAL RD, OTTAWA, ONTARIO K1A 0R6, CANADA SN 0829-8211 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD FEB PY 2002 VL 80 IS 1 BP 7 EP 16 DI 10.1139/o01-215 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 524PE UT WOS:000174021400003 PM 11908645 ER PT J AU Liu, LH Gladwell, W Teng, CT AF Liu, LH Gladwell, W Teng, CT TI Detection of exon polymorphisms in the human lactoferrin gene SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Article; Proceedings Paper CT 5th International Conference on Lactoferrin Structure, Function , and Applications CY MAY 04-09, 2001 CL BANFF, CANADA DE lactoferrin; polymorphisms; human lactoferrin; single-strand conformation polymorphism (SSCP) ID POLYMERASE CHAIN-REACTION; PCR-SSCP ANALYSIS; POINT MUTATIONS; DNA; TRANSFERRIN AB We previously demonstrated that lactoferrin gene polymorphisms occur in cancer cells of patients with leukemia and breast cancer. In this study, we established a non-radioactive polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis, one of the most sensitive and simplest methods to detect polymorphisms and mutations of the human lactoferrin gene. We optimized the PCR conditions for nine different DNA templates and 16 pairs of exon primers for SSCP analysis. The DNA templates used in the analyses were prepared from a cosmid clone (CT6-1) that contains the human lactoferrin gene, human placental tissue, leukocytes from 10 normal volunteers, leukemic cells of two patients, and previously established three breast and two leukemic cell lines. With the appropriate exon-primer sets, PCR products from exon 1 to exon 16 of the lactoferrin gene were generated from the DNA templates and analyzed by SSCP. Compared with the homogenous cloned DNA, lactoferrin gene polymorphisms were detected within exons 2, 5, 7, 9, 13, 14, and 15 of the normal placental and leukocyte DNA. In addition, abnormal migration patterns of the lactoferrin gene in cancer cells were detected in exons 4, 5, 13, 14, and 15. The PCR-SSCP band migration patterns can be attributed either to gene polymorphism in normal cells or to DNA mutations in cancer cells and the employed method cannot distinguish between them. Nonetheless, the present analysis suggests that genetic polymorphisms of the lactoferrin gene exist in selected exons and additional mutations of the lactoferrin gene do occur in the cancer cells. C1 NIEHS, Gene Regulat Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Teng, CT (reprint author), NIEHS, Gene Regulat Sect, Reprod & Dev Toxicol Lab, NIH, 111 Alexander Dr,POB 12233,MD E2-01, Res Triangle Pk, NC 27709 USA. NR 22 TC 16 Z9 17 U1 0 U2 0 PU NATL RESEARCH COUNCIL CANADA PI OTTAWA PA RESEARCH JOURNALS, MONTREAL RD, OTTAWA, ONTARIO K1A 0R6, CANADA SN 0829-8211 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD FEB PY 2002 VL 80 IS 1 BP 17 EP 22 DI 10.1139/o01-207 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 524PE UT WOS:000174021400004 PM 11908638 ER PT J AU Zhang, ZP Teng, CT AF Zhang, ZP Teng, CT TI Methoxychlor stimulates the mouse lactoferrin gene promoter through a GC-rich element SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Article; Proceedings Paper CT 5th International Conference on Lactoferrin Structure, Function , and Applications CY MAY 04-09, 2001 CL BANFF, CANADA DE xenoestrogen; methoxychlor; environmental; lactoferrin gene; promoter ID ESTROGEN-RECEPTOR-ALPHA; EPIDERMAL GROWTH-FACTOR; EXPRESSION; UTERUS; LACTOTRANSFERRIN; PROGESTERONE; ACTIVATION; MECHANISM; BINDING; PROTEIN AB The lactoferrin gene in the mouse uterus is a target gene for natural estrogens and xenoestrogens. One of the xenoestrogens is methyoxychlor, an insecticide that displays both estrogenic and antiandrogenic activities. Recently, methyoxychlor was found to stimulate lactoferrin gene expression in the uterus of an estrogen receptor null mouse. The present study is designed to uncover the methoxychlor response region in the mouse lactoferrin gene promoter. A series of different lengths of the mouse lactoferrin gene 5' flanking region were linked to a chloramphenicol acetyltransferase (CAT) reporter construct and transfected into human endometrial carcinoma HEC-1B cells, an estrogen receptor null cell line, in order to examine the methoxychlor response. The transfected cells were treated with methoxychlor or the metabolite of methoxychlor, HPTE, and the CAT reporter activities were measured. Constructs that contain a mouse lactoferrin 5' region longer than 100 bp were activated more than twofold by both methoxychlor and HPTE. The activation of the CAT reporter by the chemicals was dose dependent and reached saturation. Additional deletion mutants within the 100-bp region were tested, and a GC-rich sequence (GC-II) that we have previously characterized as an epidermal growth factor (EGF) response element was identified to be the region for the methoxychlor response. GC-II binds Sp1, Sp3, and IKLF transcription factors, collaborates with the AP1/CREB binding element, and confers the EGF response. Whether the effect of methoxychlor requires the AP1/CREB binding element has yet to be established; however, the present finding provides an alternative signaling pathway for the xenoestrogens. C1 NIEHS, Gene Regulat Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Teng, CT (reprint author), NIEHS, Gene Regulat Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233,MDE2-01, Res Triangle Pk, NC 27709 USA. NR 23 TC 4 Z9 4 U1 0 U2 0 PU NATL RESEARCH COUNCIL CANADA PI OTTAWA PA RESEARCH JOURNALS, MONTREAL RD, OTTAWA, ONTARIO K1A 0R6, CANADA SN 0829-8211 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD FEB PY 2002 VL 80 IS 1 BP 23 EP 26 DI 10.1139/o01-177 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 524PE UT WOS:000174021400005 PM 11908639 ER PT J AU Wolf, YI Karev, G Koonin, EV AF Wolf, YI Karev, G Koonin, EV TI Scale-free networks in biology: new insights into the fundamentals of evolution? SO BIOESSAYS LA English DT Article ID SMALL-WORLD NETWORKS; GENOMES AB Scale-free network models describe many natural and social phenomena. In particular, networks of interacting components of a living cell were shown to possess scale-free properties. A recent study((1)) compares the system-level properties of metabolic and information networks in 43 archaeal, bacterial and eukaryal species and claims that the scale-free organization of these networks is more conserved during evolution than their content. BioEssays 24:105-109, 2002. Published 2002 Wiley Periodicals, Inc.(dagger). 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, Bethesda, MD 20894 USA. NR 25 TC 56 Z9 58 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0265-9247 J9 BIOESSAYS JI Bioessays PD FEB PY 2002 VL 24 IS 2 BP 105 EP 109 DI 10.1002/bies.10059 PG 5 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 519FE UT WOS:000173713600001 PM 11835273 ER PT J AU Gonzalez, M Woodgate, R AF Gonzalez, M Woodgate, R TI The "tale" of UmuD and its role in SOS mutagenesis SO BIOESSAYS LA English DT Review ID ESCHERICHIA-COLI DINB; DNA-POLYMERASE-ETA; XERODERMA-PIGMENTOSUM; RECA PROTEIN; INTERMOLECULAR CLEAVAGE; INDUCIBLE MUTAGENESIS; UV MUTAGENESIS; CLP PROTEASE; GENE; PROTEOLYSIS AB Recently, the Escherichia coli umuD and umuC genew have been shown to encode E. coli's fifth DNA polymerase, pol V (consisting of a heterotrimer of UmuD'C-2). The main function of pol V appears to be the bypass of DNA lesions that would otherwise block replication by pols I-IV. This process is error-prone and leads to a striking increase in mutations at sites of DNA damage. While the enzymatic properties of pol V are now only beginning to be fully appreciated, a great deal is known about how E. coli regulates the intracellular levels of the Umu proteins so that the lesion-bypassing activity of pol V is available to help cells survive the deleterious consequences of DNA damage, yet keeps any unwarranted activity on undamaged templates to a minimum. Our review summarizes the multiple restrictions imposed upon pol V, so as to limit its activity in vivo and, in particular, highlights the pivotal role that the N-terminal tail of UmuD plays in regulating SOS mutagenesis. BioEssays 24:1,41-148, 2002. Published 2002 Wiley Periodicals, Inc.(dagger). C1 Univ Colorado, Dept Biol, Denver, CO 80202 USA. NICHHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. RP Woodgate, R (reprint author), Bldg 6,Room 1A13,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 86 TC 21 Z9 22 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0265-9247 J9 BIOESSAYS JI Bioessays PD FEB PY 2002 VL 24 IS 2 BP 141 EP 148 DI 10.1002/bies.10040 PG 8 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 519FE UT WOS:000173713600006 PM 11835278 ER PT J AU Wendler, D AF Wendler, D TI What research with stored samples teaches us about research with human subjects SO BIOETHICS LA English DT Article AB There is widespread discussion concerning the safeguards appropriate for human research subjects. Less discussed is the fact that the safeguards one deems appropriate depend, in large part, on the model of research participation that one assumes. Therefore, to determine what safeguards are appropriate, it is necessary first to clarify the competing models of research participation. The ostensibly obscure debate over informed consent for research on stored biological samples is of particular interest in this regard because such research can involve varying subsets of the three central elements of research involvement. As a result, analysis of this debate provides an opportunity to identify the competing models of research participation. Based on this analysis, this paper describes, a new model of research participation that is emerging, and considers its implications for clinical research. C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH, Dept Clin Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. NR 16 TC 16 Z9 16 U1 0 U2 0 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 0269-9702 J9 BIOETHICS JI Bioethics PD FEB PY 2002 VL 16 IS 1 BP 33 EP 54 DI 10.1111/1467-8519.00266 PG 22 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 517WH UT WOS:000173633100004 PM 12061383 ER PT J AU Kimbrell, TA Ketter, TA George, MS Little, JT Benson, BE Willis, MW Herscovitch, P Post, RM AF Kimbrell, TA Ketter, TA George, MS Little, JT Benson, BE Willis, MW Herscovitch, P Post, RM TI Regional cerebral glucose utilization in patients with a range of severities of unipolar depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE depression; unipolar; positron emission tomography; cingulate; prefrontal cortex; severity ID OBSESSIVE-COMPULSIVE DISORDER; POSITRON EMISSION TOMOGRAPHY; SUBGENUAL PREFRONTAL CORTEX; BLOOD-FLOW; MOOD DISORDERS; MAJOR DEPRESSION; PSYCHOMOTOR RETARDATION; SYMPTOM PROVOCATION; PARKINSONS-DISEASE; NEURAL RESPONSE AB Background: Patients with unipolar depression are most often reported to have decreased regional cerebral glucose metabolism (rCMRglu) in dorsal prefrontal and anterior cingulate cortices compared with healthy control subjects, often correlating inversely with severity of depression. Methods: We measured rCMRglu with fluorine-18 deoxyglucose positron emission tomography (PET) in 38 medication-free patients with unipolar depression and 37 healthy control subjects performing an auditory continuous performance task to further investigate potential prefrontal and anterior paralimbic rCMRglu abnormalities in patients attending to this task. Results: Compared with control subjects, the subgroup of patients with Hamilton depression scores of 22 or greater demonstrated decreased absolute rCMRglu in right prefrontal cortex and paralimbic/amygdala regions as well as bilaterally in the insula and temporoparietal cortex (right > left); they also exhibited increased normalized metabolic activity bilaterally in the cerebellum, lingula/cuneus, and brain stem. Severity of depression negatively correlated with absolute rCMRglu in almost the entire extent of the right cingulate cortex as well as bilaterally in prefrontal cortex, insula, basal ganglia, and temporoparietal cortex (right > left). Conclusions: Areas of frontal, cingulate, insula, and temporal cortex appear hypometabolic in association with different components of the severity and course of illness in treatment-resistant unipolar depression. Biol Psychiatry 2002;51:237-252 (C) 2002 Society of Biological Psychiatry. C1 NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. N Little Rock VA Med Ctr, N Little Rock, AK USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Johns Hopkins Sch Med, Div Psychiat Neuroimaging, Baltimore, MD USA. NIH, Positron Emiss Tomog Sect, Dept Nucl Med, Ctr Clin, Bethesda, MD USA. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, Bldg 10,Room 35239,10 Ctr Dr MSC 1272, Bethesda, MD 20892 USA. NR 73 TC 168 Z9 176 U1 7 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 1 PY 2002 VL 51 IS 3 BP 237 EP 252 DI 10.1016/S0006-3223(01)01216-1 PG 16 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 520YH UT WOS:000173811000006 PM 11839367 ER PT J AU Obrocea, GV Dunn, RM Frye, MA Ketter, TA Luckenbaugh, DA Leverich, GS Speer, AM Osuch, EA Jajodia, K Post, RM AF Obrocea, GV Dunn, RM Frye, MA Ketter, TA Luckenbaugh, DA Leverich, GS Speer, AM Osuch, EA Jajodia, K Post, RM TI Clinical predictors of response to lamotrigine and gabapentin monotherapy in refractory affective disorders SO BIOLOGICAL PSYCHIATRY LA English DT Article DE predictors; affective disorders; lamotrigine; gabapentin; monotherapy; anticonvulsants ID CYCLING BIPOLAR DISORDER; DOUBLE-BLIND; ESSENTIAL TREMOR; MOOD DISORDERS; MAINTENANCE TREATMENT; CONTROLLED TRIAL; ACUTE MANIA; LITHIUM; PLACEBO; CARBAMAZEPINE AB Background: The objective of the current study was to examine possible clinical predictors of positive response to lamotrigine or gabapentin monotherapy in treatment-refractory affectively ill patients. Methods: Forty-five patients with treatment refractory bipolar (n=35) or unipolar (n=10) affective disorder participated in a clinical study evaluating six weeks of treatment with lamotrigine, gabapentin, or placebo monotherapy given in a double-blind, randomized fashion with two subsequent cross-overs to the other agents. Patients received daily mood ratings and weekly cross-sectional scales. Much or very much improved on the Clinical Global Impression scale modified for bipolar illness was considered a positive response. Degree of response was correlated with a number of baseline demographic and course of illness variables in a univariate analysis and then by linear regression. Results: Response rates to lamotrigine (51%) exceeded those to gabapentin (28%) and placebo (21%). A positive response to lamotrigine monotherapy was associated with a bipolar diagnosis; fewer hospitalizations; fewer prior medication trials; and male gender (of which the latter two variables survived logistic regression). For gabapentin, degree of response correlated with shorter duration of illness; younger age; and lower baseline weight (with the latter two surviving linear regression). Conclusions: In this highly treatment-refractory population, lamotrigine appeared most effective for male patients with fewer prior medication trials. Gabapentin monotherapy, although not better than placebo, appeared most effective in those with younger age and lower baseline weight. These preliminary data in a treatment refractory subgroup may help in the further definition of the range of clinical utility of these widely used anticonvulsants. Biol Psychiatry 2002;51:253-260 (C) 2002 Society of Biological Psychiatry. C1 NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Vet Affairs Med Ctr, Boston, MA USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, 10 Ctr Dr,Bldg 10,Room 3S239, Bethesda, MD 20892 USA. RI Osuch, Elizabeth/B-5009-2015 OI Osuch, Elizabeth/0000-0001-5946-1862 NR 75 TC 64 Z9 65 U1 0 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 FEB 1 PY 2002 VL 51 IS 3 BP 253 EP 260 DI 10.1016/S0006-3223(01)01206-9 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 520YH UT WOS:000173811000007 PM 11839368 ER PT J AU Nadano, D Sugihara, K Paria, BC Saburi, S Copeland, NG Gilbert, DJ Jenkins, NA Nakayama, J Fukuda, MN AF Nadano, D Sugihara, K Paria, BC Saburi, S Copeland, NG Gilbert, DJ Jenkins, NA Nakayama, J Fukuda, MN TI Significant differences between mouse and human trophinins are revealed by their expression patterns and targeted disruption of mouse trophinin gene SO BIOLOGY OF REPRODUCTION LA English DT Article DE early development; embryo; female reproductive tract; implantation; placenta; pregnancy; trophoblast; uterus ID ENDOMETRIAL EPITHELIAL-CELLS; SEX-CHROMOSOME EVOLUTION; GROWTH-FACTOR; EMBRYO IMPLANTATION; X-CHROMOSOME; TROPHOBLAST; UTERUS; TASTIN; BLASTOCYSTS; ADHESION AB Trophinin has been identified as a membrane protein mediating apical cell adhesion between two human cell lines: trophoblastic HT-H cells, and endometrial epithelial SNG-M cells. Expression patterns of trophinin in humans suggested its involvement in embryo implantation and early placental development. The mouse trophinin gene maps to the distal part of the X chromosome and corresponds to human chromosome Xp11.21-22, the locus where the human trophinin gene maps. Western blot analysis indicates that the molecular weight of mouse trophinin is I 10 kDa, which is consistent with the calculated value of 107 kDa. Positive signals for trophinin proteins were detected in preimplantation mouse embryos at the morula and blastocyst stages. Implanting blastocysts do not show detectable levels of trophinin protein, demonstrating that trophinin is not involved in blastocyst adhesion to the uterus in the mouse. Mouse embryo strongly expressed trophinin in the epiblast I day after implantation. Trophinin protein was not found in the mouse uteri and placenta after 5.5 days postcoitus (dpc). Targeted disruption of the trophinin gene in the mouse showed a partial embryonic lethality in a 129/SvJ background, but the cause of this lethality remains undetermined. The present study indicates significant differences between mouse and human trophinins in their expression patterns, and it suggests that trophinin is not involved in embryo implantation and placental development in the mouse. C1 Burnham Inst, Glycobiol Program, La Jolla, CA 92037 USA. Univ Kansas, Med Ctr, Dept Pediat & Mol & Integrat Physiol, Kansas City, KS 66160 USA. NCI, Basic Mouse Canc Genet Program, Frederick, MD 21702 USA. Shinshu Univ, Grad Sch Med, Inst Organ Transplants Reconstruct Med & Tissue E, Matsumoto, Nagano 390, Japan. RP Fukuda, MN (reprint author), Burnham Inst, Glycobiol Program, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. FU NICHD NIH HHS [HD37934, HD34394, R01 HD34108] NR 42 TC 24 Z9 28 U1 0 U2 2 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 FEB PY 2002 VL 66 IS 2 BP 313 EP 321 DI 10.1095/biolreprod66.2.313 PG 9 WC Reproductive Biology SC Reproductive Biology GA 515EF UT WOS:000173481900008 PM 11804944 ER PT J AU Riedlinger, G Okagaki, R Wagner, KU Rucker, EB Oka, T Miyoshi, K Faws, JA Hennighausen, L AF Riedlinger, G Okagaki, R Wagner, KU Rucker, EB Oka, T Miyoshi, K Faws, JA Hennighausen, L TI Bcl-x is not required for maintenance of follicles and corpus luteum in the postnatal mouse ovary SO BIOLOGY OF REPRODUCTION LA English DT Article DE apoptosis; corpus luteum; follicle; granulosa cells ID GENE-EXPRESSION; GRANULOSA-CELLS; MAMMARY-GLAND; APOPTOSIS; BCL-X(L); STAT5; PHOSPHORYLATION; DIFFERENTIATION; DELETION; ANEMIA AB It has been proposed that Bcl-x is a key survival factor in many cell types, and that the bcl-x gene is activated by the transcription factor Stat5 through cytokine signals. In support of this, it has been demonstrated that the survival of mouse primordial germ cells during embryogenesis depends on the presence of Bcl-x. We have now investigated whether, in the mouse, Bcl-x is required for the postnatal maintenance of follicles. and luteal cells, and whether Stat5 activates the bcl-x gene. The bcl-x gene was deleted, in these cells within the mouse using Cre-IoxP recombination. Loss of the bcl-x gene did not affect the numbers of primordial, primary, and antral follicles. Furthermore, expression of the bcl-x gene in the ovary was independent of Stat5 and its activating hormone, prolactin. To determine whether the prolactin receptor (PrIR), Stat5, and Bcl-x were required for establishment and maintenance of the corpus luteum, we induced pseudopregnancies in the respective gene-deletion mice. Whereas luteal cells underwent apoptosis in the absence of the PrIR, no changes were observed in the absence of Stat5 or Bcl-x. C1 NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. Univ Missouri, Anim Sci Unit, Columbia, MO 65211 USA. Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. RP Hennighausen, L (reprint author), NIDDKD, Lab Genet & Physiol, NIH, Bldg 8,Room 101,8 Ctr Dr, Bethesda, MD 20892 USA. RI Wagner, Kay-Uwe/B-6044-2009 FU NICHD NIH HHS [R01 HD 38955] NR 17 TC 19 Z9 19 U1 0 U2 1 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 FEB PY 2002 VL 66 IS 2 BP 438 EP 444 DI 10.1095/biolreprod66.2.438 PG 7 WC Reproductive Biology SC Reproductive Biology GA 515EF UT WOS:000173481900024 PM 11804960 ER PT J AU Colarusso, P Spring, KR AF Colarusso, P Spring, KR TI Reticulated lipid probe fluorescence reveals MDCK cell apical membrane topography SO BIOPHYSICAL JOURNAL LA English DT Article ID PLASMA-MEMBRANE; TIGHT JUNCTION; DIFFUSION; DOMAINS; ORIENTATION; CHOLESTEROL; MICROVILLI; RETENTION; ASYMMETRY; EPITHELIA AB High spatial resolution confocal microscopy of young MDCK cells stained with the lipophilic probe 1,1'dihexadecyl-3,3,3',3'- tetramethylindocarbocyanine perchlorate (DiIC(16)) revealed a reticulated fluorescence pattern on the apical membrane. DiIC(16) was delivered as crystals to live cells to minimize possible solvent perturbations of the membrane lipids. The ratio of the integrated fluorescence intensities in the bright versus dim regions was 1.6 +/- 0.1 (n = 13). Deconvolved images of the cells were consistent with exclusive plasma membrane staining. Multi-spectral and fluorescence anisotropy microscopy did not reveal differences between bright and dim regions. Bright regions coincided with microvilli and microridges observed by differential interference contrast microscopy and were stable for several minutes. Fluorescence recovery after photobleaching yielded similar diffusion coefficients (pooled D = 1.5 +/- 0.6 x 10(-9) cm(2)/s, n = 40) for both bright and dim regions. Line fluorescence recovery after photobleaching showed that the reticulated pattern was maintained as the fluorescence recovered in the bleached areas. Cytochalasin D did not affect the staining pattern, but the pattern was eliminated by cholesterol depletion with methyl-beta-cyclodextrin. We conclude that the reticulated fluorescence pattern was caused by increased optical path lengths through the microvilli and microridges compared with the flat areas on the apical membrane. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Colarusso, P (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bldg 10,Room 6N260,10 Ctr Dr, Bethesda, MD 20892 USA. NR 24 TC 8 Z9 8 U1 1 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 FEB PY 2002 VL 82 IS 2 BP 752 EP 761 PG 10 WC Biophysics SC Biophysics GA 515LP UT WOS:000173497600018 PM 11806917 ER PT J AU Kullman, L Winterhalter, M Bezrukov, SM AF Kullman, L Winterhalter, M Bezrukov, SM TI Transport of maltodextrins through maltoporin: A single-channel study SO BIOPHYSICAL JOURNAL LA English DT Article ID COLI OUTER-MEMBRANE; BACTERIOPHAGE-LAMBDA RECEPTOR; ESCHERICHIA-COLI; SUGAR-TRANSPORT; PROTEIN; PORINS; BINDING; MALTOSE; NOISE; SELECTIVITY AB Transport of sugars through maltoporin channels reconstituted into planar lipid membranes has traditionally been addressed using multichannel preparations. Here we show that single-channel experiments offer new possibilities to reveal molecular details of the interaction between the sugar and the channel. We analyze time-resolved transient interruptions in the maltoporin ionic current in the presence of differently sized maltodextrins. We find for all studied sugars, from maltotriose to maltoheptaose, that only one sugar molecule is required to completely block one of the pores in the maltoporin trimer. The probability of simultaneous blockage of different pores increases with sugar concentration in a manner that demonstrates their mutual independence. The maltoporin channel is asymmetric and, added from one side only, predominantly inserts in an oriented manner. The asymmetry of the channel structure manifests itself in two ways. First, it is seen as an asymmetrical response to applied voltage at otherwise symmetrical conditions; second, as asymmetrical rates of sugar entry into the channel with asymmetrical (one-sided) sugar addition. Importantly, we find that the sugar residence time in the pore does not depend on which side the sugar is added. This voltage-dependent time is the same for symmetrical, cis, or trans sugar addition. This observation suggests that once a sugar molecule is captured by the "greasy slide" of the channel, it spends enough time there to "forget" from what entrance it was captured. This also means that the blockage events studied here represent sugar translocation events, and not just binding at and release from the same entrance of the channel. C1 NICHHD, LPSB, NIH, Bethesda, MD 20892 USA. Biozentrum, Dept Biophys Chem, Basel, Switzerland. Inst Pharmacol & Biol Struct, Toulouse, France. St Petersburg Nucl Phys Inst, Gatchina 188350, Russia. RP Bezrukov, SM (reprint author), NICHHD, LPSB, NIH, Bldg 9,Rm 1E-122, Bethesda, MD 20892 USA. NR 40 TC 97 Z9 98 U1 1 U2 6 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD FEB PY 2002 VL 82 IS 2 BP 803 EP 812 PG 10 WC Biophysics SC Biophysics GA 515LP UT WOS:000173497600023 PM 11806922 ER PT J AU Tcherkasskaya, O Klushin, L Gronenborn, AM AF Tcherkasskaya, O Klushin, L Gronenborn, AM TI Effective lattice behavior of fluorescence energy transfer at lamellar macromolecular interfaces SO BIOPHYSICAL JOURNAL LA English DT Article ID BLOCK-COPOLYMER INTERFACES; ACCEPTORS; SYSTEMS; FILMS; MICROSTRUCTURES; GEOMETRY AB Fluorescence energy transfer between donors and acceptors confined to macromolecular interfaces is considered. In particular, we discuss two theoretical models for the ensemble-average fluorescence intensity decay of the donor when both fluorophores are incorporated into a planar (e.g., lamellar) interface. The first model is based on a continuous distribution of donor and acceptor molecules on a two-dimensional surface, whereas the other assumes a discrete distribution of fluorophores along the nodes of a two-dimensional square lattice. Results for the discrete model show that the fluorescence intensity kinetics of a donor depends strongly on the geometry of the molecular distribution (i.e., the lattice constant) and the photophysics of fluorophores (i.e., critical radius of the energy transfer). Furthermore, a "discrete molecular distribution" might manifest itself in the experimental data as an increase in the apparent dimensionality of the energy transfer with increasing acceptor concentration. Altogether, the experimental and theoretical underpinnings indicate the enormous potential of using fluorescence energy-transfer kinetics for revealing structural features of molecular ensembles (i.e., geometry, shape) based on a single experimental measurement. However, further understanding the effects of restricted geometries on the fluorescence energy transfer is required to take full advantage of this information. Basic theoretical considerations to that end are provided. C1 NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. Russian Acad Sci, Inst Macromol Cpds, Lab Theory Polymers, St Petersburg 199004, Russia. Amer Univ Beirut, Dept Phys, Beirut, Lebanon. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tcherkasskaya, O (reprint author), Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. NR 34 TC 7 Z9 7 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 FEB PY 2002 VL 82 IS 2 BP 988 EP 995 PG 8 WC Biophysics SC Biophysics GA 515LP UT WOS:000173497600039 PM 11806938 ER PT J AU Schuck, P Perugini, MA Gonzales, NR Howlett, GJ Schubert, D AF Schuck, P Perugini, MA Gonzales, NR Howlett, GJ Schubert, D TI Size-distribution analysis of proteins by analytical ultracentrifugation: Strategies and application to model systems SO BIOPHYSICAL JOURNAL LA English DT Article ID SEDIMENTATION COEFFICIENT DISTRIBUTION; INTEGRAL-EQUATIONS; TRANSPORT EXPERIMENTS; BOUNDARY ANALYSIS; LIGHT-SCATTERING; LAMM EQUATION; VELOCITY DATA; REGULARIZATION; SOLUTES; IDENTIFICATION AB Strategies for the deconvolution of diffusion in the determination of size-distributions from sedimentation velocity experiments were examined and developed. On the basis of four different model systems, we studied the differential apparent sedimentation coefficient distributions by the time-derivative method, g(s*), and by least-squares direct boundary modeling, ls-g*(s), the integral sedimentation coefficient distribution by the van Holde-Weischet method, G(s), and the previously introduced differential distribution of Lamm equation solutions, c(s). It is shown that the least-squares approach ls-g*(s) can be extrapolated to infinite time by considering area divisions analogous to boundary divisions in the van Holde-Weischet method, thus allowing the transformation of interference optical data into an integral sedimentation coefficient distribution G(s). However, despite the model-free approach of G(s), for the systems considered, the direct boundary modeling with a distribution of Lamm equation solutions c(s) exhibited the highest resolution and sensitivity. The c(s) approach requires an estimate for the size-dependent diffusion coefficients D(s), which is usually incorporated in the form of a weight-average frictional ratio of all species, or in the form of prior knowledge of the molar mass of the main species. We studied the influence of the weight-average frictional ratio on the quality of the fit, and found that it is well-determined by the data. As a direct boundary model, the calculated c(s) distribution can be combined with a nonlinear regression to optimize distribution parameters, such as the exact meniscus position, and the weight-average frictional ratio. Although c(s) is computationally the most complex, it has the potential for the highest resolution and sensitivity of the methods described. C1 NIDDKD, Div Bioengn & Phys Sci, Off Res Serv, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Melbourne, Dept Biochem & Mol Biol, Parkville, Vic 3052, Australia. Goethe Univ Frankfurt, Inst Biophys, D-6000 Frankfurt, Germany. RP Schuck, P (reprint author), NIDDKD, Div Bioengn & Phys Sci, Off Res Serv, NIH, Bldg 13,Rm 3N17,13 South Dr, Bethesda, MD 20892 USA. EM pschuck@helix.nih.gov OI Schuck, Peter/0000-0002-8859-6966 NR 43 TC 450 Z9 452 U1 7 U2 37 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB PY 2002 VL 82 IS 2 BP 1096 EP 1111 PG 16 WC Biophysics SC Biophysics GA 515LP UT WOS:000173497600050 PM 11806949 ER PT J AU Kohn, MC Tohmaz, AS Giroux, KJ Blumenthal, GM Feezor, MD Millington, DS AF Kohn, MC Tohmaz, AS Giroux, KJ Blumenthal, GM Feezor, MD Millington, DS TI Robustness of MetaNet graph models: Predicting control of urea production in humans SO BIOSYSTEMS LA English DT Article DE graph models; robustness; metabolic regulation; urea cycle ID RAT-LIVER MITOCHONDRIA; METABOLIC NETWORKS; KINETIC-PROPERTIES; INBORN-ERRORS; AMINO-ACID; ASPARTATE; CARRIER; IDENTIFICATION; PURIFICATION; GLUTAMATE AB Urea production in human liver was described by a MetaNet graph, a flowchart-like representation of metabolic pathways that includes parameters for the kinetic constants of the constituent enzymes. Formal operations on the graph facilitate the identification of ligand-binding equilibria that participate in feedback regulation in the network of biochemical reactions. The state of the biochemical network is specified by the concentrations of the intermediates. At any particular time, the influence of an identified locus of regulation is proportional to the respective fractional saturation of the corresponding binding site. Enzymes that make or consume the feedback chemicals share in the control of the strength of the feedback signal in proportion to their fractional saturation. This model predicts control of urea production by the processes that deliver amino groups to the urea cycle enzymes more than by the cycle enzymes themselves. Mitochondrial membrane transport processes are important for transmission of information through the network, but irreversible enzymes and processes far from equilibrium control the strength of the feedback signal. Systematic variation of the parameter values by amounts comparable to the expected variability of their measured values indicated a high probability of invariance in the identities of the predicted control points. The properties of the model are consistent with those of error-tolerant scale-free networks. These results demonstrate the robustness of a MetaNet model's predictions with respect to uncertainties in the values of its parameters. Published by Elsevier Science Ireland Ltd. C1 NIEHS, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. BioKinet Inc, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Med Genet Program, Inst Mass Spectrometry, Res Triangle Pk, NC 27709 USA. RP Kohn, MC (reprint author), NIEHS, Lab Computat Biol & Risk Anal, POB 12233,Mail Dro A3-06, Res Triangle Pk, NC 27709 USA. NR 69 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0303-2647 J9 BIOSYSTEMS JI Biosystems PD FEB PY 2002 VL 65 IS 1 BP 61 EP 78 AR PII S0303-2647(02)00002-3 DI 10.1016/S0303-2647(02)00002-3 PG 18 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 584KX UT WOS:000177466700006 PM 11888664 ER PT J AU Hamadeh, HK Bushel, P Tucker, CJ Martin, K Paules, R Afshari, CA AF Hamadeh, HK Bushel, P Tucker, CJ Martin, K Paules, R Afshari, CA TI Detection of diluted gene expression alterations using cDNA microarrays SO BIOTECHNIQUES LA English DT Article ID NECROSIS-FACTOR-ALPHA; LOCALIZATION; TISSUE; CELLS AB The use of DNA microarrays has spanned numerous disciplines of life science research. Despite the volume of studies utilizing this technology, no consensus exists on basic issues such as the determination of significantly altered genes in a given experiment, often leading to either false-negative or false-positive data. In this report, we study the effect of dilution of biological alterations on the detection level of gene expression differences using cDNA microarrays. We propose that subtle alterations in transcript levels of genes below the 2-fold level should be considered when replicate hybridizations are performed, because these subtle gene expression changes may be due to a robust response in few cells. We measured the effect of dilution of gene expression and found that differences in gene expression between the two cell lines assayed (HaCaT and MCF-7) were detected even after a 20-fold dilution factor These results better our understanding of biological alterations that comprise a relatively small percentage of an assayed organ and help in the interpretation of gene expression data. C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Afshari, CA (reprint author), POB 12233 MD2-04 111 Alexander Dr Bldg 101, Res Triangle Pk, NC 27709 USA. NR 11 TC 11 Z9 12 U1 0 U2 0 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD FEB PY 2002 VL 32 IS 2 BP 322 EP + PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 520EK UT WOS:000173767500017 PM 11848409 ER PT J AU Kang, EM Areman, EM David-Ocampo, V Fitzhugh, C Link, ME Read, EJ Leitman, SF Rodgers, GP Tisdale, JF AF Kang, EM Areman, EM David-Ocampo, V Fitzhugh, C Link, ME Read, EJ Leitman, SF Rodgers, GP Tisdale, JF TI Mobilization, collection, and processing of peripheral blood stem cells in individuals with sickle cell trait SO BLOOD LA English DT Article ID BONE-MARROW; HIGH-ALTITUDE; TRANSPLANTATION; FILGRASTIM; MORBIDITY; DISEASE; CRISIS; TRIAL AB Mobilized peripheral blood is increasingly used as the source of hematopoietic stem cells for allogeneic transplantation, currently the only curative approach for sickle cell anemia. However, the safety and feasibility of stem cell mobilization in individuals with sickle cell trait (SCT) has not been documented. This study is a prospective controlled trial to evaluate the safety and feasibility of peripheral blood stem cell (PBSC) mobilization in 8 SCT subjects and 8 control subjects matched for age and race. Mobilization with filgrastim 10 mug/kg subcutaneous daily for 5 days was followed by 12-L apheresis on the fifth day. Filgrastim administration was accompanied by similar symptoms in all subjects; no untoward adverse events occurred in either group, including sickle cell crises. CD34(+) cell mobilization response was not significantly different between SCT and control subjects. Median CD34(+) cell content was also similar in PBSCs collected from SCT versus control subjects, 6.8 versus 3.9 x 10(6), CD34(+) cells/70 kg, P = .165. Red cell depletion from SCT products was not possible by using hydroxyethyl starch sedimentation but was achievable with ammonium chloride lysis. There was no evidence of gelling of SCT products after thaw, and no difference in cell recovery was seen among red cell-depleted versus nondepleted products. Cryopreservation in 5% dimethyl sulfoxide/6% pentastarch was associated with superior cell recovery (both SCT and control subjects) compared with 10% dimethyl sulfoxide (P = .001). The study concluded that filgrastim mobilization, large volume apheresis, processing, and cryopreservation appears to be safe in donors with SCT, allowing PBSC use for transplantation in patients with sickle cell anemia. (C) 2002 by The American Society of Hematology. C1 NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. RP Tisdale, JF (reprint author), NIDDKD, Mol & Clin Hematol Branch, NIH, 9000 Rockville Pike,Bldg 10,Rm 9N116, Bethesda, MD 20892 USA. NR 25 TC 36 Z9 37 U1 0 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 FEB 1 PY 2002 VL 99 IS 3 BP 850 EP 855 DI 10.1182/blood.V99.3.850 PG 6 WC Hematology SC Hematology GA 515ZQ UT WOS:000173527000019 PM 11806986 ER PT J AU Myers, LA Patel, DD Puck, JM Buckley, RH AF Myers, LA Patel, DD Puck, JM Buckley, RH TI Hematopoietic stem cell transplantation for severe combined immunodeficiency in the neonatal period leads to superior thymic output and improved survival SO BLOOD LA English DT Article ID IN-UTERO TRANSPLANTATION; BONE-MARROW; MUTATION; GENE; DISEASE; PATIENT; HUMANS AB All genetic types of severe combined Immunodeficiency (SCID) can be cured by stem cell transplantation from related donors. The survival rate approaches 80%, and most deaths result from opportunistic infections acquired before transplantation. It was hypothesized that the survival rate and kinetics of immune reconstitution would be improved for infants receiving transplants in the neonatal period (first 28 days of life), prior to the development of infections. A 19.2-year retrospective/prospective analysis compared immune function in 21 SCID infants receiving transplants in the neonatal period with that in 70 SCID infants receiving transplants later. Lymphocyte phenotypes, proliferative responses to mitogens, immunoglobulin levels, and T-cell antigen receptor excision circles (TRECs) were measured before transplantation and sequentially after transplantation. Of 21 SCID infants with transplantations in the neonatal period, 20 (95%) survive. Neonates were lymphopenic at birth (1118 +/- 128 lymphocytes per cubic millimeter). Infants receiving transplants early developed higher lymphocyte responses to phytohemagglutinin and higher numbers of CD3(+) and CD45RA(+) T cells in the first 3 years of life than those receiving transplants late (P < .05). TRECs peaked earlier and with higher values (P < .01) in the neonatal transplantations (181 days to 1 year) than in the late transplantations (11 to 3 years). SCID recipients of allogeneic, related hematopoietic stem cells in the neonatal period had higher levels of T-cell reconstitution and thymic output and a higher survival rate than those receiving transplants after 28 days of life. An improved outcome for this otherwise fatal syndrome could be achieved with newborn screening for lymphopenia so that transplantation could be performed under favorable thymopoietic conditions. (C) 2002 by The American Society of Hematology. C1 Duke Univ, Med Ctr, Durham, NC 27710 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Myers, LA (reprint author), Duke Univ, Med Ctr, Box 3559, Durham, NC 27710 USA. FU NIAID NIH HHS [AI 42951, AI 47604, AI 47605] NR 25 TC 170 Z9 176 U1 1 U2 7 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 FEB 1 PY 2002 VL 99 IS 3 BP 872 EP 878 DI 10.1182/blood.V99.3.872 PG 7 WC Hematology SC Hematology GA 515ZQ UT WOS:000173527000022 PM 11806989 ER PT J AU Murray, L McCarron, P Bailie, K Middleton, R Smith, GD Dempsey, S McCarthy, A Gavin, A AF Murray, L McCarron, P Bailie, K Middleton, R Smith, GD Dempsey, S McCarthy, A Gavin, A TI Association of early life factors and acute lymphoblastic leukaemia in childhood: historical cohort study SO BRITISH JOURNAL OF CANCER LA English DT Article DE ALL; childhood; early life factors; historical cohort ID GROWTH-FACTOR-I; MATERNAL REPRODUCTIVE HISTORY; CHILDRENS CANCER GROUP; ACUTE-LEUKEMIA; BIRTH CHARACTERISTICS; INFANT LEUKEMIA; RISK FACTOR; WEIGHT; PREGNANCY; ETIOLOGY AB In a historical cohort study of all singleton live births in Northern Ireland from 1971-86 (n=434933) associations between early life factors and childhood acute lymphoblastic leukaemia were investigated. Multivariable analyses showed a positive association between high paternal age (greater than or equal to 35 years) and acute lymphoblastic leukaemia (relative risk=1.49: 95% confidence interval (CI)=0.96-2.31) but no association with maternal age. High birth weight (greater than or equal to 3500 g) was positively associated with acute lymphoblastic leukaemia (relative risk=1.66; 95% CI=1.18-2.33). Children of mothers with a previous miscarriage or increased gestation (greater than or equal to40 weeks) had reduced risks of ALL (respective relative risks=0.49; 95% CI=0.29-0.80, and 0.67; 95% CI=048-0.94). Children born into more crowded households (greater than or equal to 1 person per room) had substantially lower risks than children born into less crowded homes with also some evidence of a lower risk for children born into homes with three adults (relative risks=0.56; 95% CI=0.35-0.91 and 0,58: 95% CI=0.21-1.61 respectively). These findings indicate that several early life factors, including living conditions in childhood and maternal miscarriage history, influence risk of acute lymphoblastic leukaemia in childhood. C1 Queens Univ Belfast, Dept Epidemiol & Publ Hlth, No Ireland Canc Registry, Belfast BT9 5EE, Antrim, North Ireland. NCI, Div Canc Control & Populat Sci, Rockville, MD USA. Ulster Community & Hosp Trust, Belfast, Antrim, North Ireland. Univ Bristol, Dept Social Med, Bristol, Avon, England. Royal Grp Hosp Trust, Belfast, Antrim, North Ireland. RP Murray, L (reprint author), Queens Univ Belfast, Dept Epidemiol & Publ Hlth, No Ireland Canc Registry, Riddel Hall,Stranmillis Rd, Belfast BT9 5EE, Antrim, North Ireland. OI Monsalve, Beatriz Elena/0000-0002-5994-866X; Davey Smith, George/0000-0002-1407-8314 NR 30 TC 64 Z9 65 U1 0 U2 1 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 FEB 1 PY 2002 VL 86 IS 3 BP 356 EP 361 DI 10.1038/sj/bjc/6600012 PG 6 WC Oncology SC Oncology GA 532AK UT WOS:000174449300010 PM 11875699 ER PT J AU Fend, F Martinez, A Quintanilla-Martinez, L Sanz, L Combalia, N Raffeld, M Jaffe, ES Montserrat, E Campo, E AF Fend, F Martinez, A Quintanilla-Martinez, L Sanz, L Combalia, N Raffeld, M Jaffe, ES Montserrat, E Campo, E TI Clonally unrelated Hodgkin's disease following autologous stem cell transplant for B-cell lymphoma SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE autologous stem cell transplant; Hodgkin's disease; post-transplant lymphoproliferative disorder; immunoglobulin gene rearrangement; microdissection ID BONE-MARROW TRANSPLANTATION; LYMPHOPROLIFERATIVE DISORDER; MALIGNANCIES; LEUKEMIA; ORIGIN AB Lymphoproliferative disorders after autologous stem cell transplantation (SCT) are rare. We describe two cases of Hodgkin's disease (HD) as a late secondary neoplasia following autologous SCT for mantle cell lymphoma and B-cell chronic lymphocytic leukaemia respectively. Both HD cases were of mixed cellularity type, showed Epstein-Barr virus (EBV) positivity and followed an aggressive course. Clonal analysis of rearranged immunoglobulin genes from the primary B-cell neoplasm and the secondary HD provided evidence of separate clonal origins of the two tumours in both patients, thus excluding secondary transformation of the original B-cell clone through EBV as the causative event for development of HD. C1 Tech Univ Munich, Dept Pathol, D-81675 Munich, Germany. GSF Natl Res Ctr Environm & Hlth Neuherberg, Munich, Germany. NCI, Pathol Lab, Hematopathol Sect, Bethesda, MD 20892 USA. Univ Barcelona, IDIBAPS, Hosp Clin, Dept Haematol, Barcelona, Spain. Hosp Parc Tauli, Dept Pathol, Sabadell, Spain. RP Fend, F (reprint author), Tech Univ Munich, Dept Pathol, Ismaningerstr 22, D-81675 Munich, Germany. RI Martinez, Antonio/D-8188-2012; OI Martinez, Antonio/0000-0003-0790-9017; Campo, elias/0000-0001-9850-9793 NR 12 TC 5 Z9 5 U1 0 U2 0 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 FEB PY 2002 VL 116 IS 2 BP 329 EP 333 DI 10.1046/j.1365-2141.2002.03267.x PG 5 WC Hematology SC Hematology GA 525GN UT WOS:000174060700012 PM 11841433 ER PT J AU Gladwin, MT Shelhamer, JH Ognibene, FP Pease-Fye, ME Nichols, JS Link, B Patel, DB Jankowski, MA Pannell, LK Schechter, AN Rodgers, GP AF Gladwin, MT Shelhamer, JH Ognibene, FP Pease-Fye, ME Nichols, JS Link, B Patel, DB Jankowski, MA Pannell, LK Schechter, AN Rodgers, GP TI Nitric oxide donor properties of hydroxyurea in patients with sickle cell disease SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE sickle cell anaemia; nitric oxide; nitrite; nitrate ID ACUTE CHEST SYNDROME; S-NITROSOHEMOGLOBIN; RIBONUCLEOTIDE REDUCTASE; ENDOTHELIAL ADHESIVENESS; ADHESION MOLECULES; ANEMIA PATIENTS; BLOOD-FLOW; HEMOGLOBIN; THERAPY; NITROSATION AB Hydroxyurea therapy reduces the rates of vasoocclusive crisis in patients with sickle cell anaemia and recent data suggest that hydroxyurea treatment can generate nitric oxide (NO). Nitric oxide has been proposed as a novel therapy for sickle cell disease via a number of pathways. We therefore sought to determine whether hydroxyurea has NO donor properties in patients with sickle cell anaemia and explore potential mechanisms by which NO production could be therapeutic. Venous blood was collected from 19 fasting sickle cell anaemia patients, on chronic hydroxyurea therapy, at baseline and 2 and 4 h after a single morning dose of hydroxyurea, as well as 10 patients not taking hydroxyurea. The plasma and red cell NO reaction products nitrate, nitrite and nitrosylated-haemoglobin were measured using ozone-based chemiluminescent assays (using vanadium, KI and I-3(-) reductants respectively). Consistent with NO release from hydroxyurea, baseline levels of total nitrosylated haemoglobin increased from 300 nmol/l to 500 nmol/l (P = 0.01). Plasma nitrate and nitrite levels also significantly increased with peak levels observed at 2 h. Glutathionyl-haemoglobin levels were unchanged, while plasma secretory vascular cellular adhesion molecule-1 levels were reduced in patients taking hydroxyurea (419 +/- 40 ng/ml) compared with control patients with sickle cell anaemia (653 +/- 55 ng/ml; P = 0.003), and were inversely correlated with fetal haemoglobin levels (r = -0.72; P = 0.002). These results demonstrate that hydroxyurea therapy is associated with the intravascular and intraerythrocytic generation of NO. The role of NO in the induction of fetal haemoglobin and possible synergy between NO donor therapy and classic cytostatic and differentiating medications should be explored. C1 NIDDKD, Warren G Magnuson Clin Ctr, Dept Crit Care Med, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Struct Mass Spectrometry Facil, NIH, Bethesda, MD 20892 USA. NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), NIDDKD, Warren G Magnuson Clin Ctr, Dept Crit Care Med, NIH, Bldg 10,Room 7D43,10 Ctr Dr,MSC 1662, Bethesda, MD 20892 USA. OI Schechter, Alan N/0000-0002-5235-9408 NR 51 TC 120 Z9 122 U1 1 U2 8 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 FEB PY 2002 VL 116 IS 2 BP 436 EP 444 DI 10.1046/j.1365-2141.2002.03274.x PG 9 WC Hematology SC Hematology GA 525GN UT WOS:000174060700028 PM 11841449 ER PT J AU Michon, JJ Lau, J Chan, WS Ellwein, LB AF Michon, JJ Lau, J Chan, WS Ellwein, LB TI Prevalence of visual impairment, blindness, and cataract surgery in the Hong Kong elderly SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article ID QUALITY-OF-LIFE; DOUMEN COUNTY; SHUNYI COUNTY; CHINA; ACUITY; OUTCOMES; VISION; INDIA; NEPAL AB Background: The prevalence of vision impairment, unilateral/bilateral blindness, and cataract surgery were estimated in a population based survey among the elderly in a suburban area of Hong Kong. Methods: 15 public, private, and home ownership scheme housing estates in the Shatin area of Hong Kong were subjected to cluster sampling to randomly select a cross section of people 60 years of age or older. Visual acuity measurements and ocular examinations were conducted at a community site within each estate. The principal cause of reduced vision was identified for eyes with presenting visual acuity worse than 6/18. Results: A total of 3441 subjects from an enumerated population of 4487 (76.7%) completed an eye examination. The prevalence of presenting visual acuity less than 6/18 in at least one eye was 41.3%; and 73.1% in those 80 years of age or older. Unilateral blindness (acuity <6/60) was found in 7.9% of subjects and bilateral blindness in 1.8%. Refractive error and cataract were, respectively, the main causes of vision impairment and blindness. Visual impairment with either eye <6/18 increased with advancing age and was more prevalent in males, the less educated, and those living in public housing estates. The prevalence of cataract surgery was 9.1% and was associated with advancing age and less education. Conclusions: Blindness and visual disability were common in this socioeconomically advanced population, with most of it easily remedied, Because of a rapidly ageing population, healthcare planners in Hong Kong must prepare for an increasing burden of visual disability and blindness. C1 NEI, NIH, Bethesda, MD 20892 USA. Chinese Univ Hong Kong, Dept Ophthalmol & Visual Sci, Hong Kong, Hong Kong, Peoples R China. Chinese Univ Hong Kong, Ctr Clin Trials & Epidemiol Res, Hong Kong, Hong Kong, Peoples R China. RP Ellwein, LB (reprint author), NEI, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. FU NEI NIH HHS [N01-EY-2103] NR 13 TC 69 Z9 80 U1 0 U2 6 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD FEB PY 2002 VL 86 IS 2 BP 133 EP 139 DI 10.1136/bjo.86.2.133 PG 7 WC Ophthalmology SC Ophthalmology GA 519QN UT WOS:000173737100005 PM 11815334 ER PT J AU Ko, MCH Naughton, NN Traynor, JR Song, MS Woods, JH Rice, KC McKnight, AT AF Ko, MCH Naughton, NN Traynor, JR Song, MS Woods, JH Rice, KC McKnight, AT TI Orphanin FQ inhibits capsaicin-induced thermal nociception in monkeys by activation of peripheral ORL1 receptors SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE antinociception; orphanin FQ; ORL1 receptors; capsaicin; peripheral tissues; primary afferent nociceptors; hyperalgesia ID INFLAMED KNEE-JOINT; OPIOID RECEPTOR; RHESUS-MONKEYS; INTRADERMAL INJECTION; ORL(1) RECEPTOR; PAIN; INFLAMMATION; HYPERALGESIA; MODULATION; ANTINOCICEPTION AB 1 Orphanin FQ (OFQ), an endogenous peptide for ORL1 receptors, has been identified. Although the actions of OFQ have much in common with those of opioid peptides at the cellular level, behavioral studies in rodents seem conflicting. 2 The aim of this study was to investigate the potential pronociceptive or antinociceptive function of peripheral ORL1 receptors in primates. Experiments were conducted to verify whether local administration of OFQ can attenuate capsaicin-induced nociception and whether peripheral ORL1 receptors selectively mediate the local action of OFQ in monkeys. 3 Capsaicin (100 mug) was administered subcutaneously in the tail to locally evoke a nociceptive response (thermal allodynia/hyperalgesia), which was manifested as a reduced tail-withdrawal latency in normally innocuous 46degreesC warm water. 4 Co-administration of OFQ (1-30 mug) with capsaicin in the tail dose-dependently inhibited thermal nociception. However, a locally effective dose of OFQ (30 mug), when applied in the back, did not inhibit capsaicin-induced nociception. 5 OFQ-induced local antinociception was antagonized by a small dose (10 mug) of J-113397, a selective ORL1 receptor antagonist, in the tail, Similarly, s.c. administration of 10 mug of J-113397 in the back did not antagonize local antinociception of OFQ. 6 In addition, s.e. administration of either OFQ or J-113397 in the tail alone did not change its thermal nociceptive threshold. Local administration of opioid receptor antagonists selective for mu, kappa, and delta opioid receptors did not antagonize OFQ-induced local antinociception. Local administration of J-113397 also did not interfere with the local actions of mu, kappa, and delta opioid agonists in the tail. 7 These results provide the first functional evidence that activation of peripheral ORL1 receptors produces thermal antinociception in primates and this action is independent of antinociception produced at classical opioid receptors. C1 Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Med, Dept Anesthesiol, Ann Arbor, MI 48109 USA. NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. Oxford Nat Prod, Charlbury, Oxon, England. RP Ko, MCH (reprint author), Univ Michigan, Sch Med, Dept Pharmacol, 1301 MSRB 3, Ann Arbor, MI 48109 USA. RI Ko, Mei-Chuan/C-9468-2009 OI Ko, Mei-Chuan/0000-0003-2436-4506 FU NIDA NIH HHS [DA00254, DA13685, K21 DA000254, P01 DA000254, P50 DA000254, R01 DA013685] NR 42 TC 39 Z9 39 U1 0 U2 1 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 FEB PY 2002 VL 135 IS 4 BP 943 EP 950 DI 10.1038/sj.bjp.0704535 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 526BJ UT WOS:000174108300012 PM 11861322 ER PT J AU Hauser, DS Mevissen, M Weiss, R Portier, CJ Scholtysik, G Studer, UE Danuser, H AF Hauser, DS Mevissen, M Weiss, R Portier, CJ Scholtysik, G Studer, UE Danuser, H TI Effects of ketanserin and DOI on spontaneous and 5-HT-evoked peristalsis of the pig ureter in vivo SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE ureteral peristalsis; pig ureter; receptors; 5-hydroxytryptamine; DOI; ketanserin; 5-HT2A receptor antagonists ID RECEPTOR-BINDING; SEROTONIN; R-41-468; RATS AB 1 The influence of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on the ureter motility was investigated in vivo on intact ureters of anaesthetized pigs. Drugs were administered intravenously or topically. 2 5-HT induced a dose-dependent increase in the frequency of ureter contractions in anaesthetized pigs when given intravenously (0.0001 - 1 mg kg(-1); ED50 0.066 mg kg(-1)) or topically (0.001 - 1 mg ml(-1); EC50 0.043 mg ml(-1)). Significant increases in heart rate and blood pressure were observed when the drug was given intravenously but not topically. 3 The 5-HT2A agonist, DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) increased the frequency of ureteral contractions in a dose-dependent manner (I - 300 mug kg(-1) i.v.). Calculation of ED50 indicated this compound to be about 1.5 times more potent with an efficacy of 23% compared to 5-HT. 4 The 5-HT2A/2C antagonist, ketanserin (0.5 mg kg(-1)) and the 5-HT2c antagonist, methysergide (I mg kg-1) antagonized the 5-HT-induced ureter peristalsis when given intravenously. Contraction amplitude, blood pressure and heart rate were not affected by the antagonists. 5 Intravenous (0.0001 - 1 mg kg(-1)) and topical (0.0001 - 1 mug ml(-1)) ketanserin significantly decreased the frequency of spontaneous ureteral contractions to about 30% of controls, which could be partly reversed by 5-HT (0.3 mg kg(-1) i.v.). The contraction amplitude, contractions of the contralateral, saline perfused ureter, heart rate and mean arterial blood pressure were not affected. 6 Thus, contractility of porcine ureter is mediated by 5-HT, receptors. Their antagonists ketanserin and methysergide seem to be promising drugs for treatment of acute ureteric colic or in preparing p the ureter for ureteroscopy. C1 Univ Bern, Dept Urol, CH-3010 Bern, Switzerland. Univ Bern, Inst Vet Pharmacol, CH-3012 Bern, Switzerland. NIEHS, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. RP Danuser, H (reprint author), Univ Bern, Dept Urol, CH-3010 Bern, Switzerland. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 29 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 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD FEB PY 2002 VL 135 IS 4 BP 1026 EP 1032 DI 10.1038/sj.bjp.0704536 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 526BJ UT WOS:000174108300021 PM 11861331 ER PT J AU Velasco, A Hewitt, SM Albert, PS Saboorian, MH Rosenberg, H Martinez, C Sagalowsky, AI McConnell, JD Linehan, WM Leach, FS AF Velasco, A Hewitt, SM Albert, PS Saboorian, MH Rosenberg, H Martinez, C Sagalowsky, AI McConnell, JD Linehan, WM Leach, FS TI Differential expression of the mismatch repair gene hMSH2 in malignant prostate tissue is associated with cancer recurrence SO CANCER LA English DT Article DE mismatch repair; prostate carcinoma; microsatellite instability; hMSH2 immunohistochemistry; prostate specific antigen recurrence ID NONPOLYPOSIS COLORECTAL-CANCER; MICROSATELLITE INSTABILITY; COLON-CANCER; SUSCEPTIBILITY LOCUS; SOMATIC MUTATIONS; MUTATOR PHENOTYPE; NATURAL-HISTORY; DNA; HOMOLOG; CELLS AB BACKGROUND. Mismatch repair (MMR) genes are responsible for coordinated correction of misincorporated nucleotides formed during DNA replication. Inactivating mutations in MMR genes have been described in sporadic cancers and a hereditary cancer predisposition syndrome. Mismatch repair deficiency causes instability at microsatellites and increased mutation rates. Although microsatellite instability (MSI) has been described in high-grade and lymph node positive prostate carcinoma specimens, an analysis comparing hMSH2 expression, MSI, and outcome in clinically organ confined prostate carcinoma has not been reported. METHODS. Immunohistochemical analysis of benign and malignant prostate tissue from 101 patients was performed using a monoclonal antibody specific for the hMSH2 protein. Expression was correlated with MSI using dinucleotide repeat markers and laser-captured microdissected DNA from normal and tumor cells. hMSH2 protein expression and MSI were assessed with respect to pathologic stage, Gleason score, and time to detectable serum prostate specific antigen (PSA) after prostatectomy in patients with clinically localized prostate carcinoma. RESULTS. in normal glands, hMSH2 staining was minimal to low and confined to the basal cell layer. In 32% of benign prostatic hyperplasia cases, hMSH2 staining was increased in the basal and luminal cell layers whereas 71% of cancer specimens had uniform moderate to high staining. Microsatellite instability was detected in 60% of absent to low staining and 26% of moderate to high staining prostate carcinoma specimens. Differential staining in benign versus malignant prostate tissues was statistically significant (P < 0.001) as was the correlation between absent to low hMSH2 staining and presence of MSI (P = 0.028). Decreased risk for PSA recurrence after radical prostatectomy correlated with absent to low hMSH2 staining in malignant prostate tissue but was only marginally significant (P = 0.05 for 24 month recurrence and P = 0.08 for overall time to PSA recurrence). CONCLUSIONS. The results of the current study demonstrate differential hMSH2 expression in benign and malignant prostate tissue. Moreover, hMSH2 expression is altered In a Subset of clinically localized prostate carcinoma specimens independent of pathologic stage and Gleason pattern. A statistically significant correlation between hMSH2 immunohistochemical staining intensity and MSI also was identified in prostate carcinoma specimens. Furthermore, the time to cancer recurrence as determined by detectable serum PSA after prostatectomy was associated with hMSH2 staining intensity. Taken together, our results suggest that hMSH2 gene expression in prostate carcinoma may be a useful prognostic marker for outcome in men with clinically organ confined prostate carcinoma. Cancer 2002;94:690-9. (C) 2002 American Cancer Society. C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX USA. Catholic Univ Chile, Dept Pathol, Santiago, Chile. Catholic Univ Chile, Dept Urol, Santiago, Chile. Univ Texas, SW Med Ctr, Dept Urol, Dallas, TX USA. RP Leach, FS (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,Bldg 10 Room 2B47, Bethesda, MD 20892 USA. OI Hewitt, Stephen/0000-0001-8283-1788 FU NIDDK NIH HHS [P50-DK47657] NR 47 TC 41 Z9 42 U1 1 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD FEB 1 PY 2002 VL 94 IS 3 BP 690 EP 699 DI 10.1002/cncr.10247 PG 10 WC Oncology SC Oncology GA 517QB UT WOS:000173620400014 PM 11857301 ER PT J AU Acevedo, CM Henriquez, M Emmert-Buck, MR Chuaqui, RF AF Acevedo, CM Henriquez, M Emmert-Buck, MR Chuaqui, RF TI Loss of heterozygosity on chromosome arms 3p and 6q in microdissected adenocarcinomas of the uterine cervix and adenocarcinoma in situ SO CANCER LA English DT Article; Proceedings Paper CT 92nd Annual Meeting of the American-Association-for-Cancer-Research CY MAR 24-28, 2001 CL NEW ORLEANS, LOUISIANA SP Amer Assoc Canc Res DE endocervical carcinoma; glandular dysplasia; laser capture microdissection; deletions; chromosomes 3p and 6q ID EPITHELIAL OVARIAN-TUMORS; FREQUENT LOSS; ALLELIC LOSS; LUNG-CANCER; BRCA2 GENE; CARCINOMAS; DELETIONS; TUMORIGENESIS; MUTATIONS; REGIONS AB BACKGROUND. Despite the increasing frequency of adenocarcinomas of the uterine cervix, little is known regarding inactivation of tumor suppressor genes (TSGs) in this tumor type. The authors analyzed loss of heterozygosity (LOH) in 36 carcinomas of the cervix with glandular differentiation, and 5 adenocarcinoma in situ in 40 patients. METHODS. The authors analyzed samples using laser capture microdissection from archival material and DNA amplified with microsatellite markers on the following loci: 3p14.2 (D3S1234, D3S1300), 3p21.3 (D3S1029, D3S1447), 3p22-24 (D3S1537, D3S1351), 6q21-23.3 (D6S250), 6q25.1 (ESR), 6q25.2 (D6S255), 8p21 (D8S136, D8S1820), 13q12.3 (D13S220, D13S267), 17q21 (D17S579, D17S855). Eight additional markers spanning the short arm of chromosome 3 (3p12-p25) and six spanning the long arm of chromosome 6 (6q11-q27) were studied in the cases showing LOH to further define the deletion intervals. RESULTS. The frequency of allelic loss in cancers was chromosome 3p: 49% (p14.2: 35%, p21.3: 23%, p22-24:41%), 6q: 48% (q21-23.1:39%, q25.1:45%, q25.2:7%),13q: 22%, 17q: 6%, and 8p: 18%. On chromosome arm 3p, the authors' data suggest at least two discrete areas of deletion: a proximal area between markers D3S1234 (p12) and D3S1766 (p14.2-14.3), and a second distal interval, telomeric from marker D3S4623 (p21.3). On chromosome 6q, the deletion area is between marker D6S300 (q22) and D6S255 (q25.2). Two of five preneoplastic lesions showed LOH on chromosome arm 3p, and two five showed allelic loss on chromosome arm on 6q, suggesting the genes might be inactivated early in cervical tumorigenesis. CONCLUSIONS. The authors have identified three chromosomal regions that may harbor TSGs involved in the development/progression of adenocarcinomas of the uterine cervix, 3p12-14.2, 3p21.3-pter, and 6q22-25.2. Deletions also were detected in adenocarcinoma in situ, suggesting the genes may be inactivated early in cervical tumorigenesis. Cancer 2002;94:793-802. (C) 2002 American Cancer Society. C1 Catholic Univ Chile, Dept Pathol, Santiago, Chile. NCI, Pathol Lab, Pathogenet Unit, Bethesda, MD 20892 USA. RP Acevedo, CM (reprint author), Catholic Univ Chile, Dept Pathol, Santiago, Chile. NR 37 TC 31 Z9 34 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD FEB 1 PY 2002 VL 94 IS 3 BP 793 EP 802 DI 10.1002/cncr.10275 PG 10 WC Oncology SC Oncology GA 517QB UT WOS:000173620400028 PM 11857315 ER PT J AU Tarone, RE Chu, KC AF Tarone, RE Chu, KC TI The greater impact of menopause on ER- than ER+ breast cancer incidence: a possible explanation (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE age-period-cohort model; breast cancer; estrogen receptor; incidence rates; progesterone receptor; menopause ID ESTROGEN-RECEPTOR EXPRESSION; BIRTH COHORT PATTERNS; RISK-FACTORS; PROGESTERONE-RECEPTOR; PROLIFERATING CELLS; PRECANCEROUS BREAST; HORMONE RECEPTORS; FEMALE BREAST; TISSUE; BENIGN AB Objective: Analysis of 3359 Danish breast cancer cases indicated that menopause exerted a greater protective effect on estrogen- receptor negative (ER-) breast cancer than on estrogen- receptor positive (ER+) breast cancer. We examined US age-specific breast cancer rates by hormone receptor status in white and black women and men to investigate this unexpected result. Methods: Age-specific breast cancer incidence rates from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute were analyzed by joint estrogen receptor and progesterone receptor (ER/PR) status of 101,140 white female and 8870 black female cases and by ER status in 706 white male and black male cases diagnosed from 1992 to 1998. Changes in the rate of increase in rates with age were identified using Poisson regression analyses. Results: For both white women and black women the age-specific rates of ER- breast cancer cease increasing after 50 years of age, but age-specific rates of ER+ breast cancer continue to increase after 50 years of age. For men the incidence of ER- cancers may increase at a slower rate than incidence of ER+ cancers in older ages. In women the black rates of ER+ cancers are greater than white rates only until age 35, but black rates of ER- cancers are greater than white rates for all ages. Conclusions: Differences in age-specific breast cancer incidence patterns by hormone receptor status are similar for black women and white women. The incidence pattern for ER- cancers is consistent with a paracrine model for hormone-stimulated growth in normal breast tissue. The continued increase in ER+ cancers after menopause may be explained by both the paracrine growth model and an increase in the proliferation rate of ER+ cells with age. C1 NCI, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD 20892 USA. NCI, Ctr Reduce Canc Hlth Dispar, Bethesda, MD 20892 USA. RP Tarone, RE (reprint author), NCI, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD 20892 USA. NR 51 TC 47 Z9 51 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD FEB PY 2002 VL 13 IS 1 BP 7 EP 14 DI 10.1023/A:1013960609008 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 516XV UT WOS:000173582800002 PM 11899120 ER PT J AU Klausner, RD AF Klausner, RD TI The fabric of cancer cell biology - Weaving together the strands SO CANCER CELL LA English DT Editorial Material ID TELOMERE DYSFUNCTION; ADHESION MOLECULES; TUMOR-CELLS; METASTASIS; PROGRESSION; EXPRESSION; RECEPTORS C1 NCI, Canc Res Ctr, Bethesda, MD 20891 USA. RP Klausner, RD (reprint author), NCI, Canc Res Ctr, Bethesda, MD 20891 USA. NR 31 TC 28 Z9 32 U1 0 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 FEB PY 2002 VL 1 IS 1 BP 3 EP 10 DI 10.1016/S1535-6108(02)00020-X PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 599QZ UT WOS:000178347800002 PM 12086880 ER PT J AU Orsulic, S Li, Y Soslow, RA Vitale-Cross, LA Gutkind, JS Varmus, HE AF Orsulic, S Li, Y Soslow, RA Vitale-Cross, LA Gutkind, JS Varmus, HE TI Induction of ovarian cancer by defined multiple genetic changes in a mouse model system SO CANCER CELL LA English DT Article ID K-RAS PROTOONCOGENE; A AVIAN-LEUKOSIS; SURFACE EPITHELIUM; RETROVIRAL VECTORS; SARCOMA-VIRUSES; CELL-LINE; C-MYC; MICE; ACTIVATION; TUMORS AB We have developed a mouse model for ovarian carcinoma by using an avian retroviral gene delivery technique for the introduction of multiple genes into somatic ovarian cells of adult mice. Ovarian cells from transgenic mice engineered to express the gene encoding the avian receptor TVA were efficiently infected in vitro with multiple vectors carrying coding sequences for oncogenes and marker genes. When target cells were derived from TVA transgenic mice deficient for p53, the addition of any two of the oncogenes c-myc, K-ras, and Akt were sufficient to induce ovarian tumor formation when infected cells were injected at subcutaneous, intraperitoneal, or ovarian sites. We demonstrated that the ovarian surface epithelium is the precursor tissue for these ovarian carcinomas, and that introduction of oncogenes causes phenotypic changes in the ovarian surface epithelial cells. The induced ovarian tumors in mice resembled human ovarian carcinomas in their rapid progression and intraperitoneal metastatic spread. C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NIH, Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. RP Orsulic, S (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. RI Gutkind, J. Silvio/A-1053-2009; OI Li, Yi/0000-0002-9976-518X FU NCI NIH HHS [R01 CA103924-04, R01 CA103924, R01 CA103924-01, R01 CA103924-02, R01 CA103924-03] NR 45 TC 228 Z9 236 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD FEB PY 2002 VL 1 IS 1 BP 53 EP 62 DI 10.1016/S1535-6108(01)00002-2 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 599QZ UT WOS:000178347800010 PM 12086888 ER PT J AU Shu, XO Potter, JD Linet, MS Severson, RK Han, DH Kersey, JH Neglia, JP Trigg, ME Robison, LL AF Shu, XO Potter, JD Linet, MS Severson, RK Han, DH Kersey, JH Neglia, JP Trigg, ME Robison, LL TI Diagnostic X-rays and ultrasound exposure and risk of childhood acute lymphoblastic leukemia by immunophenotype SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID IONIZING-RADIATION; PATERNAL EXPOSURE; OXFORD SURVEY; CANCER; IRRADIATION; PREGNANCY; CHILDREN; MICE; SURVIVORS; LYMPHOMA AB The objective of this study was to evaluate the association between in utero diagnostic X-rays and childhood acute lymphoblastic leukemia (ALL) and the less well-studied relationship of this malignancy to preconception and postnatal diagnostic X-rays or fetal ultrasound exposures. The Children's Cancer Group conducted a case-control study including interviews with parents of 1842 ALL cases diagnosed under the age of 15 years and 1986 individually matched controls. Associations of self-reported parental preconception, in utero, and postnatal X-ray exposure with risk of childhood ALL were examined using odds ratios (ORs) and corresponding 95% confidence intervals (CIS) obtained from logistic regression models among the overall group of ALL cases as well as immunophenotypic and age-specific subgroups. Overall, in utero pelvimetric diagnostic X-rays were not associated with the risk of pediatric ALL (OR, 1.2; 95% Cl, 0.8-1.7). Childhood ALL, all types combined (OR, 1.1; 95% CI, 0.9-1.2) and specific types were also not linked with postnatal diagnostic X-ray exposures. Neither maternal (OR, 0.9; 95% CI, 0.8-1.2) nor paternal (OR, 1.1; 95% CI, 0.8-1.4) lower abdominal preconception diagnostic X-rays were associated with risk of childhood ALL. Among the multiple comparisons for age-, sex-, and subtype-specific subgroups, we observed an elevated risk of total ALL among children ages 11-14 at diagnosis (OR, 2.4; 95% CI, 1.1-5.0) in relation to in utero pelvimetric diagnostic X-ray exposures and a small increase in pre-B ALL for all ages combined (OR, 1.7; 95% CI, 1.1-2.7) in relation to postnatal diagnostic Xrays. In utero diagnostic ultrasound tests were not linked with risk of childhood ALL. We found little consistent evidence that in utero diagnostic ultrasound tests or X-rays were linked with an increased risk of childhood ALL. Small increases in total or pre-B ALL risks for children in selected age groups to very low ionizing radiation exposures from postnatal or preconception diagnostic X-ray exposures may represent chance findings or biases. Future studies of diagnostic X-rays and childhood leukemia in the United States will require extensive additional efforts and resources to quantify risk because of declining in utero exposures in the general population (thus necessitating large numbers of subjects, particularly cases) and the difficulty in validating reported exposures. C1 Univ Minnesota, Minneapolis, MN USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NCI, Bethesda, MD 20892 USA. Karmanos Canc Inst, Detroit, MI USA. Alfred I Dupont Hosp Children, Wilmington, DE USA. RP Shu, XO (reprint author), Childrens Oncol Grp, POB 60012, Arcadia, CA 91066 USA. OI Potter, John/0000-0001-5439-1500 FU NCI NIH HHS [CA 48051] NR 59 TC 67 Z9 70 U1 1 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 FEB PY 2002 VL 11 IS 2 BP 177 EP 185 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 528FE UT WOS:000174233100004 PM 11867505 ER PT J AU Freedman, AN Pfeiffer, R Gail, MH AF Freedman, AN Pfeiffer, R Gail, MH TI Individualized Cancer Risk Prediction Models: How strong do risk factors have to be to accurately predict an individual's cancer risk? SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. RI Pfeiffer, Ruth /F-4748-2011 NR 0 TC 0 Z9 0 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 FEB PY 2002 VL 11 IS 2 BP 221 EP 221 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 528FE UT WOS:000174233100017 ER PT J AU Kawakami, M Kawakami, K Puri, RJ AF Kawakami, M Kawakami, K Puri, RJ TI Apoptotic pathways of cell death induced by an interleukin-13 receptor-targeted recombinant cytotoxin in head and neck cancer cells SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE interleukin-13; cytotoxin; head and neck squamous cell carcinoma; apoptosis; nitric oxide ID PSEUDOMONAS EXOTOXIN; CARCINOMA-CELLS; SIGNAL-TRANSDUCTION; TUMOR-CELLS; PROTEIN; LINES; CASPASES; GROWTH; BCL-2; IL-13 AB Interleukin 13 receptor (IL-13R)-targeted cytotoxin, IL13-PE38QQR, composed of IL-13 and a mutated form of Pseudomonas exotoxin (PE), is found to be highly and specifically cytotoxic to human solid cancer cell lines. However, the mechanism of tumor cell death mediated by IL-13 toxin is still not known. To elucidate the mechanism, we utilized four head and neck cancer cell lines (SCC-25, HN12, KCCT873, and YCUM911), which express high levels of IL-13R, and IL-13 toxin is highly cytotoxic to these cells. We observed chromatin condensation and DNA fragmentation, indicating apoptotic cell death, after treatment with IL-13 toxin, as determined by bis-benzimide staining and DNA ladder assays. However, IL-13 did not induce cell death. Flow cytometric analysis suggested that these cancer cell lines increased the sub-G1/G0 phase DNA population in a dose- and time-dependent manner (ranged between 10 and 30%) after treatment with IL-13 toxin. By Western blot analysis, cleavage of caspase-3 and PARP was observed after treatment with a high concentration of IL-13 toxin, also suggesting apoptotic cell death. In addition, the results of immunofluorescence and RT-PCR assays showed that the apoptosis-regulator, Bcl-2 was downregulated after treatment with IL-13 toxin. while Bax was upregulated. Moreover, significant nitrite production was detected in the HN12 cell line after treatment with IL-13 toxin for 48-96 h. Taken together, our results suggest that IL-13 toxin-induced cytotoxicity is at least partially mediated by the apoptosis and nitric oxide pathways. This information may be useful in developing specific approaches where apoptotic bodies from tumor cells may be used to pulse antigen-presenting cells for immunotherapy of cancer. C1 US FDA, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Puri, RJ (reprint author), US FDA, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, NIH Bldg 29B,Room 2NN10,29 Lincoln Dr MSC 4555, Bethesda, MD 20892 USA. NR 41 TC 24 Z9 25 U1 1 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD FEB PY 2002 VL 50 IS 12 BP 691 EP 700 DI 10.1007/s00262-001-0242-6 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA 531LG UT WOS:000174416400006 PM 11862421 ER PT J AU Calzone, KA Biesecker, BB AF Calzone, KA Biesecker, BB TI Genetic testing for cancer predisposition SO CANCER NURSING LA English DT Article DE genetic testing; cancer susceptibility; informed consent ID BREAST-OVARIAN-CANCER; FOLLOW-UP CARE; SUSCEPTIBILITY GENE; PSYCHOLOGICAL CONSEQUENCES; INHERITED PREDISPOSITION; BRCA1; FAMILIES; DISCRIMINATION; MUTATIONS; RECOMMENDATIONS AB The onslaught of genetic innovations in the past decade has resulted in the ongoing identification of a spectrum of genes, some of which, when mutated, result in cancer susceptibility. The impact of these discoveries on healthcare provides an opportunity to enhance health promotion and long-term health outcomes by identifying at-risk individuals before cancer develops. This provides the healthcare provider with the potential to intervene much earlier to either reduce the risk or diagnose a cancer early when the chances for effective treatment are greatest. Even though genetic testing is increasingly being employed clinically, there remains a gap between the technology and effective interventions. Genetic tests also provide information that is distinct from other tests used routinely in health promotion, because of the personal and family nature of the information. This results in unique clinical, ethical, legal, and social issues that further affect the effective diffusion of this technology clinically. This article provides an overview of the distinguishing characteristics of genetic testing, outlines the essential components of informed consent, and discusses the potential implications of testing on individuals' lives and the nurse's role in offering genetic testing. C1 Univ Penn, Ctr Canc, Philadelphia, PA 19104 USA. Natl Human Genome Res Inst, NIH, Bethesda, MD USA. RP Calzone, KA (reprint author), Univ Penn, Ctr Canc, 3400 Spruce St 2007 Penn Tower, Philadelphia, PA 19104 USA. NR 61 TC 11 Z9 11 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 FEB PY 2002 VL 25 IS 1 BP 15 EP 25 DI 10.1097/00002820-200202000-00005 PG 11 WC Oncology; Nursing SC Oncology; Nursing GA 519EP UT WOS:000173712200003 PM 11838716 ER PT J AU Weinrich, S Royal, C Pettaway, CA Dunston, G Faison-Smith, L Priest, JH Roberson-Smith, P Frost, J Jenkins, J Brooks, KA Powell, I AF Weinrich, S Royal, C Pettaway, CA Dunston, G Faison-Smith, L Priest, JH Roberson-Smith, P Frost, J Jenkins, J Brooks, KA Powell, I TI Interest in genetic prostate cancer susceptibility testing among African American men SO CANCER NURSING LA English DT Article ID BREAST-OVARIAN CANCER; COLON-CANCER; HEREDITARY BREAST; CHROMOSOME 1Q; LOCUS; RISK; ATTITUDES; FAMILIES AB Six regions for prostate cancer genes have been identified, and it is anticipated that prostate cancer susceptibility testing will be available in the future. This correlational study identified predictors for interest in prostate cancer susceptibility testing among African American men. Participants were 320 African American men from the African American Hereditary Prostate Cancer Study and the South Carolina Prostate Cancer Education and Screening Study participated. Two questions measured interest in genetic prostate cancer susceptibility testing and family history of prostate cancer. Chi-square analyses by family history as well as demographics (age, education, marital status) were performed. Most of the men (277 [87%]) indicated an interest in genetic prostate cancer susceptibility testing. Interest in undergoing testing did not vary by family history, age, or education. Marital status was the only significant demographic predictor. Men who were married were significantly more likely to respond with a "yes" to interest in prostate cancer susceptibility testing than were men who were not married. The high "yes" response rate and the men's confusion between the genetic prostate cancer susceptibility testing and prostate cancer screening highlight the need for public education once prostate cancer genes are identified and available for public testing. C1 Univ Louisville, Sch Nursing, Louisville, KY 40292 USA. Univ S Carolina, S Carolina Canc Ctr, Columbia, SC USA. Howard Univ, Natl Human Genome Ctr, Washington, DC USA. MD Anderson Canc Ctr, Houston, TX USA. Howard Univ, Coll Med, Washington, DC USA. Natl Naval Med Res Inst, NCI, Bethesda, MD USA. Univ S Carolina, Sch Med, Genet Ctr, Columbia, SC USA. Wayne State Univ, Detroit, MI USA. RP Weinrich, S (reprint author), Univ Louisville, Sch Nursing, Louisville, KY 40292 USA. EM sally.weinrich@louisville.edu NR 42 TC 12 Z9 12 U1 1 U2 1 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 FEB PY 2002 VL 25 IS 1 BP 28 EP 34 DI 10.1097/00002820-200202000-00007 PG 7 WC Oncology; Nursing SC Oncology; Nursing GA 519EP UT WOS:000173712200004 PM 11838717 ER PT J AU Nishi, H Nishi, KH Johnson, AC AF Nishi, H Nishi, KH Johnson, AC TI Early growth response-1 gene mediates up-regulation of epidermal growth factor receptor expression during hypoxia SO CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; A-CHAIN PROMOTER; TRANSCRIPTION FACTORS; ENHANCED EXPRESSION; OXYGEN DISTRIBUTION; UTERINE CERVIX; TUMOR HYPOXIA; FACTOR-I; KAPPA-B; EGR-1 AB Hypoxia occurs during development of cancers and is correlated with cancer progression. Hypoxia also induces epidermal growth factor receptor (EGFR) expression. The EGFR plays a vital role in cell growth, an its overexpression can lead to transformation. We sought to determine the regulator(s) of EGFR expression during hypoxia. We demonstrate that early growth response factor 1 (Egr-1), which is induced by hypoxia, can activate the basal transcriptional activity of the EGFR promoter. Egr-1 not only transactivates the EGFR promoter activity but also enhances endogenous EGFR expression. Using a series of EGFR promoter deletion mutants, we show that the region between -484 and -389, which contains a putative Egr-1 consensus motif, is crucial for EGFR transactivation by Egr-1. Electrophoretic mobility shift assays show that Egr-1 binds to the oligonucleotide containing this Egr-1 motif. Also, introduction of an antisense oligonucleotide for Egr-1 diminishes EGFR expression during hypoxia, indicating that the up-regulation of EGFR by hypoxia is mediated through Egr-1. Our results provide evidence that regulation of EGFR promoter activity by Egr-1 represents a mechanism for epidermal cell growth during hypoxia. C1 NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Johnson, AC (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37,Room 5002,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. NR 68 TC 101 Z9 110 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2002 VL 62 IS 3 BP 827 EP 834 PG 8 WC Oncology SC Oncology GA 519TB UT WOS:000173740600032 PM 11830539 ER PT J AU Kobayashi, H Shirakawa, K Kawamoto, S Saga, T Sato, N Hiraga, A Watanabe, I Heike, Y Togashi, K Konishi, J Brechbiel, MW Wakasugi, H AF Kobayashi, H Shirakawa, K Kawamoto, S Saga, T Sato, N Hiraga, A Watanabe, I Heike, Y Togashi, K Konishi, J Brechbiel, MW Wakasugi, H TI Rapid accumulation and internalization of radiolabeled herceptin in an inflammatory breast cancer xenograft with vasculogenic mimicry predicted by the contrast-enhanced dynamic MRI with the macromolecular contrast agent G6-(1B4M-Gd)(256) SO CANCER RESEARCH LA English DT Article ID ENDOTHELIAL PROGENITOR CELLS; SINGLE-CHAIN FV; MONOCLONAL-ANTIBODY; RECOMBINANT IMMUNOTOXIN; IN-VIVO; POSTNATAL NEOVASCULARIZATION; 3-DIMENSIONAL STRUCTURE; PHASE-II; RADIOIMMUNOTHERAPY; TUMOR AB The rapid blood flow and perfusion of macromolecules in the inflammatory breast cancer xenograft (WIBC-9), which exhibits a "vasculogenic mimicry" type of angiogenesis without the participation of endothelial cells and expresses high levels of the HER-2/neu antigen, was evaluated in mice using 3D-micro-MR angiography using a novel macromolecular MR contrast agent [G6-(1B4M-Gd)(256)]. Herceptin, which recognizes the HER2/neu antigen and has similar size (10 nm) to G6-(1B4M-Gd)(256), accumulated and internalized in the WIBC-9 tumors more quickly than in the control MC-5 tumors that progress with normal angiogenesis. Three dimensional micro-MRI with the G6-(1B4M-Gd)(256) macromolecular MRI contrast agent distinguishes between the different types of angiogenesis and is predictive of the rapid accumulation and internalization of Herceptin in the WIBC-9 inflammatory breast cancer xenograft. C1 Hitachi Med Co, Chaired Dept Diagnost & Intervent Imagiol, Kyoto 6068507, Japan. Hitachi Med Co, Chaired Dept Nucl Med & Diagnost Imaging, Kyoto 6068507, Japan. Natl Canc Ctr, Res Inst, Div Pharmacol, Tokyo 1040045, Japan. NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Metab Branch, NIH, Bldg 10,Room 4N109,10 Ctr Dr, Bethesda, MD 20892 USA. NR 42 TC 59 Z9 67 U1 1 U2 8 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2002 VL 62 IS 3 BP 860 EP 866 PG 7 WC Oncology SC Oncology GA 519TB UT WOS:000173740600037 PM 11830544 ER PT J AU Ueda, E Kurebayashi, S Sakaue, M Backlund, M Koller, B Jetten, AM AF Ueda, E Kurebayashi, S Sakaue, M Backlund, M Koller, B Jetten, AM TI High incidence of T-cell lymphomas in mice deficient in the retinoid-related orphan receptor ROR gamma SO CANCER RESEARCH LA English DT Article ID ACUTE PROMYELOCYTIC LEUKEMIA; NUCLEAR RECEPTOR; P53-DEFICIENT MICE; TRANSGENIC MICE; ALPHA; STAGGERER; GENE; TUMORIGENESIS; EXPRESSION; APOPTOSIS AB Nuclear receptors are critical regulators of many physiological processes and have been shown to be involved in a variety of disease processes, including malignant neoplasms. Our laboratory is investigating the function of the retinoid-related orphan receptor gamma (RORgamma) and its possible role in disease. Studies of mice deficient in the expression of RORgamma demonstrated that this receptor plays a crucial role in the regulation of thymopoiesis and lymph node organogenesls. In this study, we show that changes in homeostasis in the thymus of RORgamma(-/-) mice are associated with a high incidence of T-cell lymphomas. Over 50% of the deficient mice of mixed genetic background die within the first 4 months as a result of thymic lymphomas. A high incidence of lymphomas was also observed in RORgamma-/- 129/SvEv mice. The lymphoblastic cells metastasized frequently to spleen and liver. No other tumor types were detected in any of RORgamma(-/-) mice that died during the course of the experiment, and none of the heterozygous rnice developed thymic lymphomas. Lymphoma formation was associated with increased cellular proliferation and an increase in the number of apoptotic cells. When placed in culture, the RORgamma(-/-)lymphoblastic cells underwent accelerated "spontaneous" apoptosis at a rate similar to that of RORgamma(-/-) thymocytes. Upon prolonged culture, several lymphoblastic cell lines could be established. Analysis of the immunophenotype of the lymphoblastic cells showed that the CD4 and CD8 subpopulations varied substantially among different lymphomas. The established cell lines consisted mostly of CD44(-)CD25(+)CD4(-)CD8(-)cells. Our studies indicate that loss of RORgamma disturbs homeostasis in the thymus by enhancing apoptosis and cellular proliferation. The latter may enhance the probability of individual cells to acquire genetic alterations that make them escape negative selection and normal differentiation programs and as a consequence lead to increased susceptibility to the development of T-cell lymphoma. C1 NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA. RP Ueda, E (reprint author), NIEHS, Cell Biol Sect, Div Intramural Res, NIH, 111 TW Alexander Dr,Room D-242, Res Triangle Pk, NC 27709 USA. OI Jetten, Anton/0000-0003-0954-4445 FU NCI NIH HHS [R01 CA 82423-02] NR 41 TC 27 Z9 29 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2002 VL 62 IS 3 BP 901 EP 909 PG 9 WC Oncology SC Oncology GA 519TB UT WOS:000173740600043 PM 11830550 ER PT J AU Perez-Diez, A Marincola, FM AF Perez-Diez, A Marincola, FM TI Immunotherapy against antigenic tumors: a game with a lot of players SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE antigenic tumors; cancer vaccines; immune response; tumor microenvironment; microarrays ID COLONY-STIMULATING FACTOR; RECOMBINANT VACCINIA VIRUS; IN-VITRO STIMULATION; DENDRITIC CELLS; METASTATIC MELANOMA; IMMUNE-RESPONSES; T-LYMPHOCYTES; INFILTRATING LYMPHOCYTES; ADOPTIVE IMMUNOTHERAPY; GENE-EXPRESSION AB Our understanding of how immune responses are generated and regulated drives the design of possible immunotherapies for cancer patients. For that reason, we first describe briefly the actual immunological theories and their common perspectives about cancer vaccine development. Second, we describe cancer vaccines that are able to induce tumor-specific immune responses in cancer patients. However, these responses are not always followed by tumor rejection. At the end of the review, we discuss two possible reasons that might explain this dichotomy of cancer immunology. First, the immune response generated, although detectable, may not be quantitatively sufficient to reject the tumor. Second, the tumor microenvironment may modulate tumor cell susceptibility to the systemic immune response induced by the immunization. Finally, we discuss what, in our opinion, might be the best way to improve cancer vaccine strategies and how the relationship between the tumor and its surroundings might be studied in more details. C1 NCI, Surg Branch, Bethesda, MD 20892 USA. NCI, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NCI, Surg Branch, Bldg 10,Room 2B42,10 Ctr Dr MSC, Bethesda, MD 20892 USA. NR 64 TC 13 Z9 13 U1 0 U2 0 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD FEB PY 2002 VL 59 IS 2 BP 230 EP 240 DI 10.1007/s00018-002-8419-5 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 526YC UT WOS:000174156600005 PM 11915941 ER PT J AU Flowers, A Onwueme, K Creveling, CR Daly, JW AF Flowers, A Onwueme, K Creveling, CR Daly, JW TI Reserpine: Interactions with batrachotoxin and brevetoxin sites on voltage-dependent sodium channels SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE sodium channels; batrachotoxin; brevetoxin; reserpine ID PIG CEREBRAL-CORTEX; RAT-BRAIN; LOCAL-ANESTHETICS; RECEPTOR-SITE; PHOSPHOINOSITIDE BREAKDOWN; ALLOSTERIC MODULATION; A 20-ALPHA-BENZOATE; NEUROTOXIN BINDING; INHIBITION; DRUGS AB Reserpine inhibited batrachotoxin-elicited sodium influx in guinea pig brain synaptoneurosomes with an IC50 of about 1 muM. In the presence of brevetoxin the IC50 increased to about 80 muM. Reserpine inhibited binding of batrachotoxinin-A [H-3]benzoate ([H-3]BTX-B) binding in a complex manner causing a partial inhibition from 0.001 to 0.08 muM, then a rebound stimulation from 0.1 to 0.8 muM, followed by complete inhibition by 80 muM. The stimulation was prevented by the presence of brevetoxin; reserpine then smoothly inhibited binding with an IC50 of about 1 muM. Reserpine at 1 muM slightly reduced the off-rate of [H-3]BTX-B binding measured in the presence of veratridine, while at a concentration of 50 muM it enhanced the off-rate, presumably by an allosteric mechanism. Reserpine at 0.3-10 muM elicited a partial inhibition of the binding of [H-3]brevetoxin-3. The local anesthetic dibucaine had effects similar to reserpine: It partially inhibited binding of [H-3]brevetoxin. The presence of brevetoxin reduced the potency of dibucaine as an inhibitor of batrachotoxin-elicited sodium influx from an IC50 of about 2 muM to an IC50 of about 50 muM. The results suggest that reserpine binds at both a local anesthetic site to cause allosteric inhibition of batrachotoxin-binding and action, but that it also binds to another site causing, like brevetoxin, an enhancement of batrachotoxin-binding and action. Local anesthetics also may bind to the brevetoxin site. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Daly, JW (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bldg 8,Room 1A17, Bethesda, MD 20892 USA. NR 22 TC 1 Z9 1 U1 1 U2 1 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD FEB PY 2002 VL 22 IS 1 BP 1 EP 12 AR UNSP 0272-4340/02/0200-0001/0 DI 10.1023/A:1015301610349 PG 12 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 550CZ UT WOS:000175487200001 PM 12064513 ER PT J AU Goransson, O Resjo, S Ronnstrand, L Manganiello, V Degerman, E AF Goransson, O Resjo, S Ronnstrand, L Manganiello, V Degerman, E TI Ser-474 is the major target of insulin-mediated phosphorylation of protein kinase B beta in primary rat adipocytes SO CELLULAR SIGNALLING LA English DT Article DE PKB beta; adipocyte; phosphorylation; insulin; translocation; phosphopeptide ID NUCLEOTIDE PHOSPHODIESTERASE 3B; GLYCOGEN-SYNTHASE KINASE-3; PLECKSTRIN HOMOLOGY DOMAIN; SERINE-THREONINE KINASE; MOLECULAR-CLONING; PHOSPHATIDYLINOSITOL 3-KINASE; CAMP-PHOSPHODIESTERASE; MEMBRANE TRANSLOCATION; ADIPOSE-TISSUE; FAT-CELLS AB The mechanism of activation for protein kinase B (PKB), an important target for insulin signaling, has been scarcely investigated in primary cells, In this study, we have characterized the insulin-induced phosphorylation and activation of PKB in primary rat adipocytes. Insulin stimulation resulted in a translocation of PKBbeta from cytosol to membranes, and phosphorylation and activation of PKBbeta. Phosphoamino acid analysis and phosphopeptide mapping demonstrated that the phosphorylation occurred mainly on serines, also when using calyculin A, and that these were localized within one major phosphopeptide. Radiosequencing showed that the radioactivity was released in Cycle No. 7. In addition, the peptide was specifically immunoprecipitated from a tryptic digest of PKBbeta using the anti-phospho-PKB (Ser-473) antibody. Taken together, these results show that rat adipocyte PKBbeta mainly is phosphorylated on Ser-474 in response to insulin stimulation, in contrast to previous studies in human embryonic kidney (HEK) 293 cells demonstrating, in addition, phosphorylation of Thr-309. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Lund Univ, Dept Cell & Mol Biol, Sect Mol Signalling, S-22184 Lund, Sweden. Biomed Ctr, Ludwig Inst Canc Res, S-75124 Uppsala, Sweden. Natl Heart Lung & Blood Inst, Pulm Crit Care Med Branch, Bethesda, MD 20892 USA. RP Goransson, O (reprint author), Lund Univ, Dept Cell & Mol Biol, Sect Mol Signalling, BMC C11, S-22184 Lund, Sweden. RI Ronnstrand, Lars/A-2429-2011 NR 46 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD FEB PY 2002 VL 14 IS 2 BP 175 EP 182 DI 10.1016/S0898-6568(01)00242-X PG 8 WC Cell Biology SC Cell Biology GA 514HK UT WOS:000173433000012 PM 11781143 ER PT J AU Pauly, GT Peterson, LA Moschel, RC AF Pauly, GT Peterson, LA Moschel, RC TI Mutagenesis by O-6-[4-oxo-4-(3-pyridyl)butyl]guanine in Escherichia coli and human cells SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID TOBACCO-SPECIFIC NITROSAMINES; 3 O-6-SUBSTITUTED GUANINES; CHEMICAL CARCINOGENESIS; F344 RATS; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; GAPPED PLASMIDS; MOUSE LUNG; DNA; 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE; N'-NITROSONORNICOTINE AB Site-specific mutagenesis by O-6-[4-oxo-4-(3-pyridyl)butyl]guanine (O-6-pobGua), a product of DNA pyridyloxobutylation by metabolites of the tobacco-specific nitrosamines N-nitrosonor-nicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), was studied in Escherichia coli strain DH10B and human kidney cells (293) when the modified base was incorporated in either a double-stranded or a gapped shuttle vector. In the repair-competent E. coli strain, less than 3% of the colonies produced by double-stranded vectors harboring the modified base were mutant whereas 96% were mutant when DH10B cells were transformed with modified gapped vectors. By contrast, transformation of DH10B cells with plasmids derived from O-6-pobGua-containing double-stranded and gapped vectors previously replicated in 293 cells produced 7 and 16% mutant colonies, respectively. These percentages increased to 42 and 82%, respectively, when the 293 cells were pretreated with O-6-benzylguanine to inactivate the O-6-alkylguanine-DNA alkyltransferase protein. These findings confirm that the adduct is readily repaired by the human O-6-alkylguanine-DNA alkyltransferase in both double-stranded and gapped vectors and suggest that it is also highly mutagenic in both human cells and E. coli. In the E. coli strain, the adduct produced exclusively G-->A transition mutations although in human 293 cells it also produced G-->T transversions and more complex mutations in addition to G-->A transitions. These data suggest that O-6[4-oxo-4-(3-pyridyl)butyl]guanine can contribute significantly to the mutagenic risk posed by exposure to both NNN and NNK in tobacco smoke. C1 NCI, Chem Carcinogenesis Lab, Frederick, MD 21702 USA. Univ Minnesota, Div Environm & Occupat Hlth, Minneapolis, MN 55455 USA. Univ Minnesota, Canc Ctr, Minneapolis, MN 55455 USA. RP Peterson, LA (reprint author), NCI, Chem Carcinogenesis Lab, Frederick, MD 21702 USA. OI Peterson, Lisa/0000-0001-8715-4480 FU NCI NIH HHS [CA-59887, CA-77598] NR 23 TC 47 Z9 47 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD FEB PY 2002 VL 15 IS 2 BP 165 EP 169 DI 10.1021/tx0101245 PG 5 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 524VM UT WOS:000174033600009 PM 11849042 ER PT J AU Harik-Khan, RI Fleg, JL Wise, RA AF Harik-Khan, RI Fleg, JL Wise, RA TI Body mass index and the risk of COPD SO CHEST LA English DT Article DE body mass index; body weight; lung diseases; obstructive ID OBSTRUCTIVE PULMONARY-DISEASE; LUNG-FUNCTION; NUTRITIONAL-STATUS; ENERGY-BALANCE; WEIGHT; MORTALITY; RATS; STARVATION; VENTILATION; PRESSURE AB Background: Previous studies have documented the prognostic value of low body weight in patients with COPD and also in general populations. However, it is not clear whether low body weight is a risk factor for COPD or a consequence of established disease. Study objective: To determine whether asymptomatic subjects with low initial body mass were at a greater risk of having COPD develop during subsequent follow-up. Design and subjects: Observational retrospective study of 458 male and 192 female participants (age range, 40 to 73 years) in the Baltimore Longitudinal Study of Aging. At baseline, the participants did not have COPD. After mean follow-up periods of 10.2 years for the men and 6.4 years for the women, 40 men and 7 women received a diagnosis of COPD. Methods: Cox proportional-hazards regression models were used to assess the relationship between COPD diagnosis and baseline body mass index (BMI) in men. Results: The risk of COPD developing in men varied inversely with baseline BMI, even after adjusting for other risk factors, including cigarette smoking, age, FEV1 percent predicted, abdominal obesity, and educational status. In men, the relative risk of COPD developing for the lowest BMI tertile relative to the highest tertile was 2.76 (95% confidence interval, 1.15 to 6.59). The small number of women who had COPD did not allow us to draw conclusions regarding BMI as a risk factor for COPD. Conclusion:After controlling for confounding variables, men with low BMI are at increased risk for getting COPD. C1 NIA, Clin Res Branch, Longitudinal Study Sect, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Johns Hopkins Asthma & Allergy Ctr, Div Pulm & Crit Care Med, Baltimore, MD USA. RP Harik-Khan, RI (reprint author), NIA, Clin Res Branch, Longitudinal Study Sect, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Wise, Robert/0000-0002-8353-2349 NR 40 TC 53 Z9 58 U1 0 U2 1 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD FEB PY 2002 VL 121 IS 2 BP 370 EP 376 DI 10.1378/chest.121.2.370 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 521JJ UT WOS:000173836600014 PM 11834645 ER PT J AU Luo, YJ Jiang, Y Tang, YY Parasuraman, R AF Luo, YJ Jiang, Y Tang, YY Parasuraman, R TI Neural mechanisms of unconscious visual motion priming SO CHINESE SCIENCE BULLETIN LA English DT Article ID REPETITION BLINDNESS; PERCEPTION; SIGNALS AB The neural correlates of the motion priming were examined In normal young subjects using event-related brain potentials (ERPs) and functional magnetic resonance imaging (fMRI). Visual motion perception can be unconsciously biased in favor of a particular direction by a preceding motion in that direction. Motion priming first involved an enhancement of ERP amplitude about 100 ms following the onset of motion. The amplitudes of ERP components after 350 ms were also increased. The fMRI results suggest that the early-latency effect reflects modulation of neural responses in extrastriate cortex. Higher-level visual processing areas, including cortical regions MT/MST and the intraparietal cortices were also activated. The findings provide direct evidence that unconscious priming of motion perception is the result of interaction of direction-selective neural responses to motion stimuli. The results cannot be accounted for by refractoriness of neural responses, but instead support a theory of motion priming based on motion opponency, as proposed in computational models. C1 Chinese Acad Sci, Inst Psychol, Beijing 100101, Peoples R China. NIMH, Bethesda, MD 20892 USA. Catholic Univ Amer, Washington, DC 20064 USA. RP Luo, YJ (reprint author), Chinese Acad Sci, Inst Psychol, Beijing 100101, Peoples R China. NR 15 TC 1 Z9 1 U1 0 U2 4 PU SCIENCE CHINA PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1001-6538 J9 CHINESE SCI BULL JI Chin. Sci. Bull. PD FEB PY 2002 VL 47 IS 3 BP 193 EP 197 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 528UX UT WOS:000174263500005 ER PT J AU Suzuki, K Yanagi, M Mori-Aoki, A Moriyama, E Ishii, KJ Kohn, LD AF Suzuki, K Yanagi, M Mori-Aoki, A Moriyama, E Ishii, KJ Kohn, LD TI Transfection of single-stranded hepatitis A virus RNA activates MHC class I pathway SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE infectious immunity-virus; MHC; antigen presentation; protein kinases/phosphatases ID NF-KAPPA-B; MAJOR HISTOCOMPATIBILITY COMPLEX; DEPENDENT PROTEIN-KINASE; NECROSIS-FACTOR-ALPHA; GENE-EXPRESSION; A VIRUS; ANTIGEN PRESENTATION; V(D)J RECOMBINATION; IMMUNE-RESPONSES; CDNA CLONE AB Although infection of single-stranded RNA viruses can enhance expression of major histocompatibility complex (MHC) class I genes, the mechanism underlying this process remains unclear. Recent studies have indicated that exposure of non-immune cells to double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) of viral origin can directly increase the expression of MHC class I and related molecules without immune cell interaction. In this report, we show that transfection of single-stranded hepatitis A virus RNA into cultured hepatocytes results in the induction of genes for MHC class I, LMP2 and transporter for antigen processing (TAP1), in addition to the generation of viral proteins. We suggest that this stimulatory effect is due to the double-stranded RNA formed during replication of single-stranded viral RNA, and involves both double-stranded, RNA-dependent protein kinase PKR and the secretion of IFNbeta. C1 Natl Inst Infect Dis, Leprosy Res Ctr, Dept Microbiol, Tokyo 1890002, Japan. NIDDKD, Cell Regulat Sect, Metab Dis Branch, NIH, Bethesda, MD USA. Kanazawa Univ, Sch Med, Dept Internal Med, Kanazawa, Ishikawa 920, Japan. Tottori Univ, Sch Med, Dept Internal Med, Tottori 680, Japan. US FDA, Sect Retroviral Immunol, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. Ohio Univ, Coll Med, Edison Biotechnol Inst, Athens, OH 45701 USA. RP Suzuki, K (reprint author), Natl Inst Infect Dis, Leprosy Res Ctr, Dept Microbiol, 4-2-1 Aoba Cho, Tokyo 1890002, Japan. RI Ishii, Ken/B-1685-2012 OI Ishii, Ken/0000-0002-6728-3872 NR 58 TC 10 Z9 10 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD FEB PY 2002 VL 127 IS 2 BP 234 EP 242 DI 10.1046/j.1365-2249.2002.01767.x PG 9 WC Immunology SC Immunology GA 548JP UT WOS:000175385100008 PM 11876745 ER PT J AU Bruce, S Tack, C Patel, J Pacak, K Goldstein, DS Woltz, P Brentzel, S Holmes, C AF Bruce, S Tack, C Patel, J Pacak, K Goldstein, DS Woltz, P Brentzel, S Holmes, C TI Local sympathetic function in human skeletal muscle and adipose tissue assessed by microdialysis SO CLINICAL AUTONOMIC RESEARCH LA English DT Article DE norepinephrine; sympathetic; microdialysis; skeletal muscle; adipose; orthostasis; trimethaphan ID NOREPINEPHRINE RELEASE; QUANTITATIVE MICRODIALYSIS; NERVOUS-SYSTEM; BLOOD-FLOW; NORADRENALINE; BRAIN; SPILLOVER; HEART; DIHYDROXYPHENYLGLYCOL; INNERVATION AB Background In response to stressors and pathophysiologic conditions, sympathetic neuronal outflows can change heterogeneously among body organs and tissues. This study examined the validity of microdialysis and measurements of microdialysate concentrations of catechols, to assess local sympathetic function in skeletal muscle and adipose tissue in humans. Methods Based on preliminary experiments, a microdialysate perfusion rate of 3 mul/min and collection duration of 30 minutes were chosen. To assess responses to a stimulus that increases sympathetic outflow to skeletal muscle, microdialysate norepinephrine and dihydroxyphenylglycol concentrations in quadriceps muscle, abdominal subcutaneous adipose tissue, and plasma were measured during orthostasis in 8 healthy normal volunteers. To assess responses to decreased postganglionic sympathetic nerve traffic, norepinephrine and dihydroxyphenylglycol concentrations were measured during i.v. infusion of trimethaphan in 5 volunteers. Results All subjects had detectable norepinephrine and dihydroxyphenylglycol in microdialysate from both skeletal muscle and adipose tissue. Orthostasis significantly increased microdialysate norepinephrine in skeletal muscle (0.38 +/- (SEM) 0.07 nmol/L supine to 1.48 +/- 0.24 nmol/L standing, p < 0.01) and in adipose tissue (0.31 +/- 0.02 nmol/L supine to 0.68 +/- 0.11 nmol/L standing, p < 0.01). Orthostasis also increased microdialysate dihydroxyphenylglycol in both tissues (1.76 +/- 0.30 nmol/L to 3.08 +/- 0.43 nmol/L, p < 0.01; 1.37 +/- 0.15 nmol/L supine to 1.99 +/- 0.34 nmol/L standing, p < 0.01). Trimethaphan decreased norepinephrine concentrations in skeletal muscle microdialysate by 50 %, adipose tissue by 70 %, and antecubital venous plasma 50 %, with non-significant decreases in dihydroxyphenylglycol concentrations at each site. Conclusions Microdialysate concentrations of norepinephrine and dihydroxyphenylglycol can be detected reliably and respond appropriately during manipulations that increase or decrease the sympathetically mediated release and turnover of norepinephrine. This approach may provide a means to assess sympathetic neuronal function in skeletal muscle and adipose tissue in humans with known or suspected dysautonomias. C1 NINCDS, NIH, Bethesda, MD 20892 USA. Univ Nijmegen, Dept Internal Med, Nijmegen, Netherlands. UCL, London, England. NINCDS, Clin Neuroscardiol Sect, NIH, Bethesda, MD 20892 USA. RP Bruce, S (reprint author), NINCDS, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. EM sbruce@erols.com; goldsteind@ninds.nih.gov RI Tack, Cees/A-2368-2014 NR 37 TC 9 Z9 9 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0959-9851 J9 CLIN AUTON RES JI Clin. Auton. Res. PD FEB PY 2002 VL 12 IS 1 BP 13 EP 19 DI 10.1007/s102860200005 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 536XL UT WOS:000174727100005 PM 12102443 ER PT J AU O'Shaughnessy, JA Kelloff, GJ Gordon, GB Dannenberg, AJ Hong, WK Fabian, CJ Sigman, CC Bertagnolli, MM Stratton, SP Lam, S Nelson, WG Meyskens, FL Alberts, DS Follen, M Rustgi, AK Papadimitrakopoulou, V Scardino, PT Gazdar, AF Wattenberg, LW Sporn, MB Sakr, WA Lippman, SM Von Hoff, DD AF O'Shaughnessy, JA Kelloff, GJ Gordon, GB Dannenberg, AJ Hong, WK Fabian, CJ Sigman, CC Bertagnolli, MM Stratton, SP Lam, S Nelson, WG Meyskens, FL Alberts, DS Follen, M Rustgi, AK Papadimitrakopoulou, V Scardino, PT Gazdar, AF Wattenberg, LW Sporn, MB Sakr, WA Lippman, SM Von Hoff, DD TI Treatment and prevention of intraepithelial neoplasia: An important target for accelerated new agent development - Recommendations of the American Association for Cancer Research Task Force on the Treatment and Prevention of Intraepithelial Neoplasia SO CLINICAL CANCER RESEARCH LA English DT Review ID SQUAMOUS-CELL CARCINOMA; FINE-NEEDLE-ASPIRATION; FAMILIAL ADENOMATOUS POLYPOSIS; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; PROLIFERATIVE BREAST DISEASE; HEART-TRANSPLANT RECIPIENTS; COLUMNAR-LINED ESOPHAGUS; NONMELANOMA SKIN-CANCER; ABERRANT CRYPT FOCI; IMMUNOSUPPRESSIVE THERAPY REGIMENS AB Precancer or intraepithelial neoplasia (TEN) is a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer and that predicts for a substantial likelihood of developing invasive cancer. The AACR Task Force on the Treatment and Prevention of TEN has delineated the relationship between TEN and cancer risk as well as the clinical benefit that can be derived from reducing TEN burden. Although several effective endoscopic and surgical treatments for TEN have become standard medical practice, these interventions can confer morbidity and do not treat the entire epithelial field at risk. The incidence of many epithelial cancers is continuing to rise, the number of individuals at risk is increasing with the aging population, and the rapid advancement of imaging and molecular diagnostics is bringing to light precancers that were heretofore clinically silent. There is therefore an urgent need to rapidly develop new treatment and prevention agents for TEN. The AACR TEN Task Force recommends focusing on established precancers as the target for new agent development because of the close association between dysplasia and invasive cancer and because a convincing reduction in TEN burden provides patient benefit by reducing cancer risk and/or by decreasing the need for invasive interventions. The TEN Task Force proposes several clinical trial designs that provide practical and feasible approaches to the rapid development of new agents to treat and prevent precancer. C1 Baylor Sammons Canc Ctr, US Oncol, Dallas, TX 75246 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. Ovat Pharmaceut, Lincolnshire, IL USA. Cornell Univ, Weill Med Coll, New York, NY USA. Strang Canc Prevent Ctr, New York, NY USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. CCS Associates, Mountain View, CA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Arizona, Arizona Canc Ctr, Tucson, AZ USA. British Columbia Canc Ctr, Vancouver, BC, Canada. Johns Hopkins Oncol Ctr, Baltimore, MD USA. Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Irvine, CA USA. Univ Penn, Philadelphia, PA 19104 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Texas, SW Med Ctr, Hamon Canc Ctr, Dallas, TX USA. Univ Minnesota, Minneapolis, MN USA. Dartmouth Coll Sch Med, Hanover, NH USA. Wayne State Univ, Harper Hosp, Detroit, MI USA. RP O'Shaughnessy, JA (reprint author), Baylor Sammons Canc Ctr, US Oncol, Collins 5,3535 Worth St, Dallas, TX 75246 USA. NR 329 TC 256 Z9 264 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 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB PY 2002 VL 8 IS 2 BP 314 EP 346 PG 33 WC Oncology SC Oncology GA 522QN UT WOS:000173908600003 PM 11839647 ER PT J AU Einstein, MH Cruz, Y El-Awady, MK Popescu, NC DiPaolo, JA van Ranst, M Kadish, AS Romney, S Runowicz, CD Burk, RD AF Einstein, MH Cruz, Y El-Awady, MK Popescu, NC DiPaolo, JA van Ranst, M Kadish, AS Romney, S Runowicz, CD Burk, RD TI Utilization of the human genome sequence localizes human papillomavirus type 16 DNA integrated into the TNFAIP2 gene in a fatal cervical cancer from a 39-year-old woman SO CLINICAL CANCER RESEARCH LA English DT Article ID CARCINOMA CELL-LINE; CHROMOSOME REGION 12Q14-Q15; TRANS-RETINOIC ACID; VIRAL INTEGRATION; FRAGILE SITES; RECURRENT INTEGRATION; INSITU HYBRIDIZATION; CYTOGENETIC ANALYSIS; TRANSFORMING GENES; GENITAL CARCINOMAS AB Purpose: The purpose of our study was to characterize a human papillomavirus (HPV) 16 DNA integration in the genome of a rapidly progressive, lethal cervical cancer in a 39-year-old woman. Experimental Design: An HPV 16 integration site from cervical cancer tissue was cloned and analyzed using Southern blot hybridization, nucleotide sequencing, fluorescence in situ hybridization analysis for chromosomal localization and comparison with the draft human genome sequence. Results: HPV 16 DNA (3826 lip) was integrated into the genome of the tumor sample and contained an intact upstream regulatory region and E6 and E7 open reading frames. Both 5' and 3' viral-cell junction regions contained direct repeat and palindrome sequences. The chromosomal location of the viral integration and cellular deletion was mapped to chromosome 14q32.3 using both a somatic cell hybrid panel and fluorescence in situ hybridization. Search of the draft human genome sequence confirmed the chromosomal location and revealed a disruption of the TNFAIP2 cytokine/retinoic acid-inducible gene. Conclusions: On the basis of the lack of sequence homology between the viral and cellular site of integration and the structure of the viral-cell junctions, it seems that HPV 16 DNA integrates into the host: genome by a mechanism of nonhomologous recombination. We suggest that, taken together, maintenance of E6 and E7 expression, loss of the E2 gene and disruption of the TNFAIP2 gene through viral integration contributed to the rapid progression of cervical cancer in this patient. Availability of the human genome sequence will facilitate identification of cellular genes involved in cervical cancer by high-throughput analysis of viral integration sites. C1 Montefiore Med Ctr, Albert Einstein Coll Med, Div Gynecol Oncol, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY 10461 USA. Albert Einstein Comprehens Canc Res Ctr, Bronx, NY 10461 USA. NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Montefiore Med Ctr, Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA. Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10461 USA. Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY 10461 USA. RP Burk, RD (reprint author), Albert Einstein Coll Med, Canc Res Ctr, Ullmann Room 515,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM burk@aecom.yu.edu OI El Awady, Mostafa/0000-0002-1453-763X; Dawood, Reham/0000-0003-3255-6129 NR 48 TC 18 Z9 19 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB PY 2002 VL 8 IS 2 BP 549 EP 554 PG 6 WC Oncology SC Oncology GA 522QN UT WOS:000173908600032 PM 11839676 ER PT J AU Cho, YS Kim, MK Tan, LZ Srivastava, R Agrawal, S Cho-Chung, YS AF Cho, YS Kim, MK Tan, LZ Srivastava, R Agrawal, S Cho-Chung, YS TI Protein kinase A RI alpha antisense inhibition of PC3M prostate cancer cell growth: Bcl-2 hyperphosphorylation, Bax up-regulation, and Bad-hypophosphorylation SO CLINICAL CANCER RESEARCH LA English DT Article ID CYCLIC-AMP; GENE-TRANSCRIPTION; ANTITUMOR-ACTIVITY; RESPONSE ELEMENT; OVARIAN-CANCER; MESSENGER-RNA; PHOSPHORYLATION; SUBUNIT; APOPTOSIS; EXPRESSION AB It has been shown that expression of the RIalpha subunit of cyclic AMP (cAMP)-dependent protein kinase is enhanced in human cancer cell lines, primary tumors, and cells after transformation. Using an antisense strategy, we have shown that RIalpha has a role in neoplastic cell growth in vitro and in vivo. In the present study, we have investigated the sequence- and target-specific effects of exogenous RIalpha antisense oligodeoxynucleotides (ODNs) and endogenous antisense gene on tumor growth, apoptosis, and cAMP signaling in androgen-insensitive prostate cancer cells, both in vitro and in nude mice. Here, we show that an RIalpha antisense, RNA/DNA mixed backbone ODN exerts a reduction in RIalpha expression at both the mRNA and protein levels, up-regulation of both the RIIbeta subunit of cAMP-dependent protein kinase or protein kinase A and c-AMP-phosphodiesterase IV expression, and inhibition of cell growth. Growth inhibition was accompanied by changes in cell morphology and the appearance of apoptotic nuclei. In addition, Bcl-2 hyperphosphorylation; increase in the proapoptotic proteins Bax, Bak, and Bad; and Bad hypophosphorylation occurred in the antisense-treated cells. These effects of exogenously supplied antisense ODN mirrored those induced by endogenous antisense gene overexpression. The RIalpha antisense ODNs, which differed in sequence or chemical modification, promoted a sequence- and target-specific reduction in RIalpha protein levels and inhibited tumor growth in nude mice. These results demonstrate that in a sequence-specific manner, RIalpha antisense, via efficient depletion of the growth stimulatory molecule RIalpha, induces growth inhibition, apoptosis, and phenotypic (cell morphology) changes, providing an innovative approach to combat hormone-insensitive prostate cancer cell growth. C1 NCI, Cellular Biochem Sect, Basic Res Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. Hybridon Inc, Cambridge, MA 02139 USA. RP Cho-Chung, YS (reprint author), NCI, Cellular Biochem Sect, Basic Res Lab, Ctr Canc Res,NIH, Bldg 10,Room 5B05,9000 Rockville Pike, Bethesda, MD 20892 USA. FU NCI NIH HHS [N02-BC-76212] NR 46 TC 46 Z9 48 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 FEB PY 2002 VL 8 IS 2 BP 607 EP 614 PG 8 WC Oncology SC Oncology GA 522QN UT WOS:000173908600039 PM 11839683 ER PT J AU Truccolo, WA Ding, MZ Knuth, KH Nakamura, R Bressler, SL AF Truccolo, WA Ding, MZ Knuth, KH Nakamura, R Bressler, SL TI Trial-to-trial variability of cortical evoked responses: implications for the analysis of functional connectivity SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE cerebral cortex; event-related potential; evoked response variability; effective connectivity; correlation; coherence ID VISUAL-CORTEX; NEURONAL TRANSIENTS; BRAIN ACTIVITY; SYNCHRONIZATION; MODULATION; POTENTIALS; DYNAMICS; MODEL; TASK; RECOGNITION AB Objectives: The time series of single trial cortical evoked potentials typically have a random appearance. and their trial-to-trial variability is commonly explained by a model in which random ongoing background noise activity is linearly combined with a stereotyped evoked response. In this paper, we demonstrate that more realistic models, incorporating amplitude and latency variability of the evoked response itself. can explain statistical properties of cortical potentials that have often been attributed to stimulus-related changes in functional connectivity or other intrinsic neural parameters. Methods: Implications of trial-to-trial evoked potential variability for variance. power spectrum, and interdependence measures like cross-correlation and spectral coherence, are first derived analytically. These implications are then illustrated using model simulations and verified experimentally by the analysis of intracortical local field potentials recorded from monkeys performing a visual pattern discrimination task. To further investigate the effects of trial-to-trial variability on the aforementioned statistical measures, a Bayesian inference technique is used to separate single-trial evoked responses front the ongoing background activity. Results: We show that. when the average event-related potential (AERP) is subtracted from single-trial local field potential time series, a stimulus phase-locked component remains in the residual time series, in stark contrast to the assumption of the common model that no such phase-locked component should exist. Two main consequences of this observation ire demonstrated for statistical measures that are computed on the residual time series. First, even though the AERP has been subtracted, the power spectral density, computed as a function of time with a short sliding window, can nonetheless show signs of modulation by the AERP waveform. Second, if the residual time series of two channels co-vary. then their cross-correlation and spectral coherence time functions can also be modulated according to the shape of the AERP waveform. Bayesian estimation of single-trial evoked responses provides further proof that these time-dependent statistical changes are due to remnants of the evoked phase-locked component in the residual time series. Conclusions: Because trial-to-trial variability of the evoked response is commonly ignored as a contributing factor in evoked potential studies, stimulus-related modulations of power spectral density, cross-correlation, and spectral coherence measures is often attributed to dynamic changes of the connectivity within and among neural populations. This work demonstrates that trial-to-trial variability of the evoked response must be considered as a possible explanation of such modulation. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Florida Atlantic Univ, Ctr Complex Syst & Brain Sci, Boca Raton, FL 33431 USA. Nathan S Kline Inst Psychiat Res, Ctr Adv Brain Imaging & Cognit Neurosci, Orangeburg, NY 10962 USA. Nathan S Kline Inst Psychiat Res, Schizophrenia Dept, Orangeburg, NY 10962 USA. NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Bressler, SL (reprint author), Florida Atlantic Univ, Ctr Complex Syst & Brain Sci, 777 Glades Rd, Boca Raton, FL 33431 USA. FU NIMH NIH HHS [MH42900, MH58190] NR 62 TC 119 Z9 124 U1 0 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD FEB PY 2002 VL 113 IS 2 BP 206 EP 226 AR PII S1388-2457(01)00739-8 DI 10.1016/S1388-2457(01)00739-8 PG 21 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 536FF UT WOS:000174689500004 PM 11856626 ER PT J AU Gordon, SM Brahim, J Picco, C Rowan, J Dionne, R AF Gordon, SM Brahim, J Picco, C Rowan, J Dionne, R TI Etanercept suppresses acute pain and PGE(2) at the site of injury. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NIDCR, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2002 VL 71 IS 2 BP P38 EP P38 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 527GP UT WOS:000174178600138 ER PT J AU Iadarola, MJ Martin, B Yang, H Keller, J Lewin, S Gaiser, R Mannes, A AF Iadarola, MJ Martin, B Yang, H Keller, J Lewin, S Gaiser, R Mannes, A TI Cystatin C as a biochemical marker for pain in human CSF. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NIDCR, NIH, Bethesda, MD USA. NIMH, NIH, Bethesda, MD USA. Univ Penn, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2002 VL 71 IS 2 BP P39 EP P39 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 527GP UT WOS:000174178600140 ER PT J AU Khan, AA Iadarola, M Yang, H Dionne, R AF Khan, AA Iadarola, M Yang, H Dionne, R TI Expression of cyclooxygenase-1 and-2 in acute inflammation following surgical trauma in human subjects. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA Chinese DT Meeting Abstract C1 Univ Maryland, Sch Dent, College Pk, MD 20742 USA. NIDCR, NIH, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2002 VL 71 IS 2 BP P76 EP P76 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 527GP UT WOS:000174178600274 ER PT J AU Kim, H Neubert, J Xu, K Guillot, P Iadarola, J Goldman, D Dionne, R AF Kim, H Neubert, J Xu, K Guillot, P Iadarola, J Goldman, D Dionne, R TI Evaluation of single nucleotide polymorphisms in opioid receptors and vanilloid receptor in human response to painful thermal stimulation. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NIDCR, PNMB, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2002 VL 71 IS 2 BP P35 EP P35 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 527GP UT WOS:000174178600127 ER PT J AU Lakhani, N Gordon, S Figg, W Dionne, R AF Lakhani, N Gordon, S Figg, W Dionne, R TI Absorption and adverse effects of topical thalidomide. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NCI, NIH, NIDCR, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2002 VL 71 IS 2 BP P83 EP P83 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 527GP UT WOS:000174178600301 ER PT J AU Lee, CR Pieper, JA Frye, RF Hinderliter, AL Blaisdell, JA Goldstein, JA AF Lee, CR Pieper, JA Frye, RF Hinderliter, AL Blaisdell, JA Goldstein, JA TI Assessment of CYP2C9 phenotypic : genotypic relationships with potential probes SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 Univ N Carolina, Chapel Hill, NC 27515 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2002 VL 71 IS 2 BP P25 EP P25 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 527GP UT WOS:000174178600094 ER PT J AU Mannes, AJ Brown, D Perkowski, S Keller, J Caudle, R Iadarola, M Meng, Q AF Mannes, AJ Brown, D Perkowski, S Keller, J Caudle, R Iadarola, M Meng, Q TI Measurement of resiniferatoxin in cerebrospinal fluid. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 Univ Penn, Philadelphia, PA 19104 USA. NIDCR, PPCS, NIH, Bethesda, MD USA. Univ Florida, Coll Dent, Gainesville, FL USA. NIDCR, PNB, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2002 VL 71 IS 2 BP P89 EP P89 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 527GP UT WOS:000174178600325 ER PT J AU Neubert, JK Kim, H Karai, L Iadarola, M Dionne, R AF Neubert, JK Kim, H Karai, L Iadarola, M Dionne, R TI Vanilloid receptor inactivation for preemptive analgesia. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NIDCR, PNMB, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2002 VL 71 IS 2 BP P39 EP P39 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 527GP UT WOS:000174178600141 ER PT J AU Pieper, JA Lee, CR Hinderliter, AL Clarke, MJ Blaisdell, JA Goldstein, JA AF Pieper, JA Lee, CR Hinderliter, AL Clarke, MJ Blaisdell, JA Goldstein, JA TI Effect of CYP2C9 genotype on losartan disposition. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 Univ N Carolina, Chapel Hill, NC 27515 USA. NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2002 VL 71 IS 2 BP P68 EP P68 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 527GP UT WOS:000174178600247 ER PT J AU Preston, KL Umbricht, A Schroeder, JR Abreu, M Pickworth, WB AF Preston, KL Umbricht, A Schroeder, JR Abreu, M Pickworth, WB TI Cyclazocine: Mu and kappa opioid effects and interaction with cocaine. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 Sinai Hosp, Addict Recovery Program, Baltimore, MD 21215 USA. NIDA, Intramural Res Program, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2002 VL 71 IS 2 BP P18 EP P18 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 527GP UT WOS:000174178600067 ER PT J AU Tanus-Santos, JE Rosenberg, L DeSantis, P Carlson, O Soldatov, N Yie, S Abernethy, DR AF Tanus-Santos, JE Rosenberg, L DeSantis, P Carlson, O Soldatov, N Yie, S Abernethy, DR TI Effects of the T-786C polymorphism of endothelial nitric oxide synthase (eNOS) gene on vascular relaxation. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NIA, Gerontol Res Ctr, Rockville, MD USA. RI Tanus-Santos, Jose/A-4451-2008 NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2002 VL 71 IS 2 BP P44 EP P44 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 527GP UT WOS:000174178600163 ER PT J AU Cardiff, RD AF Cardiff, RD TI Contributions of mouse biology to breast cancer research SO COMPARATIVE MEDICINE LA English DT Editorial Material ID MAMMARY-GLAND; TRANSGENIC MICE; PATHOLOGY; TUMORS; MODEL; TUMORIGENESIS; METASTASIS; ETS2 C1 Univ Calif Davis, Davis, CA 95616 USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA. NCI, Bethesda, MD 20892 USA. Baylor Coll Med, Houston, TX 77030 USA. Lawrence Natl Lab, Berkeley, CA USA. Univ Calif San Diego, San Diego, CA 92103 USA. Burnham Inst, La Jolla, CA 92037 USA. RP Cardiff, RD (reprint author), Univ Calif Davis, Davis, CA 95616 USA. NR 39 TC 18 Z9 18 U1 0 U2 1 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD FEB PY 2002 VL 52 IS 1 BP 12 EP 31 PG 20 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 527PH UT WOS:000174194200002 PM 11900409 ER PT J AU McNay, LA Tavel, JA Oseekey, K McDermott, CM Mollerup, D Bebchuk, JD AF McNay, LA Tavel, JA Oseekey, K McDermott, CM Mollerup, D Bebchuk, JD TI Regulatory approvals in a large multinational clinical trial: the ESPRIT experience SO CONTROLLED CLINICAL TRIALS LA English DT Article DE regulations; bioethics; international; clinical trials AB While accepted as serving an important function to safeguard human subjects, the process of obtaining regulatory approvals to conduct clinical trials is generally regarded as cumbersome and time-consuming. For large multinational trials, U.S. federally sponsored human subject research abroad involves specific U.S. regulatory requirements, in addition to those of the host country, that act as further hurdles. These requirements may include obtaining an Assurance of Protection for Human Subjects from the Office of Human Research Protection of the U.S. Department of Health and Human Services, maintaining specific Ethics Committee/Institutional Review Board (EC/IRB) composition, and incorporating mandated elements in informed consents, all of which may differ from local policies and guidelines. Specific examples of issues that led to delays in regulatory approvals for sites participating in the multinational clinical trial entitled Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) are presented here. While the goal of these requirements is to protect the rights and welfare of human subjects, they may create substantial delays and engender resentment over the notion of lack of respect for individual country sovereignty. Substudies within ESPRIT have been undertaken to obtain feedback from EC/IRB chairpersons, site personnel responsible for processing the required assurances, ESPRIT investigators, and study participants regarding aspects of current U.S. regulatory requirements related to human subject protection and ethical issues in multinational research. The purpose of these substudies is to compare the attitudes and experiences across countries regarding important ethical issues associated with conducting ESPRIT. One objective of the substudies is to gather additional insight to the impact of U.S. regulatory processes. Another is to help to inform the debate about how to best maximize the rights and welfare of clinical trial participants without delaying the initiation of research, while respecting the importance of national sensitivities. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NIAID, NIH, Bethesda, MD 20892 USA. Social & Sci Syst, Rockville, MD USA. HS Hvidovre Univ Hosp, Dept Infect Dis, Hvidovre, Denmark. Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. RP McNay, LA (reprint author), NIAID, NIH, 9000 Rockville Pike,Bldg 10,Room 11N223, Bethesda, MD 20892 USA. NR 5 TC 10 Z9 10 U1 0 U2 2 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 FEB PY 2002 VL 23 IS 1 BP 59 EP 66 DI 10.1016/S0197-2456(01)00183-0 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 517BA UT WOS:000173590200008 PM 11852166 ER PT J AU Hammer, JA Wu, XFS AF Hammer, JA Wu, XFS TI Rabs grab motors: defining the connections between Rab GTPases and motor proteins SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID KINESIN-RELATED PROTEIN; CLASS-V MYOSIN; SACCHAROMYCES-CEREVISIAE; MELANOSOME DISTRIBUTION; UNCONVENTIONAL MYOSIN; ACTIN CYTOSKELETON; SECRETORY VESICLES; POLARIZED DELIVERY; DILUTE MELANOCYTES; WILD-TYPE AB Rab GTPases and their effectors regulate membrane traffic by determining, along with cognate SNAREs, the specificity of transport vesicle docking and fusion steps. Recent studies have also implicated Rabs in the movement of these transport vesicles from their site of formation to their site of fusion, and several Rabs have been linked to specific microtubule- or actin-based motor proteins. Analyses of Rab and motor protein mutants, coupled with advanced imaging techniques, have led to the suggestion that certain Rabs function as essential components of the vesicle receptor for specific motor proteins. C1 NIH, Cell Biol Lab, Bethesda, MD 20892 USA. RP Hammer, JA (reprint author), NIH, Cell Biol Lab, Bldg 50,Room 2523, Bethesda, MD 20892 USA. NR 51 TC 108 Z9 110 U1 0 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD FEB PY 2002 VL 14 IS 1 BP 69 EP 75 DI 10.1016/S0955-0674(01)00296-4 PG 7 WC Cell Biology SC Cell Biology GA 510DQ UT WOS:000173193800009 PM 11792547 ER PT J AU Mousses, S Kallioniemi, A Kauraniemi, P Elkahloun, A Kallioniemi, OP AF Mousses, S Kallioniemi, A Kauraniemi, P Elkahloun, A Kallioniemi, OP TI Clinical and functional target validation using tissue and cell microarrays SO CURRENT OPINION IN CHEMICAL BIOLOGY LA English DT Review ID DENSITY OLIGONUCLEOTIDE ARRAYS; GENE-EXPRESSION PATTERNS; DRAFT HUMAN GENOME; COMPLEMENTARY-DNA; BREAST-CANCER; MOLECULAR CLASSIFICATION; RNA INTERFERENCE; PROSTATE-CANCER; CDNA MICROARRAY; COPY-NUMBER AB Expression levels of thousands of genes or proteins can be readily determined using microarray techniques. However, this represents only the first step in understanding the biological and medical significance of these molecules. New high-throughput techniques, such as tissue and cell microarrays, will facilitate clinical and functional analysis of molecular targets. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Tampere Univ Hosp, FIN-33101 Tampere, Finland. Tampere Univ, Inst Med Technol, Canc Genet Lab, FIN-33101 Tampere, Finland. RP Mousses, S (reprint author), NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. EM okalli@nhgri.nih.gov 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 44 TC 26 Z9 26 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1367-5931 J9 CURR OPIN CHEM BIOL JI Curr. Opin. Chem. Biol. PD FEB PY 2002 VL 6 IS 1 BP 97 EP 101 DI 10.1016/S1367-5931(01)00283-6 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 517VX UT WOS:000173632100016 PM 11827831 ER PT J AU Wakefield, LM Roberts, AB AF Wakefield, LM Roberts, AB TI TGF-beta signaling: positive and negative effects on tumorigenesis SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Review ID GROWTH-FACTOR-BETA; ACTIVATED PROTEIN-KINASE; CELL-CYCLE ARREST; TRANSFORMING GROWTH-FACTOR-BETA-1; C-MYC; EPITHELIAL-CELLS; TUMOR-SUPPRESSOR; SMAD PROTEINS; CANCER; PATHWAY AB TGF-beta binding to the cell surface triggers activation of multiple signal transduction pathways that are connected in intricate ways with each other, and with other response networks involved in sensing cellular information input. Recent data indicate that changes in signal intensity and connectivity of these pathways may underlie the complex transition of the TGF-beta pathway from tumor suppressor to oncogene during tumorigenesis. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Wakefield, LM (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bldg 41,Room C629,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA. NR 63 TC 581 Z9 622 U1 0 U2 16 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 FEB PY 2002 VL 12 IS 1 BP 22 EP 29 DI 10.1016/S0959-437X(01)00259-3 PG 8 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 513BF UT WOS:000173357500003 PM 11790550 ER PT J AU Bulavin, DV Amundson, SA Fornace, AJ AF Bulavin, DV Amundson, SA Fornace, AJ TI p38 and Chk1 kinases: different conductors for the G(2)/M checkpoint symphony SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Review ID DNA-DAMAGE CHECKPOINT; PROTEIN-KINASE; RADIOSENSITIZING AGENT; NUCLEAR-LOCALIZATION; UV-RADIATION; HUMAN-CELLS; CYCLIN B1; PHOSPHORYLATION; CDC25C; CAFFEINE AB The mechanism controlling G(2)/M checkpoint activation after DNA damage was thought to be mediated primarily by nuclear Chk1/Chk2 kinases. Recent evidence indicates that this checkpoint is more complex, involving at least two different biochemical systems that target the Cdc25B and Cdc25C phosphatases. Following genotoxic stress, different kinases integrate signaling from the damaged DNA and other damaged cellular components to regulate Cdc25 inactivation. Our current model for G2/M checkpoint activation after genotoxic stress is discussed emphasizing the roles for Chk1 and p38 kinases in checkpoint regulation. C1 NCI, Ctr Canc Res, Gene Response Sect, NIH, Bethesda, MD 20892 USA. RP Bulavin, DV (reprint author), NCI, Ctr Canc Res, Gene Response Sect, NIH, Bethesda, MD 20892 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 35 TC 137 Z9 143 U1 1 U2 4 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 FEB PY 2002 VL 12 IS 1 BP 92 EP 97 DI 10.1016/S0959-437X(01)00270-2 PG 6 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 513BF UT WOS:000173357500014 PM 11790561 ER PT J AU Germain, RN Harding, CV AF Germain, RN Harding, CV TI Antigen processing and recognition SO CURRENT OPINION IN IMMUNOLOGY LA English DT Editorial Material C1 NIAID, Immunol Lab, Lymphocyte Biol Sect, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. RP Germain, RN (reprint author), NIAID, Immunol Lab, Lymphocyte Biol Sect, NIH, Bldg 10,Room 11N311,10 Ctr Dr MSC-1892, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 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 FEB PY 2002 VL 14 IS 1 BP 13 EP 14 DI 10.1016/S0952-7915(01)00292-8 PG 2 WC Immunology SC Immunology GA 510DR UT WOS:000173193900001 ER PT J AU Hiltbold, EM Roche, PA AF Hiltbold, EM Roche, PA TI Trafficking of MHC class II molecules in the late secretory pathway SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID COMPLEX CLASS-II; INVARIANT CHAIN COMPLEXES; ANTIGEN-PROCESSING COMPARTMENTS; AP-3 ADAPTER COMPLEX; DENDRITIC CELLS; HLA-DR; ENDOCYTIC PATHWAY; EARLY ENDOSOMES; B-LYMPHOCYTES; LYSOSOMAL COMPARTMENTS AB Antigen presenting cells (APCs) alert the immune system to attack by extracellular organisms; APCs achieve this via internalization, degradation, and display of antigenic fragments on the cell surface by MHC class 11 molecules. These class 11 molecules bind to an accessory protein, termed the invariant chain, that ensures proper folding of the molecules. Invariant-chain binding also directs class 11 molecules to lysosomes, which are probably the most important sites for antigen loading. Endosomes are intermediates in the transport of class-II-invariant chain complexes to antigen-processing compartments, whereas trafficking of class II-peptide complexes to the membrane (and beyond) is less-well understood. Unlike other APCs, dendritic cells alter their capacity to present peptides via MHC class 11 molecules during differentiation, revealing a complex level of regulated antigen-presentation by this APC subtype. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Roche, PA (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 62 TC 70 Z9 71 U1 0 U2 5 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 FEB PY 2002 VL 14 IS 1 BP 30 EP 35 DI 10.1016/S0952-7915(01)00295-3 PG 6 WC Immunology SC Immunology GA 510DR UT WOS:000173193900004 PM 11790530 ER PT J AU Ernst, ND Cleeman, JI AF Ernst, ND Cleeman, JI TI National cholesterol education program keeps a priority on lifestyle modification to decrease cardiovascular disease risk SO CURRENT OPINION IN LIPIDOLOGY LA English DT Review AB The National Cholesterol Education Program's updated third Adult Treatment Panel report on clinical guidelines for cholesterol testing and management adds to the base of knowledge provided by two previous Adult Treatment Panel reports. Similar to the other reports, it has distinctive features and goals that are in accord with the most currently available clinical trial evidence. The major new feature of the third report is a focus on primary prevention of coronary heart disease in persons with multiple coronary heart disease risk factors. The guidelines provide the rationale for intensive cholesterol-lowering therapy in clinical management, and they provide detailed information to help inform clinical judgment for implementation of both medical nutrition management (therapeutic lifestyle changes) and drug therapy for treatment of high blood cholesterol. Curr Opin Lipidol 13:69-73. (C) 2002 Lippincott Williams Wilkins. C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Ernst, ND (reprint author), 333 Chesapeake Dr, Irvington, VA 22480 USA. NR 8 TC 19 Z9 20 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0957-9672 J9 CURR OPIN LIPIDOL JI Curr. Opin. Lipidology PD FEB PY 2002 VL 13 IS 1 BP 69 EP 73 DI 10.1097/00041433-200202000-00010 PG 5 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Peripheral Vascular Disease SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Cardiovascular System & Cardiology GA 525PV UT WOS:000174080900010 PM 11790965 ER PT J AU Fekete, DM Wu, DK AF Fekete, DM Wu, DK TI Revisiting cell fate specification in the inner ear SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID HAIR-CELLS; LUNATIC FRINGE; COMPARTMENT BOUNDARIES; OTIC PLACODE; EXPRESSION; NOTCH; GENES; DIFFERENTIATION; COCHLEA; MICE AB Generating the diversity of cell types in the inner ear may require an interplay between regional compartmentalization and local cellular interactions. Recent evidence has come from gene targeting, lineage analysis, fate mapping and gene expression studies. Notch signaling and neurogenic gene regulation are involved in patterning or specification of sensory organs, ganglion cells and hair cell mechanoreceptors. C1 Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. Natl Inst Deafness & Other Commun Disorders, Rockville, MD 20850 USA. RP Fekete, DM (reprint author), Purdue Univ, Dept Biol Sci, 1392 Lilly Hall Sci, W Lafayette, IN 47907 USA. RI Fekete, Donna/B-9170-2009 OI Fekete, Donna/0000-0003-0662-0246 NR 65 TC 179 Z9 188 U1 0 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD FEB PY 2002 VL 12 IS 1 BP 35 EP 42 DI 10.1016/S0959-4388(02)00287-8 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 520ZE UT WOS:000173813000004 PM 11861162 ER PT J AU Hall, TMT AF Hall, TMT TI Poly(A) tail synthesis and regulation: recent structural insights SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Review ID DNA-POLYMERASE-BETA; INITIATION-FACTOR 4A; RNA-BINDING DOMAINS; POLY(A)-BINDING PROTEIN; MESSENGER-RNA; CRYSTAL-STRUCTURE; U1A PROTEIN; IN-VITRO; PREMESSENGER RNA; CATALYTIC DOMAIN AB Polyadenylation at the 3' ends of mRNAs is critical to the translation and stability of the messages. Recently determined structures of poly(A) polymerase, U 1 A and domains of the poly(A)-binding protein provide a framework for understanding the synthesis and regulation of the poly(A) tail. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Hall, TMT (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233,MD F3-05, Res Triangle Pk, NC 27709 USA. NR 48 TC 20 Z9 22 U1 1 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 FEB PY 2002 VL 12 IS 1 BP 82 EP 88 AR UNSP 0959-440X/02/$ DI 10.1016/S0959-440X(02)00293-2 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 522FJ UT WOS:000173884800012 PM 11839494 ER PT J AU Roberts, AB AF Roberts, AB TI The ever-increasing complexity of TGF-beta signaling SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Roberts, AB (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bldg 41,Room C629,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA. NR 5 TC 65 Z9 71 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD FEB PY 2002 VL 13 IS 1 BP 3 EP 5 DI 10.1016/S1359-6101(01)00027-2 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 521CW UT WOS:000173822100002 PM 11750874 ER PT J AU Telford, WG Komoriya, A Packard, BZ AF Telford, WG Komoriya, A Packard, BZ TI Detection of localized caspase activity in early apoptotic cells by laser scanning cytometry SO CYTOMETRY LA English DT Article DE apoptosis; caspase; LSC ID FLUOROCHROME-LABELED INHIBITORS; FLOW-CYTOMETRY; MULTIPARAMETER ANALYSIS; ACTIVATION; DEATH; TRANSLOCATION; MITOCHONDRIAL; THYMOCYTES; BINDING; TISSUE AB Background: Caspase activation is a critical early step in the onset of apoptosis. Cell-permeable fluorogenic caspase substrates have proven valuable in detecting caspase activation by flow cytometry. Nevertheless, detection of early low-level caspase activation has been difficult using conventional area or peak fluorescence analysis by flow cytometry, despite the apparent presence of these cells as observed by microscopy. We describe a method utilizing maximum fluorescence pixel analysis by laser scanning cytometry (LSC) to detect early apoptotic cells. Methods: The PhiPhiLux-G(1)DZ caspase 3/7 substrate was used in combination with DNA dye exclusion and annexin V binding to identify several stages of apoptosis in EL4 murine thymoma cells by both traditional flow and LSC. LSC analysis of maximum pixel brightness in individual cells demonstrated an intermediate caspase-low subpopulation not detectable by flow or LSC integral analysis. LSC analysis of caspase activity was then carried out using the larger UMR-106 rat osteosarcoma cell line to determine if this apparent early caspase activity could be correlated with localized, punctate caspase activity observed by microscopy. Results: The caspase-low subpopulation found in apoptotic EL4 cells was also observable in UMR-106 cells. Relocation to cells with low fluorescence due to caspase activity and subsequent examination by microscopy demonstrated that these latter cells indeed show punctate, highly localized caspase activation foci that might represent an early stage in caspase activation. Conclusions: Cells with low-level, localized caspase expression can be detected using maximum pixel analysis by LSC. This methodology allows an early step of apoptotic activation to be resolved for further analysis. Cytometry 47:81-88, 2002. (C) 2002 Wiley-Liss, Inc. C1 NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. OncoImmunin Inc, Gaithersburg, MD USA. RP NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Med Branch Bldg 10 Room 12N226,9000 Rockville Pik, Bethesda, MD 20892 USA. EM telfordw@box-t.nih.gov NR 27 TC 45 Z9 49 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-4763 J9 CYTOMETRY JI Cytometry PD FEB 1 PY 2002 VL 47 IS 2 BP 81 EP 88 DI 10.1002/cyto.10052 PG 8 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 519AE UT WOS:000173700600001 PM 11813197 ER PT J AU Tanaka, TS Ikenishi, K AF Tanaka, TS Ikenishi, K TI Possible role of the 38 kDa protein, lacking in the gastrula-arrested Xenopus mutant, in gastrulation SO DEVELOPMENT GROWTH & DIFFERENTIATION LA English DT Article DE gastrula-arrested mutant; 38 kDa protein; perturbation experiment with an antibody; Xenopus ID CELL-MIGRATION; HOMEOBOX GENE; LAEVIS; EMBRYOS; FIBRONECTIN; MESODERM; EXPRESSION; ANTIBODIES; INDUCTION; DIFFERENTIATION AB An acidic, 38 kDa protein that is present in Xenopus wild-type embryos has been previously shown to be lacking in gastrula-arrested mutant embryos. To gain understanding of the role of this protein, its spatio-temporal distribution and involvement in gastrulation was investigated using the monoclonal antibody (9D10) against it. The protein was prominent in the cortical cytoplasm of cells facing the outside in the animal hemisphere of embryos until the gastrula stage, and in ciliated epithelial cells of embryos at stages later than the late neurula. When the 9D10 antibody was injected into fertilized wild-type eggs, they cleaved normally, but most of them had arrested development, always at the early stage of gastrulation, as in the mutant embryos. In contrast, the majority of the control anti body-injected eggs gastrulated normally and developed further. Cytoskeletal F-actin, which was mainly observed in the area beneath the plasma membrane facing the outside of the epithelial layer of not only the dorsal involuting marginal zone but also the dorsal, vegetal cell mass of the control anti body-injected embryos at the early gastrula stage, was scarcely recognized in the corresponding area of the 9D10 antibody-injected embryos. It is likely that the paucity of the F-actin caused by the 9D10 antibody inhibition of the 38kDa protein might lead to a failure of cell movement in gastrulation, resulting in developmental arrest. C1 Osaka City Univ, Grad Sch Sci, Dept Biol Funct, Osaka 5588585, Japan. NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Ikenishi, K (reprint author), Osaka City Univ, Grad Sch Sci, Dept Biol Funct, 3-3-138 Sugimoto, Osaka 5588585, Japan. NR 52 TC 4 Z9 4 U1 1 U2 1 PU BLACKWELL PUBLISHING ASIA PI CARLTON PA 54 UNIVERSITY ST, P O BOX 378, CARLTON, VICTORIA 3053, AUSTRALIA SN 0012-1592 J9 DEV GROWTH DIFFER JI Dev. Growth Diff. PD FEB PY 2002 VL 44 IS 1 BP 23 EP 33 PG 11 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 551KB UT WOS:000175558900003 PM 11869289 ER PT J AU Azuma, Y Dasso, M AF Azuma, Y Dasso, M TI A new clue at the nuclear pore: RanBP2 is an E3 enzyme for SUMO1 SO DEVELOPMENTAL CELL LA English DT Editorial Material ID UBIQUITIN; PROTEIN AB A recent paper in Cell shows that the large nucleoporin RanBP2 can act as an E3 enzyme for the ubiquitin-like protein SUMO1. These intriguing results raise important questions about the mechanism of SUMO1 conjugation, the relationship of SUMO1 to nuclear transport, and the regulation of RanBP2 in the pore. C1 NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Azuma, Y (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Room 106,Bldg 18, Bethesda, MD 20892 USA. NR 9 TC 20 Z9 20 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD FEB PY 2002 VL 2 IS 2 BP 130 EP 131 DI 10.1016/S1534-5807(02)00124-7 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 546XQ UT WOS:000175302000004 PM 11832237 ER PT J AU Kim, SJ Mitra, D Salerno, JR Hegde, RS AF Kim, SJ Mitra, D Salerno, JR Hegde, RS TI Signal sequences control gating of the protein translocation channel in a substrate-specific manner SO DEVELOPMENTAL CELL LA English DT Article ID ENDOPLASMIC-RETICULUM MEMBRANE; RECOGNITION PARTICLE; PRION PROTEIN; ER MEMBRANE; SECRETORY PROTEINS; CRYSTAL-STRUCTURE; CALRETICULIN; TRANSPORT; UBIQUITINATION; ENVIRONMENT AB N-terminal signal sequences mediate targeting of nascent chains to the endoplasmic reticulum and facilitate opening of the protein translocation channel to the passage of substrate. We have assessed each of these steps for a diverse set of mammalian signals. While minimal differences were seen in their targeting function, signal sequences displayed a remarkable degree of variation in initiating nascent chain access to the lumenal environment. Such substrate-specific properties of signals were evolutionarily conserved, functionally matched to their respective mature domains, and important for the proper biogenesis of some proteins. Thus, the sequence variations of signals do not simply represent functional degeneracy, but instead encode critical differences in translocon gating that are coordinated with their respective passengers to facilitate efficient translocation. C1 NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Hegde, RS (reprint author), NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. NR 40 TC 72 Z9 74 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD FEB PY 2002 VL 2 IS 2 BP 207 EP 217 DI 10.1016/S1534-5807(01)00120-4 PG 11 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 546XQ UT WOS:000175302000013 PM 11832246 ER PT J AU Vozarova, B Weyer, C Lindsay, RS Pratley, RE Bogardus, C Tataranni, PA AF Vozarova, B Weyer, C Lindsay, RS Pratley, RE Bogardus, C Tataranni, PA TI High white blood cell count is associated with a worsening of insulin sensitivity and predicts the development of type 2 diabetes SO DIABETES LA English DT Article ID INNATE IMMUNE-SYSTEM; MIDDLE-AGED ADULTS; PIMA-INDIANS; RISK-FACTORS; SECRETORY DYSFUNCTION; ATHEROSCLEROSIS RISK; LEUKOCYTE COUNT; RESISTANCE; MELLITUS; INFLAMMATION AB Chronic low-grade inflammation may be involved in the pathogenesis of insulin resistance and type 2 diabetes. We examined whether a high white blood cell count (WBC), a marker of inflammation, predicts a worsening of insulin action, insulin secretory function, and the development of type 2 diabetes in Pima Indians. We measured WBC in 352 nondiabetic Pima Indians (215 men and 137 women, aged 27 +/- 6 years [means +/- SD], body fat 32 +/- 8%, WBC 8,107 +/- 2,022 cells/mm(3)) who were characterized for body composition (by hydrodensitometry or dual-energy X-ray absorptiometry), glucose tolerance (by 75-g oral glucose tolerance test), insulin action (M; by hyperinsulinemic clamp), and acute insulin secretory response (AIR; by 25-g intravenous glucose challenge). Among 272 subjects who were normal glucose tolerant (NGT) at baseline, 54 developed diabetes over an average follow-up of 5.5 +/- 4.4 years. Among those who remained nondiabetic, 81 subjects had follow-up measurements of M and AIR. Cross-sectionally, WBC was related to percent body fat (r = 0.32, P < 0.0001) and M (r = -0.24, P < 0.0001), but not to AIR (r = 0.06, P = 0.4). In a multivariate analysis, when adjusted for age and sex, both percent body fat (P < 0.0001) and M (P = 0.03) were independently associated with WBC. A high WBC value predicted diabetes (relative hazard 90th vs. 10th percentiles [95%CI] of 2.7 [1.3-5.4], P = 0.007) when adjusted for age and sex. The predictive effect of WBC persisted after additional adjustment for established predictors of diabetes, i.e., percent body fat, M, and AIR (relative hazard 2.6 [1.1-6.2], P = 0.03). After adjustment for follow-up duration, a high WBC at baseline was associated with a subsequent worsening of M (P = 0.003), but not a worsening of AIR. A high WBC predicts a worsening of insulin action and the development of type 2 diabetes in Pima Indians. These findings are consistent with the hypothesis that a chronic activation of the immune system may play a role in the pathogenesis of type 2 diabetes. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. RP Vozarova, B (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16Th St,Rm 5-41, Phoenix, AZ 85016 USA. OI de Courten, Barbora/0000-0001-8760-2511 NR 30 TC 232 Z9 245 U1 3 U2 14 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2002 VL 51 IS 2 BP 455 EP 461 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 516HU UT WOS:000173548500025 PM 11812755 ER PT J AU Bogardus, C Tataranni, PA AF Bogardus, C Tataranni, PA TI Reduced early insulin secretion in the etiology of type 2 diabetes mellitus in Pima Indians SO DIABETES LA English DT Article; Proceedings Paper CT 2nd Servier-IGIS Symposium CY MAR 22-24, 2001 CL ST JEAN CAP FERRAT, FRANCE ID DYSFUNCTION; RESISTANCE AB We report the results of cross-sectional, prospective, and longitudinal studies identifying etiologic metabolic factors in the susceptibility to type 2 diabetes mellitus of the Pima Indians of Arizona, whose prevalence and incidence rates of the disease are the highest in the world. Diabetic Pima Indians axe metabolically prototypic, with obesity, insulin resistance, a reduced acute insulin response to glucose, and increased endogenous glucose production. Cross-sectional studies show that the acute insulin response is absent in diabetic subjects and lower in impaired than in normal glucose-tolerant subjects. Prospective studies using proportional hazards analyses indicate that insulin resistance and a relatively low acute insulin response predict diabetes independently of age, gender, and each other, with obesity increasing susceptibility by worsening one or both predictors. Longitudinal studies show that glucose tolerance deteriorates as the degree of obesity increases due to worsening insulin resistance and decreases in early insulin secretion. Furthermore, since the children of diabetic pregnancies are at much greater risk of developing diabetes at a young age than those of nondiabetic pregnancies, the diabetic uterine environment may induce insulin resistance and/or reduced insulin secretion: early evidence confirms that adult normal glucose-tolerant offspring show a substantially decreased acute insulin response-the clearest demonstration yet of an environmental condition increasing susceptibility to type 2 diabetes mellitus. However, the genetic determinants require elucidation: correlation of the acute insulin response with the age of parental diabetes onset in fathers as well as mothers indicates a mechanism independent of the diabetic uterine environment. Diabetes 51 (Suppl. 1):S262-5264, 2002. C1 Natl Inst Diabet & Digest & Kidney Diseases, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. RP Bogardus, C (reprint author), Natl Inst Diabet & Digest & Kidney Diseases, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. NR 8 TC 27 Z9 28 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 FEB PY 2002 VL 51 SU 1 BP S262 EP S264 DI 10.2337/diabetes.51.2007.S262 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 517FF UT WOS:000173599900042 PM 11815490 ER PT J AU Harris, MI AF Harris, MI TI Effect of private health insurance on health care access and health status of diabetic patients covered by medicare SO DIABETES CARE LA English DT Letter C1 NIDDK, Bethesda, MD USA. RP Harris, MI (reprint author), 6707 Democracy Blvd,Room 695, Bethesda, MD 20892 USA. NR 1 TC 3 Z9 3 U1 1 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2002 VL 25 IS 2 BP 405 EP 406 DI 10.2337/diacare.25.2.405-a PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 515XU UT WOS:000173522600033 PM 11815524 ER PT J AU Kearns, DN Weiss, SJ Panlilio, LV AF Kearns, DN Weiss, SJ Panlilio, LV TI Conditioned suppression of behavior maintained by cocaine self-administration SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE conditioned suppression; cocaine self-administration; stimulus compounding; aversive stimuli; rats ID STRESS-INDUCED RELAPSE; APPETITIVE-AVERSIVE INTERACTIONS; SEEKING BEHAVIOR; INDUCED REINSTATEMENT; CUE REACTIVITY; RATS; STIMULI; CORTICOSTERONE; HEROIN; EXTINCTION AB Shock-paired stimuli have produced conditioned suppression of behavior maintained by a variety of reinforcers such as food, water, sucrose, and intracranial self-stimulation. With the ongoing pursuit of animal models for drug abuse treatment, it is surprising that this procedure for suppressing positively reinforced behavior has never been applied to drug-maintained behavior. The present study applied the conditioned suppression paradigm to behavior maintained by cocaine self-administration in rats. If shock-paired stimuli suppress ongoing cocaine self-administration, this would contrast with recent studies reporting that aversive stimuli can enhance the acquisition and reinstatement of behavior reinforced by cocaine. Rats were trained to bar-press for intravenous cocaine infusions on a variable-interval schedule. Then, a tone conditioned stimulus (CS) and a light CS were each paired with foot-shock while the rats were bar-pressing for cocaine. These CSs each came to reliably suppress responding in all subjects, just as shock-paired CSs suppressed responding by the positive reinforcers mentioned above. When the tone and the light were presented simultaneously in testing, suppression was significantly enhanced over that controlled by the single CSs. These results demonstrate that (1) cocaine-maintained behavior can be suppressed by environmental stimuli associated with non-drug reinforcers; and (2) combining stimuli that decrease drug self-administration can enhance their suppressive effects. Thus, the present findings can have implications for drug treatment. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 American Univ, Dept Psychol, Washington, DC 20016 USA. NIDA, Preclin Pharmacol Sect, Baltimore, MD 21224 USA. RP Kearns, DN (reprint author), American Univ, Dept Psychol, 4400 Massachusetts Ave NW, Washington, DC 20016 USA. FU NIDA NIH HHS [DA-08651] NR 68 TC 15 Z9 15 U1 2 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD FEB 1 PY 2002 VL 65 IS 3 BP 253 EP 261 DI 10.1016/S0376-8716(01)00167-3 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 521DK UT WOS:000173823400007 PM 11841897 ER PT J AU Kakizaki, S Karami, S Negishi, M AF Kakizaki, S Karami, S Negishi, M TI Retinoic acids repress constitutive active receptor-mediated induction by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene of the CYP2B10 gene in mouse primary hepatocytes SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID CAR; EXPRESSION AB The nuclear orphan receptor constitutive active receptor (CAR) can be activated to induce CYP2B genes by the potent phenobarbital-type inducer 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in which the receptor forms a heterodimer with the retinoid X receptor (RXR) and binds to a conserved enhancer element NR1. Effects of retinoic acids on the activation of CAR were examined. Treatment with 9-cis- or all-trans-retinoic acid markedly repressed TCPOBOP induction of CYP2B10 mRNA in mouse primary hepatocytes. Both retinoic acids also repressed TCPOBOP-induced NR1 enhancer activity in both transfected hepatocytes and HepG2 cells. Moreover, coexpression of the retinoic acid receptor (RAR) increased the repression in the cotransfected HepG2 cells, whereas that of RXR decreased the repression. Thus, the increased heterodimerization of RXR with RAR by retinoic acid treatment seemed to reduce the RXR available for CAR heterodimerization, resulting in the repression of CAR activity. This type of nuclear receptor signaling may play an important role as a modulator in the CYP2B regulation. C1 NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Kakizaki, S (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 12 TC 13 Z9 17 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD FEB PY 2002 VL 30 IS 2 BP 208 EP 211 DI 10.1124/dmd.30.2.208 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 515VZ UT WOS:000173518500017 PM 11792692 ER PT J AU Mulatu, MS AF Mulatu, MS TI Psychometric properties of scores on the preliminary Amharic version of the State-Trait Anxiety Inventory in Ethiopia SO EDUCATIONAL AND PSYCHOLOGICAL MEASUREMENT LA English DT Article ID SEX-DIFFERENCES AB Psychometric properties of scores on the Amharic version of the State-Trait Anxiety Inventory (STAI-A) were explored with 551 students in Ethiopia. Results show strong correlations (r[62] greater than or equal to .89) between the corresponding scores on State Anxiety (SA) and Trait Anxiety (TA) scales of the STAI-A and the original STAI. High levels of internal consistency reliabilities (alphas greater than or equal to .85) and moderately high median item-remainder correlations (rs greater than or equal to .47) were found for scores on the two scales of STAI-A. As predicted, SA scores were higher on a hypothetical exam condition than on a normal condition. SA scores were also more strongly correlated with life event stress scores than were TA scores. TA scores, in turn, were more strongly related to global psychopathology scores than were SA scores. These findings suggest that scores on STAI-A have acceptable reliability and validity and that STAI-A can be used for clinical and research purposes in Ethiopia. C1 NIMH, Sect SocioEnvironm Studies, Bethesda, MD 20892 USA. RP Mulatu, MS (reprint author), NIMH, Sect SocioEnvironm Studies, Fed Bldg Room B1A-14, Bethesda, MD 20892 USA. NR 27 TC 3 Z9 4 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0013-1644 J9 EDUC PSYCHOL MEAS JI Educ. Psychol. Meas. PD FEB PY 2002 VL 62 IS 1 BP 130 EP 146 DI 10.1177/0013164402062001009 PG 17 WC Psychology, Educational; Mathematics, Interdisciplinary Applications; Psychology, Mathematical SC Psychology; Mathematics GA 509WR UT WOS:000173173300009 ER PT J AU Sanders, JM Cunningham, ML AF Sanders, JM Cunningham, ML TI Determination of tamoxifen and metabolites in mouse fetal tissue using nonaqueous capillary electrophoresis SO ELECTROPHORESIS LA English DT Article DE antiestrogen; metabolism; nonaqueous capillary electrophoresis; tamoxifen ID BREAST-CANCER; BUFFER SYSTEM; CHEMOPREVENTION; INDUCTION; RAT AB Tamoxifen (TAM), an antiestrogen, has been approved for use by women at risk for developing hormone-dependent breast cancer. Administration of TAM to pregnant CD-1 mice apparently results in reproductive tract toxicity in female offspring. However, there is little or no data describing potential TAM-induced fetal toxicity to women who may become pregnant while receiving prophylactic TAM treatment. In support of the National Toxicology Program's characterization of reproductive and developmental effects of TAM, the present work describes a capillary electrophoresis (CE)-based analytical technique used for detection of TAM and two major metabolites, N-desmethyltarnoxifen (DMT), and 4-hydroxytamoxifen (4-HT) in CD-1 mouse fetal tissue. TAM-derived material was extracted from CD-1 mouse fetuses 2-12 h following TAM administration (100 mg/kg) to dams on gestation day 16. The presence of TAM, DMT, and 4-HT was confirmed in the solvent extracts by nonaqueous CE. The limit of detection of TAM by UV absorption was approximately 675 amol at a signal-to-noise ratio of 2:1. This work demonstrates both transplacental transport of TAM in CD-1 mice and a sensitive analytical technique for detecting low concentrations of TAM and similar compounds in biological tissues. C1 Natl Inst Environm Hlth Sci, Natl Toxicol Program, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Sanders, JM (reprint author), Natl Inst Environm Hlth Sci, Natl Toxicol Program, Lab Pharmacol & Chem, MD C3-02 POB 12233, Res Triangle Pk, NC 27709 USA. EM sandersm@niehs.nih.gov NR 15 TC 10 Z9 12 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD FEB PY 2002 VL 23 IS 3 BP 502 EP 505 DI 10.1002/1522-2683(200202)23:3<502::AID-ELPS502>3.0.CO;2-S PG 4 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 527EQ UT WOS:000174174100020 PM 11870753 ER PT J AU Li, BS Zhang, L Takahashi, S Ma, W Jaffe, H Kulkarni, AB Pant, HC AF Li, BS Zhang, L Takahashi, S Ma, W Jaffe, H Kulkarni, AB Pant, HC TI Cyclin-dependent kinase 5 prevents neuronal apoptosis by negative regulation of c-Jun N-terminal kinase 3 SO EMBO JOURNAL LA English DT Article DE apoptosis; cdk5; c-Jun; JNK; phosphorylation ID DEVELOPING NERVOUS-SYSTEM; PROGRAMMED CELL-DEATH; PROTEIN-KINASE; SYMPATHETIC NEURONS; ACTIVATION DOMAIN; CDC2-LIKE KINASE; MICE LACKING; PHOSPHORYLATION; STRESS; CDK5 AB Cyclin-dependent kinase 5 (cdk5) is a serine/threonine kinase activated by associating with its neuron-specific activators p35 and p39. Analysis of cdk5(-/-) and p35(-/-) mice has demonstrated that both cdk5 and p35 are essential for neuronal migration, axon pathfinding and the laminar configuration of the cerebral cortex, suggesting that the cdk5-p35 complex may play a role in neuron survival. However, the targets of cdk5 that regulate neuron survival are unknown. Here, we show that cdk5 directly phosphorylates c-Jun N-terminal kinase 3 (JNK3) on Thr131 and inhibits its kinase activity, leading to reduced c-Jun phosphorylation. Expression of cdk5 and p35 in HEK293T cells inhibits c-Jun phosphorylation induced by UV irradiation. These effects can be restored by expression of a catalytically inactive mutant form of cdk5. Moreover, cdk5-deficient cultured cortical neurons exhibit increased sensitivity to apoptotic stimuli, as well as elevated JNK3 activity, and c-Jun phosphorylation. Taken together, these findings show that cdk5 may exert its role as a key element by, negatively, regulating the c-Jun N-terminal kinase/stress-activated protein kinase signaling pathway during neuronal apoptosis. C1 NINCDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NIMH, Behav & Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIDCR, Funct Genom Unit, Gene Targeting Facil, NIH, Bethesda, MD 20892 USA. USN, Ctr Biomol Sci & Engn, Res Lab, Washington, DC 20375 USA. RP Pant, HC (reprint author), NINCDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NR 65 TC 105 Z9 110 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD FEB 1 PY 2002 VL 21 IS 3 BP 324 EP 333 DI 10.1093/emboj/21.3.324 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 521WV UT WOS:000173865100014 PM 11823425 ER PT J AU Horowitz, DS Lee, EJ Mabon, SA Misteli, T AF Horowitz, DS Lee, EJ Mabon, SA Misteli, T TI A cyclophilin functions in pre-mRNA splicing SO EMBO JOURNAL LA English DT Article DE cyclophilin; cyclosporin A; hPrp4; hPrp18; pre-mRNA splicing ID CRYSTAL-STRUCTURE; CYCLOSPORINE-A; 90KD PROTEINS; IN-VIVO; RNA; COMPLEX; DOMAIN; SPLICEOSOME; MECHANISM; IDENTIFICATION AB We report that the cyclophilin USA-CyP is part of distinct complexes with two spliceosomal proteins and is involved in both steps of pre-mRNA splicing. The splicing factors hPrp18 and hPrp4 have a short region of homology that defines a high affinity binding site for USA-CyP in each protein. USA-CyP forms separate, stable complexes with hPrp18 and hPrp4 in which the active site of the cyclophilin is exposed. The cyclophilin inhibitor cyclosporin A slows pre-mRNA splicing in vitro, and we show that its inhibition of the second step of splicing is caused by blocking the action of USA-CyP within its complex with hPrp18. Cyclosporin A also slows splicing in vivo, and we show that this slowing results specifically from inhibition of USA-CyP. Our results lead to a model in which USA-CyP is carried into the spliceosome in complexes with hPrp4 and hPrp18, and USA-CyP acts during splicing within these complexes. These results provide an example of the function of a cyclophilin in a complex process and provide insight into the mechanisms of action of cyclophilins. C1 Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Horowitz, DS (reprint author), Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA. FU NIGMS NIH HHS [GM57267, R01 GM057267] NR 37 TC 70 Z9 74 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD FEB 1 PY 2002 VL 21 IS 3 BP 470 EP 480 DI 10.1093/emboj/21.3.470 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 521WV UT WOS:000173865100028 PM 11823439 ER PT J AU Schwan, TG Piesman, J AF Schwan, TG Piesman, J TI Vector interactions and molecular adaptations of Lyme disease and relapsing fever spirochetes associated with transmission by ticks SO EMERGING INFECTIOUS DISEASES LA English DT Article ID OUTER-SURFACE-PROTEIN; BORRELIA-BURGDORFERI TRANSMISSION; IXODES-DAMMINI; DIFFERENTIAL EXPRESSION; ANTIGENIC VARIATION; SALIVARY-GLANDS; MICE; SCAPULARIS; GROWTH; OSPC AB Pathogenic spirochetes in the genus Borrelia are transmitted primarily by two families of ticks. The Lyme disease spirochete, Borrelia burgdorferi, is transmitted by the slow-feeding ixodid tick Ixodes scapularis, whereas the relapsing fever spirochete, B. hermsii, is transmitted by Ornithodoros hermsi, a fast-feeding argasid tick. Lyme disease spirochetes are generally restricted to the midgut in unfed I. scapularis. When nymphal ticks feed, the bacteria pass through the hemocoel to the salivary glands and are transmitted to a new host in the saliva after 2 days. Relapsing fever spirochetes infect the midgut in unfed O. hermsi but persist in other sites including the salivary glands. Thus, relapsing fever spirochetes are efficiently transmitted in saliva by these fast-feeding ticks within minutes of their attachment to a mammalian host. We describe how B. burgdorferi and B. hermsii change their outer surface during their alternating infections in ticks and mammals, which in turn suggests biological functions for a few surface-exposed lipoproteins. C1 Ctr Dis Control & Prevent, Ft Collins, CO USA. NIH, Hamilton, MT USA. RP Schwan, TG (reprint author), NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, 903 S 4th St, Hamilton, MT 59840 USA. NR 55 TC 81 Z9 84 U1 1 U2 8 PU CENTER DISEASE CONTROL PI ATLANTA PA ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD FEB PY 2002 VL 8 IS 2 BP 115 EP 121 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 520AM UT WOS:000173757800001 PM 11897061 ER PT J AU Pandey, SK He, HJ Chesley, A Juhaszova, M Crow, MT Bernier, M AF Pandey, SK He, HJ Chesley, A Juhaszova, M Crow, MT Bernier, M TI Wortmannin-sensitive pathway is required for insulin-stimulated phosphorylation of inhibitor kappa B alpha SO ENDOCRINOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; PROTEIN-KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOINOSITIDE 3-KINASE; SIGNAL-TRANSDUCTION; DNA-BINDING; IN-VITRO; ACTIVATION; DEGRADATION; CELLS AB The aim of this study was to examine the signaling pathways by which insulin promotes activation of nuclear factor KB (NFKB) through the regulation of inhibitor KBalpha (IKBalpha). We show here that although insulin increased KB-dependent reporter gene expression and augmented nuclear translocation of the p65/RelA subunit of NFKB and its DNA binding, it was able to induce a time-dependent accumulation of phosphorylated and ubiquitinated IKBalpha without its proteolytic degradation. In contrast, cell stimulation with the cytokine TNFalpha allowed activation of NFKB through phosphorylation, ubiquitination, and subsequent degradation of IKBalpha. Immunofluorescence studies revealed the presence of a large pool of phosphorylated IKBalpha in the nucleus of unstimulated and insulin-treated cells. IKB kinase alpha and beta, central players in the phosphorylation of IKBalpha, were rapidly induced following exposure to TNFalpha but not insulin. Furthermore, insulin-stimulated IKBalpha phosphorylation did not depend on activation of the Ras/ERK cascade. Expression of a dominant-negative mutant of Akt1 or class I PI3K inhibited the insulin stimulation of PI3K/Akt1 signaling without affecting phosphorylation of IKBalpha. Interestingly, the PI3K inhibitors wortmannin and LY294002 blocked insulin-stimulated class I PI3K-dependent events at much lower doses than that required to inhibit phosphorylation of IKBalpha. These data demonstrate that insulin regulates IKBalpha function through a distinct low-affinity wortmannin-sensitive pathway. C1 NIA, Clin Invest Lab, Diabet Sect, NIH, Baltimore, MD 21224 USA. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. NIA, Res Resource Branch, NIH, Baltimore, MD 21224 USA. RP Bernier, M (reprint author), NIA, Clin Invest Lab, Diabet Sect, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Bernier, Michel/0000-0002-5948-368X NR 56 TC 10 Z9 10 U1 0 U2 2 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2002 VL 143 IS 2 BP 375 EP 385 DI 10.1210/en.143.2.375 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 514KA UT WOS:000173437000006 PM 11796489 ER PT J AU Zivadinovic, D Tomic, M Yuan, D Stojilkovic, SS AF Zivadinovic, D Tomic, M Yuan, D Stojilkovic, SS TI Cell-type specific messenger functions of extracellular calcium in the anterior pituitary SO ENDOCRINOLOGY LA English DT Article ID THYROTROPIN-RELEASING-HORMONE; SENSING RECEPTOR; GROWTH-HORMONE; PROLACTIN SECRETION; CA2+ OSCILLATIONS; ACTION-POTENTIALS; RAT LACTOTROPES; NERVE-TERMINALS; CHANNELS; EXPRESSION AB Calcium can serve not only as an intracellular messenger, but also as an extracellular messenger controlling the gating properties of plasma membrane channels and acting as an agonist for G protein-coupled Ca2+-sensing receptors. Here we studied the potential extracellular messenger functions of this ion in anterior pituitary cells. Depletion and repletion of the extracellular Ca2+ concentration ([Ca2+](e)) induced transient elevations in the intracellular Ca2+ concentration ([Ca2+](i)), and elevations in [Ca2+](e) above physiological levels decreased [Ca2+](i) in somatotrophs and lactotrophs, but not in gonadotrophs. The amplitudes and duration of [Ca2+](i) responses depended on the [Ca2+](e) and its rate of change, which resulted exclusively from modulation of spontaneous voltage-gated Ca2+ influx. Changes in [Ca2+](e) also affected GH and PRL secretion. The PRL secretory profiles paralleled the [Ca2+](i) profiles in lactotrophs, whereas GH secretion was also stimulated by [Ca2+](e) independently of the status of voltage-gated Ca2+ influx. [Ca2+](e) modulated GH secretion in a dose-dependent manner, with EC50 values of 0.75 and 2.25 mM and minimum secretion at about 1.5 mM. In a parallel experiment, cAMP accumulation progressively increased with elevation of [Ca2+](e,) whereas inositol phosphate levels were not affected. These results indicate the cell type-specific role of [Ca2+](e) in the control of Ca2+ signaling and secretion. C1 NICHHD, Sect Cellular Signaling, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Stojilkovic, SS (reprint author), NICHHD, Sect Cellular Signaling, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. RI Tomic, Melanija/C-3371-2016 NR 46 TC 17 Z9 17 U1 0 U2 0 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2002 VL 143 IS 2 BP 445 EP 455 DI 10.1210/en.143.2.445 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 514KA UT WOS:000173437000014 PM 11796497 ER PT J AU Lin, KH Wang, WJ Wu, YH Cheng, SY AF Lin, KH Wang, WJ Wu, YH Cheng, SY TI Activation of antimetastatic Nm23-H1 gene expression by estrogen and its alpha-receptor SO ENDOCRINOLOGY LA English DT Article ID NUCLEOSIDE DIPHOSPHATE KINASE; BREAST-CANCER-CELLS; DOMINANT-NEGATIVE ACTIVITY; THYROID-HORMONE RECEPTOR; RETINOID-X RECEPTOR; HEPATOCELLULAR-CARCINOMA; RESPONSE ELEMENTS; TUMOR-METASTASIS; DNA-BINDING; SUPPRESSOR AB Metastasis of various malignant cells is inversely related to the abundance of the Nm23-H1 protein. The role of estrogens in tumor metastasis has now been investigated by examining the effect of E2 on the expression of the Nm23-H1 gene. Three human breast carcinoma cell lines, in which endogenous ERalpha is expressed at different levels, were used as a tool to assess the role of ERalpha in Nm23-H1 gene-mediated metastasis. E2 induced time-dependent increases in the abundance of Nm23-H1 mRNA and protein, with the extent of these effects correlating with the level of expression of ERalpha. E2 induced a marked decrease in the invasive activity of MCF-7 and BT-474 cells but had no effect on BCM-1 cells, which had virtually no ERalpha. Consistent with these results, the ER-mediatedNm23-H1 promoter activity was inhibited 3-fold by the E2 antagonist, ICI 182,780. Deletion analysis of the promoter region of the Nm23-H1 gene identified a positive estrogen-responsive element located in -108/-94. ER protein bound specifically to the -108/-79 fragment with high avidity. These results indicate that E2, acting through ERalpha, activated transcription of the Nm23-H1 gene via a positive estrogen-responsive element in the promoter region of the gene. These results suggest that E2 could suppress tumor metastasis by activating the expression of the Nm23-H1 gene. C1 Chang Gung Univ, Dept Biochem, Tao Yuan, Taiwan. NCI, Gene Regulat Sect, Lab Mol Biol, Combined Canc Res Ctr, Bethesda, MD 20892 USA. RP Lin, KH (reprint author), Chang Gung Univ, Dept Biochem, Tao Yuan, Taiwan. NR 52 TC 48 Z9 51 U1 0 U2 2 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2002 VL 143 IS 2 BP 467 EP 475 DI 10.1210/en.143.2.467 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 514KA UT WOS:000173437000016 PM 11796500 ER PT J AU Goehl, TJ AF Goehl, TJ TI Reviews in environmental health, 2002 - Introduction SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material ID TWINS C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Goehl, TJ (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 23 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 FEB PY 2002 VL 110 SU 1 BP 1 EP 2 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 538BV UT WOS:000174794900001 ER PT J AU Liu, J Zheng, BS Aposhian, HV Zhou, YS Chen, ML Zhang, AH Waalkes, MP AF Liu, J Zheng, BS Aposhian, HV Zhou, YS Chen, ML Zhang, AH Waalkes, MP TI Chronic arsenic poisoning from burning high-arsenic-containing coal in Guizhou, China SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material DE arsenic; ascites; cirrhosis; coal; food contamination; hepatomegaly; liver cancer; skin cancer ID I/II NULL MICE; NEPHROTOXICITY; CADMIUM; HEALTH AB Arsenic is an environmental hazard and the reduction of drinking water arsenic levels is under consideration. People are exposed to arsenic not only through drinking water but also through arsenic-contaminated air and food. Here we report the health effects of arsenic exposure from burning high arsenic-containing coal in Guizhou, China. Coal in this region ha's undergone mineralization and thus produces high concentrations of arsenic. Coal is burned inside the home in open pits for daily cooking and crop drying, producing a high concentration of arsenic in indoor air. Arsenic in the air coats and permeates food being dried producing high concentrations in Food; however, arsenic concentrations in the drinking water are in the normal range. The estimated sources of total arsenic exposure in this area are from arsenic-contaminated food (50-80%), air (10-20%), water (1-5%), and direct contact in coal-mining workers (1%). At least 3,000 patients with arsenic poisoning were found in the Southwest Prefecture of Guizhou, and approximately 200,000 people are at risk for such overexposures. Skin lesions are common, including keratosis of the hands and feet, pigmentation on the trunk, skin ulceration, and skin cancers. Toxicities to internal organs, including lung dysfunction, neuropathy, and nephrotoxicity, are clinically evident. The prevalence of hepatomegaly was 20%, and cirrhosis, ascites, and liver cancer are the most serious outcomes of arsenic poisoning. The Chinese government and international organizations are attempting to improve the house conditions and the coal source, and thereby protect human health in this area. C1 NIEHS, Inorgan Carcinogenesis Sect, NCI, Comparat Carcinogenesis Lab, Res Triangle Pk, NC 27713 USA. Acad Sinica, Inst Geochem, Guiyang 550002, Peoples R China. Univ Arizona, Dept Mol & Cellular Biol, Tucson, AZ 85721 USA. SW Prefecture Endem Prevent Stn, Guizhou, Peoples R China. Guiyang Med Coll, Guiyang, Peoples R China. RP Liu, J (reprint author), NIEHS, Inorgan Carcinogenesis Sect, NCI, Comparat Carcinogenesis Lab, Mail Drop F09-09,Room F-017,111 Alexander Dr, Res Triangle Pk, NC 27713 USA. FU NIEHS NIH HHS [ES 06694] NR 31 TC 115 Z9 121 U1 2 U2 30 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2002 VL 110 IS 2 BP 119 EP 122 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 526KR UT WOS:000174130100017 PM 11836136 ER PT J AU Naar, J Bourdelais, A Tomas, C Kubanek, J Whitney, PL Flewelling, L Steidinger, K Lancaster, J Baden, DG AF Naar, J Bourdelais, A Tomas, C Kubanek, J Whitney, PL Flewelling, L Steidinger, K Lancaster, J Baden, DG TI A competitive ELISA to detect brevetoxins from Karenia brevis (formerly Gymnodinium breve) in seawater, shellfish, and mammalian body fluid SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE antibody; brevetoxin; detection; ELISA; immunoassay; neurotoxic shellfish poisoning; PbTx; seawater; serum; shellfish; urine ID RED TIDE; EPITOPE RECOGNITION; PTYCHODISCUS-BREVIS; ANTIBODIES; TOXINS; FLORIDA; DINOFLAGELLATE; IMMUNOASSAY AB We developed a competitive enzyme-linked immunosorbent assay (ELISA) to analyze brevetoxins, using goat anti-brevetoxin antibodies obtained after immunization with keyhole limpet hemocyanin-brevetoxin conjugates, in combination with a three-step signal amplification process. The procedure, which used secondary biotinylated antibodies, streptavidine-horseradish peroxidase conjugate, and chromogenic enzyme substrate, was useful in reducing nonspecific background signals commonly observed with complex matrices. This competitive ELISA detected brevetoxins in seawater, shellfish extract and homogenate, and mammalian body fluid such as urine and serum without pretreatment, dilution, or purification. We investigated the application of this technique for shellfish monitoring by spiking shellfish meat with brevetoxins and by analyzing oysters from two commercial shellfish beds in Florida that were exposed to a bloom of Karenia brevis (formerly Gymnodinium breve). We performed brevetoxin analysis of shellfish extracts and homogenates by ELISA and compared it with the mouse bioassay and receptor binding assay. The detection limit for brevetoxins in spiked oysters was 2.5 mug/100 g shellfish meat. This assay appears to be a useful tool for neurotoxic shellfish poisoning monitoring in shellfish and seawater, and for mammalian exposure diagnostics, and significantly reduces the time required for analyses. C1 Univ N Carolina, Ctr Marine Sci, Wilmington, NC 28401 USA. Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, NIEHS, Marine & Freshwater Biomed Sci Ctr, Miami, FL 33149 USA. Florida Marine Res Inst, St Petersburg, FL 33701 USA. RP Baden, DG (reprint author), Univ N Carolina, Ctr Marine Sci, 5600 Marvin K Moss Lane, Wilmington, NC 28401 USA. FU NIEHS NIH HHS [P01 ES010594, P01 ES010594-02] NR 40 TC 110 Z9 116 U1 5 U2 23 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2002 VL 110 IS 2 BP 179 EP 185 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 526KR UT WOS:000174130100028 PM 11836147 ER PT J AU Hinnebusch, AG Natarajan, K AF Hinnebusch, AG Natarajan, K TI Gcn4p, a master regulator of gene expression, is controlled at multiple levels by diverse signals of starvation and stress SO EUKARYOTIC CELL LA English DT Review ID YEAST SACCHAROMYCES-CEREVISIAE; TRANSCRIPTION FACTOR GCN4; PROTEIN-KINASE GCN2; AMINO-ACID CONTROL; POLYMERASE-II HOLOENZYME; UNCHARGED TRANSFER-RNA; FACTOR 2-ALPHA KINASE; BUDDING YEAST; ENVIRONMENTAL-CHANGES; NUCLEAR-LOCALIZATION C1 NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. NR 99 TC 187 Z9 201 U1 1 U2 17 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 J9 EUKARYOT CELL JI Eukaryot. Cell PD FEB PY 2002 VL 1 IS 1 BP 22 EP 32 DI 10.1128/EC.1.1.22-32.2002 PG 11 WC Microbiology; Mycology SC Microbiology; Mycology GA 606HT UT WOS:000178729100003 PM 12455968 ER PT J AU Singleton, TL Levin, HL AF Singleton, TL Levin, HL TI A long terminal repeat retrotransposon of fission yeast has strong preferences for specific sites of insertion SO EUKARYOTIC CELL LA English DT Article ID RNA-POLYMERASE-III; POSITION-SPECIFIC INTEGRATION; SCHIZOSACCHAROMYCES-POMBE; DROSOPHILA-MELANOGASTER; TRANSPOSABLE ELEMENTS; REVERSE-TRANSCRIPTASE; DOSAGE COMPENSATION; SILENT CHROMATIN; Y-CHROMOSOME; HISTONE H3 AB The successful dispersal of transposons depends on the critical balance between the fitness of the host and the ability of the transposon to insert into the host genome. One method transposons may use to avoid the disruption of coding sequences is to target integration into safe havens. We explored the interaction between the long terminal repeat retrotransposon Tf1 and the genome of the yeast Schizosaccharomyces pombe. Using techniques that were specifically designed to detect integration of Tf1 throughout the genome and to avoid bias in this detection, we generated 51 insertion events. Although 60.2% of the genome of S. pombe is coding sequence, all but one of the insertions occurred in intergenic regions. We also found that Tf1 was significantly more likely to insert into intergenic regions that included polymerase II promoters than into regions between convergent gene pairs. Interestingly, 8 of the 51 insertion sites were isolated multiple times from genetically independent cultures. This result suggests that specific sites in intergenic regions are targeted by Tf1. Perhaps the most surprising observation was that per kilobase of nonrepetitive sequence, Tf1 was significantly more likely to insert into chromosome 3 than into one of the other two chromosomes. This preference was found not to be due to differences in the distribution or composition of intergenic sequences within the three chromosomes. C1 NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. Delaware State Univ, Dept Sci Biol, Dover, DE 19901 USA. RP NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM Henry_Levin@nih.gov NR 44 TC 51 Z9 51 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 EI 1535-9786 J9 EUKARYOT CELL JI Eukaryot. Cell PD FEB PY 2002 VL 1 IS 1 BP 44 EP 55 DI 10.1128/EC.1.1.44-55.2002 PG 12 WC Microbiology; Mycology SC Microbiology; Mycology GA 606HT UT WOS:000178729100005 PM 12455970 ER PT J AU Matko, J Bodnar, A Vereb, G Bene, L Vamosi, G Szentesi, G Szollosi, J Gaspar, R Horejsi, V Waldmann, TA Damjanovich, S AF Matko, J Bodnar, A Vereb, G Bene, L Vamosi, G Szentesi, G Szollosi, J Gaspar, R Horejsi, V Waldmann, TA Damjanovich, S TI GPI-microdomains (membrane rafts) and signaling of the multi-chain interleukin-2 receptor in human lymphoma/leukemia T cell lines SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Article DE cytokine receptors; lipid rafts; cell proliferation; T lymphocytes; fluorescence energy transfer ID RESONANCE ENERGY-TRANSFER; HLA CLASS-I; GLYCOSYLPHOSPHATIDYLINOSITOL-ANCHORED PROTEINS; PLASMA-MEMBRANE; BETA-CHAIN; FLOW-CYTOMETRY; GAMMA-CHAIN; ALPHA-CHAIN; LIPID RAFTS; MOLECULES AB Subunits (alpha, beta and gamma) of the interleukin-2 receptor complex (IL-2R) are involved in both proliferative and activation-induced cell death (AICD) signaling of T cells. In addition, the signaling beta and gamma chains are shared by other cytokines (e.g. IL-7, IL-9, IL-15). However, the molecular mechanisms responsible for recruiting/sorting the alpha chains to the signaling chains at the cell surface are not clear. Here we show, in four cell lines of human adult T cell lymphoma/leukemia origin, that the three IL-2R subunits are compartmented together with HLA glycoproteins and CD48 molecules in the plasma membrane, by means of fluorescence resonance energy transfer (FRET), confocal microscopy and immunobiochemical techniques. In addition to the beta and gamma(c) chains constitutively expressed in detergent-resistant membrane fractions (DRMs) of T cells, IL-2Ralpha (CD25) was also found in DRMs, independently of its ligand-occupation, Association of CD25 with rafts was also confirmed by its colocalization with GM-I ganglioside. Depletion of membrane cholesterol using methyl-beta-cyclodextrin substantially reduced co-clustering of CD25 with CD48 and HLA-DR, as well as the IL-2 stimulated tyrosine-phosphorylation of STATs (signal transducer and activator of transcription). These data indicate a GPI-microdomain (raft)-assisted recruitment of CD25 to the vicinity of the signaling beta and gamma(c) chains. Rafts may promote rapid formation of a high affinity IL-2R complex, even at low levels of IL-2 stimulus, and may also form a platform for the regulation of IL-2 induced signals by GPI-proteins (e.g. CD48). Based on these data, the integrity of these GPI-microdomains seems critical in signal transduction through the IL-2R complex. C1 Eotvos Lorand Univ, Dept Immunol, H-1518 Budapest, Hungary. Univ Debrecen, Ctr Hlth Sci, Dept Biophys & Cell Biol, Debrecen, Hungary. Univ Debrecen, Ctr Hlth Sci, Hungarian Acad Sci, Cell Biophys Res Grp, Debrecen, Hungary. Acad Sci Czech Republic, Inst Mol Genet, Prague, Czech Republic. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Matko, J (reprint author), Eotvos Lorand Univ, Dept Immunol, POB 120, H-1518 Budapest, Hungary. EM Matko@cerberus.elte.hu RI Vamosi, Gyorgy/C-9351-2009; Bodnar, Andrea/A-9286-2011; Damjanovich, Sandor/A-9284-2011; Matko, Janos/C-9008-2013; Horejsi, Vaclav/G-3113-2014; Vereb, Gyorgy/A-4241-2008 OI Matko, Janos/0000-0001-9434-934X; Vereb, Gyorgy/0000-0003-2157-3265 NR 53 TC 66 Z9 69 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD FEB PY 2002 VL 269 IS 4 BP 1199 EP 1208 DI 10.1046/j.0014-2956.2002.02759.x PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 526XD UT WOS:000174154400019 PM 11856346 ER PT J AU Shugart, YY O'Connell, JR Wilson, AF AF Shugart, YY O'Connell, JR Wilson, AF TI An evaluation of the variance components approach: type I error, power and size of the estimated effect SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE variance components approach; power; type I error; simulation ID TRAIT LINKAGE ANALYSIS; MATRIX MIXED MODELS; QUANTITATIVE TRAITS; ROBUST INFERENCE; FAMILIES; PEDIGREES; PHENOTYPE; PROBANDS; LOCI AB In order to evaluate the statistical properties of the variance components method implemented in SOLAR and GENEHUNTER2, the type I error rate, power and estimated size of modelled effects were determined using computer simulation. Results suggested that the type I error rate was quite conservative when the variance was completely due to random effects. However, when either a polygenic effect or an unlinked single locus component effect was included in the generating models the type I error rate was closer to the nominal level. The size of the polygenic or single locus effect appeared to influence the type I error rate. Results suggested that the variance components method underestimated the variance attributed to a single locus effect and overestimated the variance attributed to a polygenic effect in the models considered regardless of the source of variation. C1 Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21218 USA. Johns Hopkins Univ, Ctr Inherited Dis Res, Baltimore, MD USA. Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. NHGRI, Inherited Dis Res Branch, Genometr Sect, NIH, Baltimore, MD USA. RP Shugart, YY (reprint author), Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21218 USA. RI Wilson, Alexander/C-2320-2009 FU NCI NIH HHS [R03 CA85135-01]; NIA NIH HHS [AG16992] NR 24 TC 7 Z9 7 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD FEB PY 2002 VL 10 IS 2 BP 133 EP 136 DI 10.1038/sj/ejhg/5200772 PG 4 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 541RF UT WOS:000174997000008 PM 11938444 ER PT J AU Petralia, RS Wang, YX Wenthold, RJ AF Petralia, RS Wang, YX Wenthold, RJ TI NMDA receptors and PSD-95 are found in attachment plaques in cerebellar granular layer glomeruli SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE AMPA; cadherin; catenin; contactus acherens; puncta adherentia ID SUBUNIT MESSENGER-RNAS; LONG-TERM POTENTIATION; GLUTAMATE RECEPTORS; POSTNATAL-DEVELOPMENT; HIPPOCAMPAL SYNAPSES; AMPA RECEPTORS; M-CADHERIN; RAT-BRAIN; LOCALIZATION; EXPRESSION AB N-methyl-D-aspartate (NMDA) receptors mediate long-term changes in excitatory synapses in response to glutamate release. In the cerebellar granular layer, most glutamatergic synapses are formed between mossy terminals and granule cell dendrites, which together with some other components, make up complex glomerular structures. Glomeruli contain numerous attachment plaques (or puncta adherentia), which are sites of adhesion between cells. These structures are found mainly between granule cell dendrites, and probably help maintain the integrity of glomeruli. Attachment plaques contain adhesive proteins such as cadherins. In this study, we show that NMDA receptors are common at these attachment plaques, in addition to being found at synapses. We used four different antibodies to the NMDA receptor subunit, NR1, and another to NR2A/B. In contrast, labelling for an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) glutamate receptor antibody was seen only in a few attachment plaques, although AMPA receptors were seen frequently at glomerular synapses. We also show that substantial levels of the NMDA receptor-associated protein, PSD-95, are found in both synapses and attachment plaques. One way that NMDA receptors mediate changes in synapses is through effects on synaptic cadherins, which change their adhesive properties in response to NMDA receptor activation and consequently may alter synaptic function. The presence of NMDA receptors in attachment plaques suggests that these receptors mediate changes in the adhesive properties of these plaques, similar to this function in synapses. C1 NIDCD, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Petralia, RS (reprint author), NIDCD, Neurochem Lab, NIH, 50-4142,50 S Dr MSC 8027, Bethesda, MD 20892 USA. NR 43 TC 30 Z9 32 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD FEB PY 2002 VL 15 IS 3 BP 583 EP 587 DI 10.1046/j.1460-9568.2002.01896.x PG 5 WC Neurosciences SC Neurosciences & Neurology GA 531QZ UT WOS:000174428300020 PM 11876787 ER PT J AU Fujita, M Seibyl, JP Vaupel, DB Tamagnan, G Early, M Zoghbi, SS Baldwin, RM Horti, AG Koren, AO Mukhin, AG Khan, S Bozkurt, A Kimes, AS London, ED Innis, RB AF Fujita, M Seibyl, JP Vaupel, DB Tamagnan, G Early, M Zoghbi, SS Baldwin, RM Horti, AG Koren, AO Mukhin, AG Khan, S Bozkurt, A Kimes, AS London, ED Innis, RB TI Whole-body biodistribution, radiation absorbed dose, and brain SPET imaging with [I-123]5-I-A-85380 in healthy human subjects SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE nicotinic acetylcholine receptors; [I-123]5-I-A-85380; biodistribution; SPET; dosimetry ID NICOTINIC ACETYLCHOLINE-RECEPTORS; IN-VIVO; RADIOLIGAND; 5-I-A-85380; DIVERSITY; ALPHA-3; LIGAND AB The biodistribution of radioactivity after the administration of a new tracer for alpha4beta2 nicotinic acetylcholine receptors (nAChRs), [I-123]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380), was studied in ten healthy human subjects. Following administration of 98+/-6 MBq [I-123]5-I-A-85380, serial whole-body images were acquired over 24 h and corrected for attenuation. One to four brain single-photon emission tomography (SPET) images were also acquired between 2.5 and 24 h. Estimates of radiation absorbed dose were calculated using MIRDOSE 3.1 with a dynamic bladder model and a dynamic gastrointestinal tract model. The estimates of the highest absorbed dose (muGy/MBq) were for the urinary bladder wall (71 and 140), lower large intestine wall (70 and 72), and upper large intestine wall (63 and 64), with 2.4-h and 4.8-h urine voiding intervals, respectively. The whole brain activity at the time of the initial whole-body imaging at 14 min was 5.0% of the injected dose. Consistent with the known distribution of alpha4beta2 nAChRs, SPET images showed the highest activity in the thalamus. These results suggest that [I-123]5-I-A-85380 is a promising SPET agent to image alpha4beta2 nAChRs in humans, with acceptable dosimetry and high brain uptake. C1 Yale Univ, Sch Med, Dept Psychiat, West Haven, CT 06516 USA. VA Connecticut Healthcare Syst, VA Connecticut 116A2, West Haven, CT 06516 USA. Inst Neurodegenerat Disorders, New Haven, CT USA. Yale Univ, Sch Med, Dept Radiol, West Haven, CT 06516 USA. NIDA, Brain Imaging Ctr, Intramural Res Program, Baltimore, MD USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. Univ Calif Los Angeles, Dept Biobehav Sci, Los Angeles, CA USA. NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. RP Fujita, M (reprint author), Yale Univ, Sch Med, Dept Psychiat, 950 Campbell Ave, West Haven, CT 06516 USA. FU NIDA NIH HHS [P50 DA84733] NR 30 TC 55 Z9 56 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD FEB PY 2002 VL 29 IS 2 BP 183 EP 190 DI 10.1007/s00259-001-0695-z PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 551LA UT WOS:000175562100004 PM 11926380 ER PT J AU Munzar, P Justinova, Z Kutkat, SW Goldberg, SR AF Munzar, P Justinova, Z Kutkat, SW Goldberg, SR TI Differential involvement of 5-HT2A receptors in the discriminative-stimulus effects of cocaine and methamphetamine SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE 5-HT2A receptor; cocaine; DOI; ketanserin; methamphetamine; drug discrimination, (rat) ID VENTRAL TEGMENTAL AREA; SEROTONIN 2A RECEPTOR; NUCLEUS-ACCUMBENS; AGONIST DOI; RATS; DOPAMINE; AMPHETAMINE; WITHDRAWAL; RITANSERIN; MODULATION AB involvement of 5-HT2A receptors in the discriminative-stimulus effects of cocaine versus methamphetamine was studied in Sprague Dawley rats (n = 10) trained to discriminate 10 mg/kg cocaine, i.p., from saline under a fixed-ratio 10 (FR10) schedule of food presentation. The ability of (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2A receptor agonist, and ketanserin, a 5-HT2A receptor antagonist, to either substitute for or block the discriminative-stimulus effects of cocaine, or to shift the cocaine dose-response curve, was evaluated. DOI (0.18-1.0 mg/kg) partially substituted for the training dose of 10 mg/kg cocaine, but only at doses that decreased rates of responding. At the highest dose of DOI tested (1.0 mg/kg), there was about 65% cocaine-approptiate responding. Substitution of DOI for cocaine and DOI-induced decreases in rates of responding were completely reversed by ketanserin (3.0 mg/kg). Ketanserin (3.0 mg/kg) also produced a significant shift to the tight of the cocaine dose-response curve and antagonized increases in rates of responding produced by lower doses of cocaine. Ketanserin (1.0-10.0 mg/kg), however, did not block the discriminative-stimulus effects of the training dose of cocaine. When DOI (0.3 mg/kg) was co-administered with different doses of cocaine, there was a slight leftward shift in the cocaine dose-response curve, which was not significant and appeared to reflect simple additive effects of DOI and cocaine. In contrast, the same dose of DOI (0.3 mg/kg) produced a marked and highly significant shift to the left of the methamphetamine (0.18-1.0 mg/kg) dose-response curve in the same subjects and the effects of DOI and methamphetamine were clearly more than additive. The present findings provide new evidence that there is some serotonergic modulation of cocaine's discriminative-stimulus actions, which appears to involve stimulation of 5HT(2A) receptors. However, involvement of 5-HT2A receptor activity in the discriminative-stimulus actions of cocaine appears to be less pronounced than in similar actions of methamphetamine. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Coll Med, Richmond, VA 23298 USA. Natl Inst Hlth, Natl Inst Drug Abuse, Intramural Res Program, Behav Neurosci Branch, Baltimore, MD 21224 USA. RP Munzar, P (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Coll Med, Smith Bldg,410 N 12th St, Richmond, VA 23298 USA. RI Justinova, Zuzana/A-9109-2011 OI Justinova, Zuzana/0000-0001-5793-7484 NR 38 TC 19 Z9 20 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD FEB 1 PY 2002 VL 436 IS 1-2 BP 75 EP 82 AR PII S0014-2999(01)01598-9 DI 10.1016/S0014-2999(01)01598-9 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 522VG UT WOS:000173917200010 PM 11834249 ER PT J AU Bagrov, AY Bagrov, YY Fedorov, OV Kashkin, VA Patkina, NA Zvartau, EE AF Bagrov, AY Bagrov, YY Fedorov, OV Kashkin, VA Patkina, NA Zvartau, EE TI Endogenous digitalis-like ligands of the sodium pump: possible involvement in mood control and ethanol addiction SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Review DE ethanol addiction; mood disorders; Na/K-ATPase; endogenous digitalis-like factors ID OUABAIN-LIKE COMPOUND; PROTEIN-KINASE-C; BRAIN (NA+,K+)ATPASE ACTIVITY; NA+,K+-ATPASE ALPHA-SUBUNIT; HUMAN CEREBROSPINAL-FLUID; NA,K-ATPASE BETA-SUBUNIT; CENTRAL-NERVOUS-SYSTEM; K+-ATPASE ACTIVITY; 2 MOLECULAR-FORMS; NA+/K+-ATPASE AB This review addresses possible involvement of endogenous digitalis-like sodium pump ligands (SPL) in the mood control and ethanol addiction. Endogenous SPL include cardenolide and bufadienolide classes. Multiple SPL and multiple isoforms of the Na/K-ATPase, one of the key membrane enzymes. comprise a complex regulatory system. In the nervous system, pattern of expression of Na/K-ATPase is based on multiple alpha/beta isoform combinations. Clinical studies demonstrate changes in the activity of Na/K-ATPase in patients with bipolar and unipolar mood disorders. The effects of ethanol on the Na/K-ATPase are concentration-dependent and are associated with both inhibition and activation of enzyme activity. Reinforcing effect of ethanol as well as its voluntary consumption may be affected by digitalis glycosides and endogenous SPL. (C) 2002 Elsevier Science B.V./ECNP. All rights reserved. C1 Pavlov Med Univ, Valdman Inst Pharmacol, St Petersburg 197089, Russia. IM Sechenov Evolutionary Physiol & Biochem Inst, Lab Membrane Barrier Funct & Pharmacol, St Petersburg 194223, Russia. NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. RP Zvartau, EE (reprint author), Pavlov Med Univ, Valdman Inst Pharmacol, St Petersburg 197089, Russia. OI Kashkin, Vladimir/0000-0002-7202-0233 NR 171 TC 15 Z9 16 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD FEB PY 2002 VL 12 IS 1 BP 1 EP 12 DI 10.1016/S0924-977X(01)00127-4 PG 12 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 518NF UT WOS:000173674200001 PM 11788235 ER PT J AU Konstantinidis, A Stastny, J Ptak-Butta, J Hilger, E Winkler, D Barnas, C Neumeister, A Kasper, S AF Konstantinidis, A Stastny, J Ptak-Butta, J Hilger, E Winkler, D Barnas, C Neumeister, A Kasper, S TI Intravenous mirtazapine in the treatment of depressed inpatients SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article; Proceedings Paper CT 56th Annual Scientific Convention of the Society-of-Biological-Psychiatry CY MAY 03-05, 2001 CL NEW ORLEANS, LOUISIANA DE intravenous mirtazapine; depressed inpatients; antidepressant ID DOUBLE-BLIND; MAJOR DEPRESSION; DOUBLE-DUMMY; EFFICACY; AMITRIPTYLINE; TOLERABILITY; PLACEBO; CITALOPRAM; ORG-3770; DISORDER AB Mirtazapine is a novel antidepressant with a noradrenergic and specific serotonergic mode of action. So far, mirtazapine has been administered orally. This naturalistic study evaluates the antidepressant efficacy, safety, and tolerability of mirtazapine 15 mg/day administered intravenously to 27 inpatients with moderate to severe major depression. Compared with baseline. we found a significant decrease of the Hamilton Depressive Rating Scale (HDRS) total score (P<0.001). Side effects were mild and transient. Altogether, the results of this preliminary study show that intravenous mirtazapine is an effective, safe and well tolerated treatment for depressed inpatients. (C) 2002 Elsevier Science B.V./ECNR All rights reserved. C1 Univ Vienna, Dept Gen Psychiat, A-1090 Vienna, Austria. NIMH, Mood & Anxiety Disorders Res Program, NIH, Bethesda, MD 20892 USA. RP Kasper, S (reprint author), Univ Vienna, Dept Gen Psychiat, Waehringer Guertel 18-20, A-1090 Vienna, Austria. NR 33 TC 9 Z9 9 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD FEB PY 2002 VL 12 IS 1 BP 57 EP 60 DI 10.1016/S0924-977X(01)00132-8 PG 4 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 518NF UT WOS:000173674200007 PM 11788241 ER PT J AU Singleton, EG Trotman, AJM Zavahir, M Taylor, RC Heishman, SJ AF Singleton, EG Trotman, AJM Zavahir, M Taylor, RC Heishman, SJ TI Determination of the reliability and validity of the Marijuana Craving Questionnaire using imagery scripts SO EXPERIMENTAL AND CLINICAL PSYCHOPHARMACOLOGY LA English DT Article; Proceedings Paper CT World Psychiatric Association Congress CY JUN, 2000 CL PARIS, FRANCE ID ABSTINENCE SYMPTOMS; COEFFICIENT-ALPHA; SMOKED MARIJUANA; NEGATIVE AFFECT; SMOKING URGES; WITHDRAWAL; DEPENDENCE; INTENSITY; HUMANS AB The purpose of this study was to determine the reliability and validity of the Marijuana Craving Questionnaire (MCQ) by using active imagery of auditorily presented scripts. Current marijuana users (n = 48) imagined scripts that varied in amount of descriptors of desire to smoke marijuana, from no-urge to high-urge content. Self-reported marijuana craving significantly increased as a function of script-urge intensity on Factors 1, 3, and 4 of the MCQ, Homogeneity of items comprising each MCQ factor was examined, indicating no significant departures from unidimensionality. These results verify and extend the reliability and validity of the MCQ as a multidimensional measurement of marijuana craving. The data also suggest that drug craving is not an all-or-none phenomenon. C1 NIDA, Clin Pharmacol & Therapeut Branch, Baltimore, MD 21224 USA. Univ Baltimore, Div Appl Psychol, Baltimore, MD 21201 USA. RP Heishman, SJ (reprint author), NIDA, Clin Pharmacol & Therapeut Branch, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Singleton, Edward G./0000-0003-3442-877X NR 25 TC 31 Z9 31 U1 3 U2 6 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1064-1297 J9 EXP CLIN PSYCHOPHARM JI Exp. Clin. Psychopharmacol. PD FEB PY 2002 VL 10 IS 1 BP 47 EP 53 DI 10.1037//1064-1297.10.1.47 PG 7 WC Psychology, Biological; Psychology, Clinical; Pharmacology & Pharmacy; Psychiatry SC Psychology; Pharmacology & Pharmacy; Psychiatry GA 520XZ UT WOS:000173810200006 PM 11871362 ER PT J AU Beldarrain, MG Gafman, J de Velasco, IR Pascual-Leone, A Garcia-Monco, JC AF Beldarrain, MG Gafman, J de Velasco, IR Pascual-Leone, A Garcia-Monco, JC TI Prefrontal lesions impair the implicit and explicit learning of sequences on visuomotor tasks SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE procedural learning; visuomotor sequences; prefrontal lobe-human ID PARKINSONS-DISEASE; WORKING-MEMORY; FRONTAL-LOBE; MOTOR SKILL; HUNTINGTONS-DISEASE; FUNCTIONAL MRI; CORTEX; FMRI; AREAS; PET AB Objective: (1) To verify whether the prefrontal cortex (PFC) is specifically involved in visuomotor sequence learning as opposed to other forms of motor learning and (2) to establish the role of executive functions in visuomotor sequence learning, Background: Visuomotor skill learning depends on the integrity of the premotor and parietal cortex the prefrontal cortex, however, is essential when the learning of a sequence is required. Methods: We studied 25 patients with PFC lesions and 86 controls matched for age and educational level. Participants performed: (1) a Pursuit Tracking Task (PTT). composed of a random tracking task (perceptual learning) and a pattern tracking task (explicit motor sequence learning with teaming indicated by the decrease in mean root square error across trial blocks), (2) a 12-item sequence version of a serial reaction time task (SRTT) with specific implicit motor sequence learning indicated by the rebound increase in response time when comparing the last sequence block with the next random block. and (3) a neuropsychological battery that assessed executive functions. Results: PFC patients were impaired in sequence learning on the pattern tracking task of the PTT and on the SRTT as compared to controls. but performed normally on the PTT random tracking task. Learning on the PTT did not correlate with learning on the SRTT. PTT performance correlated with planning functions while SRTT performance correlated with working memory capacity. Conclusions: The PFC is specifically involved in explicit and implicit motor sequence learning. Different PFC regions may be selectively involved in such learning depending on the cognitive demands of the sequential task. C1 Hosp Galdacano, Serv Neurol, Vizcaya 48960, Spain. Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, NIH, Bethesda, MD USA. Beth Israel Deaconess Med Ctr, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Beldarrain, MG (reprint author), Hosp Galdacano, Serv Neurol, Vizcaya 48960, Spain. NR 44 TC 31 Z9 31 U1 0 U2 7 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD FEB PY 2002 VL 142 IS 4 BP 529 EP 538 DI 10.1007/s00221-001-0935-2 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 530MU UT WOS:000174362100008 ER PT J AU Huber, A Yee, C Darling, TN Yancey, KB AF Huber, A Yee, C Darling, TN Yancey, KB TI Comprehensive analysis of gene expression profiles in keratinocytes from patients with generalized atrophic benign epidermolysis bullosa SO EXPERIMENTAL DERMATOLOGY LA English DT Article DE cDNA microarrays; gene expression; bullous disease; collagen; nonsense-mediated mRNA decay trans-acting; factor ID 5 AUSTRIAN FAMILIES; PEMPHIGOID ANTIGEN; DELETION MUTATION; COL17A1; PROTEIN; CODONS; BPAG2 AB Generalized atrophic benign epidermolysis bullosa [GABEB (OMIM no. 226650)] is an inherited subepidermal blistering disease typically caused by null mutations in COL17A1, the gene encoding type XVII collagen. Studies of GABEB keratinocytes homozygous for 4003delTC showed that this 2bp deletion results in markedly reduced COL17A1 transcripts due to nonsense mediated-mRNA decay. To explore consequences of this null mutation in COLI17A1 on the expression of other genes, RNA samples from reference GABEB and normal keratinocytes were profiled in comparative screens of microarrays of known cDNAs (n = 6180) and expressed sequence tags (ESTs) (n 15 144). All comparative hybridization experiments were performed twice; data were quantitated by densitometry and analyzed using peak quantification statistical comparative analysis (P-SCAN) software to identify differentially expressed genes. Representative genes found to be differentially expressed were verified using real-time reverse transcription-polymerase chain reaction (RT-PCR). These experiments determined that expression of nonsense-mediated mRNA decay trans-acting factor (NMD-F), the regulator of nonsense transcripts (i.e. the human homolog of the yeast Upf1 protein), was upregulated in GABEB keratinocytes. NMD-F was subsequently found to be upregulated in cultured keratinocytes from other GABEB patients homozygous for 4003delTC. These findings indicate that the gene responsible for nonsense-mediated mRNA decay is upregulated in keratinocytes known to eliminate mutant COL17A1 transcripts via this highly conserved mechanism. C1 NCI, Dermatol Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Dermatol, Bethesda, MD 20814 USA. RP Yancey, KB (reprint author), Med Coll Wisconsin, Dept Dermatol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. OI Darling, Thomas/0000-0002-5161-1974 NR 17 TC 5 Z9 5 U1 0 U2 0 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 FEB PY 2002 VL 11 IS 1 BP 75 EP 81 DI 10.1034/j.1600-0625.2002.110108.x PG 7 WC Dermatology SC Dermatology GA 534XE UT WOS:000174614400008 PM 11952829 ER PT J AU Sosne, G Szliter, EA Barrett, R Kernacki, KA Kleinman, H Hazlett, LD AF Sosne, G Szliter, EA Barrett, R Kernacki, KA Kleinman, H Hazlett, LD TI Thymosin beta 4 promotes corneal wound healing and decreases inflammation in vivo following alkali injury SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE thymosin beta 4; cornea; alkali injury; wound healing; inflammation; cytokines; chemokines ID AERUGINOSA OCULAR INFECTION; CYTOKINE EXPRESSION; IN-VIVO; INTERLEUKIN-1; MODEL; ULCERATION; CHEMOKINES; LEUKOCYTES; PROTEIN-2; MONOCYTES AB Previously, thymosin beta 4 (Tbeta(4)) was found to promote wound healing in full thickness skin wounds and heptanol debrided corneas. Here, the effect of Tbeta(4) was examined treatment on corneal wound healing and inflammation in vivo after alkali injury, a more severe wound of the eye, Corneas from 129 Sv mice were chemically burned with a 2 mm disc soaked in I N NaOH for 30 sec. Eyes were irrigated copiously with phosphate buffered saline (PBS) and then treated topically with either Tbeta(4) (5 mug/5 mul PBS) or 5 mul PBS twice daily. Animals were killed, the eyes were enucleated, fixed and embedded in plastic resin or prepared for mRNA analysis. Mouse corneas topically treated with 5 mug of Tbeta(4) twice daily after alkali injury demonstrated accelerated re-epithelialization at all time points and decreased polymorphonuclear leukocyte (PMN) infiltration at 7 days post injury (p.i.) when compared to PBS-treated controls. mRNA transcript levels were decreased several fold for interleukin (IL)-1beta, and the chemokines macrophage inflammatory protein (NHP)-1alpha, MIP-1beta, MIP-2 and monocyte chemoattractant protein (MCP)-1 from I to 7 days after injury in the Tbeta(4)- VS. PBS-treated corneas. Thus, Tbeta(4) may provide a new clinical treatment for severe traumatic corneal wound disorders by promoting rapid corneal wound healing and decreasing both PMN infiltration and inflammatory cytokine and chemokine mRNA levels. (C) 2002 Elsevier Science Ltd. C1 Henry Ford Hosp, Eye Care Serv Dept, Detroit, MI 48202 USA. Wayne State Univ, Dept Anat & Cell Biol, Detroit, MI USA. Natl Inst Dental & Craniofacial Res, Dev Biol Lab, NIH, Bethesda, MD USA. RP Sosne, G (reprint author), Henry Ford Hosp, Eye Care Serv Dept, 2799 W Grand Blvd K10, Detroit, MI 48202 USA. FU NEI NIH HHS [K08 EY 13412, P30 EY 04068, R01 EY 02986] NR 37 TC 138 Z9 146 U1 1 U2 4 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD FEB PY 2002 VL 74 IS 2 BP 293 EP 299 DI 10.1006/exer.2001.1125 PG 7 WC Ophthalmology SC Ophthalmology GA 551AT UT WOS:000175537800014 PM 11950239 ER PT J AU Robinson, MR Baffi, J Yuan, P Sung, C Byrnes, G Cox, TA Csaky, KG AF Robinson, MR Baffi, J Yuan, P Sung, C Byrnes, G Cox, TA Csaky, KG TI Safety and pharmacokinetics of intravitreal 2-methoxyestradiol implants in normal rabbit and pharmacodynamics in a rat model of choroidal neovascularization SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE 2-methoxyestradiol; implant; vitreous; drug release; age-related macular degeneration; choroidal neovascularization; animal model ID ENDOGENOUS ESTROGEN METABOLITE; ENDOTHELIAL GROWTH-FACTOR; MACULAR DEGENERATION; INHIBITS ANGIOGENESIS; DELIVERY SYSTEM; TUMOR-GROWTH; EXPRESSION; RELEASE; CELLS AB Choroidal neovascularization (CNV) is the leading cause of severe vision loss associated with age-related macular degeneration, As the pathogenesis of CNV formation is better understood, mechanism-based therapies, including the use of antiangiogenesis inhibitors, have been investigated, 2-methoxyestradiol (2ME2), an endogenous metabolite of estradiol, has been shown in the chick allantoic membrane model and the corneal micropocket assay to have antiangiogenic properties. The authors sought to determine the safety and pharmacokinetics of sustained-release intravitreal 2ME2 implants in normal rabbit and their efficacy in a rat model of CNV. 2ME2 implants were constructed using two designs: implant A, a silicone-based reservoir implant for the rabnbit eye, and implant B, a microimplant matrix design for the rat eye. In vitro release rates of both implants were determined. New Zealand white (NZW) rabbits had implant A placed in the vitreous cavity of one eye and the ocular toxicity was evaluated by clinical examination, serial electroretinography (ERG), and histopathology over a 28 week period. The steady state clearance of 2ME2 in the rabbit eye was calculated from in vivo release rates divided by steady state vitreous concentrations. A CNV model in the Brown-Norway rat was performed by injecting an adenoviral vector encoding human vascular endothelial growth factor in the subretinal space, Following the injection, a 2ME2 or sham (no drug) microimplant was placed in the vitreous cavity. Animals were killed over a 3 week period and the eyes examined for CNV by histopathology. Results showed that following a short burst, the release rate of implant A followed zero-order kinetics, typical of reservoir devices, and the cumulative release of implant B was proportional to the square root of time, as expected for a matrix delivery device. The safety studies in normal rabbit showed no ocular toxicities by clinical examination, ERG, and histopathology. Pharmacokinetic evaluation in the rabbit showed mean 2ME2 vitreous levels within the therapeutic range for the inhibition of endothelial cell proliferation. The experimental rat model showed a significant reduction in CNV in eyes treated with the 2ME2 implant. In conclusion, sustained-release 2ME2 intravitreal implants, which can be designed to deliver potentially therapeutic vitreous levels of 2ME2 for an extended period of time, appeared to be safe in normal rabbit and effective in a rat model of CNV. Sustained-release 2ME2 intravitreal implants may hold promise in the treatment of recurrent CNV refractory to standard therapy. C1 NEI, NIH1, Bethesda, MD 20892 USA. NIH2, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. NIH3, Bioengn & Phys Sci Div, ORS, Bethesda, MD 20892 USA. RP Robinson, MR (reprint author), NEI, NIH, 10 Ctr Dr,Msc 1863,Bldg10,Room10N112, Bethesda, MD 20892 USA. NR 32 TC 30 Z9 33 U1 0 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD FEB PY 2002 VL 74 IS 2 BP 309 EP 317 DI 10.1006/exer.2001.1132 PG 9 WC Ophthalmology SC Ophthalmology GA 551AT UT WOS:000175537800016 PM 11950241 ER PT J AU Panisko, EA Conrads, TP Goshe, MB Veenstra, TD AF Panisko, EA Conrads, TP Goshe, MB Veenstra, TD TI The postgenomic age: Characterization of proteomes SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID 2-DIMENSIONAL GEL-ELECTROPHORESIS; IONIZATION MASS-SPECTROMETRY; ELECTROSPRAY-IONIZATION; PROTEIN IDENTIFICATION; GENE-EXPRESSION; SEQUENCE INFORMATION; DNA MICROARRAY; ACID-ANALYSIS; CELL-LINES; PHOSPHORYLATION AB Global analysis of biological systems is becoming increasingly feasible as technologies that facilitate genome-wide analyses of gene expression are developed. Proteomics is the global analysis of expressed proteins (including posttranslational modifications) and seeks to establish the relationship between genome sequence, expressed proteins, protein-protein interactions, and cell and tissue phenotype. While the relative abundance of transcripts can be quantified using gene expression microarrays, the identification and quantitation of expressed proteins is more challenging. Nevertheless, the potential payoff for global protein analyses is immense because identification of distinctive protein signatures associated with cell function may provide novel therapeutic targets, molecular markers of disease, and increased understanding of determinants of cell phenotype. The challenges and promises of applications of established and emerging proteome strategies to detect and quantify differentially expressed proteins in culture cells are discussed. (C) 2002 International Society for Experimental Hematology. Published by Elsevier Science, Inc. C1 NCI, SAIC Frederick, Frederick, MD 21702 USA. Pacific NW Natl Lab, Environm & Mol Sci Lab, Richland, WA 99352 USA. RP Veenstra, TD (reprint author), NCI, SAIC Frederick, POB B,Bldg 469,Rm 160, Frederick, MD 21702 USA. NR 74 TC 23 Z9 27 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD FEB PY 2002 VL 30 IS 2 BP 97 EP 107 AR PII S0301-472X(01)00771-8 DI 10.1016/S0301-472X(01)00771-8 PG 11 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 526KJ UT WOS:000174129400001 PM 11823044 ER PT J AU De Giorgi, F Lartigue, L Bauer, MKA Schubert, A Grimm, S Hanson, GT Remington, SJ Youle, RJ Ichas, F AF De Giorgi, F Lartigue, L Bauer, MKA Schubert, A Grimm, S Hanson, GT Remington, SJ Youle, RJ Ichas, F TI The permeability transition pore signals apoptosis by directing Bax translocation and multimerization SO FASEB JOURNAL LA English DT Article DE apoptosis; bax; cytochrome c; FRET; permeability transition pore ID CYTOCHROME-C RELEASE; ADENINE-NUCLEOTIDE TRANSLOCATOR; MITOCHONDRIAL INNER MEMBRANE; DEPENDENT ANION CHANNEL; CELL-DEATH; CASPASE ACTIVATION; CA2+; BCL-2; OLIGOMERIZATION; CYCLOPHILIN AB Mitochondria are key players of apoptosis and can irreversibly commit the cell to death by releasing cytochrome c (Cyt.c) to the cytosol, where caspases 9 and 3 subsequently get activated. Under conditions of oxidative stress, opening of the mitochondrial permeability transition pore (PTP) represents an early trigger and is crucial in causing Cyt.c release. To account for the latter, current models propose that PTP gating would result, as is the case in vitro, in the rupture of the outer mitochondrial membrane caused by mitochondrial matrix swelling. Using live cell imaging and recombinant fluorescent probes based on the green fluorescent protein (GFP) and its mutants, we report that directed repetitive gating of the PTP triggers a delayed Cyt.c efflux, which is not associated with mitochondrial swelling. Instead, subcellular imaging shows that PTP opening signals the redistribution of the cytosolic protein Bax to the mitochondria, where it secondarily forms clusters that appear to be a prerequisite for Cyt.c release. Fluorescence resonance energy transfer imaging further reveals that Bax clustering coincides with the formation of Bax multimers. We conclude that the PTP is not itself a component of the Cyt.c release machinery, but that it acts indirectly by signaling Bax translocation and multimerization. C1 Univ Bordeaux 2, European Inst Chem & Biol, INSERM, E9929, F-33076 Bordeaux, France. Max Planck Inst Biochem, D-82152 Martinsried, Germany. Univ Oregon, Dept Chem, Eugene, OR 97403 USA. Univ Oregon, Dept Phys, Eugene, OR 97403 USA. Univ Oregon, Inst Mol Biol, Eugene, OR 97403 USA. NINCDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Ichas, F (reprint author), Univ Bordeaux 2, European Inst Chem & Biol, INSERM, E9929, F-33076 Bordeaux, France. EM ichas@u-bordeaux2.fr RI lartigue, lydia/I-9548-2014 NR 37 TC 188 Z9 192 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD FEB PY 2002 VL 16 IS 2 BP 607 EP + DI 10.1096/fj.01-0269fje PG 20 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 527TM UT WOS:000174203700007 PM 11919169 ER PT J AU Sinaii, N Cleary, SD Ballweg, ML Nieman, LK Stratton, P AF Sinaii, N Cleary, SD Ballweg, ML Nieman, LK Stratton, P TI Autoimmune and related diseases among women with endometriosis: a survey analysis. SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 NICHHD, NIH, Bethesda, MD 20892 USA. NICHHD, NIH, Bethesda, MD 20892 USA. George Washington Univ, Washington, DC USA. Endometriosis Assoc, Int Headquarters, Milwaukee, WI 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD FEB PY 2002 VL 77 IS 2 SU 1 MA O20 BP S7 EP S8 DI 10.1016/S0015-0282(01)03031-X PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 523EA UT WOS:000173939700021 ER PT J AU Sinaii, N Winkel, CA Merino, MJ Zimmer, C Nieman, LK Stratton, P AF Sinaii, N Winkel, CA Merino, MJ Zimmer, C Nieman, LK Stratton, P TI Do color, size, depth, and volume predict endometriosis in lesions resected at surgery? SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 NICHHD, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Sch Med, Washington, DC USA. NCI, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, 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 FEB PY 2002 VL 77 IS 2 SU 1 MA O14 BP S5 EP S6 DI 10.1016/S0015-0282(01)03025-4 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 523EA UT WOS:000173939700015 ER PT J AU Egan, SK Tao, SSH Pennington, JAT Bolger, PM AF Egan, SK Tao, SSH Pennington, JAT Bolger, PM TI US Food and Drug Administration's total diet study: Intake of nutritional and toxic elements, 1991-96 SO FOOD ADDITIVES AND CONTAMINANTS LA English DT Article DE Total Diet Study (TDS); dietary intakes; nutritional elements; toxic elements; monitoring ID FDA TOTAL DIET; UNITED-STATES; PESTICIDES; CHEMICALS; MINERALS; HISTORY AB The Food and Drug Administration (FDA) has conducted the Total Diet Study (TDS) annually since 1961. The TDS is designed to monitor the US food supply for levels of toxic chemical contaminants (pesticide residues, industrial chemicals and toxic elements) and nutritional elements. Foods are generally collected four times a year, once from each of four regions of the country. The foods are prepared table-ready before being analysed. From the results of the TDS, dietary intakes of these analytes are estimated for selected age- sex groups in the US population. This paper reports on the dietary intake of 10 nutritional and four toxic elements based on measurements made in foods collected in the TDS between 1991 and late 1996. Average daily intakes were estimated for 14 age- sex groups in the US population, as well as the contribution of specific food groups to total intakes. For most nutritional elements, teenage boys and adult males had the highest daily intakes. Intakes by infants were below the intake references for seven of 10 nutritional elements, and young girls and women had inadequate intakes of at least half the nutritional elements. Intakes by children between 2 and 10 years of age, teenage boys, and adult males met or exceeded the reference intakes for the majority of nutritional elements. Intakes by all population groups were well below the reference intakes for all toxic elements. C1 US FDA, Ctr Food Safety & Appl Nutr, Washington, DC 20204 USA. NIH, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. RP Egan, SK (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 200 C St SW, Washington, DC 20204 USA. NR 28 TC 67 Z9 73 U1 0 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK,, ABINGDON OX14 4RN, OXON, ENGLAND SN 0265-203X J9 FOOD ADDIT CONTAM JI Food Addit. Contam. PD FEB PY 2002 VL 19 IS 2 BP 103 EP 125 DI 10.1080/02652030110071354 PG 23 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA 512AJ UT WOS:000173298700001 PM 11824417 ER PT J AU Wright, LJ Kalantaridou, SN Calis, KA AF Wright, LJ Kalantaridou, SN Calis, KA TI Update on the benefits and risks of hormone replacement therapy SO FORMULARY LA English DT Article ID EPITHELIAL OVARIAN-CANCER; CORONARY HEART-DISEASE; BONE-MINERAL DENSITY; POSTMENOPAUSAL WOMEN; ESTROGEN REPLACEMENT; OLDER WOMEN; VENOUS THROMBOEMBOLISM; ENDOMETRIAL CANCER; ALZHEIMERS-DISEASE; MENOPAUSE AB New data are continually refining our understanding of the benefits and risks of hormone replacement therapy (HRT) in postmenopausal women. The current state of evidence reveals unequivocally that HRT increases bone mineral density, reduces the risk of osteoporotic fracture, and relieves postmenopausal symptoms and vaginal atrophy. The role of HRT for secondary prevention of coronary heart disease (CHD) has recently been. repudiated, while its role for primary prevention remains to be fully elucidated. Proven risks of HRT include endometrial cancer (but only with unopposed estrogen therapy), thromboembolism, elevations In triglyceride levels, and gallbladder disease. There is strong evidence for an association between breast cancer and use of HRT for more than 5 years. More data are needed to clarify potential protective effects against colorectal cancer and dementia and a potential association with ovarian cancer. C1 Purdue Univ, Dept Pharm Practice, W Lafayette, IN 47907 USA. Univ Ioannina, Sch Med, Dept Obstet & Gynecol, GR-45110 Ioannina, Greece. NIH, Drug Informat Serv, Dept Pharm, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Wright, LJ (reprint author), Purdue Univ, Dept Pharm Practice, Wishard Hlth Serv, D711 Myers Bldg,1001 W 10th St, Indianapolis, IN 46202 USA. NR 73 TC 0 Z9 0 U1 1 U2 1 PU ADVANSTAR COMMUNICATIONS PI DULUTH PA 131 W FIRST ST, DULUTH, MN 55802 USA SN 1082-801X J9 FORMULARY JI Formulary PD FEB PY 2002 VL 37 IS 2 BP 78 EP + PG 8 GA 521FF UT WOS:000173828000006 ER PT J AU Manal, K McClay, I Richards, J Galinat, B Stanhope, S AF Manal, K McClay, I Richards, J Galinat, B Stanhope, S TI Knee moment profiles during walking: errors due to soft tissue movement of the shank and the influence of the reference coordinate system SO GAIT & POSTURE LA English DT Article DE skin movement; motion analysis; relative motion; video; tracking targets; bone ID MOUNTED MARKERS; GAIT AB The effect soft tissue movement of the shank had on knee joint moments during natural cadence walking was investigated in this study. This was examined by comparing knee moments determined from bone-anchored and surface mounted tracking targets. Six healthy adult subjects participated in this study. The largest difference (3 N m) occurred about the AP axis, with smaller differences of approximately 2 and 1 N in about the flexion/extension (F/E) and longitudinal (Long) axes, respectively. The magnitude of these differences would not likely affect the clinical interpretation of the data. The effect of reporting knee moments in two different orthogonal reference systems was also examined. The peak extension moment was significantly greater when expressed about an anatomical axis following the line of the malleoli than when the moment was reported about an axis parallel to the frontal plane of the shank. In contrast, the first peak abduction moment was significantly greater when expressed about an axis perpendicular to the frontal plane of the shank. Care should therefore be exercised whenever comparisons between studies are made in which the reference axes are not aligned. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Delaware, Spencer Labs 126, Biomed Engn Res Ctr, Newark, DE 19716 USA. Joyner Sports Med Inst, Lexington, KY 40517 USA. Univ Delaware, Newark, DE 19716 USA. Delaware Orthopaed Ctr, Newark, DE 19808 USA. NIH, Biomech Lab, Bethesda, MD 20892 USA. RP Manal, K (reprint author), Univ Delaware, Spencer Labs 126, Biomed Engn Res Ctr, Newark, DE 19716 USA. NR 13 TC 37 Z9 37 U1 0 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0966-6362 J9 GAIT POSTURE JI Gait Posture PD FEB PY 2002 VL 15 IS 1 BP 10 EP 17 AR PII S0966-6362(01)00174-6 DI 10.1016/S0966-6362(01)00174-6 PG 8 WC Neurosciences; Orthopedics; Sport Sciences SC Neurosciences & Neurology; Orthopedics; Sport Sciences GA 571JV UT WOS:000176715000002 PM 11809576 ER PT J AU Szalai, AJ McCrory, MA Cooper, GS Wu, J Kimberly, RP AF Szalai, AJ McCrory, MA Cooper, GS Wu, J Kimberly, RP TI Association between baseline levels of C-reactive protein (CRP) and a dinucleotide repeat polymorphism in the intron of the CRP gene SO GENES AND IMMUNITY LA English DT Article DE inflammation; risk factors; acute phase proteins ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; FC-GAMMA-RIIA; TRANSGENIC MICE; DNA-SEQUENCE; BINDING; INFLAMMATION; POLYSACCHARIDE; AUTOIMMUNITY; COMPONENTS; COMPLEXES AB Elevation of baseline C-reactive protein (CRP) is associated with increased risk of cardiac disease. This increase might reflect low-grade inflammation, but differences in CRP serum levels might also have a genetic component. To test this possibility, we investigated whether a polymorphic GT-repeat in the intron of the CRP gene contributes to variation in baseline CRP. We found that the polymorphism was associated with differences in baseline CRP in both normal individuals and in patients with the inflammatory disease systemic lupus erythematosus, viz. donors carrying two GT(16) alleles, two GT(21) alleles, or GT(16/21) heterozygotes had two-fold lower serum CRP than those with other genotypes. The frequency of GT(16) and GT(21) was two-fold higher in Caucasians than in African-Americans, but there was no difference in allele distribution between patients and controls. It is not yet known how this genetic polymorphism mediates its effect on CRP expression, and it probably is not a systemic lupus erythematosus susceptibility factor. Rather, the CRP intron polymorphism likely modifies the disease phenotype. On the other hand, the fact that baseline CRP does have a genetic component suggests that in coronary disease, stratification of risk assessment based on CRP levels might be enhanced by consideration of this polymorphism. C1 Univ Alabama Birmingham, Div Clin Immunol & Rheumatol, Dept Med, Birmingham, AL 35294 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Szalai, AJ (reprint author), Univ Alabama Birmingham, Div Clin Immunol & Rheumatol, Dept Med, Birmingham, AL 35294 USA. EM Alex.Szalai@ccc.uab.edu OI Kimberly, Robert/0000-0002-5330-3086 FU NIAID NIH HHS [R29 AI42183]; NIAMS NIH HHS [P50 AR45231] NR 43 TC 98 Z9 103 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD FEB PY 2002 VL 3 IS 1 BP 14 EP 19 DI 10.1038/sj/gene/6363820 PG 6 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 524TA UT WOS:000174027900004 PM 11857055 ER PT J AU Swalwell, JI Vocke, CD Yang, YF Walker, JR Grouse, L Myers, SH Gillespie, JW Bostwick, DG Duray, PH Linehan, WM Emmert-Buck, MR AF Swalwell, JI Vocke, CD Yang, YF Walker, JR Grouse, L Myers, SH Gillespie, JW Bostwick, DG Duray, PH Linehan, WM Emmert-Buck, MR TI Determination of a minimal deletion interval on chromosome band 8p21 in sporadic prostate cancer SO GENES CHROMOSOMES & CANCER LA English DT Article ID TUMOR-SUPPRESSOR GENE; ALLELIC LOSS; INTRAEPITHELIAL NEOPLASIA; COLORECTAL-CANCER; LUNG-CANCER; CARCINOMA; LOCI; HETEROZYGOSITY; MULTIPLE; REVEALS AB Loss of the short arm of chromosome 8 is :a common event in prostatic neoplasms. Previous studies indicate that there may be up to three separate tumor suppressor genes on chromosome arm 8p, based on patterns of allelic loss. The responsible gene or genes have yet to be identified. In the present study, we used laser-capture microdissection of primary human Prostate tumors and 17 microsatellite markers across Chromosome band 8p21 to determine a minimal deletion interval. From an initial set of 120 cases, three tumors contained overlapping interstitial deletions on chromosome band 8p21. The three cases define an internally consistent minimal candidate tumor suppressor gene interval of approximately two megabases. C1 NCI, Pathol Lab, Pathogenet Unit, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NCI, Off Director, Canc Genome Anat Project, Bethesda, MD 20892 USA. Bostwick Labs, Richmond, VA USA. RP Emmert-Buck, MR (reprint author), NCI, Pathol Lab, Pathogenet Unit, Bldg 10,Room 2A33,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 28 TC 40 Z9 41 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 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD FEB PY 2002 VL 33 IS 2 BP 201 EP 205 DI 10.1002/gcc.10015 PG 5 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 508UB UT WOS:000173107000011 PM 11793446 ER PT J AU West, AG Gaszner, M Felsenfeld, G AF West, AG Gaszner, M Felsenfeld, G TI Insulators: many functions, many mechanisms SO GENES & DEVELOPMENT LA English DT Review ID ENHANCER-BLOCKING ACTIVITY; MATRIX-ATTACHMENT REGIONS; HAIRY-WING PROTEIN; BETA-GLOBIN LOCUS; CHROMATIN DOMAIN BOUNDARY; GAGA TRANSCRIPTION FACTOR; POLYMERASE-II HOLOENZYME; DROSOPHILA-MELANOGASTER; BITHORAX COMPLEX; DNA-BINDING C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. OI West, Adam/0000-0003-3502-7804 NR 133 TC 408 Z9 428 U1 0 U2 21 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD FEB 1 PY 2002 VL 16 IS 3 BP 271 EP 288 DI 10.1101/gad.954702 PG 18 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 517RN UT WOS:000173623800001 PM 11825869 ER PT J AU Chen, HW Chen, X Oh, SW Marinissen, MJ Gutkins, JS Hou, SX AF Chen, HW Chen, X Oh, SW Marinissen, MJ Gutkins, JS Hou, SX TI mom identifies a receptor for the Drosophila JAK/STAT signal transduction pathway and encodes a protein distantly related to the mammalian cytokine receptor family SO GENES & DEVELOPMENT LA English DT Article DE Drosophila; JAK/STAT; signal transduction; cytokine receptor ID JAK-STAT PATHWAY; SEX-DETERMINATION; KINASE; GENE; DIFFERENTIATION; MELANOGASTER; TYROSINE; LETHAL; PHOSPHORYLATION; TRANSCRIPTION AB The JAK/STAT signal transduction pathway controls numerous events in Drosophila melanogaster development. Receptors for the pathway have yet to be identified. Here we have identified a Drosophila gene that shows embryonic mutant phenotypes identical to those in the hopscotch (hop)/JAK kinase and marelle (mrl)/Stat92e mutations. We named this gene master of marelle (mom). Genetic analyses place mom's function between upd (the ligand) and hop. We further show that cultured cells transfected with the mom gene bind UPD and activate the HOP/STAT92E signal transduction pathway. mom encodes a protein distantly related to the mammalian cytokine receptor family. These data show that mom functions as a receptor of the Drosophila JAK/STAT signal transduction pathway. C1 NCI, Frederick Canc Res & Dev Ctr, Immunobiol Lab, NIH, Frederick, MD 21702 USA. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Hou, SX (reprint author), NCI, Frederick Canc Res & Dev Ctr, Immunobiol Lab, NIH, Frederick, MD 21702 USA. RI Chen, Hua-Wei/A-8018-2011 NR 48 TC 113 Z9 114 U1 0 U2 7 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD FEB 1 PY 2002 VL 16 IS 3 BP 388 EP 398 DI 10.1101/gad.955202 PG 11 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 517RN UT WOS:000173623800011 PM 11825879 ER PT J AU Mishina, Y Hanks, MC Miura, S Tallquist, MD Behringer, RR AF Mishina, Y Hanks, MC Miura, S Tallquist, MD Behringer, RR TI Generation of Bmpr/Alk3 conditional knockout mice SO GENESIS LA English DT Article ID BONE MORPHOGENETIC PROTEINS; MOUSE EMBRYOGENESIS; RECEPTOR; EXPRESSION C1 NIEHS, Lab Reprod & Dev Toxicol, Res Triangle Pk, NC 27709 USA. Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX USA. Procter & Gamble Pharmaceut, Hlth Care Res Ctr, Mason, OH USA. Fred Hutchinson Canc Res Ctr, Program Dev Biol, Seattle, WA USA. Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA USA. RP Mishina, Y (reprint author), NIEHS, Lab Reprod & Dev Toxicol, Res Triangle Pk, NC 27709 USA. OI Tallquist, Michelle/0000-0002-1383-144X FU NIAMS NIH HHS [AR42919] NR 14 TC 154 Z9 157 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1526-954X J9 GENESIS JI Genesis PD FEB PY 2002 VL 32 IS 2 SI SI BP 69 EP 72 DI 10.1002/gene.10038 PG 4 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 527DB UT WOS:000174169900004 PM 11857780 ER PT J AU Huang, SX Tang, BW Usoskin, D Lechleider, RJ Jamin, SP Li, CL Anzano, MA Ebendal, T Deng, CX Roberts, AB AF Huang, SX Tang, BW Usoskin, D Lechleider, RJ Jamin, SP Li, CL Anzano, MA Ebendal, T Deng, CX Roberts, AB TI Conditional knockout of the Smad1 gene SO GENESIS LA English DT Article ID RECEPTOR; GROWTH; CELLS C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Uppsala Univ, Biomed Ctr, Dept Neurosci, Uppsala, Sweden. Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX USA. NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. RP Roberts, AB (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, 41-C629, Bethesda, MD 20892 USA. RI Jamin, Soazik/F-6796-2015; deng, chuxia/N-6713-2016 NR 13 TC 31 Z9 32 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 1526-954X J9 GENESIS JI Genesis PD FEB PY 2002 VL 32 IS 2 SI SI BP 76 EP 79 DI 10.1002/gene.10059 PG 4 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 527DB UT WOS:000174169900006 PM 11857782 ER PT J AU Yang, X Li, CL Herrera, PL Deng, CX AF Yang, X Li, CL Herrera, PL Deng, CX TI Generation of Smad4/Dpc4 conditional knockout mice SO GENESIS LA English DT Article ID SUPPRESSOR C1 NIDDK, GDDB, Mammalian Genet Sect, NIH, Bethesda, MD 20892 USA. Univ Geneva, Med Sch, Dept Morphol, Geneva, Switzerland. RP Deng, CX (reprint author), NIDDK, GDDB, Mammalian Genet Sect, NIH, 10-9N105 10 Ctr Dr, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016; OI /0000-0003-0771-9504 NR 9 TC 135 Z9 151 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1526-954X J9 GENESIS JI Genesis PD FEB PY 2002 VL 32 IS 2 SI SI BP 80 EP 81 DI 10.1002/gene.10029 PG 2 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 527DB UT WOS:000174169900007 PM 11857783 ER PT J AU Xu, XL Qiao, WH Li, CL Deng, CX AF Xu, XL Qiao, WH Li, CL Deng, CX TI Generation of Fgfr1 conditional knockout mice SO GENESIS LA English DT Article ID CRE RECOMBINASE; GROWTH; CELLS C1 NIDDK, GDDB, Mammalian Genet Sect, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDK, GDDB, Mammalian Genet Sect, 10-9N105 10 Ctr Dr, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 13 TC 35 Z9 38 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 1526-954X J9 GENESIS JI Genesis PD FEB PY 2002 VL 32 IS 2 SI SI BP 85 EP 86 DI 10.1002/gene.10028 PG 2 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 527DB UT WOS:000174169900009 PM 11857785 ER PT J AU Swope, DL Castranio, T Harrell, JC Mishina, Y Korach, KS AF Swope, DL Castranio, T Harrell, JC Mishina, Y Korach, KS TI AF-2 knock-in mutation of estrogen receptor alpha: Cre-LoxP excision of a PGK-neo cassette from the 3 ' UTR SO GENESIS LA English DT Article ID MOUSE; GENE C1 Natl Inst Environm Hlth Sci, Lab Reprod & Dev Toxicol, Res Triangle Pk, NC 27709 USA. RP Swope, DL (reprint author), Natl Inst Environm Hlth Sci, Lab Reprod & Dev Toxicol, 111 T W Alexander Dr, Res Triangle Pk, NC 27709 USA. OI Korach, Kenneth/0000-0002-7765-418X NR 8 TC 2 Z9 2 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 1526-954X J9 GENESIS JI Genesis PD FEB PY 2002 VL 32 IS 2 SI SI BP 99 EP 101 DI 10.1002/gene.10075 PG 3 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 527DB UT WOS:000174169900013 PM 11857789 ER PT J AU Andrews, J Oliver, B AF Andrews, J Oliver, B TI Sex determination signals control ovo-B transcription in Drosophila melanogaster germ cells SO GENETICS LA English DT Article ID OVARIAN TUMOR GENE; INDUCTIVE SIGNALS; X-CHROMOSOME; LINE; LETHAL; LOCUS; SOMA; MAINTENANCE; SELECTION; MUTATIONS AB Nonautonomous inductive signals from the soma and autonomous signals due to a 2X karyotype determine the sex of Drosaphila melanogaster germ cells. These two signals have partially overlapping influences on downstream sex determination genes. The upstream OVO-B transcription factor is required for the viability of 2X germ cells, regardless of sexual identity, and for female germline sexual identity. The influence of inductive and autonomous signals on ovo expression has been controversial. We show that ovo-B is strongly expressed in the 2X germ cells in either a male or a female soma. This indicates that a 2X karyotype controls ovo-B expression in the absence of inductive signals from the female soma. However, we also show that female inductive signals positively regulate ovo-B transcription in the 1X germ cells that do not require ovo-B function. Genetic analysis clearly indicates that inductive signals from the soma are not required for ovo-B function in 2X germ cells. Thus, while somatic inductive signals and chromosome karyotype have overlapping regulatory influences, a 2X karyotype is a critical germline autonomous determinant of ovo-B function in the germline. C1 NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Oliver, B (reprint author), NIDDK, LCDB, NIH, 50 South Dr, Bethesda, MD 20892 USA. NR 36 TC 5 Z9 5 U1 0 U2 3 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD FEB PY 2002 VL 160 IS 2 BP 537 EP 545 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 525WT UT WOS:000174097600019 PM 11861560 ER PT J AU Davis, ES Wille, L Chestnut, BA Sadler, PL Shakes, DC Golden, A AF Davis, ES Wille, L Chestnut, BA Sadler, PL Shakes, DC Golden, A TI Multiple subunits of the Caenorhabditis elegans anaphase-promoting complex are required for chromosome segregation during meiosis I SO GENETICS LA English DT Article ID FUNCTIONAL GENOMIC ANALYSIS; SISTER-CHROMATID COHESION; C-ELEGANS; SACCHAROMYCES-CEREVISIAE; SCHIZOSACCHAROMYCES-POMBE; TETRATRICOPEPTIDE REPEAT; CELL-DIVISION; IDENTIFICATION; MITOSIS; GENE AB Two genes, originally identified in genetic screens for Caenorhabditis elegans mutants that arrest in metaphase of meiosis 1, prove to encode subunits of the anaphase-promoting complex or cyclosome (APC/C). RNA interference studies reveal that these and other APC/C subunits are essential for the segregation of chromosomal homologs during meiosis I. Further, chromosome segregation during meiosis I requires APC/C functions in addition to the release of sister chromatid cohesion. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. Coll William & Mary, Dept Biol, Williamsburg, VA 23187 USA. RP Golden, A (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bldg 8,Rm 323,8 Ctr Dr,MSC 0840, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [R15 GM60359-01] NR 45 TC 53 Z9 60 U1 1 U2 3 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD FEB PY 2002 VL 160 IS 2 BP 805 EP 813 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 525WT UT WOS:000174097600040 PM 11861581 ER PT J AU Anisimov, SV Tarasov, KV Tweedie, D Stern, MD Wobus, AM Boheler, KR AF Anisimov, SV Tarasov, KV Tweedie, D Stern, MD Wobus, AM Boheler, KR TI SAGE identification of gene transcripts with profiles unique to pluripotent mouse R1 embryonic stem cells SO GENOMICS LA English DT Article DE embryonic stem cells; SAGE technique; Q-PCR; transcriptome; pluripotentiality; gene expression; gene profile ID KRUPPEL-LIKE FACTOR; SERIAL ANALYSIS; SELF-RENEWAL; DIFFERENTIATION; EXPRESSION; LINE; ACTIVATION; ESTABLISHMENT; INHIBITION; CULTURE AB The identification of signals that regulate pluripotentiality and self-renewal is fundamental to the understanding of stem cell biology. To quantify the functionally active genome of pluripotent R1 embryonic stem (ES) cells, we used the method of serial analysis of gene expression (SAGE) to sequence a total of 140,313 SAGE tags. Of 44,569 unique transcripts, 9% matched known genes in the nonredundant GenBank database, whereas > 35% of the unique tags did not match any known mouse sequence. Comparisons of relatively abundant (greater than or equal to 20) tags in the ES cell SAGE catalog with publicly available SAGE data sets identified 16 transcripts with an abundance profile unique to pluripotent R1 ES cells. We confirmed 12 by RTPCR including those encoding KLF2, a transcription factor; galanin, a hypothalamic neurohormone; BAX, a proapoptotic signaling factor; and CDK4 and PAL31, cell cycle progression associated proteins. The data from this study provide a starting point for detailed transcriptome analyses of stem cells. C1 NIA, NIH, Baltimore, MD 21224 USA. Inst Plant Genet, D-06466 Gatersleben, Germany. RP Boheler, KR (reprint author), NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 40 TC 74 Z9 78 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 0888-7543 J9 GENOMICS JI Genomics PD FEB PY 2002 VL 79 IS 2 BP 169 EP 176 DI 10.1006/geno.2002.6687 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 517UG UT WOS:000173628100006 PM 11829487 ER PT J AU Sierra, DA Gilbert, DJ Householder, D Grishin, NV Yu, K Ukidwe, P Barker, SA He, W Wensel, TG Otero, G Brown, G Copeland, NG Jenkins, NA Wilkie, TM AF Sierra, DA Gilbert, DJ Householder, D Grishin, NV Yu, K Ukidwe, P Barker, SA He, W Wensel, TG Otero, G Brown, G Copeland, NG Jenkins, NA Wilkie, TM TI Evolution of the regulators of G-protein signaling multigene family in mouse and human SO GENOMICS LA English DT Article DE GAP; GTPase accelerating protein (GAP); G gamma-like (GGL); G-protein coupled receptor (GPCR); multigene family; phylogenetic tree ID GTPASE-ACTIVATING PROTEIN; HETEROTRIMERIC G-PROTEINS; GENETIC-LINKAGE MAP; RGS PROTEINS; CHROMOSOMAL LOCALIZATION; CAENORHABDITIS-ELEGANS; BETA; INHIBITION; DOMAINS; CLONING AB The regulators of G-protein signaling (RGS) proteins are important regulatory and structural components of G-protein coupled receptor complexes. RGS proteins are GTPase activating proteins (GAPS) of Gi- and Gq-class Galpha proteins, and thereby accelerate signaling kinetics and termination. Here, we mapped the chromosomal positions of all 21 Rgs genes in mouse, and determined human RGS gene structures using genomic sequence from partially assembled bacterial artificial chromosomes (BACs) and Celera fragments. In mice and humans, 18 of 21 RGS genes are either tandemly duplicated or tightly linked to genes encoding other components of G-protein signaling pathways, including Galpha, Ggamma, receptors (GPCR), and receptor kinases (GPRK). A phylogenetic tree revealed seven RGS gene subfamilies in the yeast and metazoan genomes that have been sequenced. We propose that similar systematic analyses of all multigene families from human and other mammalian genomes will help complete the assembly and annotation of the human genome sequence. C1 UT SW, Dept Pharmacol, Dallas, TX USA. NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. UT SW, Dept Biochem, Howard Hughes Med Inst, Dallas, TX USA. Baylor Coll Med, Houston, TX 77030 USA. DoubleTwist, Oakland, CA 94612 USA. RP Wilkie, TM (reprint author), UT SW, Dept Pharmacol, Dallas, TX USA. EM thomas.wilkie@utsouthwestern.edu OI Wensel, Theodore/0000-0003-3518-9352 NR 51 TC 63 Z9 63 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD FEB PY 2002 VL 79 IS 2 BP 177 EP 185 DI 10.1006/geno.2002.6693 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 517UG UT WOS:000173628100007 PM 11829488 ER PT J AU Trudeau, M Stuart, G Hirte, H Drouin, P Plante, M Bessette, P Dulude, H Lebwohl, D Fisher, B AF Trudeau, M Stuart, G Hirte, H Drouin, P Plante, M Bessette, P Dulude, H Lebwohl, D Fisher, B TI A phase II trial of JM-216 in cervical cancer: An NCICCTG study SO GYNECOLOGIC ONCOLOGY LA English DT Article ID ORAL PLATINUM COMPLEX; CARCINOMA; JM216; CISPLATIN; RECURRENT AB Objective. BMS-182751 (JM-216) is an orally bioavailable platinum compound with activity in platinum-sensitive and platinum-resistant preclinical models. The objective was to determine its activity in recurrent/metastatic squamous cell carcinoma of the cervix. Methods. We conducted a phase 11 study of BMS-182751 given at a dose of 30 mg/m(2) daily for 14 days every 5 weeks. Results. Eighteen patients (pts) with advanced/recurrent squamous cancer of the cervix not amenable to curative therapy with measurable disease who had received no prior chemotherapy for systemic disease were entered, all of whom are evaluable for response and toxicity. Median age was 47 years (35-74 years); all pts had received prior pelvic irradiation (RT); 4 pts had received cisplatin as adjustment therapy with radiation; PS was 0 (45 pts), 1 (7 pts), and 2 (5 pts); sites of disease included nodes (10 pts), pelvis (5 pts), lung (4 pts), and bone (3 pts). Median number of cycles was two (1-6) with 8 pts receiving three or more cycles. Toxicity was modest and usually grade 1 or 2 in severity with the most frequent drug related toxicity being nausea (56%), fatigue (50%), anorexia (39%), diarrhea (39%), vomiting (39%), constipation (28%), and altered taste (22%). Six pis had grade 3 or 4 granulocytopenia and only I pt, grade 3 or 4 thrombocytopenia. Two pts had grade 2 or 3 creatinine increases. There were no treatment-related deaths. One pt with a treatment-free interval of 30 years achieved a partial response, while 12 pts had a best response of stable disease. Conclusions. BMS-182751 is generally well tolerated, but has limited activity in pts with recurrent cervical cancer. (C) 2002 Elsevier Science. C1 NCI, Canada Clin Trials Grp, Kingston, ON, Canada. Bristol Myers Squibb, Wallingford, CT USA. RP Trudeau, M (reprint author), Royal Victoria Hosp, Div Med Oncol, 687 Pine Ave W, Montreal, PQ H3A 1A1, Canada. NR 14 TC 21 Z9 22 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 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2002 VL 84 IS 2 BP 327 EP 331 DI 10.1006/gyno.2001.6409 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 520UE UT WOS:000173799100023 PM 11812095 ER PT J AU Beck, KH Hartos, J Simons-Morton, B AF Beck, KH Hartos, J Simons-Morton, B TI Teen driving risk: The promise of parental influence and public policy SO HEALTH EDUCATION & BEHAVIOR LA English DT Article ID GRADUATED LICENSING PROGRAM; MOTOR-VEHICLE CRASHES; LONGITUDINAL EXAMINATION; 16-YEAR-OLD DRIVERS; YOUNG DRIVERS; UNITED-STATES; SUBSTANCE USE; DRINKING; ADOLESCENTS; INVOLVEMENT AB An analysis is presented of adolescent driving risk, the advantages of graduated licensing programs, and the potential for parent-based programs to moderate teen driving risks. Risk factors associated with youthful driving illustrate the potential importance and benefits of limiting the amount and conditions under which teens can drive. State policies, such as graduated driver licensing systems that formalize restrictions on youthful driving, have been shown to be effective. However, teen driving risks remain elevated. Parents are in a prime position to extend the benefits of state restrictions by developing and implementing their own tailored family policies on adolescent driving. Unfortunately, parents of adolescent drivers are often under-aware of the need to do so and fail to impose effective driving restrictions. An ongoing parent-based intervention to increase parental restriction on teen driving is described, and issues involved in implementing and evaluating family-centered approaches to reduce teen driving risk are raised. C1 Univ Maryland, Dept Publ & Community Hlth, College Pk, MD 20742 USA. NICHHD, Div Epidemiol Stat & Prevent Res, Prevent Res Branch, Bethesda, MD 20892 USA. RP Beck, KH (reprint author), Univ Maryland, Dept Publ & Community Hlth, Hlth & Human Performance Bldg, College Pk, MD 20742 USA. OI Simons-Morton, Bruce/0000-0003-1099-6617 NR 67 TC 19 Z9 19 U1 1 U2 8 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 FEB PY 2002 VL 29 IS 1 BP 73 EP 84 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 512MA UT WOS:000173327100006 PM 11822554 ER PT J AU Bourdi, M Masubuchi, Y Reilly, TP Amouzadeh, HR Martin, JL George, JW Shah, AG Pohl, LR AF Bourdi, M Masubuchi, Y Reilly, TP Amouzadeh, HR Martin, JL George, JW Shah, AG Pohl, LR TI Protection against acetaminophen-induced liver injury and lethality by interleukin 10: Role of inducible nitric oxide synthase SO HEPATOLOGY LA English DT Article; Proceedings Paper CT 13th International Symposium on Microsomes and Drug Oxidations CY JUL, 2000 CL STRESA, ITALY ID IN-VIVO; MICE; HEPATOTOXICITY; INDUCTION; TOLERANCE; FIBROSIS; DISEASE; FAILURE; HEPATOCYTES; EXPRESSION AB Mechanistic study of idiosyncratic drug-induced hepatitis (DIH) continues to be a challenging problem because of the lack of animal models. The inability to produce this type of hepatotoxicity in animals, and its relative rarity in humans, may be linked to the production of anti-inflammatory factors that prevent drug-protein adducts from causing liver injury by immune Z, p and nonimmune mechanisms. We tested this hypothesis by using a model of acetaminophen (APAP)-induced liver injury in mice. After APAP treatment, a significant increase was observed in serum levels of interleukin (IL)-4, IL-10, and IL-13, cytokines that regulate inflammatory mediator production and cell-mediated autoimmunity. When IL-10 knockout (KO) mice were treated with APAP, most of these mice died within 24 to 48 hours from liver injury. This increased susceptibility to APAP-induced liver injury appeared to correlate with an elevated expression of liver proinflammatory cytokines, tumor necrosis factor (TNF)-alpha, and IL-1, as well as inducible nitric oxide synthase (iNOS). In this regard, mice lacking both IL-10 and iNOS genes were protected from APAP-induced liver injury and lethality when compared with IL-10 KO mice. All strains, including wild-type animals, generated similar amounts of liver APAP-protein adducts, indicating that the increased susceptibility of IL-10 KO mice to APAP hepatotoxicity was not caused by an enhanced formation of APAP-protein adducts. In conclusion, these findings suggest that an important feature of the normal response to drug-induced liver injury may be the increased expression of anti-inflammatory factors such as IL-10. Certain polymorphisms of these factors may have a role in determining the susceptibility of individuals to idiosyncratic DIH. C1 NHLBI, Lab Mol Immunol, Mol & Cellular Toxicol Sect, NIH, Bethesda, MD 20892 USA. Chiba Univ, Grad Sch Pharmaceut Sci, Dept Biopharmaceut, Chiba, Japan. Johns Hopkins Med Inst, Dept Anesthesiol, Baltimore, MD 21205 USA. RP Bourdi, M (reprint author), NHLBI, Lab Mol Immunol, Mol & Cellular Toxicol Sect, NIH, Bldg 10,Room 8N110, Bethesda, MD 20892 USA. NR 52 TC 176 Z9 184 U1 0 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD FEB PY 2002 VL 35 IS 2 BP 289 EP 298 DI 10.1053/jhep.2002.30956 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 516GT UT WOS:000173546100006 PM 11826401 ER PT J AU Nguyen, VA Gao, B AF Nguyen, VA Gao, B TI Expression of interferon alfa signaling components in human alcoholic liver disease SO HEPATOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; CHRONIC HEPATITIS-C; STIMULATED JAK/STAT PATHWAY; DEPENDENT MECHANISM; NEGATIVE REGULATOR; DIFFERENTIAL REGULATION; VIRAL-HEPATITIS; ETHANOL; CELLS; THERAPY AB Interferon alfa (IFN-alpha) is currently the only well-established therapy for viral hepatitis. However, its effectiveness is much reduced (<10%) in alcoholic patients. The mechanism underlying this resistance is not fully understood. In this study, we examined the expression of IFN-alpha signaling components and its inhibitory factors in 9 alcoholic liver disease (ALD) and 8 healthy control liver tissues. In comparison with normal control livers, expression of IFN-beta, IFN-alpha receptor 1/2, Jak1, and Tyk2 remained unchanged in ALD livers, whereas expression of IFN-alpha, signal transducer and activator of transcription factor 1 (STAT1), and p48 were up-regulated and expression of STAT2 was down-regulated. Expression of antiviral MxA a karyophilic 75 kd protein induced by IFN in mouse cells carrying the influenza virus resistance allele Mx(+) and 2'-5' oligoadenylate synthetase (OAS) proteins was not regulated, whereas expression of double-stranded RNA-activated protein kinase (PKR) was decreased by 55% in ALD livers. Three families of inhibitory factors for the JAK-STAT signaling pathway were examined in ALD livers. Members of the suppressor of cytokine signaling (SOCS) family, including SOCS 1, 2, 3, and CIS, and the protein tyrosine phosphatases, including Shp-1, Shp-2, and CD45, were not up-regulated in ALD livers, whereas the phosphorylation of and protein levels of p42/44 mitogen-activated protein kinase (p42/44MAP kinase) were increased about 3.9- and 3.2-fold in ALD livers in comparison with normal control livers, respectively. In conclusion, these findings suggest that chronic alcohol consumption down-regulates STAT2 and PKR, but up-regulates p42/44 mitogen-activated protein kinase (p42/44MAP kinase), which may cause down-regulation of IFN-a signaling in the liver of ALD patients. C1 NIAAA, NIH, Sect Liver Biol, Lab Physiol Studies, Bethesda, MD 20892 USA. RP Gao, B (reprint author), NIAAA, NIH, Sect Liver Biol, Lab Physiol Studies, Pk Bldg Rm 120,12420 Parklawn Dr, Bethesda, MD 20892 USA. NR 49 TC 17 Z9 20 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 FEB PY 2002 VL 35 IS 2 BP 425 EP 432 DI 10.1053/jhep.2002.31169 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 516GT UT WOS:000173546100024 PM 11826419 ER PT J AU Singh, GK Siahpush, M AF Singh, GK Siahpush, M TI Ethnic-immigrant differentials in health behaviors, morbidity, and cause-specific mortality in the United States: An analysis of two national data bases SO HUMAN BIOLOGY LA English DT Article DE immigrant; nativity; race/ethnicity; mortality; morbidity; chronic disease; socioeconomic status; smoking; acculturation; Cox regression ID BORN US RESIDENTS; NEW-YORK-CITY; LONGITUDINAL MORTALITY; SOCIOECONOMIC-STATUS; ALCOHOL-CONSUMPTION; INSURANCE COVERAGE; CANCER MORTALITY; ADULT MORTALITY; WELFARE-REFORM; POPULATION AB This study examines the extent to which various ethnic-immigrant and US-born groups differ in their risks of all-cause and cause-specific mortality, morbidity, and health behaviors. Using data from the National Longitudinal Mortality Study, 1979-1989, we estimated, for major US racial and ethnic groups, mortality risks of immigrants relative to those of the US-born. The Cox regression model was used to adjust mortality differentials by age, sex, marital status, rural/urban residence, education, and family income. Logistic regression was fitted to the National Health Interview Survey data to determine whether health status and behaviors vary among ethnic-immigrant groups and by length of US residence. Compared with US-born whites of equivalent socioeconomic and demographic background, foreign-born blacks, Hispanics, and Asians/Pacific Islanders (APIs), US-born APIs, US-born Hispanics, and foreign-born whites had, respectively, 48%, 45%, 43%, 32%, 26%, and 16% lower mortality risks. While American Indians did not differ significantly from US-born whites, US-born blacks had an 8% higher mortality risk. Black and Hispanic immigrants experienced, respectively, 52% and 26% lower mortality risks than their US-born counterparts. Considerable differentials were also found in mortality for cancer, cardiovascular, respiratory, infectious disease, and injury, and in morbidity and health behaviors, with API and Hispanic immigrants generally experiencing the lowest risks. Consistent with the acculturation hypothesis, immigrants' risks of smoking, obesity, hypertension, and chronic condition, although substantially lower than those for the US-born, increased with increasing length of US residence. Given the substantial nativity differences in health status and mortality, future waves of immigrants of diverse ethnic and cultural backgrounds will likely have a sizeable impact on the overall health, disease, and mortality patterns in the United States. C1 NIH, Bethesda, MD 20892 USA. Anti Canc Council Victoria, Canc Control Res Inst, VicHlth Ctr Tobacco Control, Carlton, Vic, Australia. RP Singh, GK (reprint author), NIH, 616 Execut Blvd,Suite 504, Bethesda, MD 20892 USA. NR 55 TC 381 Z9 383 U1 5 U2 42 PU WAYNE STATE UNIV PRESS PI DETROIT PA 4809 WOODWARD AVE, DETROIT, MI 48201-1309 USA SN 0018-7143 J9 HUM BIOL JI Hum. Biol. PD FEB PY 2002 VL 74 IS 1 BP 83 EP 109 DI 10.1353/hub.2002.0011 PG 27 WC Biology; Genetics & Heredity SC Life Sciences & Biomedicine - Other Topics; Genetics & Heredity GA 540MX UT WOS:000174933700007 PM 11931581 ER PT J AU Martin, KR Barrett, JC AF Martin, KR Barrett, JC TI Reactive oxygen species as double-edged swords in cellular processes: low-dose cell signaling versus high-dose toxicity SO HUMAN & EXPERIMENTAL TOXICOLOGY LA English DT Article ID OXIDATIVE STRESS; REDOX REGULATION; FREE-RADICALS; ANTIOXIDANTS; OXIDANTS; CANCER; TRANSDUCTION; FIBROBLASTS; INHIBITION; GENERATION AB ROS are diverse and abundant in biological systems. While excessive ROS production clearly damages DNA, low levels of ROS affect cell signaling particularly at the level of redox modulation. Moreover, the specific contributions of ROS to apoptosis and mitogenesis in maintenance of cell number homeostasis remains to be elucidated. ROS dose is a critical parameter in determining the ultimate cellular response; however the shape of the dose response curve is unpredictable. When cells are stimulated with ROS, cell-signaling cascades are activated. It appears that the cellular redox potential is an important determinant of cell function and interruption of redox balance may adversely affect cell function. As a result, compounds such as antioxidants may intercept critical ROS signaling molecules and both protect cells and foster pathogenesis. As a result, further study is needed to unravel the role of ROS in redox regulation and the potential outcome of antioxidant administration on cellular responses. C1 NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. NCI, Lab Biophys & Canc, Bethesda, MD 20892 USA. RP Martin, KR (reprint author), NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. RI Bell, Tiffany/F-4403-2010 NR 25 TC 145 Z9 152 U1 0 U2 3 PU ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 0960-3271 J9 HUM EXP TOXICOL JI Hum. Exp. Toxicol. PD FEB PY 2002 VL 21 IS 2 BP 71 EP 75 DI 10.1191/0960327102ht213oa PG 5 WC Toxicology SC Toxicology GA 560UB UT WOS:000176098800005 PM 12102499 ER PT J AU Stadtman, ER Levine, RL AF Stadtman, ER Levine, RL TI Why have cells selected reactive oxygen species to regulate cell signaling events? SO HUMAN & EXPERIMENTAL TOXICOLOGY LA English DT Article DE apoptosis; H2O2; ROS AB There is a growing body of evidence demonstrating that exposure of cells to reactive oxygen species (ROS) leads to oxidative modification of nucleic acids, proteins, and lipids, and that such modifications can contribute to the development of a number of diseases and aging. This raises the question: If ROS are so damaging to cells, why have cells selected ROS to trigger activation of so many cell signaling pathways? C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Stadtman, ER (reprint author), NHLBI, Biochem Lab, NIH, 50 South Dr,Room 2140,MSC 8012, Bethesda, MD 20892 USA. RI Levine, Rodney/D-9885-2011 NR 0 TC 11 Z9 11 U1 0 U2 2 PU ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 0960-3271 J9 HUM EXP TOXICOL JI Hum. Exp. Toxicol. PD FEB PY 2002 VL 21 IS 2 BP 83 EP 83 DI 10.1191/0960327102ht215oa PG 1 WC Toxicology SC Toxicology GA 560UB UT WOS:000176098800007 PM 12102501 ER PT J AU Otsu, M Hershfield, MS Tuschong, LM Muul, LM Onodera, M Ariga, T Sakiyama, Y Candotti, F AF Otsu, M Hershfield, MS Tuschong, LM Muul, LM Onodera, M Ariga, T Sakiyama, Y Candotti, F TI Flow Cytometry analysis of adenosine deaminase (ADA) expression: A simple and reliable tool for the assessment of ADA-deficient patients before and after gene therapy SO HUMAN GENE THERAPY LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; CELL-LINES; RETROVIRAL VECTORS; IMMUNE-DEFICIENCY; BONE-MARROW; MUTATIONS; LYMPHOCYTES; PHENOTYPE; GENOTYPE; LEUKEMIA AB Clinical gene therapy trials for adenosine deaminase (ADA) deficiency have shown limited success of corrective gene transfer into autologous T lymphocytes and CD34(+) cells. In these trials, the levels of gene transduction and expression in hematopoietic cells have been assessed by DNA- or RNA-based assays and measurement of ADA enzyme activity. Although informative, these methods are rarely applied to clonal analysis. The results of these assays therefore provide best estimates of transduction efficiency and gene expression in bulk populations based on the assumption that gene transfer and expression are uniformly distributed among transduced cells. As a useful additional tool for evaluation of ADA gene expression, we have developed a flow cytometry (fluorescence-activated cell sorting, FACS) assay capable of estimating the levels of intracellular ADA on a single-cell basis. We validated this technique with T cell lines and peripheral blood mononuclear cells (PBMCs) from ADA-deficient patients that showed severely reduced levels of ADA expression (ADA-dull) by FACS and Western blot analyses. After retrovirus-mediated ADA gene transfer, these cells showed clearly distinguishable populations exhibiting ADA expression (ADA-bright), thus allowing estimation of transduction efficiency. By mixing ADA-deficient and normal cells and using enzymatic amplification, we determined that our staining procedure could detect as little as 5% ADA-bright cells. This technique, therefore, will be useful to quickly assess the expression of ADA in hematopoietic cells of severe combined immunodeficient patients and represents an important tool for the follow-up of patients treated in clinical gene transfer protocols. C1 NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Div Rheumatol & Immunol, Durham, NC 27710 USA. NHGRI, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. Univ Tsukuba, Inst Clin Med, Dept Hematol, Tsukuba, Ibaraki 3058575, Japan. Hokkaido Univ, Sch Med, Dept Human Gene Therapy, Sapporo, Hokkaido 0608638, Japan. RP Candotti, F (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 10C103,MSC 1851, Bethesda, MD 20892 USA. RI Ariga, Tadashi/A-4252-2012; OI Otsu, Makoto/0000-0002-9769-0217 NR 36 TC 9 Z9 9 U1 0 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD FEB PY 2002 VL 13 IS 3 BP 425 EP 432 DI 10.1089/10430340252792558 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 526GC UT WOS:000174120900008 PM 11860709 ER PT J AU Rozenblum, E Vahteristo, P Sandberg, T Bergthorsson, JT Syrjakoski, K Weaver, D Haraldsson, K Johannsdottir, HK Vehmanen, P Nigam, S Golberger, N Robbins, C Pak, E Dutra, A Gillander, E Stephan, DA Bailey-Wilson, J Juo, SHH Kainu, T Arason, A Barkardottir, RB Nevanlinna, H Borg, A Kallioniemi, OP AF Rozenblum, E Vahteristo, P Sandberg, T Bergthorsson, JT Syrjakoski, K Weaver, D Haraldsson, K Johannsdottir, HK Vehmanen, P Nigam, S Golberger, N Robbins, C Pak, E Dutra, A Gillander, E Stephan, DA Bailey-Wilson, J Juo, SHH Kainu, T Arason, A Barkardottir, RB Nevanlinna, H Borg, A Kallioniemi, OP TI A genomic map of a 6-Mb region at 13q21-q22 implicated in cancer development: identification and characterization of candidate genes SO HUMAN GENETICS LA English DT Article ID CELL-LINES; HYBRIDIZATION; PROGESTERONE; OVEREXPRESSION; LYMPHOCYTES; FAMILIES; SEQUENCE; REVEALS; BINDING; PROTEIN AB Chromosomal region 13q21-q22 harbors a putative breast cancer susceptibility gene and has been implicated as a common site for somatic deletions in a variety of malignant tumors. We have built a complete physical clone contig for a region between D13S1308 and AFM220YE9 based on 18 yeast artificial chromosome and 81 bacterial artificial chromosome (BAC) clones linked together by 22 genetic markers and 61 other sequence tagged sites. Combining data from 47 sequenced BACs (as of June 2001), we have assembled in silico an integrated 5.7-Mb genomic map with 90% sequence coverage. This area contains eight known genes, two hypothetical proteins, 24 additional Unigene clusters, and approximately 100 predicted genes and exons. We have determined the cDNA and genomic sequence, and tissue expression profiles for the KIAA1008 protein (homologous to the yeast mitotic control protein dis3+), KLF12 (AP-2 repressor), progesterone induced blocking factor 1, zinc finger transcription factor KLF5, and LIM domain only-7, and for the hypothetical proteins FLJ22624 and FLJ21869. Mutation screening of the five known genes in 19 breast cancer families has revealed numerous polymorphisms, but no deleterious mutations. These data provide a basis and resources for further analyses of this chromosomal region in the development of cancer. C1 NHGRI, NIH, Canc Genet Branch, Bethesda, MD 20892 USA. NHGRI, NIH, Inherited Dis Res Branch, Bethesda, MD 20892 USA. NHGRI, NIH, Genet Dis Res Branch, Bethesda, MD 20892 USA. Tampere Univ, Canc Genet Lab, Tampere 33520, Finland. Tampere Univ Hosp, Tampere 33520, Finland. Univ Helsinki, Cent Hosp, Helsinki 00029, Finland. Univ Lund Hosp, Dept Oncol, S-22185 Lund, Sweden. Univ Hosp Iceland, Cell Biol Lab, Dept Pathol, IS-101 Reykjavik, Iceland. RP Kallioniemi, OP (reprint author), NHGRI, NIH, Canc Genet Branch, Bethesda, MD 20892 USA. EM okalli@nhgri.nih.gov RI Juo, Suh-Hang/A-1765-2010; Kallioniemi, Olli/H-5111-2011; Juo, Suh-Hang/C-9545-2009; Kallioniemi, Olli/H-4738-2012; OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332; Arason, Adalgeir/0000-0003-0480-886X; Bailey-Wilson, Joan/0000-0002-9153-2920; Nevanlinna, Heli/0000-0002-0916-2976 NR 30 TC 50 Z9 54 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD FEB PY 2002 VL 110 IS 2 BP 111 EP 121 DI 10.1007/s00439-001-0646-6 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 536GF UT WOS:000174691800001 PM 11935316 ER PT J AU Chang, BL Zheng, SL Hawkins, GA Isaacs, SD Wiley, KE Turner, A Carpten, JD Bleecker, ER Walsh, PC Trent, JM Meyers, DA Isaacs, WB Xu, JF AF Chang, BL Zheng, SL Hawkins, GA Isaacs, SD Wiley, KE Turner, A Carpten, JD Bleecker, ER Walsh, PC Trent, JM Meyers, DA Isaacs, WB Xu, JF TI Polymorphic GGC repeats in the androgen receptor gene are associated with hereditary and sporadic prostate cancer risk SO HUMAN GENETICS LA English DT Article ID PARENTAL-GENOTYPE RECONSTRUCTION; FAMILY HISTORY; CAG REPEAT; TRANSMISSION/DISEQUILIBRIUM TEST; LINKAGE DISEQUILIBRIUM; DOMINANT INHERITANCE; MEN; POPULATION; CHROMOSOME; 1Q42.2-43 AB Androgen receptor (AR) has long been hypothesized to play an important role in prostate cancer etiology. Two trinucleotide repeat polymorphisms (CAG and GGC repeats in exon 1 of the AR gene) have been investigated as risk factors for prostate cancer in several studies. However, the results are inconclusive, probably because of the variations of study designs, characteristics of study samples, and choices of analytical methods. In this study, we evaluated evidence for linkage and association between the two AR repeats and prostate cancer by using the following comprehensive approaches: (1) a combination of link-age and association studies, (2) a test for linkage by parametric analysis and the male-limited X-linked transmission/disequilibrium test (XLRC-TDT), (3) a test for association by using both population-based and family-based tests, and (4) a study of both hereditary and sporadic cases. A positive but weak link-age score (HLOD=0.49, P=0.12) was identified in the AR region by parametric analysis; however, stronger evidence for link-age in the region, especially at the GGC locus, was observed in the subset of families whose proband had less than or equal to16 GGC repeats (HLOD=0.70, P=0.07) or by using XLRC-TDT (z'=2.65, P=0.008). Significantly increased frequencies of the less than or equal to16 GGC repeat alleles in 159 independent hereditary cases (71%) and 245 sporadic cases (68%) cases compared with 211 controls (59%) suggested that GGC repeats were associated with prostate cancer (P=0.02). Evidence for the association between the less than or equal to16 GGC repeats and prostate cancer risk was stronger with XLRC-TDT (z'=2.66, P=0.007). No evidence for association between the CAG repeats and prostate cancer risk was observed. The consistent results from both linkage and association studies strongly implicate the GGC repeats in the AR as a prostate cancer susceptibility gene. Further studies on this polymorphism in other independent data sets and functional analysis of the GGC repeat length on AR activity are warranted. C1 Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC 27157 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Xu, JF (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Med Ctr Blvd, Winston Salem, NC 27157 USA. FU NCI NIH HHS [CA58236] NR 50 TC 59 Z9 61 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 FEB PY 2002 VL 110 IS 2 BP 122 EP 129 DI 10.1007/s00439-001-0662-6 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 536GF UT WOS:000174691800002 PM 11935317 ER PT J AU Bukoski, RD Batkai, S Jarai, Z Wang, YL Offertaler, L Jackson, WF Kunos, G AF Bukoski, RD Batkai, S Jarai, Z Wang, YL Offertaler, L Jackson, WF Kunos, G TI CB1 receptor antagonist SR141716A inhibits Ca2+-induced relaxation in CB1 receptor-deficient mice SO HYPERTENSION LA English DT Article DE mesenteric arteries; calcium; relaxation; potassium channels ID ISOLATED MESENTERIC-ARTERY; CANNABINOID RECEPTOR; SELECTIVE ANTAGONIST; INTERSTITIAL CA2+; ANANDAMIDE; POTENT; BINDS; CELLS AB Mesenteric branch arteries isolated from cannabinoid type 1 receptor knockout (CB1-/-) mice, their wild-type littermates (CB1+/+ mice), and C57BL/J wild-type mice were studied to test the hypothesis that murine arteries undergo high sensitivity Ca2+-induced relaxation that is CB1 receptor dependent. Confocal microscope analysis of mesenteric branch arteries from wild-type mice showed the presence of Ca2+ receptor-positive periadventitial nerves. Arterial segments of C57 control mice mounted on wire myographs contracted in response to 5 mumol/L norepinephrine and responded to the cumulative addition of extracellular Ca2+ with a concentration-dependent relaxation that reached a maximum of 72.0+/-6.3% of the prerelaxation tone and had an EC50 for Ca2+ of 2.90+/-0.54 mmol/L. The relaxation was antagonized by precontraction in buffer containing 100 mmol/L K+ and by pretreatment with 10 mmol/L tetraethylammonium. Arteries from CB1-/- and CB1+/+ mice also relaxed in response to extracellular Ca2+ with no differences being detected between the knockout and their littermate controls. SR141716A, a selective CB1 antagonist, caused concentration-dependent inhibition of Ca2+-induced relaxation in both the knockout and wild-type strains (60% inhibition at 1 mumol/L). O-1918, a cannabidiol analog, had a similar blocking effect in arteries of both wild-type and CB1-/- mice at 10 mumol/L. In contrast, 1 mumol/L SR144538, a cannabinoid type 2 receptor antagonist, or 50 mumol/L 18alpha-glycyrrhetinic acid, a gap junction blocker, were without effect. SR141716A (1 to 30 mumol/L) was also assessed for nonspecific actions on whole-cell K+ currents in isolated vascular smooth muscle cells. SR141716A inhibited macroscopic K+ currents at concentrations higher than those required to inhibit Ca2+-induced relaxation, and appeared to have little effect on currents through large conductance Ca2+-activated K+ channels. These data indicate that arteries of the mouse relax in response to cumulative addition of extracellular Ca2+ in a hyperpolarization-dependent manner and rule out a role for CB1 or CB2 receptors in this effect. The possible role of a nonclassical cannabinoid receptor is discussed. C1 N Carolina Cent Univ, Julius L Chambers Biomed Biotechnol Res Inst, Cardiovasc Dis Res Program, Durham, NC 27707 USA. NIAAA, NIH, Bethesda, MD USA. Western Michigan Univ, Dept Biol Sci, Kalamazoo, MI 49008 USA. RP Bukoski, RD (reprint author), N Carolina Cent Univ, Julius L Chambers Biomed Biotechnol Res Inst, Cardiovasc Dis Res Program, 700 George St, Durham, NC 27707 USA. RI Batkai, Sandor/G-3889-2010; Jackson, William/K-5523-2012; Batkai, Sandor/H-7983-2014 OI Jackson, William/0000-0002-9657-0141; FU NHLBI NIH HHS [R01 HL032469, R01 HL064761, R25 HL059868, UH1 HL059868] NR 23 TC 44 Z9 44 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD FEB PY 2002 VL 39 IS 2 BP 251 EP 257 DI 10.1161/hy0202.102702 PN 1 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 525AU UT WOS:000174045700012 PM 11847193 ER PT J AU Fedorova, OV Dorofeeva, NA Lopatin, DA Lakatta, EG Bagrov, AY AF Fedorova, OV Dorofeeva, NA Lopatin, DA Lakatta, EG Bagrov, AY TI Phorbol diacetate potentiates Na+-K+ ATPase inhibition by a putative endogenous ligand, marinobufagenin SO HYPERTENSION LA English DT Article DE drug therapy; ouabain; Na+-K+-exchanging ATPase; vasoconstriction; protein kinases; blood pressure; bufanolides ID PROTEIN-KINASE-C; DIGITALIS-LIKE FACTORS; RAT AORTA; PUMP INHIBITORS; ALPHA-1 SUBUNIT; ANGIOTENSIN-II; SMOOTH-MUSCLE; NA+,K+-ATPASE; OUABAIN; PHOSPHORYLATION AB Several vasoconstrictor agents can regulate the phosphorylation status of the Na+-K+ ATPase (NKA). We have recently demonstrated that mammalian tissues contain an endogenous bufadienolide, digitalis-like alpha(1)-NKA-selective ligand, marinobufagenin (MBG). Protein kinase C induces phosphorylation of the alpha(1)-NKA isoform, the major isoform in vascular smooth muscle, kidney, and heart cells. We hypothesized that protein kinase C-induced phosphorylation of NKA can potentiate the effect of endogenous digitalis-like ligands, and that such potentiation can occur in an NKA isoform-specific fashion. A protein kinase C activator, phorbol 12,13-diacetate (PDA, 50 nmol/L), induced phosphorylation of the alpha(1)-NKA from human mesenteric artery (HMA) sarcolemma and rat kidney but not that of the alpha(3)-NKA from rat fetal brain. In HMA sarcolemma, which predominantly contains alpha(1)-NKA, PDA (50 nmol/L) potentiated the NKA-inhibitory effect of MBG at the level of high-affinity binding sites (0.05+/-0.03 nmol/L versus 4.0+/-1.7 nmol/L, P<0.05). In contrast, PDA did not affect the NKA inhibition by ouabain, an a3-NKA ligand. In isolated endothelium-denuded HMA artery rings, 50 nmol/L PDA potentiated the MBG-induced vasoconstriction (EC50 17+/-6 nmol/L versus 150+/-40 nmol/L; P<0.01). Our results suggest that alpha(1)-isoform-specific NKA inhibition by the endogenous digitalis-like ligand, MBG, is substantially enhanced via NKA phosphorylation by protein kinase C. Thus, an interaction of protein kinase C-dependent phosphorylation and MBG on NKA activity may underlie the synergistic vasoactive effects of MBG and other endogenous vasoconstrictors in hypertension. C1 NIA, Intramural Res Program, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. IM Sechenov Evolutionary Physiol & Biochem Inst, Pharmacol Lab, St Petersburg, Russia. RP Bagrov, AY (reprint author), NIA, Intramural Res Program, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 31 TC 19 Z9 20 U1 1 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 FEB PY 2002 VL 39 IS 2 BP 298 EP 302 DI 10.1161/hy0202.104344 PN 1 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 525AU UT WOS:000174045700020 PM 11847201 ER PT J AU Brooks, HL Allred, AJ Beutler, KT Coffman, TM Knepper, MA AF Brooks, HL Allred, AJ Beutler, KT Coffman, TM Knepper, MA TI Targeted proteomic profiling of renal Na+ transporter and channel abundances in angiotensin II type 1a receptor knockout mice SO HYPERTENSION LA English DT Article; Proceedings Paper CT 55th Annual Fall Conference and Scientific Sessions of the American-Heart-Association-Council-for-High-Blood-Presure-Research CY SEP 23-25, 2001 CL CHICAGO, ILLINOIS SP Amer Heart Assoc Council High Blood Pressure Res DE sodium; angiotensin II; receptors, angiotensin II; kidney; mice ID THICK ASCENDING LIMB; RAT-KIDNEY; MEDIATED REGULATION; BLOOD-PRESSURE; ALDOSTERONE; COTRANSPORTER; EXPRESSION; ABSORPTION; SUBUNIT; ENAC AB The renal tubule transporters responsible for Na+ and water transport along the nephron have been identified and cloned, permitting comprehensive analysis of transporter protein abundance changes in complex physiological models by using a "targeted proteomics" approach. Here, we apply this approach to screen renal homogenates from mice in which the gene for the angiotensin II type 1a (AT(1alpha)) receptor has been deleted (versus wild-type mice) to determine which sodium transporters and channels are regulated by the AT(1alpha) receptor at the protein abundance level. In mice maintained on a low NaCl diet (<0.02% NaCl), (1) the abundances of 2 aldosterone-regutated transporters were markedly decreased in knockout versus wild-type mice, namely, the thiazide-sensitive cotransporter and the alpha-subunit of the amiloride-sensitive Na+ channel (alpha-ENaC); (2) the abundances of beta-ENaC and gamma-ENaC were markedly increased; and (3) there were no significant changes in the abundances of the proximal tubule Na+-H' exchanger or the Na+-K+-2Cl(-) cotransporter of the thick ascending limb, When the experiment was repeated on higher NaCl diets (0.4% or 6% NaCl), the decrease in alpha-ENaC abundance persisted, whereas the other changes were abolished. Analysis of serum aldosterone concentration in AT(1alpha) knockout mice and wild-type inice on the low NaCl diet revealed the absence of a decrease with AT(1alpha) gene deletion (11.8+/-2.3 nmol/L for knockout inice and 5.7 +/- 0.8 nmol/L for wild-type mice [significantly increased]). These results reveal that the AT(1alpha) receptor plays an important role in regulation of Na+ transporter and channel proteins in the "post-macula densa" region of the renal tubule via a mechanism that is not dependent on altered circulating aldosterone concentrations. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Duke Univ, Dept Med, Durham, NC USA. RP Knepper, MA (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bldg 10,Room 6N260,10 Ctr Dr,MSC-1603, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 17 TC 57 Z9 61 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 FEB PY 2002 VL 39 IS 2 SU S BP 470 EP 473 DI 10.1161/hy02t2.102959 PN 2 PG 4 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 525RY UT WOS:000174085800029 PM 11882592 ER PT J AU Franklin, SS Wong, ND Larson, MG Kannel, WB Levy, D AF Franklin, SS Wong, ND Larson, MG Kannel, WB Levy, D TI How important is pulse pressure as a predictor of cardiovascular risk? SO HYPERTENSION LA English DT Letter ID BLOOD-PRESSURE; HYPERTENSION; DISEASE C1 Univ Calif Irvine, Prevent Cardiol Program, Irvine, CA 92717 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. RP Franklin, SS (reprint author), Univ Calif Irvine, Prevent Cardiol Program, Irvine, CA 92717 USA. NR 14 TC 8 Z9 8 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 FEB PY 2002 VL 39 IS 2 BP E12 EP E13 PN 1 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 525AU UT WOS:000174045700022 PM 11847204 ER PT J AU Ritter, TA Shrout, TR Tutwiler, R Shung, KK AF Ritter, TA Shrout, TR Tutwiler, R Shung, KK TI A 30-MHz piezo-composite ultrasound array for medical imaging applications SO IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL LA English DT Article ID HIGH-FREQUENCY; TRANSDUCERS; FABRICATION; MODEL; MHZ AB Ultrasound imaging at frequencies above 20 MHz is capable of achieving improved resolution in clinical applications requiring limited penetration depth. High frequency arrays that allow real-time imaging are desired for these applications but are not yet currently available. In this work, a method for fabricating fine-scale 2-2 composites suitable for 30-MHz linear array transducers was successfully demonstrated. High thickness coupling, low mechanical loss, and moderate electrical loss were achieved. This piezo-composite was incorporated into a 30-MHz array that included acoustic matching, an elevation focusing lens, electrical matching, and an air-filled kerf between elements. Bandwidths near 60%, 15-dB insertion loss, and crosstalk less than -30 dB were measured. Images of both a phantom and an ex vivo human eye were acquired using a synthetic aperture reconstruction method, resulting in measured lateral and axial resolutions of approximately 100 mum. C1 Penn State Univ, NIH, Resource Ctr Med Ultrasound Transducer Technol, University Pk, PA 16802 USA. RP Ritter, TA (reprint author), Penn State Univ, NIH, Resource Ctr Med Ultrasound Transducer Technol, University Pk, PA 16802 USA. FU NCRR NIH HHS [P41-RR11795] NR 57 TC 145 Z9 146 U1 4 U2 21 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 0885-3010 J9 IEEE T ULTRASON FERR JI IEEE Trans. Ultrason. Ferroelectr. Freq. Control PD FEB PY 2002 VL 49 IS 2 BP 217 EP 230 DI 10.1109/58.985706 PG 14 WC Acoustics; Engineering, Electrical & Electronic SC Acoustics; Engineering GA 522LU UT WOS:000173899400008 PM 11885679 ER PT J AU McHugh, RS Whitters, MJ Piccirillo, CA Young, DA Shevach, EM Collins, M Byrne, MC AF McHugh, RS Whitters, MJ Piccirillo, CA Young, DA Shevach, EM Collins, M Byrne, MC TI CD4(+)CD25(+) immunoregulatory T cells: Gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor SO IMMUNITY LA English DT Article ID LYMPHOCYTE-ASSOCIATED ANTIGEN-4; INTESTINAL INFLAMMATION; EFFECTOR FUNCTION; IDENTIFICATION; INDUCTION; INHIBIT; FAMILY; DIFFERENTIATION; COSTIMULATION; RESPONSES AB CD4(+)CD25(+) immunoregulatory T cells represent a unique lineage of thymic-derived cells that potently suppress both in vitro and in vivo effector T cell function. We analyzed CD4(+)CD25(+) and CD4(+)CD25(-) T cells by DNA microarray, identifying 29 genes differentially expressed in the resting subpopulations, and 77 that were differentially expressed following activation. Most of these genes were elevated in the CD4(+)CD25(+) population, suggesting a previously activated phenotype. Among these were a number of genes that antagonize signaling, including members of the SOCS family, which may contribute to their anergic phenotype. Multiple cell surface receptors also had increased expression in CD4(+)CD25(+) cells, including GITR, a member of the TNF receptor superfamily. Importantly, antibodies to GITR abrogated suppression, demonstrating a functional role for this receptor in regulating the CD4(+)CD25(+) T cell subset. C1 NIAID, Cellular Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. Wyeth Ayerst Res, Genet Inst, Cambridge, MA 02140 USA. RP Shevach, EM (reprint author), NIAID, Cellular Immunol Sect, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 52 TC 994 Z9 1054 U1 1 U2 13 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD FEB PY 2002 VL 16 IS 2 BP 311 EP 323 DI 10.1016/S1074-7613(02)00280-7 PG 13 WC Immunology SC Immunology GA 524YC UT WOS:000174039600013 PM 11869690 ER PT J AU Near, KA Stowers, AW Jankovic, D Kaslow, DC AF Near, KA Stowers, AW Jankovic, D Kaslow, DC TI Improved immunogenicity and efficacy of the recombinant 19-kilodalton merozoite surface protein 1 by the addition of oligodeoxynucleotide and aluminum hydroxide gel in a murine malaria vaccine model SO INFECTION AND IMMUNITY LA English DT Article ID BLOOD-STAGE INFECTION; CPG DNA; SYNTHETIC OLIGODEOXYNUCLEOTIDES; IMMUNOSTIMULATORY DNA; CONTAINING ADJUVANTS; PROTECTIVE IMMUNITY; TERMINAL FRAGMENT; AOTUS MONKEYS; B-CELLS; RESPONSES AB Vaccination of mice with yeast-secreted Plasmodium yoelii-derived 19-kilodalton merozoite surface protein I (yMSP1(19)) has been shown to afford protection from challenge with a lethal strain of A yoelii. Sterile immunity can be achieved when MSPI, is emulsified in Freund adjuvant but not when it is adsorbed to aluminum hydroxide gel (alum). Because complete Freund adjuvant is not an acceptable adjuvant for use in humans, alternative adjuvants must be identified for formulating MSPI 19 as a vaccine for use in humans. To determine whether oligodeoxynucleotides with CpG motifs (ODN), reported to be a powerful new class of adjuvants, could enhance the immunogenicity of yMSP1(19), C57BL/6 mice were vaccinated either with yMSP1(19) formulated with Freund adjuvant, with alum, or with ODN plus alum and challenged intravenously with A yoelii 17XL asexual blood-stage parasites. Adsorption of immunogen and adjuvant to alum was optimized by adjusting buffer (phosphate versus acetate) and pH. We found that the adjuvant combination of ODN plus alum with yMSP1(19) injected intraperitoneally (i.p.), increased immunoglobulin G (IgG) yMSP1(19)-specific antibody production 12-fold over Freund adjuvant given i.p., 3-fold over Freund adjuvant given subcutaneously (s.c.), 300-fold over alum given i.p., and 48-fold over alum given s.c. The predominant antibody isotype in the group receiving alum-ODN-yMSP1(19) was IgG1. Increased antibody levels correlated to protection from a challenge with A yoelii 17XL. Supernatant cytokine levels of gamma interferon in yMSP1(19)-stimulated splenocytes were dramatically elevated in the alum-ODN-yMSP1(19) group. Interleukin-10 (IL-10) levels were also elevated; however, no IL-5 was detected. The cytokine profile, as well as the predominant IgG1 antibody isotype, suggests the protective immune response was a mixed Th1/Th2 response. C1 NIAID, Opportunist Infect Res Branch, Therapeut Res Program, Div Aids,Lab Parasit Dis,NIH, Bethesda, MD 20892 USA. RP Near, KA (reprint author), NIAID, Opportunist Infect Res Branch, Therapeut Res Program, Div Aids,Lab Parasit Dis,NIH, 6700 B Rockledge,Rm 5226, Bethesda, MD 20892 USA. NR 49 TC 31 Z9 35 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD FEB PY 2002 VL 70 IS 2 BP 692 EP 701 DI 10.1128/IAI.70.2.692-701.2002 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 516LY UT WOS:000173555800035 PM 11796601 ER PT J AU Khan, AQ Shen, Y Wu, ZQ Wynn, TA Snapper, CM AF Khan, AQ Shen, Y Wu, ZQ Wynn, TA Snapper, CM TI Endogenous pro- and anti-inflammatory cytokines differentially regulate an in vivo humoral response to Streptococcus pneumoniae SO INFECTION AND IMMUNITY LA English DT Article ID TUMOR-NECROSIS-FACTOR; PNEUMOCOCCAL VIRULENCE PROTEINS; DENDRITIC CELL MATURATION; LEVEL IL-12 PRODUCTION; MHC CLASS-II; FACTOR-ALPHA; TNF-ALPHA; INTERFERON-GAMMA; B-CELLS; HUMAN-MONOCYTES AB Proinflammatory cytokines play a critical role in innate host defense against extracellular bacteria. However, little is known regarding the effects of these cytokines: on the adaptive humoral response. Mice injected with a neutralizing anti-tumor necrosis factor alpha (TNF-alpha) monoclonal antibody (MAb) at the time of primary immunization with intact Streptococcus pneumoniae (strain R36A) showed a substantial reduction in both the primary immunoglobulin G (IgG) response specific for the cell wall protein, pneumococcal surface protein A (PspA), as well as in the development of PspA-specific memory. In contrast, anti-TNF-alpha MAb injected only at the time of secondary immunization with R36A failed to alter the boosted anti-PspA response. TNF-alpha was required only within the first 48 to 72 h after primary immunization with R36A and was induced both by non-B and non-T cells and by lymphoid cells, within 2 to 6 h after immunization, with levels returning to normal by 24 h. Thus, the early innate release of TNF-alpha was critical for optimal stimulation of the subsequent adaptive Immoral response to R36A. Additional proinflammatory (interleukin 1 [IL-1], IL-6, IL-12, and gamma interferon [IFN-gamma]) as well as anti-inflammatory (IL-,4 and IL-10) cytokines were also transiently induced. Mice genetically deficient in IL-6, IFN-gamma, or IL-12 also showed a reduced IgG anti-PspA response of all IgG isotypes. In contrast, IL-4(-/-) and IL-10(-/-) mice immunized with R36A showed a significant elevation in the IgG anti-PspA response, except that there was decreased IgG1 in IL-4(-/-) mice. In this regard, a marked enhancement in the induction of proinflammatory cytokines was observed in the absence of IL-10, relative to controls. Ig isotype titers specific for the phosphorycholine determinant of C-polysaccharide were similarly regulated, but to a much more modest degree. These data suggest that proinflammatory and anti-inflammatory cytokines differentially regulate an in vivo protein- and polysaccharide specific Ig response to an extracellular bacteria. C1 Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Snapper, CM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Pathol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. RI Wynn, Thomas/C-2797-2011 FU NIAID NIH HHS [1R01 AI46551, 1R01 AI49192, R01 AI046551, R01 AI049192] NR 84 TC 64 Z9 69 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 FEB PY 2002 VL 70 IS 2 BP 749 EP 761 DI 10.1128/IAI.70.2.749-761.2002 PG 13 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 516LY UT WOS:000173555800042 PM 11796608 ER PT J AU Chaussee, MS Sylva, GL Sturdevant, DE Smoot, LM Graham, MR Watson, RO Musser, JM AF Chaussee, MS Sylva, GL Sturdevant, DE Smoot, LM Graham, MR Watson, RO Musser, JM TI Rgg influences the expression of multiple regulatory loci to coregulate virulence factor expression in Streptococcus pyogenes SO INFECTION AND IMMUNITY LA English DT Article ID GROUP-A STREPTOCOCCI; HYALURONIC-ACID CAPSULE; PYROGENIC EXOTOXIN-B; CYSTEINE PROTEASE; MOLECULAR CHARACTERIZATION; NEGATIVE REGULATOR; STREPTOLYSIN-S; VIR REGULON; IDENTIFICATION; GENE AB The human pathogen Streptococcus pyogenes secretes many proteins to the cell wall and extracellular environment that contribute to virulence. Rgg regulates the expression of several exoproteins including a cysteine protease (SPE B), a nuclease (MF-1), a putative nuclease (MF-3), and autolysin. The functional heterogeneity of Rgg-regulated exoproteins and the lack of a conserved regulatory motif in the promoter regions of the genes suggested that Rgg interacts with additional regulatory networks to influence gene expression. DNA microarrays were used to test this hypothesis by comparing genomewide transcript profiles of S. pyogenes NZ131 and isogenic derivative NZ131 rgg during the exponential phase of growth. Transcripts of known and putative virulence-associated genes were more abundant in the rgg mutant, including emm, scpA, orfX, scl1, hasAB, slo, sagA, ska, speH, grab, mac, mf-1, and mf-3. Increased transcription of emm, sepA, and orfX in the rgg mutant was associated with increased production of the corresponding proteins. Differences in the expression of virulence-associated genes were associated with changes in the expression of several regulatory genes, including mga, sagA, csrRS, and fasBCA. The results show that Rgg influences the expression of multiple regulatory networks to coregulate virulence factor expression in S. pyogenes. C1 NIAID, Rocky Mt Lab, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. RP Chaussee, MS (reprint author), Univ S Dakota, Coll Med, Div Basic Biomed Sci, Lee Med Bldg,414 E Clark St, Vermillion, SD 57069 USA. NR 50 TC 74 Z9 79 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 FEB PY 2002 VL 70 IS 2 BP 762 EP 770 DI 10.1128/IAI.70.2.762-770.2002 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 516LY UT WOS:000173555800043 PM 11796609 ER PT J AU McCarthy, JS Wieseman, M Tropea, J Kaslow, D Abraham, D Lustigman, S Tuan, R Guderian, RH Nutman, TB AF McCarthy, JS Wieseman, M Tropea, J Kaslow, D Abraham, D Lustigman, S Tuan, R Guderian, RH Nutman, TB TI Onchocerca volvulus glycolytic enzyme fructose-1,6-bisphosphate aldolase as a target for a protective immune response in humans SO INFECTION AND IMMUNITY LA English DT Article ID SCHISTOSOMA-MANSONI; RECOMBINANT ANTIGEN; GENE-EXPRESSION; IDENTIFICATION; VACCINATION; INFECTION; IMMUNOGENICITY; CLONING AB To identify potential vaccine candidates for the prevention of infection with the filarial nematode Onchocerca volvulus, we screened an O. volvulus L3 stage cDNA library with sera from putatively immune (PI) subjects, and a prominent immunogenic clone of 1,184 nucleotides was identified. It contained an open reading frame of 363 amino acids encoding the glycolytic enzyme fructose 1,6 bisphosphate aldolase (Ov-Jba-1). Immunolocalization experiments demonstrated that the protein was most abundantly expressed in metabolically active tissues, including body wall muscle and the reproductive tract of adult female worms. Immunoelectron microscopy of L3 demonstrated binding in the region where the cuticle separates during molting, in the channels connecting the esophagus to the cuticle, and in the basal lamina surrounding the esophagus and the body cavity. Among subjects from areas where this organism is endemic specific humoral and cellular immune responses to recombinant protein were observed in both PI and infected subjects, whereas responses were not observed among subjects who had not been exposed to O. volvulus. Despite the absence of differential responsiveness in parasite-exposed human populations, when the recombinant was tested for protective efficacy in a mouse chamber model, a reduction in survival of larvae by ca. 50% was seen. This observation provides support for the further study of this parasite enzyme as a vaccine candidate in larger animal models. C1 Univ Western Australia, Dept Med, Fremantle Hosp, Fremantle, WA 6959, Australia. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Dept Orthoped Surg, Philadelphia, PA 19107 USA. New York Blood Ctr, Lindsley F Kimball Res Inst, Mol Parasitol Lab, New York, NY 10021 USA. Hosp Vozandes, Quito, Ecuador. RP McCarthy, JS (reprint author), Univ Western Australia, Dept Med, Fremantle Hosp, Fremantle, WA 6959, Australia. FU NIAID NIH HHS [R01AI42328-02] NR 28 TC 57 Z9 62 U1 1 U2 7 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 FEB PY 2002 VL 70 IS 2 BP 851 EP 858 DI 10.1128/IAI.70.2.851-858.2002 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 516LY UT WOS:000173555800054 PM 11796620 ER PT J AU Zieler, H Huynh, CQ AF Zieler, H Huynh, CQ TI Intron-dependent stimulation of marker gene expression in cultured insect cells SO INSECT MOLECULAR BIOLOGY LA English DT Article DE insect cells; intron splicing; gene expression; luciferase ID CAP-BINDING COMPLEX; GREEN FLUORESCENT PROTEIN; HIGH-LEVEL EXPRESSION; MESSENGER-RNA; 1ST INTRON; REGULATORY ELEMENTS; TRANSGENIC MICE; RECOMBINANT BACULOVIRUSES; TRANSCRIPTIONAL CONTROL; INTERVENING SEQUENCES AB We tested in a systematic fashion the effect of an intron on the level of luciferase expression in cultured C6/36 Aedes albopictus cells. The intron was inserted in both orientations, upstream and downstream of the luciferase coding region in two different luciferase expression vectors. The two parental luciferase expression vectors differed only in their promoters, one containing the Drosophila melanogaster actin5C promoter and the other the Autographa californica nuclear polyhedrosis virus hr5/ie1 enhancer/promoter. All resulting intron-containing constructs were tested for their ability to express luciferase in transient assays following electroporation into C6/36 cells. We found that the introns stimulate luciferase expression between twelve and sixtyfold, depending on the promoter. Enhanced expression was only seen when the intron was present in the correct orientation upstream of the luciferase ORE. When the 3' splice sites of the enhanced intron-containing constructs were mutated, the expression level dropped back to below the level of the intronless parental constructs, suggesting that the intron-dependent stimulation of luciferase expression is depending on splicing and is not due to other effects the intron may have on transcription or translation. The luciferase transcripts of ail constructs were analysed by reverse transcription, PCR amplification and sequencing, and the results show a perfect correlation between efficient splicing of the intron and elevated levels of luciferase expression. Our findings have the potential to be very useful for boosting expression of foreign proteins in the widely used baculoviral or non-viral systems in insect cells. C1 NIAID, Med Entomol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Zieler, H (reprint author), Chromatin Inc, 2201 W Campbell Pk Dr, Chicago, IL 60612 USA. NR 78 TC 18 Z9 19 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0962-1075 J9 INSECT MOL BIOL JI Insect Mol. Biol. PD FEB PY 2002 VL 11 IS 1 BP 87 EP 95 DI 10.1046/j.0962-1075.2001.00312.x PG 9 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 521LZ UT WOS:000173842600010 PM 11841506 ER PT J AU Akin, C Metcalfe, DD AF Akin, C Metcalfe, DD TI Surrogate markers of disease in mastocytosis SO INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY LA English DT Article DE mastocytosis; urticaria pigmentosa; surrogate markers; tryptase; mast cells ID BLOOD MONONUCLEAR-CELLS; C-KIT; ACTIVATING MUTATION; IMPROVED DIAGNOSIS; PLASMA AB Measurement of surrogate mast cell-related products in blood or urine is often performed to assess disease extent in evaluating patients with mastocytosis. Serum tryptase and 24-hour urine histamine metabolites are the most commonly used surrogate markers of mastocytosis. In addition, several novel markers including soluble CD117 and soluble CD25 have been identified in recent studies. The utility and the pitfalls of each of these measurements are discussed. Copyright (C) 2002 S. Karger AG, Basel. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Akin, C (reprint author), NIAID, Lab Allerg Dis, NIH, 10 Ctr Dr,Room 11C205, Bethesda, MD 20892 USA. NR 21 TC 36 Z9 38 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1018-2438 J9 INT ARCH ALLERGY IMM JI Int. Arch. Allergy Immunol. PD FEB PY 2002 VL 127 IS 2 BP 133 EP 136 DI 10.1159/000048184 PG 4 WC Allergy; Immunology SC Allergy; Immunology GA 541FX UT WOS:000174975500009 PM 11919423 ER PT J AU Valent, P Akin, C Sperr, WR Horny, HP Metcalfe, DD AF Valent, P Akin, C Sperr, WR Horny, HP Metcalfe, DD TI Smouldering mastocytosis: A novel subtype of systemic mastocytosis with slow progression SO INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY LA English DT Article DE mast cells; neoplasia; disease-criteria; classification ID MAST-CELL LEUKEMIA; C-KIT MUTATION; ACTIVATING MUTATION; DISEASE AB Systemic mastocytosis (SM) is a clonal disease that shows an either indolent or an aggressive clinical course. Utilizing established criteria, indolent SM can readily be discriminated from the rare aggressive subvariants of SM in most cases. In a small group of patients, however, clinical and laboratory parameters are indicative of slow progression without signs of aggressive disease or an associated hemopoietic neoplasm. These SM patients exhibit a high burden of mast cells, hypercellular marrow and organomegaly. Because of the 'intermediate' course and uncertain prognosis, these cases have been referred to as smouldering SM. In the present article, we discuss clinical and laboratory findings in smouldering SM and review the current literature. In addition, the pathophysiology of this novel subtype of SM is discussed. Copyright (C) 2002 S. Karger AG, Basel. C1 Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol, A-1090 Vienna, Austria. NIH, Lab Allerg Dis, Bethesda, MD USA. Med Univ Lubeck, Inst Pathol, D-23538 Lubeck, Germany. RP Valent, P (reprint author), Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. NR 19 TC 37 Z9 40 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1018-2438 J9 INT ARCH ALLERGY IMM JI Int. Arch. Allergy Immunol. PD FEB PY 2002 VL 127 IS 2 BP 137 EP 139 DI 10.1159/000048185 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA 541FX UT WOS:000174975500010 PM 11919424 ER PT J AU Worobec, AS Metcalfe, DD AF Worobec, AS Metcalfe, DD TI Mastocytosis: Current treatment concepts SO INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY LA English DT Article DE mastocytosis; mediators; mastocytosis, symptoms ID SYSTEMIC MASTOCYTOSIS AB An explosion of research on mastocytosis in the last decade has witnessed a greater understanding of the molecular basis of this heterogeneous group of disorders and the conclusion that similar disease phenotypes may indeed be the result of different underlying genotypes. Along with our growing knowledge base of mastocytosis, newer approaches of treating these disorders are becoming available, all under investigational use at this time. This short review highlights the state of the art of current treatment strategies for the different categories of mastocytosis. The future will undoubtedly witness an even greater array of therapeutic options, as we continue to learn more about this enigmatic disease. Copyright (C) 2002 S. Karger AG, Basel. C1 NIAID, LAD, NIH, Bethesda, MD 20892 USA. RP Worobec, AS (reprint author), NIAID, LAD, NIH, 10 Ctr Dr MSC 1881,Room 11C205, Bethesda, MD 20892 USA. NR 13 TC 32 Z9 34 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1018-2438 J9 INT ARCH ALLERGY IMM JI Int. Arch. Allergy Immunol. PD FEB PY 2002 VL 127 IS 2 BP 153 EP 155 DI 10.1159/000048189 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA 541FX UT WOS:000174975500014 PM 11919428 ER PT J AU Tawab, A Fields, J Chao, E Kurlander, RJ AF Tawab, A Fields, J Chao, E Kurlander, RJ TI Recombinant lemA without adjuvant induces extensive expansion of H2-M3-restricted CD8 effectors, which can suppress primary listeriosis in mice SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE host resistance; passive immunization; peptide-specific CD8 T cells; primary immune response ID DELAYED-TYPE HYPERSENSITIVITY; CLASS IB MOLECULE; T-CELLS; BACTERIAL-INFECTION; CTL RESPONSES; MONOCYTOGENES INFECTION; ANTIGEN PRESENTATION; PEPTIDE VACCINATION; IMMUNITY; PROTECTION AB Mice infected with Listeria monocytogenes (LM) produce large numbers of H2-M3-restricted CD8 T cells directed against the formylated peptides, f-MIGWII and f-MIVIL. To examine responsiveness to these epitopes In the absence of infection, we inoculated mice with recombinant lemA (r-lemA) containing f-MIGWII or r-vemA (a variant of r-lemA containing f-MIVIL in place of f-MIGWII) without adjuvant. To monitor responses, we measured peptide-specific cytoplasmic IFN-gamma production ex vivo by freshly harvested splenocytes at varying times post-inoculation. B6 mice inoculated with r-lemA produced substantial numbers of epitope-specific CD8 cells with peak levels on day 7 when there were 1.1 x 10(6) f-MIGWII-specific CD8 cells in the spleen (8.2% of total CD8 splenocytes). The r-vemA-treated animals accumulated 0.25 x 10(6) Cells (1.8% of total CD8 cells) at this time point. Comparable responses were observed after rechallenge of immunized animals. Other elements in the lemA moiety distinct from the immunogenic peptide were required since mice did not respond to equimolar amounts of synthetic f-MIGWII or f-MIVIL alone. In comparative studies, 136 and C3H/HeJ mice responded to r-lemA much more vigorously than BALB/c animals. When r-lemA- or r-vemA-treated B6 animals were challenged i.v. with LM 7 days later, they suppressed splenic accumulation of bacteria much more effectively than controls. On the other hand, antigen-treated animals were not protected against infection 1 month later. Thus, responsive strains of mice respond vigorously to H2-M3-restricted epitopes, even in the absence of bacterial infection or adjuvant. The resulting effectors acutely enhance antimicrobial resistance but do not confer long-term memory protection. C1 NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Kurlander, RJ (reprint author), NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. NR 33 TC 0 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD FEB PY 2002 VL 14 IS 2 BP 225 EP 232 DI 10.1093/intimm/14.2.225 PG 8 WC Immunology SC Immunology GA 519ZM UT WOS:000173755400012 PM 11809741 ER PT J AU Cooper, GS Miller, FW Germolec, DR AF Cooper, GS Miller, FW Germolec, DR TI Occupational exposures and autoimmune diseases SO INTERNATIONAL IMMUNOPHARMACOLOGY LA English DT Review DE autoimmune diseases; crystalline silica; solvents; trichloroethylene; pesticides; hexachlorobenzene; mercury; ultraviolet radiation ID SYSTEMIC LUPUS-ERYTHEMATOSUS; T-CELL ACTIVATION; SILICATE IN-VITRO; RHEUMATOID-ARTHRITIS; MULTIPLE-SCLEROSIS; ULTRAVIOLET-RADIATION; ENVIRONMENTAL-FACTORS; MACROPHAGE FUNCTION; ORGANIC-SOLVENTS; UNITED-STATES AB Autoimmune diseases are pathologic conditions defined by abnormal autoimmune responses and characterized by immune system reactivity in the form of autoantibodies and T cell responses to self-structures. Here we review the limited but growing epidemiologic and experimental literature pertaining to the association between autoimmune diseases and occupational exposure to silica, solvents, pesticides, and ultraviolet radiation. The strongest associations (i.e., relative risks of 3.0 and higher) have been documented in investigations of silica dust and rheumatoid arthritis, lupus, scleroderma and glomerulonephritis. Weaker associations are seen, however, for solvent exposures (in scleroderma, undifferentiated connective tissue disease, and multiple sclerosis) and for farming or pesticide exposures (in rheumatoid arthritis). Experimental studies suggest two different effects of these exposures: an enhanced proinflammatory (TH1) response (e.g., TNF-alpha and IL-1 cytokine production with T cell activation), and increased apoptosis of lymphocytes leading to exposure to or modification of endogenous proteins and subsequent autoantibody formation. The former is a general mechanism that may be relevant across a spectrum of autoimmune diseases, whereas the latter may be a mechanism more specific to particular diseases,(e.g., ultraviolet radiation, Ro autoantibodies, and lupus). Occupational exposures are important risk factors for some autoimmume diseases, but improved exposure assessment methods and better coordination between experimental/animal models and epidemiologic studies are needed to define these risks more precisely. Published by Elsevier Science B.V. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Off Clin Res, Bethesda, MD USA. NIEHS, Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Germolec, DR (reprint author), NIEHS, Environm Immunol Lab, 111 Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. OI Miller, Frederick/0000-0003-2831-9593 NR 103 TC 86 Z9 88 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-5769 J9 INT IMMUNOPHARMACOL JI Int. Immunopharmacol. PD FEB PY 2002 VL 2 IS 2-3 BP 303 EP 313 DI 10.1016/S1567-5769(01)00181-3 PG 11 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 513DA UT WOS:000173361600014 PM 11811933 ER PT J AU Zavras, AI Wu, TX Laskaris, G Wang, YF Cartsos, V Segas, J Lefantzis, D Joshipura, K Douglass, CW Diehl, SR AF Zavras, AI Wu, TX Laskaris, G Wang, YF Cartsos, V Segas, J Lefantzis, D Joshipura, K Douglass, CW Diehl, SR TI Interaction between a single nucleotide polymorphism in the alcohol dehydrogenase 3 gene, alcohol consumption and oral cancer risk SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE mouth neoplasms; pharyngeal neoplasms; risk factors; alcohol, alcohol dehydrogenase; polymorphism, single nucleotide; genetics; Greece ID ALCOHOL-DEHYDROGENASE-3 GENOTYPE; ALDEHYDE DEHYDROGENASE; PHARYNGEAL CANCERS; ACETALDEHYDE; SUSCEPTIBILITY; DISEQUILIBRIUM; ASSOCIATION; METABOLISM; MORTALITY; STOMACH AB We investigated effects on oral cancer (OC) risk of an interaction between a single nucleotide polymorphism (SNP) in the alcohol dehydrogenase 3 (ADH(3)) gene and alcohol consumption levels using a hospital-based study of 93 cases and 99 controls conducted in Athens, Greece. This SNP affects ethanol metabolism in vitro and appeared to interact with alcohol consumption in a previous OC study. We also evaluated a SNP in CYP2E1, another gene involved in ethanol metabolism, reported to be associated with OC risk in a European population. Data on genotypes and risk factors obtained from interviews were analyzed using multivariate logistic regression, accounting for potential confounders. No overall (marginal) association was found between OC risk and ADH3 genotypes. An interaction between ADH3 genotypes and alcohol consumption levels, however, was suggested. In non-drinkers, the ADH(3)(1-1) genotype has higher risk, than ADH(3)(1-2) or ADH(3)(2-2) genotypes, but for subjects consuming alcohol, lower risk was observed for ADH3 We fit a logistic regression model to estimate the increase in OC risk associated with each alcohol drink consumed per week. We estimated that OC risk increased by 31.5% per drink/week for the ADH(3)(2-2) genotype, 4.1% for the ADH(3)(1-2) genotype and 1.6% for the ADH(3)(1-1) genotype. Evidence of genotype-environment interaction was suggestive (p=0.048, Wald xchi p=0.145, likelihood ratio). This finding is opposite to that reported for a population in Puerto Rico, where the ADH(3)(1-1) genotype seemed more sensitive to ethanol exposure. In Greece, genetic variation at the CYP2E1 SNP is almost entirely absent, with only 1 case and 1 control heterozygous for the variant. By contrast, in a population in France where an OC association was reported, the frequency of CYP2E1 heterozygotes was 5% in controls and 9% in OC cases. These findings illustrate the importance of replicating SNP associations both within and between different racial and ethnic groups and geographic regions. C1 NIDCR, Craniofacial Epidemiol & Genet Branch, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, Boston, MA 02115 USA. Univ Athens, Sch Med, Dept Ear Nose & Throat, GR-11527 Athens, Greece. Univ Athens, Sch Med, A Sygros Hosp, Dept Oral Med, GR-11527 Athens, Greece. Hippokrate Hosp, Athens, Greece. Red Cross Hosp Athens, ENT Clin, Athens, Greece. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Diehl, SR (reprint author), NIDCR, Craniofacial Epidemiol & Genet Branch, NIH, Natcher Bldg 45,Rm 4AS-43G, Bethesda, MD 20892 USA. OI Joshipura, Kaumudi/0000-0003-1964-7579 FU NIDCR NIH HHS [DE 00659]; NIMHD NIH HHS [MD 62829, MD 726655] NR 46 TC 34 Z9 36 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 1 PY 2002 VL 97 IS 4 BP 526 EP 530 DI 10.1002/ijc.1642 PG 5 WC Oncology SC Oncology GA 508FV UT WOS:000173078800019 PM 11802217 ER PT J AU Young, NS AF Young, NS TI Immunosuppressive treatment of acquired aplastic anemia and immune-mediated bone marrow failure syndromes SO INTERNATIONAL JOURNAL OF HEMATOLOGY LA English DT Review DE autoimmunity; bone marrow; hematopoiesis; antithymocyte globulin; antilymphocyte globulin; cyclosporine ID RED-CELL APLASIA; COLONY-STIMULATING FACTOR; HIGH-DOSE CYCLOPHOSPHAMIDE; ANTI-THYMOCYTE GLOBULIN; LYMPHOCYTE-PROLIFERATIVE DISORDERS; SAA WORKING PARTY; ANTITHYMOCYTE GLOBULIN; ANTILYMPHOCYTE GLOBULIN; CYCLOSPORINE-A; RANDOMIZED TRIAL AB Modern therapeutic strategies for the treatment of acquired aplastic anemia are based on the current understanding of its pathophysiology as well as empiric observations. Most cases of aplastic anemia appear to be the result of immune-mediated destruction of hematopoietic cells, which can tie approached by stem cell transplantation in younger patients with appropriate histocompatible donors or by immunosuppression to reduce T-cell activity. Popular treatment regimens combine antithymocyte globulin with cyclosporine. Although a majority of patients respond with improved blood counts and achieve transfusion-independence, late clonal complications of myelodysplasia and cytogenetic abnormalities occur in a substantial minority of cases. Additionally, there is no clear algorithm for the treatment of refractory disease. Newer methods of treatment, including high-dose cyclophosphamide and the development of potentially tolerizing combinations of drugs, are under study. Effective therapies for aplastic anemia might also be applied to other T-cell mediated, organ-specific human diseases. Int J Hematol. 2002;75:129-140. (C)2002 The Japanese Society of Hematology. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Young, NS (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C103, Bethesda, MD 20892 USA. NR 128 TC 13 Z9 13 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 0925-5710 J9 INT J HEMATOL JI Int. J. Hematol. PD FEB PY 2002 VL 75 IS 2 BP 129 EP 140 DI 10.1007/BF02982017 PG 12 WC Hematology SC Hematology GA 534FC UT WOS:000174573000003 PM 11939258 ER PT J AU Bernstein, PS Leppert, M Singh, N Dean, M Lewis, RA Lupski, JR Allikmets, R Seddon, JM AF Bernstein, PS Leppert, M Singh, N Dean, M Lewis, RA Lupski, JR Allikmets, R Seddon, JM TI Genotype-phenotype analysis of ABCR variants in macular degeneration probands and siblings SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID DISEASE GENE ABCR; CASSETTE TRANSPORTER GENE; CONE-ROD DYSTROPHY; STARGARDT-DISEASE; RETINITIS-PIGMENTOSA; MOLECULAR-GENETICS; RETINAL DISEASE; MUTATIONS; AUTOFLUORESCENCE; PROTEIN AB PURPOSE. Single-copy variants of the autosomal recessive Stargardt disease (STGD1) gene ABCR (ABCA4) have been shown to confer enhanced susceptibility to age-related macular degeneration (AMD), To investigate the role of ABCR alleles in AMD further, genotype-phenotype analysis was performed on siblings of patients with AMD who had known ABCR variants. This genetically related population provides a cohort of subjects with similar age and ethnic background for genotype-phenotype comparison to the original probands. METHODS. All available siblings of 26 probands carrying probable disease-associated ABCR variants were examined clinically. Blood samples were collected from these siblings for genotype analysis to search for the ABCR variant alleles corresponding to the isofamilial proband. RESULTS. Nineteen of 33 siblings from 15 families carried the respective proband's variant ABCR allele. Some families exhibited concordance of ABCR alleles with macular degeneration phenotype, but others did not. Exudative AMD was uncommon among both probands and siblings. CONCLUSIONS. Although population Studies have indicated that some ABCR variant alleles may enhance susceptibility to AMD, investigation of the extent of ABCR involvement by kindred analysis is complicated by a plethora of environmental and other hereditary factors not investigated in the current study that may also play important roles. C1 Univ Utah, Sch Med, Dept Ophthalmol & Visual Sci, Moran Eye Ctr, Salt Lake City, UT 84132 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. Columbia Univ, Dept Pathol, New York, NY USA. Columbia Univ, Dept Ophthalmol, New York, NY USA. Baylor Coll Med, Huffington Ctr Aging, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. Baylor Coll Med, Dept Ophthalmol, Houston, TX 77030 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Genomic Divers, Frederick, MD USA. Univ Utah, Dept Human Genet, Salt Lake City, UT USA. RP Bernstein, PS (reprint author), Univ Utah, Sch Med, Dept Ophthalmol & Visual Sci, Moran Eye Ctr, 50 N Med Dr, Salt Lake City, UT 84132 USA. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU NCI NIH HHS [5P30CA42014]; NCRR NIH HHS [M01-RR00064]; NEI NIH HHS [EY11309, EY11600] NR 48 TC 29 Z9 35 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD FEB PY 2002 VL 43 IS 2 BP 466 EP 473 PG 8 WC Ophthalmology SC Ophthalmology GA 518PK UT WOS:000173676900024 PM 11818392 ER PT J AU Iuvone, PM Brown, AD Haque, R Weller, J Zawilska, JB Chaurasia, SS Ma, MH Klein, DC AF Iuvone, PM Brown, AD Haque, R Weller, J Zawilska, JB Chaurasia, SS Ma, MH Klein, DC TI Retinal melatonin production: Role of proteasomal proteolysis in circadian and photic control of arylalkylamine N-acetyltransferase SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID CHICKEN PINEAL-GLAND; LIGHT-INDUCED DECREASE; PHOTORECEPTOR CELLS; MESSENGER-RNA; MOUSE RETINA; AMP; EXPRESSION; ADAPTATION; PROTEIN; RHYTHM AB PURPOSE. Dynamic day-night changes in melatonin synthesis are regulated by changes in the activity of serotonin N-acetyltransterase (arylalkylamine N-acetyltransferase [AA-NAT]). Similarly, a light-induced decrease in AA-NAT activity at night rapidly suppresses melatonin synthesis. The purpose of the current study was to test the hypothesis that in vivo changes of AA-NAT activity in chicken retina homogenates parallel changes in AA-NAT protein. This led to examination of the role of proteasomal proteolysis in the regulation of retinal AA-NAT activity and protein levels. METHODS. Chickens, entrained to a 12-hour light-12-hour dark cycle, were assessed under various lighting conditions, in some cases after in vivo intravitreal administration of the protein synthesis inhibitor cycloheximide or lactacystin, an inhibitor of the 20S proteasome. Tissue homogenates were prepared, AANAT enzyme activity was measured, and immunoreactive protein was estimated by Western blot using an anti-chicken AA-NAT(1-21) serum. RESULTS. The abundance of AA-NAT protein in both the retina and pineal gland exhibited a daily rhythm that was statistically indistinguishable from that of AA-NAT's activity measured in tissue homogenates. Acute exposure to light at night rapidly decreased AA-NAT protein and activity in a parallel fashion. Administration of cycloheximide at night decreased retinal AA-NAT activity in darkness and enhanced the effect of light. The light-evoked suppression of retinal AA-NAT protein and activity was blocked by intravitreal injection of lactacystin, which also was found to increase AA-NAT activity, either at night or during the daytime. CONCLUSIONS. AA-NAT activity measured in tissue homogenates reflects the steady, state level of enzyme protein. AA-NAT protein in the retina turns over rapidly, reflecting a balance of de novo synthesis and proteasomal proteolysis. The suppressive effects of light at night are due primarily to enhanced AA-NAT proteolysis. C1 Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA. NICHHD, Sect Neuroendocrinol, Dev Neurobiol Lab, Bethesda, MD 20892 USA. RP Iuvone, PM (reprint author), Emory Univ, Sch Med, Dept Pharmacol, 1510 Clifton Rd NE, Atlanta, GA 30322 USA. FU NEI NIH HHS [R01 EY04864, R01 EY004864] NR 35 TC 48 Z9 49 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD FEB PY 2002 VL 43 IS 2 BP 564 EP 572 PG 9 WC Ophthalmology SC Ophthalmology GA 518PK UT WOS:000173676900037 PM 11818405 ER PT J AU Li, ZZ Kondo, T Murata, T Ebersole, TA Nishi, T Tada, K Ushio, Y Yamamura, K Abe, K AF Li, ZZ Kondo, T Murata, T Ebersole, TA Nishi, T Tada, K Ushio, Y Yamamura, K Abe, K TI Expression of Hqk encoding a KH RNA binding protein is altered in human glioma SO JAPANESE JOURNAL OF CANCER RESEARCH LA English DT Article DE quaking; gene structure; RNA binding protein; glioma ID FRAGILE-X SYNDROME; CAENORHABDITIS-ELEGANS; GERMLINE DEVELOPMENT; SIGNAL-TRANSDUCTION; CYTOPLASMIC PROTEIN; NUCLEIC-ACID; CELL-LINES; GENE; QUAKING; DOMAIN AB The quaking gene family encodes single KH domain RNA-binding proteins that play vital roles in cell differentiation, proliferation, and apoptotic processes. The human quaking gene, Hqk, maps to 6q25-q26, where cytogenetic alterations associated with a variety of human malignancies, including gliomas have been reported. To assess possible relationships of Hqk with human diseases such as glial tumors, we first isolated the Hqk gene, characterized its structure and expression pattern, and carried out mutational analysis of Hqk in primary tumor samples. The Hqk gene contains 8 exons spanning a similar to200 kb genomic region, and generating at least four alternatively spliced transcripts, Hqk-5, Hqk-6, Hqk-7 and Hqk-7B, of which Hqk-7 is abundantly expressed in brain. Analysis of primary tumors demonstrated a high incidence of expression alterations of Hqk in gliomas (30%; 6/20), but not in other tumors such as schwannomas (0/3), or meningiomas (0/8). Among the tumor samples showing expression alterations, two were devoid of all three major transcripts, one was missing only the Hqk-5 message, and only the Hqk-7 message was absent in two cases. Our results thus imply the involvement of Hqk in human glial tumor progression. C1 Kumamoto Univ, Inst Mol Embryol & Genet, Dept Dev Genet, Kumamoto 8620976, Japan. Yamaguchi Univ, Sch Med, Inst Lab Anim, Ube, Yamaguchi 7558505, Japan. NCI, NIH, Bethesda, MD 20892 USA. Kumamoto Univ, Sch Med, Dept Neurosurg, Kumamoto 8608556, Japan. RP Abe, K (reprint author), Kumamoto Univ, Inst Mol Embryol & Genet, Dept Dev Genet, 4-24-1 Kuhonji, Kumamoto 8620976, Japan. NR 41 TC 36 Z9 37 U1 0 U2 0 PU BUSINESS CENTER ACADEMIC SOCIETIES JAPAN PI TOKYO PA 5-16-9 HONKOMAGOME, BUNKYO-KU, TOKYO, 113-8633, JAPAN SN 0910-5050 J9 JPN J CANCER RES JI Jpn. J. Cancer Res. PD FEB PY 2002 VL 93 IS 2 BP 167 EP 177 PG 11 WC Oncology SC Oncology GA 525ZH UT WOS:000174103600008 PM 11856480 ER PT J AU Agarwal, B Ramanathan, U Lokeshwas, N Nair, R Gopal, R Bhatia, K Naresh, KN AF Agarwal, B Ramanathan, U Lokeshwas, N Nair, R Gopal, R Bhatia, K Naresh, KN TI Lymphoid neoplasms in HIV-positive individuals in India SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE human immunodeficiency virus (HIV); acquired immunodeficiency syndrome (AIDS) non-Hodgkin lymphomas; Hodgkin disease; plasmacytoma; Epstein-Barr virus (EBV); p53 ID CLASSICAL HODGKINS-DISEASE; BARR-VIRUS ASSOCIATION; AIDS; PATHOGENESIS AB The HIV epidemic in the Asian subcontinent has a significant impact on India. Patients with AIDS have an increased risk of developing non-Hodgkin lymphoma (NHL). In this study, we have investigated the pattern of distribution of lymphoid neoplasms and also studied the Epstein-Barr virus (EBV)-association and p53 expression in 35 HIV-positive patients from India, The biopsy samples were studied for histology and for expression of CD20, CD3, CD15, CD30, light chains, CD138, bcl-6. epithelial membrane antigen, EBV-latent membrane protein-1, and p53 protein. In situ hybridization was performed with digoxigenin-labeled anti-sense EBV-encoded nuclear RNA-1 (EBER-1) probe. Polymerase chain reaction (PCR) was performed on DNA extracted from paraffin sections for EBV-subtype analysis. The 35 cases included 7 cases of Hodgkin disease (HD), 4 cases of plasmacytoma (PL), and 24 cases of NHL, Among the cases of NHL, 3 were Burkitt lymphoma (BL), 4 were diffuse large B-cell lymphoma (DLBL) of centroblastic type (CBL), 10 were DLBL of immunoblastic type (IBL), 4 were high-grade B-cell lymphoma (unspecified) and the rest were other subtypes. EBV-association was noted in all cases of HD, 2 of 3 BL, and 3 of 10 IBL. PCR analysis of the EBNA-3C gene revealed amplimers corresponding to type A. A p53 protein overexpression was noted in 6 of 10 IBLs, 1 of 3 BLs, 2 of 3 CBLs, and 5 of 7 cases of HD. This is the first reported study of lymphoid malignancies in HIV-positive individuals from India. C1 Tata Mem Hosp, Lymphoma Registry, Bombay 400012, Maharashtra, India. Tata Mem Hosp, Dept Pathol, Bombay 400012, Maharashtra, India. Tata Mem Hosp, Dept Med Oncol, Bombay 400012, Maharashtra, India. NIH, Bethesda, MD 20892 USA. RP Naresh, KN (reprint author), Tata Mem Hosp, Lymphoma Registry, Bombay 400012, Maharashtra, India. NR 12 TC 17 Z9 17 U1 0 U2 1 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 FEB 1 PY 2002 VL 29 IS 2 BP 181 EP 183 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 522HK UT WOS:000173890200012 PM 11832689 ER PT J AU Pine, DS Cohen, P Johnson, JG Brook, JS AF Pine, DS Cohen, P Johnson, JG Brook, JS TI Adolescent life events as predictors of adult depression SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE anxiety; depression; prospective research; epidemiology; life events ID DIAGNOSTIC INTERVIEW SCHEDULE; MAJOR DEPRESSION; RISK-FACTORS; CHILDREN; DISORDER; ANXIETY; CHILDHOOD; WOMEN; PSYCHOPATHOLOGY; RELIABILITY AB Background: Among adults, life events predict future episodes of major depression as well as a range of anxiety disorders. While studies have begun to examine this issue in adolescents, few studies rely upon prospective epidemiological designs to document relationships between adolescent life events and adult major depression. Method: An epidemiologically-selected sample of 776 young people living in Upstate New York received DSM-based psychiatric assessments and an assessment of life events in 1986. Psychopathology was again assessed in 1992. The current study examined the predictive relationship between life events in 1986 and depression as well as anxiety in 1992, controlling for depression/anxiety in 1986. Results: Adolescent life events predicted an increased risk for major depression diagnosis in adulthood. When analyzed continuously, an association emerged with symptoms of major depression as well as with symptoms of generalized anxiety disorder. However, this association with generalized anxiety disorder was limited to females. Conclusions: Life events in adolescence predict risk for major depression during early adulthood. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIMH, Intramural Res Program, Bethesda, MD 20892 USA. New York State Psychiat Inst & Hosp, Div Epidemiol Mental Disorders, New York, NY 10032 USA. Columbia Univ, New York, NY USA. Mt Sinai Sch Med, New York, NY USA. RP Pine, DS (reprint author), NIMH, Intramural Res Program, Bldg 10,Room 4N-222, Bethesda, MD 20892 USA. FU NIDA NIH HHS [DA-03188, K05-DA-00244]; NIMH NIH HHS [K02-MH01391, MH 36971, MH-16432, MH-43878] NR 40 TC 89 Z9 91 U1 5 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD FEB PY 2002 VL 68 IS 1 BP 49 EP 57 AR PII S0165-0327(00)00331-1 DI 10.1016/S0165-0327(00)00331-1 PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 538KM UT WOS:000174815200005 PM 11869782 ER PT J AU Praschak-Rieder, N Willeit, M Winkler, D Neumeister, A Hilger, E Thierry, N Ackenheil, M Bondy, B AF Praschak-Rieder, N Willeit, M Winkler, D Neumeister, A Hilger, E Thierry, N Ackenheil, M Bondy, B TI Role of of family history and 5-HTTLPR polymorphism in female sad patients with and without premenstrual dysphoric disorder SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Meeting Abstract C1 Univ Vienna, Dept Gen Psychiat, A-1010 Vienna, Austria. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Univ Munich, Hosp Psychiat, Dept Neurochem, D-8000 Munich, Germany. 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 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD FEB PY 2002 VL 68 IS 1 BP 129 EP 130 PG 2 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 538KM UT WOS:000174815200126 ER PT J AU Foster, B Schwartz, LB Devouassoux, G Metcalfe, DD Prussin, C AF Foster, B Schwartz, LB Devouassoux, G Metcalfe, DD Prussin, C TI Characterization of mast-cell tryptase-expressing peripheral blood cells as basophils SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE basophil; mast cell; tryptase; human; asthma; mastocytosis; IgE; flow cytometry; FACS; Kit; 2D7; IgE; BB-1 ID ALLERGEN CHALLENGE; ASTHMATIC SUBJECTS; IL-4 PRODUCTION; FLOW-CYTOMETRY; IDENTIFICATION; MASTOCYTOSIS; ACTIVATION; FIBROBLASTS; ANTIBODIES; HISTAMINE AB Background: Mast-cell tryptase is a protease with proinflammatory activity, the expression of which by peripheral blood leukocytes (PBLs) has not been fully characterized. Objective: We examined tryptase expression in human PBLs to further characterize this tryptase-expressing cell population for lineage and disease association. Methods: PBLs were fixed, permeabilized, stained with antibodies to tryptase and a panel of mast cell- and basophil-specific markers, and analyzed by means of flow cytometry. Results: Tryptase expression was restricted to a population of cells that stained positive for IgE and negative for the panel of lineage markers (IgE(+), lin(-)). This IgE(+), lin(-) population did not stain for the mast-cell markers Kit or chymase but did stain for the basophil-specific granule proteins recognized by the 2D7 and BB1 mAbs. Per-cell tryptase expression demonstrated a greater than 100-fold range of expression among donors but did not correlate with disease status (asthma or mastocytosis), FEV1, or serum tryptase concentration. Tryptase was released by purified basophils after anti-IgE activation. Conclusions: The phenotype of tryptase-expressing PBLs and their lack of increase in patients with mastocytosis demonstrates that these cells are basophils. Per-cell basophil tryptase expression is highly variable between donors, with some donors expressing levels approaching those of mast cells. As such, anti-tryptase antibodies cannot be used to distinguish these 2 cell types from one another by means of flow cytometry. These results demonstrate that tryptase represents an additional mediator through which basophils may contribute to allergic inflammation. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Dept Med, Richmond, VA 23298 USA. RP Prussin, C (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C205,10 Ctr Dr MSC 1881, Bethesda, MD 20892 USA. OI Prussin, Calman/0000-0002-3917-3326 FU NIAID NIH HHS [AI20487]; NIAMS NIH HHS [AR45441] NR 28 TC 34 Z9 35 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 FEB PY 2002 VL 109 IS 2 BP 287 EP 293 DI 10.1067/mai.2002.121454 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 528EZ UT WOS:000174232600014 PM 11842299 ER PT J AU Sparber, A Wootton, JC AF Sparber, A Wootton, JC TI Surveys of complementary and alternative medicine: Part V. Use of alternative and complementary therapies for psychiatric and neurologic diseases SO JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE LA English DT Article ID UNITED-STATES; NATIONAL SURVEY AB Surveys of general complementary and alternative medicine (CAM) use have suggested an association with high levels of depression and anxiety. This raises the question of whether anxious or depressed people seek CAM, or whether there are underlying factors associated with long-term chronic illness. There is no clear indication from four surveys of psychiatric patients. These are summarized and presented. A separate table summarizes three studies of patients with neurologic diseases, two of patients with multiple sclerosis, and one of a mixed patient population. More studies are amassing in specific disease areas, although it is difficult to detect clear trends because of methodological and terminological incompatibilities. C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. Alternat Med Fdn, Bethesda, MD USA. RP Sparber, A (reprint author), NIH, Ctr Clin, 10 Ctr Dr,MSC 1664,Room 7D37, Bethesda, MD 20892 USA. NR 15 TC 10 Z9 11 U1 4 U2 5 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1075-5535 J9 J ALTERN COMPLEM MED JI J. Altern. Complement Med. PD FEB PY 2002 VL 8 IS 1 BP 93 EP 96 DI 10.1089/107555302753507230 PG 4 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 534KH UT WOS:000174585200015 PM 11890442 ER PT J AU Hurlbut, DE Lott, ME Ryan, AS Ferrell, RE Roth, SM Ivey, FM Martel, GF Lemmer, JT Fleg, JL Hurley, BF AF Hurlbut, DE Lott, ME Ryan, AS Ferrell, RE Roth, SM Ivey, FM Martel, GF Lemmer, JT Fleg, JL Hurley, BF TI Does age, sex, or ACE genotype affect glucose and insulin responses to strength training? SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE gender; genetics; glucose tolerance; angiotensin I-converting enzyme ID CONVERTING-ENZYME GENE; DEPENDENT DIABETES-MELLITUS; CORONARY HEART-DISEASE; RESISTANCE EXERCISE; ENDURANCE EXERCISE; I/D POLYMORPHISM; OLDER MEN; TOLERANCE; WOMEN; HYPERTENSION AB The purpose of the present study was to determine whether age, sex, or angiotensin I-converting enzyme (ACE) genotype influences the effects of strength training (ST) on glucose homeostasis. Nineteen sedentary young (age = 20-30 yr) men (n = 10) and women (n = 9) were studied and compared with 21 sedentary older (age = 65-75 yr) men (n = 12) and women (n = 9) before and after a 6-mo total body ST program. Fasting insulin concentrations were reduced in young men and in older men with ST (P < 0.05 in both). In addition, total insulin area under the curve decreased by 21% in young men (P < 0.05), and there was a trend for a decrease (11%) in older men (P = 0.06). No improvements in insulin responses were observed in young or older women. The ACE deletion/deletion genotype group had the lowest fasting insulin and insulin areas under the oral glucose tolerance test (OGTT) curve before training (all P < 0.05), but those with at least one insertion allele had a trend for a greater reduction in total insulin area than deletion homozygotes (P = 0.07). These results indicate that ST has a more favorable effect on insulin response to an OGTT in men than in women and offer some support for the hypothesis that ACE genotype may influence insulin responses to ST. C1 Univ Maryland, Dept Kinesiol, Coll Hlth & Human Performance, College Pk, MD 20742 USA. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Div Cardiol, Hershey, PA 17033 USA. Univ Maryland, Sch Med, Div Gerontol, Baltimore, MD 21201 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. Univ Maryland Eastern Shore, Dept Phys Therapy, Princess Anne, MD 21853 USA. Tufts Univ, Human Nutr Res Ctr Aging, Nutr Exercise & Sarcopenia Lab, Jean Mayer US Dept Agr, Boston, MA 02111 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Hurley, BF (reprint author), Univ Maryland, Dept Kinesiol, Coll Hlth & Human Performance, College Pk, MD 20742 USA. OI Roth, Stephen/0000-0002-7841-3695 FU NIA NIH HHS [AG-1620501, AG-00268, AG-05893, AG-42148] NR 38 TC 11 Z9 12 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD FEB PY 2002 VL 92 IS 2 BP 643 EP 650 PG 8 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 511YB UT WOS:000173293400030 PM 11796676 ER PT J AU Tanaka, M Ogawa, N Ihara, K Sugiyama, Y Mukohata, Y AF Tanaka, M Ogawa, N Ihara, K Sugiyama, Y Mukohata, Y TI Cytochrome aa(3) in Haloferax volcanii SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ARCHAEBACTERIAL TERMINAL OXIDASE; HALOBACTERIUM-HALOBIUM; NATRONOBACTERIUM-PHARAONIS; SULFOLOBUS-ACIDOCALDARIUS; QUINOL OXIDASE; COPPER PROTEIN; ARCHAEON; GENE; PURIFICATION; AMBIVALENS AB A cytochrome in an extremely halophilic archaeon, Haloferax volcanii, was purified to homogeneity. This protein displayed a redox difference spectrum that is characteristic of a-type cytochromes and a CN- complex spectrum that indicates the presence of heme a and heme a(3). This cytochrome aa(3) consisted of 44- and 35-kDa subunits. The amino acid sequence of the 44-kDa subunit was similar to that of the heme-copper oxidase subunit 1, and critical amino acid residues for metal binding, such as histidines, were highly conserved. The reduced cytochrome c partially purified from the bacterial membrane fraction was oxidized by the cytochrome aa(3), providing physiological evidence for electron transfer from cytochrome c to cytochrome aa(3) in archaea. C1 Nagoya Univ, Grad Sch Sci, Div Biol Sci, Nagoya, Aichi 4648602, Japan. RP Tanaka, M (reprint author), NINCDS, Genet Pharmacol Unit, Expt Therapeut Branch, NIH, 10 Ctr Dr,MSC 1406, Bethesda, MD 20892 USA. NR 24 TC 14 Z9 16 U1 0 U2 0 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 FEB PY 2002 VL 184 IS 3 BP 840 EP 845 PG 6 WC Microbiology SC Microbiology GA 513EB UT WOS:000173364000027 PM 11790755 ER PT J AU Baldwin, NE McCracken, A Dombroski, AJ AF Baldwin, NE McCracken, A Dombroski, AJ TI Two "wild-type" variants of Escherichia coli sigma(70): Context-dependent effects of the identity of amino acid 149 SO JOURNAL OF BACTERIOLOGY LA English DT Article ID CORE RNA-POLYMERASE; TRANSCRIPTION INITIATION; PROMOTER; MUTANT; SUBUNIT; REGION; RECOGNITION; SPECIFICITY; SEQUENCE; SUBTILIS AB The identity of amino acid 149 of Escherichia coli sigma(70) has been reported variably as either arginine or aspartic acid. We show that the behavior of both a region 1.2 deletion and a single-amino-acid substitution at position 122 are greatly affected by the identity of amino acid 149. C1 Univ Texas, Hlth Sci Ctr, Dept Microbiol & Mol Genet, Houston, TX 77030 USA. RP Dombroski, AJ (reprint author), NIH, Ctr Sci Review, 6701 Rocklegde Dr,Mailstop 7808, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [GM56453] NR 31 TC 1 Z9 1 U1 0 U2 0 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 FEB PY 2002 VL 184 IS 4 BP 1192 EP 1195 DI 10.1128/jb.184.4.1192-1195.2002 PG 4 WC Microbiology SC Microbiology GA 518VJ UT WOS:000173688300037 PM 11807081 ER PT J AU Ananthanarayanan, B Das, S Rhee, SG Murray, D Cho, W AF Ananthanarayanan, B Das, S Rhee, SG Murray, D Cho, W TI Membrane targeting of C2 domains of phospholipase C-delta isoforms SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; PLECKSTRIN HOMOLOGY DOMAIN; CRYSTAL-STRUCTURE; BINDING RESIDUES; COMMON FOLD; C-DELTA-1; SYNAPTOTAGMIN; LIGANDS; COMPLEX; ALPHA AB The C2 domain is a Ca2+-dependent membrane-targeting module found in many cellular proteins involved in signal transduction or membrane trafficking. To understand the mechanisms by which the C2 domain mediates the membrane targeting of PLC-delta isoforms, we measured the in vitro membrane binding of the C2 domains of PLC-delta1, -delta3, and -delta4 by surface plasmon resonance and monolayer techniques and their subcellular localization by time-lapse confocal microscopy. The membrane binding of the PLC-delta1-C2 is driven by nonspecific electrostatic interactions between the Ca2+-induced cationic surface of protein and the anionic membrane and specific interactions involving Ca2+, Asn(647), and phosphatidylserine (PS). The PS selectivity of PLC-delta1-C2 governs its specific Ca2+-dependent subcellular targeting to the plasma membrane. The membrane binding of the PLC-delta3-C2 also involves Ca2+-induced nonspecific electrostatic interactions and PS coordination, and the latter leads to specific subcellular targeting to the plasma membrane. In contrast to PLC-delta1-C2 and PLC-delta3-C2, PLC-delta4-C2 has significant Ca2+-independent membrane affinity and no PS selectivity due to the presence of cationic residues in the Ca2+-binding loops and the substitution of Ser for the Ca2+-coordinating Asp in position 717. Consequently, PLC-delta4-C2 exhibits unique prelocalization to the plasma membrane prior to Ca2+ import and non-selective Ca2+-mediated targeting to various cellular membranes, suggesting that PLC-delta4 might have a novel regulatory mechanism. Together, these results establish the C2 domains of PLC-delta isoforms as Ca2+-dependent membrane targeting domains that have distinct membrane binding properties that control their subcellular localization behaviors. C1 Univ Illinois, Dept Chem, Chicago, IL 60607 USA. Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA. NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. RP Cho, W (reprint author), Univ Illinois, Dept Chem, M-C111,845 W Taylor St, Chicago, IL 60607 USA. FU NIGMS NIH HHS [GM52598, GM53987] NR 37 TC 67 Z9 69 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 FEB 1 PY 2002 VL 277 IS 5 BP 3568 EP 3575 DI 10.1074/jbc.M109705200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 518VF UT WOS:000173688000068 PM 11706040 ER PT J AU Wolter, S Mushinski, JF Saboori, AM Resch, K Kracht, M AF Wolter, S Mushinski, JF Saboori, AM Resch, K Kracht, M TI Inducible expression of a constitutively active mutant of mitogen-activated protein kinase kinase 7 specifically activates c-JUN NH2-terminal protein kinase, alters expression of at least nine genes, and inhibits cell proliferation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID N-TERMINAL KINASE; LUNG-CARCINOMA CELLS; SIGNAL-TRANSDUCTION; SYNERGISTIC ACTIVATION; GAMMA-RADIATION; MAMMALIAN-CELLS; MAP KINASES; JNK; MKK7; GROWTH AB MKK7 is a recently discovered mitogen-activated protein kinase (MAPK) kinase that is unique in that it specifically activates only the c-JUN NH2-terminal protein kinase (JNK) family of enzymes. Very little is known about the biological role of MKK7. We generated inducible cell lines from the human embryonal kidney carcinoma cell line, HEK293, by stable transfection with a constitutively active mutant of MKK7, MKK7(3E), fused to green fluorescent protein (GFP), under the control of an ecdysone-inducible promoter. Treatment of cells with the synthetic ecdysone analog ponasterone A induced expression of GFP-MKK7(3E) and resulted in sustained activation of endogenous JNK, but neither of the other endogenous MAPKs, ERK or p38. Red and green fluorescing cDNA copies of mRNA extracted from cells obtained before and after induction of GFP-MKK7(3E) were hybridized to microarrays containing more than 6,000 cDNAs in eight independent experiments. By selection criteria, 23 genes were differentially regulated after 24 h of induction of GFP-MKK7(3E) and 16 after 48 h. The expression of 9 genes was consistently changed after both 24 and 48 h of induction. These changes included down-regulation of three genes, c-myc, angiopoietin-2, and glucose-regulated protein 58, and up-regulation of 6 genes, tissue factor pathway inhibitor-2, GRP78, autotaxin, PPP1R7, the DKFZ cDNA p434D0818, and I unknown gene. Consistent with previously described roles of several of the altered genes, MKK7(3E) inhibited cell proliferation. These data implicate active MKK7 in the negative regulation of cell proliferation and provide evidence for a new role for this kinase in the regulation of a distinct, hitherto unrecognized set of genes. C1 Hannover Med Sch, Inst Pharmacol, D-30625 Hannover, Germany. NCI, Canc Res Ctr, Genet Lab, Mol Genet Sect,NIH, Bethesda, MD 20892 USA. RP Kracht, M (reprint author), Hannover Med Sch, Inst Pharmacol, Carl Neuberg Str 1, D-30625 Hannover, Germany. NR 46 TC 18 Z9 21 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 FEB 1 PY 2002 VL 277 IS 5 BP 3576 EP 3584 DI 10.1074/jbc.M105800200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 518VF UT WOS:000173688000069 PM 11714698 ER PT J AU Hall, MC Shcherbakova, PV Kunkel, TA AF Hall, MC Shcherbakova, PV Kunkel, TA TI Differential ATP binding and intrinsic ATP hydrolysis by amino-terminal domains of the yeast Mlh1 and Pms1 proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA MISMATCH REPAIR; GYRASE-B-PROTEIN; SACCHAROMYCES-CEREVISIAE; CRYSTAL-STRUCTURE; SHUTTLE VECTORS; IN-VIVO; MUTL; FRAGMENT; MUTATIONS; GENES AB MutL homologs belong to a family of proteins that share a conserved ATP binding site. We demonstrate that amino-terminal domains of the yeast MutL homologs Mlh1 and Pms1 required for DNA mismatch repair both possess independent, intrinsic ATPase activities. Amino acid substitutions in the conserved ATP binding sites concomitantly reduce ATP binding, ATP hydrolysis, and DNA mismatch repair in vivo. The ATPase activities are weak consistent with the hypothesis that ATP binding is primarily responsible for modulating interactions with other MMR components. Three approaches, ATP hydrolysis assays, limited proteolysis protection, and equilibrium dialysis, provide evidence that the amino-terminal domain of MIh1 binds ATP with >10-fold higher affinity than does the amino-terminal domain of Pms1. This is consistent with a model wherein ATP may first bind to MIh1, resulting in events that permit ATP binding to Pms1 and later steps in DNA mismatch repair. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), NIEHS, Struct Biol Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 27 TC 37 Z9 40 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 FEB 1 PY 2002 VL 277 IS 5 BP 3673 EP 3679 DI 10.1074/jbc.M106120200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 518VF UT WOS:000173688000081 PM 11717305 ER PT J AU Gryk, MR Maciejewski, MW Robertson, A Mullen, MA Wilson, SH Mullen, GP AF Gryk, MR Maciejewski, MW Robertson, A Mullen, MA Wilson, SH Mullen, GP TI Letter to the Editor: H-1, C-13 and N-15 resonance assignments for the perdeuterated 22 kD palm-thumb domain of DNA polymerase beta SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE deuteration; DNA polymerase beta; DNA repair; Rattus norvegicus; TROSY ID NMR; PROTEINS; BINDING C1 Univ Connecticut, Ctr Hlth, Dept Biochem, Farmington, CT 06030 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Mullen, GP (reprint author), Univ Connecticut, Ctr Hlth, Dept Biochem, Farmington, CT 06030 USA. FU NIEHS NIH HHS [ES09847]; NIGMS NIH HHS [GM52738] NR 10 TC 3 Z9 3 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD FEB PY 2002 VL 22 IS 2 BP 197 EP 198 DI 10.1023/A:1014237724868 PG 2 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 523ZY UT WOS:000173988500015 PM 11883786 ER PT J AU Chen, XD Shi, ST Xu, TS Robey, PG Young, MF AF Chen, XD Shi, ST Xu, TS Robey, PG Young, MF TI Age-related osteoporosis in biglycan-deficient mice is related to defects in bone marrow stromal cells SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE biglycan; osteoporosis; bone marrow stromal cells; colony-forming unit fibroblastic; collagen ID PROTEOGLYCANS BIGLYCAN; EXTRACELLULAR-MATRIX; OSTEOBLAST APOPTOSIS; I COLLAGEN; DECORIN; FIBROMODULIN; MODULATION; PREVENTION; RECEPTORS; VITRO AB Biglycan (bgn) is an extracellular matrix proteoglycan that is enriched in bone and other skeletal connective tissues. Previously, we generated bgn-deficient mice and showed that they developed age-dependent osteopenia. To identify the cellular events that might contribute to this progressive osteoporosis, we measured the number of osteogenic precursors in the bone marrow of normal and mutant mice. The number of colonies, indicative of the colony-forming unit potential of fibroblasts (CFU-F), gradually decreased with age. By 24 weeks of age, colony formation in the bgn knockout (KO) mice was significantly more reduced than that in the wild type (wt) mice. This age-related reduction was consistent with the extensive osteopenia previously shown by X-ray analysis and histological examination of 24-week-old bgn KO mice. Because bgn has been shown previously to bind and regulate transforming growth factor beta (TGF-beta) activity, we also asked whether this growth factor would affect colony formation. TGF-beta treatment significantly increased the size of the wt colonies. In contrast, TGF-beta did not significantly influence the size of the bgn colonies. An increase in apoptosis in bgn-deficient bone marrow stromal cells (BMSCs) was observed also. The combination of decreased proliferation and increased apoptosis, if it occurred in vivo, would lead to a deficiency in the generation of mature osteoblasts and would be sufficient to account for the osteopenia developed in the bgn KO mice. The bgn KO mice also were defective in the synthesis of type I collagen messenger RNA (mRNA) and protein. This result supports the suggestion that the composition of the extracellular matrix may be regulated by specific matrix components including bgn. C1 NIDCR, NIH, Craniofacial & Skeletal Dis Branch, Bethesda, MD 20892 USA. RP Chen, XD (reprint author), NIDCR, NIH, Craniofacial & Skeletal Dis Branch, 9000 Rockville Pike,MSC 4320,Bldg 30,Rm 225, Bethesda, MD 20892 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 25 TC 98 Z9 106 U1 0 U2 2 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 FEB PY 2002 VL 17 IS 2 BP 331 EP 340 DI 10.1359/jbmr.2002.17.2.331 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 513LL UT WOS:000173380000017 PM 11811564 ER PT J AU Ginis, I Jaiswal, R Klimanis, D Liu, H Greenspon, J Hallenbeck, JM AF Ginis, I Jaiswal, R Klimanis, D Liu, H Greenspon, J Hallenbeck, JM TI TNF-alpha-induced tolerance to ischemic injury involves differential control of NF-kappa B transactivation: The role of NF-kappa B association with p300 adaptor SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE astrocytes; stress adaptation; tolerance; tumor necrosis factor; NF-kappa B; p300 adapter protein; protein kinase A ID TUMOR-NECROSIS-FACTOR; SUPEROXIDE-DISMUTASE GENE; ACTIVATED PROTEIN-KINASE; INTERCELLULAR-ADHESION MOLECULE-1; SIGNAL-REGULATED KINASE; FOCAL CEREBRAL-ISCHEMIA; TRAUMATIC BRAIN INJURY; BETA-PEPTIDE TOXICITY; CREB-BINDING PROTEIN; C-ZETA AB Preconditioning with sublethal ischemia results in natural tolerance to ischemic stress, where multiple mediators of ischemic damage are simultaneously counteracted. Tumor necrosis factor alpha (TNF-alpha) has been implicated in development of ischemic tolerance. Using cellular models of ischemic tolerance, we have demonstrated that an effector of TNF-alpha-induced preconditioning is ceramide, a sphingolipid messenger in TNF-alpha signaling. TNF-alpha/ceramide-induced preconditioning protected cultured neurons against ischemic death and cultured astrocytes against proinflammatory effects of TNF-alpha. TNF-alpha activates a transcription factor NF-kappaB that binds promoters of multiple genes, thus ensuring pleiotropic effects of TNF-alpha. We describe here a mechanism that allows selective suppression of TNF-alpha/NF-kappaB-induced harmful genes in preconditioned cells while preserving cytoprotective responses. We demonstrate that in astrocytes activation of an adhesion molecule ICAM-1 by TNF-alpha is regulated through association of the phosphorylated p65 subunit of NF-kappaB with an adapter protein, p300, and that in preconditioned cells p65 remains unphosphorylated and ICAM-1 transcription is inhibited. However, TNF-alpha-activated transcription of a protective enzyme, MnSOD, does not depend on p300 and does not become inhibited in preconditioned cells. This new understanding of TNF-alpha-induced adaptation to ischemic stress and inflammation could suggest novel avenues for clinical intervention during ischemic and inflammatory diseases. C1 NINCDS, Mol Biol Lab, Stroke Branch, NIH, Bethesda, MD 20892 USA. RP Ginis, I (reprint author), NINCDS, Mol Biol Lab, Stroke Branch, NIH, 36 Convent Dr,MSC 4092,Bldg 36,Room 3C12, Bethesda, MD 20892 USA. NR 67 TC 87 Z9 100 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD FEB PY 2002 VL 22 IS 2 BP 142 EP 152 PG 11 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 517KB UT WOS:000173608700002 PM 11823712 ER PT J AU Bagci, Z Jernigan, RL Bahar, I AF Bagci, Z Jernigan, RL Bahar, I TI Residue packing in proteins: Uniform distribution on a coarse-grained scale SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID GLOBULAR-PROTEINS; VOLUME OCCUPATION; FOLDED PROTEINS; FOLDING NUCLEUS; MOLECULAR AREA; LATTICE; DENSITY; CONFORMATIONS; ACCESSIBILITY; MATHEMATICS AB The high packing density of residues in proteins ought to be manifested in some order; to date this packing order has not been thoroughly characterized. The packing regularity in proteins is important because the internal organization of proteins can have a dominant effect on functional dynamics, and it can aid in the design, simulation and evaluation of structures. Packing metrics could also inform us about normal sequence variability, an issue that, with the accumulating genome data, becomes increasingly important. Other studies, indicating a possible correlation between packing density, sequence conservation, and folding nucleation [O. B. Ptitsyn, J. Mol. Biol. 278, 655 (1998)], have emphasized the importance of packing. Here, residue clusters from protein databank structures, each comprised of a central residue and all neighbors located within the first coordination shell, have been rigidly re-oriented and superimposed in a self-consistent optimization. About two-thirds of residues are found to follow approximately the relative orientation preferences of face-centered-cubic packing, when examined on a coarse-grained scale (one site per residue), while the remaining one-third occupy random positions. The observed regularity, which becomes more pronounced after optimal superimposition of core residues, appears to be the result of uniform sampling of the coordination space around each residue on a coarse-grained scale with hydrophobic clustering and volume exclusion, to achieve packing densities close to that of the universal closest packing of identical spheres. (C) 2002 American Institute of Physics. C1 Univ Pittsburgh, Sch Med, Ctr Computat Biol & Bioinformat, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Dept Biochem & Mol Genet, Pittsburgh, PA 15213 USA. NCI, Mol Struct Sect, Lab Expt & Computat Biol, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. Bogazici Univ, Dept Chem Engn, TR-80815 Bebek, Istanbul, Turkey. Bogazici Univ, Ctr Polymer Res, TR-80815 Bebek, Istanbul, Turkey. RP Bahar, I (reprint author), Univ Pittsburgh, Sch Med, Ctr Computat Biol & Bioinformat, Pittsburgh, PA 15213 USA. RI Jernigan, Robert/A-5421-2012; bagci, elife/B-9032-2012; Bagci, Elife/A-9660-2016 NR 48 TC 29 Z9 29 U1 0 U2 4 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 FEB 1 PY 2002 VL 116 IS 5 BP 2269 EP 2276 DI 10.1063/1.1432502 PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 514CG UT WOS:000173418600056 ER PT J AU Tian, G Zhang, TY Zhang, YB Ito, Y AF Tian, G Zhang, TY Zhang, YB Ito, Y TI Separation of tanshinones from Salvia miltiorrhiza Bunge by multidimensional counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Salvia miltiorrhiza; counter-current chromatography; plant materials; preparative chromatography; tanshinones AB Analytical and preparative high-speed counter-current chromatography (HSCCC) was successfully used for the isolation and purification of tanshinones from the roots of Salvia miltiorrhiza Bunge. Using multidimensional HSCCC, four major components including tanshinone IIA (16 mg), tanshinone I (10 mg), dihydrotanshinone I (7 mg) and cryptotanshinone (II mg) were isolated each at high purity of over 95%. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIH, NHLBI, Biophys Chem Lab, Bethesda, MD 20892 USA. Beijing Inst New Technol Applicat, Beijing 100035, Peoples R China. RP Ito, Y (reprint author), NIH, NHLBI, Biophys Chem Lab, Bldg 50,Room 3334,50 S Dr MSC 8014, Bethesda, MD 20892 USA. NR 8 TC 49 Z9 57 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD FEB 1 PY 2002 VL 945 IS 1-2 BP 281 EP 285 DI 10.1016/S0021-9673(01)01495-9 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 517KL UT WOS:000173609600023 PM 11860143 ER PT J AU Marx, SJ Nieman, LK AF Marx, SJ Nieman, LK TI Editorial: Aggressive pituitary tumors in MEN1: Do they refute the two-hit model of tumorigenesis? SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material ID MULTIPLE ENDOCRINE NEOPLASIA; ZOLLINGER-ELLISON-SYNDROME; CUSHINGS-DISEASE; ALLELIC LOSS; TYPE-1; ADENOMAS; GENE; PATHOGENESIS; MUTATIONS C1 NIDDKD, Metab Dis Branch, Bethesda, MD 20892 USA. NICHHD, Pediat & Reprod Endocrinol Branch, Bethesda, MD 20892 USA. RP Marx, SJ (reprint author), NIH, Bldg 10,Room 9C-101, Bethesda, MD 20892 USA. EM StephenM@intra.niddk.nih.gov NR 42 TC 16 Z9 16 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 FEB PY 2002 VL 87 IS 2 BP 453 EP 456 DI 10.1210/jc.87.2.453 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 530HD UT WOS:000174351500005 PM 11836267 ER PT J AU Bandyopadhyay, G Sajan, MP Kanoh, Y Standaert, ML Quon, MJ Lea-Currie, R Sen, A Farese, RV AF Bandyopadhyay, G Sajan, MP Kanoh, Y Standaert, ML Quon, MJ Lea-Currie, R Sen, A Farese, RV TI PKC-zeta mediates insulin effects on glucose transport in cultured preadipocyte-derived human Adipocytes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PROTEIN-KINASE B; C-LAMBDA; GLUCOSE-TRANSPORTER-4 TRANSLOCATION; 3T3-L1 ADIPOCYTES; RAT ADIPOCYTES; STIMULATED TRANSLOCATION; GLUT4 TRANSLOCATION; ACTIVATION LOOP; POTENTIAL ROLE; L6 MYOTUBES AB Insulin-stimulated glucose transport is impaired in the early phases of type 2 diabetes mellitus. Studies in rodent cells suggest that atypical PKC (aPKC) isoforms (zeta, lambda, and iota) and PKB, and their upstream activators, PI3K and 3-phosphoinositide-dependent protein kinase-1 (PDK-1), play important roles in insulin-stimulated glucose transport. However, there is no information on requirements for aPKCs, PKB, or PDK-1 during insulin action in human cell types. Presently, by using preadipocyte-derived adipocytes, we were able to employ adenoviral gene transfer methods to critically examine these requirements in a human cell type. These adipocytes were found to contain PKC-zeta, rather than PKC-Niota, as their major aPKC. Expression of kinase-inactive forms of PDK-1, PKC-zeta, and PKC-lambda (which functions interchangeably with PKC-zeta) as well as chemical inhibitors of PI 3-hinase and PKC-zeta/lambda, wortmannin and the cell-permeable myristoylated PKC-zeta pseudosubstrate, respectively, effectively inhibited insulin-stimulated glucose transport. In contrast, expression of a kinase-inactive, activation-resistant, triple alanine mutant form of PKB-alpha had little or no effect, and expression of wildtype and constitutively active PKC-zeta or PKC-lambda increased glucose transport. Our findings provide convincing evidence that aPKCs and upstream activators, PI 3-kinase and PDK-1, play important roles in insulin-stimulated glucose transport in preadipocyte-derived human adipocytes. C1 James A Haley Vet Hosp, Res Serv VAR 151, Tampa, FL 33612 USA. Univ S Florida, Coll Med, Dept Internal Med, Tampa, FL 33612 USA. NHLBI, Hypertens Endocrine Branch, NIH, Bethesda, MD 20892 USA. Zen Bio Inc, Res Triangle Pk, NC 27709 USA. RP James A Haley Vet Hosp, Res Serv VAR 151, 13000 Bruce B Downs Blvd, Tampa, FL 33612 USA. EM rfarese@com1.med.usf.edu RI Quon, Michael/B-1970-2008; Farese, Robert/B-3605-2015 FU NIDDK NIH HHS [R01 DK065969, R01-DK-38079-09A1] NR 22 TC 58 Z9 61 U1 2 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2002 VL 87 IS 2 BP 716 EP 723 DI 10.1210/jc.87.2.716 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 530HD UT WOS:000174351500044 PM 11836310 ER PT J AU Suzuki, K Royaux, IE Everett, LA Mori-Aoki, A Suzuki, S Nakamura, K Sakai, T Katoh, R Toda, S Green, ED Kohn, LD AF Suzuki, K Royaux, IE Everett, LA Mori-Aoki, A Suzuki, S Nakamura, K Sakai, T Katoh, R Toda, S Green, ED Kohn, LD TI Expression of PDS/Pds, the Pendred syndrome gene, in endometrium SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PDS; TRANSCRIPTION; CELLS; THYROGLOBULIN; TISSUES; PROTEIN; IODIDE AB Expression of the Pendred syndrome gene (PDS/Pds) is thought to be responsible for the iodide transport in the thyroid as well as the formation and function of the inner ear. Its mRNA is also expressed in the kidney and placenta. We report here that PDS and its encoded protein (pendrin) are also expressed in the endometrium. The RNA levels of rat PDS in the endometrium and kidney were much higher than those of the thyroid, opposite of the pattern of RNA expression in humans. In human endometrium, pendrin localization changed from the basal to apical surfaces of the epithelium during progression of the menstrual cycle. This suggests a possible role for pendrin in cationic ion transport required to maintain the physiological function of the endometrium. Since there is no evidence of endometrial abnormalities in patients with Pendred syndrome, it suggests the existence of a compensatory mechanisms for pendrin's function in the uterus. C1 Natl Inst Infect Dis, Dept Microbiol, Leprosy Res Ctr, Tokyo 1890002, Japan. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Tottori Univ, Sch Med, Dept Internal Med, Yonago, Tottori 683, Japan. Washington Hosp Ctr NW, Mol Endocrinol Lab, MedStar Res Inst, Washington, DC 20010 USA. Saitama Univ, Cell Biol Lab, Dept Regulat Biol, Urawa, Saitama 338, Japan. Yamanashi Med Univ, Dept Pathol, Tamaho, Yamanashi, Japan. Saga Med Sch, Dept Pathol, Saga, Japan. Ohio Univ, Sch Osteopath Med, Athens, OH 45701 USA. Edison Biotechnol Inst, Athens, OH USA. RP Suzuki, K (reprint author), Natl Inst Infect Dis, Dept Microbiol, Leprosy Res Ctr, 4-2-1 Aoba Cho, Tokyo 1890002, Japan. EM koichis@nih.go.jp RI Suzuki, Sayuri/L-5291-2013 NR 25 TC 42 Z9 44 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2002 VL 87 IS 2 BP 938 EP 941 DI 10.1210/jc.87.2.938 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 530HD UT WOS:000174351500076 PM 11836344 ER PT J AU Quon, MJ AF Quon, MJ TI QUICKI is a useful and accurate index of insulin sensitivity SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Letter ID MINIMAL MODEL ANALYSIS; GLUCOSE-TOLERANCE; CLAMP; HUMANS C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Quon, MJ (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10,Room 8C-218,100 Ctr Dr,MSC 1755, Bethesda, MD 20892 USA. EM quonm@nih.gov RI Quon, Michael/B-1970-2008; OI Quon , Michael /0000-0002-5289-3707 NR 22 TC 27 Z9 28 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 FEB PY 2002 VL 87 IS 2 BP 949 EP 950 DI 10.1210/jc.87.2.949 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 530HD UT WOS:000174351500083 PM 11836351 ER PT J AU Lumley, T Kronmal, RA Cushman, M Manolio, TA Goldstein, S AF Lumley, T Kronmal, RA Cushman, M Manolio, TA Goldstein, S TI A stroke prediction score in the elderly: validation and Web-based application SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE risk; proportional hazards models; aged; cerebrovascular disorders ID CARDIOVASCULAR HEALTH; HEART-DISEASE; PEOPLE AB The objective of this study was to construct a prediction model for predicting stroke in an elderly U.S. population, and to assess the accuracy in this population of other previously published prediction models. The subjects were participants in the Cardiovascular Health Study: 2,495 men and 3,393 women age 65 years and older at baseline, and followed for 6.3 years. Among 5,711 participants free of baseline stroke, 399 strokes occurred. Sex-specific prediction equations were constructed using study variables that were most importantly related to incident stroke: age, systolic blood pressure, diabetes, ECG diagnosis of atrial fibrillation or left ventricular hypertrophy, confirmed history of cardiovascular disease, diabetes, time to walk 15 ft, and serum creatinine. The prediction rule was implemented as a risk score and in a Web-based interactive Java applet. Overall, the model predicted 5-year stroke risks ranging from less than 1 to 59%. The 20% of subjects in the highest predicted risk group had a 5-year actual stroke incidence rate of 15%, while the 20% lowest risk group had a 1% incidence. Risk scores from two other studies performed well in these study participants. Effective discrimination between low and high stroke risk in the elderly was possible in this cohort with data that are easy to obtain. Evaluation of the generalizability and clinical usefulness of this prediction model requires further research. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Univ Washington, CHS Coordinating Ctr, Seattle, WA 98101 USA. Univ Vermont, Dept Med, Colchester Res Facil, Colchester, VT 05446 USA. NHLBI, Epid Biometry Program, DECA, Bethesda, MD 20892 USA. Univ Pittsburgh, UPMC Stroke Inst, Pittsburgh, PA 15213 USA. RP Lumley, T (reprint author), Univ Washington, CHS Coordinating Ctr, Plaza 600 Bldg,Suite 700,600 Stewart St, Seattle, WA 98101 USA. FU NHLBI NIH HHS [N01-HC-85079, N01-HC85080, N01-HC85081, N01-HC85082, N01-HC85083, N01-HC85084, N01-HC85085, N01-HC85086] NR 21 TC 51 Z9 52 U1 0 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD FEB PY 2002 VL 55 IS 2 BP 129 EP 136 DI 10.1016/S0895-4356(01)00434-6 PG 8 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 518WD UT WOS:000173690100005 PM 11809350 ER PT J AU Poggi, MM Cong, PJJ Coleman, CN Jaffe, ES AF Poggi, MM Cong, PJJ Coleman, CN Jaffe, ES TI Low-grade follicular lymphoma of the small intestine SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Article DE lymphoma; intestine; follicular; real ID GASTROINTESTINAL-TRACT; CLASSIFICATION; FEATURES AB Background: Although the gastrointestinal tract is the most common site of extranodal non-Hodgkin's lymphoma (NHL), primary small intestine lymphomas remain relatively rare, especially localized low-grade follicular B-cell lymphomas. When lymphomas do occur at this site, most are high grade and require aggressive therapy. We report three cases of small intestinal follicular lymphoma diagnosed on endoscopic biopsy and review the clinical history, pathologic features, and treatment outcome. Study: A review of the medical records and pathology from three cases of small intestine follicular NHL was performed. The pathology specimens were formalin-fixed, paraffin-embedded tissues processed for routine microscopic examination, immunohistochemical staining, and molecular analysis. Results: Histologic and immunophenotypical studies were diagnostic of grade I follicular lymphoma (Revised European-American Lymphoma classification/World Health Organization classification). All cases expressed bcl-2 protein, and polymerase chain reaction analysis supported the diagnosis in two cases with adequate DNA. With 23.3 months' median follow-up, one untreated and one treated patient were alive without symptoms; a third untreated patient died of a nonlymphoma cause. Conclusion: Isolated indolent lymphomas of the small intestine are rare. Accurate pathologic staging and histologic classification are paramount in delineating treatment options. C1 NCI, Radiat Oncol Sci Program, NIH, Bethesda, MD 20892 USA. NCI, Pathol Branch, NIH, Bethesda, MD 20892 USA. RP Poggi, MM (reprint author), NCI, Radiat Oncol Sci Program, NIH, B3B69 Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. NR 11 TC 21 Z9 21 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0192-0790 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD FEB PY 2002 VL 34 IS 2 BP 155 EP 159 DI 10.1097/00004836-200202000-00011 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 513DJ UT WOS:000173362400011 PM 11782611 ER PT J AU Fernandez, AM Dupont, J Farrar, RP Lee, S Stannard, B Le Roith, D AF Fernandez, AM Dupont, J Farrar, RP Lee, S Stannard, B Le Roith, D TI Muscle-specific inactivation of the IGF-I receptor induces compensatory hyperplasia in skeletal muscle SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID GROWTH-FACTOR-I; PROTEIN-KINASE PATHWAY; MYOBLAST PROLIFERATION; SIGNALING PATHWAYS; MYOGENIC PROGRAM; DIFFERENTIATION; EXPRESSION; MICE; CELLS; TWIST AB During the development of skeletal muscle, myoblasts withdraw from the cell cycle and differentiate into myotubes. The insulin-like growth factors IGF-I and IGF-II, through their cognate tyrosine kinase receptor (IGF-I receptor), are known to play a role in this process. After withdrawal of myoblasts from the cell cycle, IGF-I promotes muscle differentiation by inducing the expression or activity of myogenic regulatory factors (MyoD, myogenin) and effectors (p21). However, little is known about the intracellular mechanisms by which the IGF-I system regulates these factors during the process of myogenesis. Here we show that MKR mice, which express a dominant negative IGF-I receptor specifically in skeletal muscle, have marked muscle hypoplasia from birth to 3 weeks of age. This hypoplasia occurs concomitantly with a decrease in ERK immunoreactivity levels and decreases in MyoD and myogenin expression. BrdU immunocytochemistry showed a compensatory hyperplasia as MKR mice grew to adulthood. Interestingly, hyperplasia occurred concomitantly with an increase in p38, MyoD, myogenin, and p21 immunoreactivity levels, as well as a decrease in Twist levels. These findings suggest that regulation of these cellular elements by IGF-I may play a role in the development and differentiation of skeletal muscle in vivo. C1 NIDDKD, Mol & Cellular Physiol Sect, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, Dept Kinesiol, Austin, TX 78712 USA. RP Le Roith, D (reprint author), NIDDKD, Mol & Cellular Physiol Sect, Clin Endocrinol Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 8D12, Bethesda, MD 20892 USA. NR 33 TC 94 Z9 100 U1 0 U2 7 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 FEB PY 2002 VL 109 IS 3 BP 347 EP 355 DI 10.1172/JCI13503 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 519DW UT WOS:000173710500009 PM 11827994 ER PT J AU Pohlenz, J Dumitrescu, A Zundel, D Martine, U Schonberger, W Koo, E Weiss, RE Cohen, RN Kimura, S Refetoff, S AF Pohlenz, J Dumitrescu, A Zundel, D Martine, U Schonberger, W Koo, E Weiss, RE Cohen, RN Kimura, S Refetoff, S TI Partial deficiency of Thyroid transcription factor 1 produces predominantly neurological defects in humans and mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID FACTOR-I TTF-1; CONGENITAL HYPOTHYROIDISM; RESPIRATORY-FAILURE; CLEFT-PALATE; NKX2.1 GENE; EXPRESSION; DYSGENESIS; MUTATIONS; BINDING; PROTEIN AB Three genes, TTF1, TTF2, and PAX8, involved in thyroid gland development and migration have been identified. Yet systematic screening for defects in these genes in thyroid dysgenesis gave essentially negative results. In particular, no TTF1 gene defects were found in 76 individuals with thyroid dysgenesis even though a deletion of this gene in the mouse results in thyroid and lung agenesis and defective diencephalon. We report a 6-year-old boy with predominant dyskinesia, neonatal respiratory distress, and mild hyperthyrotropinemia. One allele of his TTF1 gene had a guarridine inserted into codon 86 producing a nonsense protein of 407, rather than 371, amino acids. The mutant TTF1 did not bind to its canonical cis-element or transactivate a reporter gene driven by the thyroglobulin promoter, a natural target of TTF1. Failure of the mutant TTF1 to interfere with binding and transactivation functions of the wild-type TTF1 suggested that the syndrome was caused by haploinsufficiency. This was confirmed in mice heterozygous for Ttf1 gene deletion, heretofore considered to be normal. Compared with wild-type littermates, Ttf1(+/-) mice had poor coordination and a significant elevation of serum thyrotropin. Therefore, haploinsufficiency of the TTF1 gene results in a predominantly neurological phenotype and secondary hyperthyrotropinemia. C1 Univ Chicago, Comm Genet, Chicago, IL 60637 USA. Univ Mainz, Childrens Hosp, Mainz, Germany. Sozialpadiat Zentrum, Bad Kreoznach, Germany. Natl Canc Inst, Lab Metabol, Bethesda, MD USA. Univ Chicago, Dept Pediat, Chicago, IL USA. RP Refetoff, S (reprint author), Univ Chicago, Comm Genet, MC3090 5841 S Maryland Ave, Chicago, IL 60637 USA. FU NCRR NIH HHS [M01 RR000055, RR-00055]; NIDDK NIH HHS [R37 DK015070, R01 DK015070, DK-58258, DK-15070] NR 26 TC 108 Z9 117 U1 1 U2 1 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 FEB PY 2002 VL 109 IS 4 BP 469 EP 473 DI 10.1172/JC1200214192 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 523QF UT WOS:000173965900007 PM 11854318 ER PT J AU Larsen, HH Masur, H Kovacs, JA Gill, VJ Silcott, VA Kogulan, P Maenza, J Smith, M Lucey, DR Fischer, SH AF Larsen, HH Masur, H Kovacs, JA Gill, VJ Silcott, VA Kogulan, P Maenza, J Smith, M Lucey, DR Fischer, SH TI Development and evaluation of a quantitative, touch-down, real-time PCR assay for diagnosing Pneumocystis carinii pneumonia SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID POLYMERASE-CHAIN-REACTION; BRONCHOALVEOLAR LAVAGE SPECIMENS; MAJOR SURFACE GLYCOPROTEIN; VIRUS-INFECTED PATIENTS; INDUCED-SPUTUM SAMPLES; DNA AMPLIFICATION; MONOCLONAL-ANTIBODIES; NESTED PCR; COLONIZATION; SPECIFICITY AB A rapid (time to completion, <4 h, including DNA extraction) and quantitative touch-down (QTD) real-time diagnostic Pneumocystis carinii PCR assay with an associated internal control was developed, using fluorescence resonance energy transfer (FRET) probes for detection. The touch-down procedure significantly increased the sensitivity of the assay compared to a non-touch-down procedure. Tenfold serial dilutions of a cloned target were used as standards for quantification. A carinii DNA has been detected in respiratory specimens from patients with P. carinii pneumonia (PCP) and from patients without clinical evidence of PCP. The latter probably represents colonization or subclinical infection. It is logical to hypothesize that quantification might prove helpful in distinguishing between infected and colonized patients: the latter group would have lower copy numbers than PCP patients. A blinded retrospective study of 98 respiratory samples (49 lower respiratory tract specimens and 49 oral washes), from 51 patients with 24 episodes of PCP and 34 episodes of other respiratory disease, was conducted. PCR-positive samples from colonized patients contained a lower concentration of P. carinii DNA than samples from PCP patients: lower respiratory tract samples from PCP and non-PCP patients contained a median of 938 (range, 2.4 to 1,040,000) and 2.6 (range, 0.3 to 248) (P < 0.0004) copies per tube, respectively. Oral washes from PCP and non-PCP patients contained a median of 49 (range, 2.1 to 2,595) and 6.5 (range, 2.2 to 10) (P < 0.03) copies per tube, respectively. These data suggest that this QTD PCR assay can be used to determine if P. carinii is present in respiratory samples and to distinguish between colonization and infection. C1 NIH, Dept Lab Med, Microbiol Serv, Ctr Clin, Bethesda, MD 20892 USA. NIH, Dept Crit Care, Ctr Clin, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Med, Baltimore, MD USA. Washington Hosp Ctr, Div Infect Dis, Washington, DC 20010 USA. RP Fischer, SH (reprint author), NIH, Dept Lab Med, Microbiol Serv, Ctr Clin, Bldg 10,Rm 2C-385,10 Ctr Dr, Bethesda, MD 20892 USA. NR 43 TC 94 Z9 101 U1 2 U2 14 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD FEB PY 2002 VL 40 IS 2 BP 490 EP 494 DI 10.1128/JCM.40.2.490-494.2002 PG 5 WC Microbiology SC Microbiology GA 519NG UT WOS:000173731900026 PM 11825961 ER PT J AU Coleman, CN Mitchell, JB Camphausen, K AF Coleman, CN Mitchell, JB Camphausen, K TI Tumor hypoxia: chicken, egg, or a piece of the farm? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID INDUCIBLE FACTOR 1-ALPHA; SQUAMOUS-CELL CARCINOMA; ENDOTHELIAL GROWTH-FACTOR; RADIATION-THERAPY; OXYGENATION STATUS; CERVICAL CANCERS; UTERINE CERVIX; NECK-CANCER; RADIOTHERAPY; ANGIOGENESIS C1 NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Coleman, CN (reprint author), NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NR 70 TC 30 Z9 30 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 FEB 1 PY 2002 VL 20 IS 3 BP 610 EP 615 PG 6 WC Oncology SC Oncology GA 518LG UT WOS:000173669400002 PM 11821437 ER PT J AU Agrawal, M Emanuel, EJ AF Agrawal, M Emanuel, EJ TI Attending to psychologic symptoms and palliative care SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID BURNOUT; ONCOLOGY; CANCER C1 NCI, Ctr Clin Bioeth, NIH, Bethesda, MD 20892 USA. NCI, Warren G Magnuson Clin Ctr, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Agrawal, M (reprint author), NCI, Ctr Clin Bioeth, NIH, Bethesda, MD 20892 USA. NR 21 TC 5 Z9 5 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 FEB 1 PY 2002 VL 20 IS 3 BP 624 EP 626 PG 3 WC Oncology SC Oncology GA 518LG UT WOS:000173669400005 PM 11821440 ER PT J AU Berry, DA Broadwater, G Klein, JP Antman, K Aisner, J Bitran, J Costanza, M Freytes, CO Stadtmauer, E Gale, RP Henderson, IC Lazarus, HM McCarthy, PL Norton, L Parnes, H Pecora, A Perry, MC Rowlings, P Spitzer, G Horowitz, MM AF Berry, DA Broadwater, G Klein, JP Antman, K Aisner, J Bitran, J Costanza, M Freytes, CO Stadtmauer, E Gale, RP Henderson, IC Lazarus, HM McCarthy, PL Norton, L Parnes, H Pecora, A Perry, MC Rowlings, P Spitzer, G Horowitz, MM TI High-dose versus standard chemotherapy in metastatic breast cancer: Comparison of cancer and leukemia group B trials with data from the autologous blood and marrow transplant registry SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID STEM-CELL TRANSPLANTATION; COMBINATION CHEMOTHERAPY; CARCINOMA; SELECTION; SURVIVAL AB Purpose: To assess survival of patients with metastatic breast cancer treated with high-dose chemotherapy (HDC) versus standard-dose chemotherapy (SDC). Patients and Methods: SDC in four Cancer and Leukemia Group B (CALGB) trials was compared with hematopoietic stem-cell support in patients from the Autologous Blood and Marrow Transplant Registry. Cox proportional hazard regression incorporated potentially confounding effects. A total of 1,509 women were enrolled onto CALGB trials, and 1, 188 women received HDC. No significant survival differences existed by CALGB trial or HDC regimen. Consideration was restricted to candidates for both SDC and HDC. The resulting sample included 635 SDC and 441 HDC patients. The outcome of interest was overall survival. Results: The HDC group displayed better performance status. The SDC group had slightly better survival in first year after treatment. The HDC group had lower hazard of death from years 1 to 4 and had somewhat higher probability of 5-year survival (adjusted probabilities [95% confidence intervals], 23% [17% to 29%] v 15% [11% to 19%], P = .03). Conclusion: After controlling for known prognostic factors in this nonrandomized analysis of two large independent data sets, women receiving HDC versus SDC for metastatic breast cancer have a similar short-term probability of survival, and might have a modestly higher long-term probability of survival. (C) 2002 by American Society of Clinical Oncology. C1 Univ Texas, MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Duke Univ, Med Ctr, Durham, NC USA. Autologous Blood & Marrow Transplant Registry, Milwaukee, WI USA. Med Coll Wisconsin, Hlth Policy Inst, Milwaukee, WI 53226 USA. Columbia Univ, Mem Sloan Kettering Canc Ctr, New York, NY USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Inst Canc Res, New Brunswick, NJ USA. Progenitor Cell Therapy LLC, Saddle Brook, NJ USA. Canc & Leukemia Grp B, Chicago, IL USA. Lutheran Gen Hosp, Park Ridge, IL 60068 USA. Univ Massachusetts, Med Ctr, Boston, MA 02125 USA. Univ Penn, Ctr Canc, Philadelphia, PA 19104 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Natl Canc Inst, Bethesda, MD USA. Univ Missouri, Ellis Fischel Canc Ctr, Columbia, MO USA. Prince Wales Hosp, Randwick, NSW 2031, Australia. Canc Ctr Carolinas, Greenville, SC USA. RP Berry, DA (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Biostat, 1515 Holcombe Blvd,Box 447, Houston, TX 77030 USA. EM dberry@odin.mdacc.tmc.edu FU NCI NIH HHS [P01-CA-40053, CA 33601, CA31946, U24-CA76518] NR 20 TC 48 Z9 49 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2002 VL 20 IS 3 BP 743 EP 750 DI 10.1200/JCO.20.3.743 PG 8 WC Oncology SC Oncology GA 518LG UT WOS:000173669400021 PM 11821456 ER PT J AU Riminucci, M Collins, MT Lala, R Corsi, A Matarazzo, P Robey, PG Bianco, P AF Riminucci, M Collins, MT Lala, R Corsi, A Matarazzo, P Robey, PG Bianco, P TI An R201H activating mutation of the GNAS 1 (GsALPHA) gene in a corticotroph pituitary adenoma SO JOURNAL OF CLINICAL PATHOLOGY-MOLECULAR PATHOLOGY LA English DT Article ID MCCUNE-ALBRIGHT-SYNDROME; HUMAN ENDOCRINE TUMORS; G-PROTEIN; FIBROUS DYSPLASIA; BONE AB In the pituitary gland, activating mutations of the GNAS1 (Gsalpha) gene at Gln227 have been identified in adrenocorticotrophin secreting, growth hormone secreting, and prolactin secreting adenomas. To date, mutations at the codon encoding R201, typically underlying the McCune-Albright syndrome and isolated fibrous dysplasia of bone, have been demonstrated only in growth hormone secreting pituitary adenomas. In this study, a polymerase chain reaction amplified target sequence in exon 8 of the GNAS1 gene was sequenced, identifying the first R201 mutation seen in an isolated basophilic adenoma which generated Cushing's disease in a child. This case adds Cushing's disease to the range of human diseases caused by R201 mutations of the GNAS1 gene. C1 Univ Roma La Sapienza, Dipartimento Med Sperimentale & Patol, I-00161 Rome, Italy. Univ Aquila, Dipartimento Med Sperimentale, I-67100 Laquila, Italy. Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. Osped Regina Margherita, Div Endocrinol Pediat, I-10126 Turin, Italy. RP Bianco, P (reprint author), Univ Roma La Sapienza, Dipartimento Med Sperimentale & Patol, Viale Regina Elena 324 Policlin, I-00161 Rome, Italy. EM p.bianco@flashnet.it RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Fondazione Telethon NR 10 TC 18 Z9 19 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1366-8714 J9 J CLIN PATHOL-MOL PA JI J. Clin. Pathol.-Mol. Pathol. PD FEB PY 2002 VL 55 IS 1 BP 58 EP 60 PG 3 WC Pathology SC Pathology GA 517JW UT WOS:000173608200009 ER PT J AU Post, RM Keck, P Rush, AJ AF Post, RM Keck, P Rush, AJ TI New designs for studies of the prophylaxis of bipolar disorder SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Editorial Material ID RANDOMIZED CLINICAL-TRIALS; WORKSHOP REPORT; I DISORDER; PLACEBO; ILLNESS; MAINTENANCE; DIVALPROEX; LITHIUM; ISSUES C1 NIH, NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. NIH, NIMH, Stanley Fdn Biopolar Network, Bethesda, MD 20892 USA. Univ Cincinnati, Coll Med, Dept Psychiat, Cincinnati, OH USA. Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX 75230 USA. RP Post, RM (reprint author), NIH, NIMH, Biol Psychiat Branch, Bldg 10, Bethesda, MD 20892 USA. OI Rush, Augustus/0000-0003-2004-2382 NR 24 TC 12 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD FEB PY 2002 VL 22 IS 1 BP 1 EP 3 DI 10.1097/00004714-200202000-00001 PG 3 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 514TM UT WOS:000173457200001 PM 11799335 ER PT J AU Magiakou, MA Chrousos, GP AF Magiakou, MA Chrousos, GP TI Cushing's syndrome in children and adolescents: Current diagnostic and therapeutic strategies SO JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION LA English DT Review DE Cushing syndrome; hypothalamic-pituitary-adrenal axis; cortisol; corticotropin ID CORTICOTROPIN-RELEASING HORMONE; DEXAMETHASONE SUPPRESSION TEST; GAMMA-KNIFE RADIOSURGERY; DIFFERENTIAL-DIAGNOSIS; PITUITARY IRRADIATION; STIMULATION TEST; ADRENOCORTICAL DISEASE; ADRENAL-HYPERPLASIA; SALIVARY CORTISOL; SURGICAL CURE C1 Univ Athens, Sch Med, P&A Kyriakou Childrens Hosp, Dept Pediat 2, Athens, Greece. Univ Athens, Sch Med, Agia Sophia Childrens Hosp, Dept Pediat 1, Athens, Greece. NICHHD, NIH, Bethesda, MD USA. RP Magiakou, MA (reprint author), Univ Athens, Dept Pediat 2, Athens 11527, Greece. NR 67 TC 36 Z9 38 U1 0 U2 1 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 0391-4097 J9 J ENDOCRINOL INVEST JI J. Endocrinol. Invest. PD FEB PY 2002 VL 25 IS 2 BP 181 EP 194 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 527LZ UT WOS:000174188700017 PM 11929092 ER PT J AU Seibel, BA Walsh, PJ AF Seibel, BA Walsh, PJ TI Trimethylamine oxide accumulation in marine animals: relationship to acylglycerol storage SO JOURNAL OF EXPERIMENTAL BIOLOGY LA English DT Review DE trimethylamine oxide; choline; phosphatidylcholine; lipid; cephalopod; buoyancy; deep sea; urea; solute ID FLAVIN-CONTAINING MONOOXYGENASE; SQUID GONATOPSIS-BOREALIS; GLYCINE BETAINE SYNTHESIS; GONATUS-ONYX CEPHALOPODA; DIACYL GLYCERYL ETHERS; PHOSPHATIDYLCHOLINE HYDROLYSIS; ELASMOBRANCH FISHES; ONTOGENIC CHANGES; DIFFERENT TISSUES; LIPID-COMPOSITION AB Trimethylamine oxide (TMAO) is a common and compatible osmolyte in muscle tissues of marine organisms that is often credited with counteracting protein-destabilizing forces. However, the origin and synthetic pathways of TMAO are actively debated. Here, we examine the distribution of TMAO in marine animals and report a correlation between TMAO and acylglycerol storage. We put forward the hypothesis that TMAO is derived, at least in part, from the hydrolysis of phosphatidylcholine, endogenous or dietary, for storage as diacylglycerol ethers and triacylglycerols. TMAO is synthesized from the trimethylammonium moiety of choline, thus released, and is retained as a compatible solute in concentrations reflecting the amount of lipid stored in the body. A variation on this theme is proposed for sharks. C1 Rosenstiel Sch Marine & Atmospher Sci, NIEHS, Marine & Freshwater Biomed Sci Ctr, Miami, FL 33149 USA. RP Seibel, BA (reprint author), Monterey Bay Aquarium Res Inst, Moss Landing, CA 95039 USA. FU NIEHS NIH HHS [ES05705] NR 101 TC 83 Z9 86 U1 1 U2 18 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0022-0949 EI 1477-9145 J9 J EXP BIOL JI J. Exp. Biol. PD FEB PY 2002 VL 205 IS 3 BP 297 EP 306 PG 10 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 523XM UT WOS:000173982900001 PM 11854367 ER PT J AU Danis, M Biddle, AK Goold, SD AF Danis, M Biddle, AK Goold, SD TI Insurance benefit preferences of the low-income uninsured SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 23rd Annual Meeting of the Society-for-General-Internal-Medicine CY MAY 02-06, 2000 CL BOSTON, MASSACHUSETTS SP Soc Gen Internal Med DE medically uninsured; managed care programs; insurance, health; Medicaid; financing, government; health care rationing; health care reform; health policy ID HEALTH-CARE; PRIORITIES; CHOICE AB OBJECTIVE: A frequently cited obstacle to universal insurance is the lack of consensus about what benefits to offer in an affordable insurance package. This study was conducted to assess the feasibility of providing uninsured patients the opportunity to define their own benefit package within cost constraints. DESIGN: Structured group exercises SETTING: Community setting PARTICIPANTS: Uninsured individuals recruited from clinical and community settings in central North Carolina. MEASUREMENTS: Insurance choices were measured using a simulation exercise, CHAT (Choosing Healthplans All Together). Participants designed managed care plans, individually and as groups, by selecting from 15 service categories having varied levels of restriction (e.g., formulary, copayments) within the constraints of a fixed monthly premium comparable to the typical per member/per month managed care premium paid by U.S. employers. MAIN RESULTS: Two hundred thirty-four individuals who were predominantly male (70%), African American (55%), and socioeconomically disadvantaged (53% earned <$15,000 annually) participated in 22 groups and were able to design health benefit packages individually and In groups. All 22 groups chose to cover hospitalization, pharmacy, dental, and specialty care, and 21 groups chose primary care and mental health. Although individuals' choices differed from their groups' selections, 86% of participants were willing to abide by group choices. CONCLUSIONS: Groups of low-income uninsured individuals are able to identify acceptable benefit packages that are comparable in cost but differ in benefit design from managed care contracts offered to many U.S. employees today. C1 NIH, Dept Clin Bioeth, Sect Eth & Hlth Policy, Bethesda, MD 20892 USA. Univ N Carolina, Chapel Hill, NC USA. Univ Michigan, Ann Arbor, MI 48109 USA. RP Danis, M (reprint author), NIH, Dept Clin Bioeth, Sect Eth & Hlth Policy, Bldg 10,Rm 1C118, Bethesda, MD 20892 USA. OI Biddle, Andrea/0000-0003-0273-7439; Goold, Susan Dorr/0000-0002-0258-9774 NR 33 TC 19 Z9 19 U1 0 U2 3 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 FEB PY 2002 VL 17 IS 2 BP 125 EP 133 DI 10.1046/j.1525-1497.2002.10609.x PG 9 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 543UG UT WOS:000175119100006 PM 11841528 ER PT J AU Lindholm, LH Moser, M AF Lindholm, LH Moser, M TI The status of hypertension therapy SO JOURNAL OF HYPERTENSION LA English DT Editorial Material C1 Umea Univ, Dept Publ Hlth & Clin Med, SE-90185 Umea, Sweden. Yale Univ, Sch Med, New Haven, CT 06520 USA. NHLBI, Natl High Blood Pressure Educ Program, Bethesda, MD USA. RP Lindholm, LH (reprint author), NUS, Allman Med, S-90185 Umea, Sweden. NR 2 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD FEB PY 2002 VL 20 SU 1 BP S1 EP S1 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 532FK UT WOS:000174460800001 PM 11996194 ER PT J AU Moser, M AF Moser, M TI Current recommendations for the treatment of hypertension: are they still valid? SO JOURNAL OF HYPERTENSION LA English DT Article DE hypertension; therapy; recommendations ID RANDOMIZED TRIAL; ANTIHYPERTENSIVE AGENTS; CALCIUM-ANTAGONISTS; DRUG-THERAPY; MORTALITY; MORBIDITY; OUTCOMES AB Recent trials have helped to clarify indications for the initial pharmacological therapy of hypertension. Both the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) and World Health Organization-international Society of Hypertension (WHO-ISH) recommendations should be revised. The more recent trials indicate that: (1) diuretics and beta-blockers appear to be as effective in reducing overall morbidity/ mortality as other agents (Swedish Trial in Old Patients with Hypertension [STOP-2], United Kingdom Prospective Diabetes Study [UKPDS], Intervention as a Goal in Hypertension Treatment [INSIGHT], Nordic diltiazem [NORDIL]); (2) the use of an (x-blocker results in more cardiovascular events, especially congestive heart failure, when compared with a diuretic (Antihypertensive Therapy and Lipid Lowering Heart Attack Trial [ALLHAT]); (3)the use of an angiotensin-converting enzyme (ACE) inhibitor results in fewer myocardial infarctions and episodes of heart failure than calcium channel blockers in the elderly and in diabetic patients (Fosinopril vs. Amlodipine Cardiovascular Events Randomized Trial [FACET], Appropriate Blood Pressure Control in Diabetes [ABCD], STOP-2) - other data (Captopril Prevention Project (CAPPP]) suggest that the use of an ACE inhibitor is preferred in diabetic patients; (4) overall cardiovascular events are similar with calcium channel blockers compared with a diuretic - however, there are fewer strokes with nondihydropyridine calcium channel blockers (NORDIL) and a trend towards an increase in heart failure and myocardial infarctions with either a dihydropyridine or non-dihydropyridine calcium channel blockers compared with a diuretic (INSIGHT, NORDIL); (5)angiotensin receptor blockers (ARBs) will decrease proteinuria and slow progression of renal disease in type 2 diabetic patients when compared with regimens that do not include an ARB or an ACE inhibitor (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan [RENAAL], Irbesartan Type II Diabetic Nephropathy Trial [IDNT], Irbesartan Type II Diabetes with Microalbuminuria [IRMA II]). The debate over initial therapy may be moot. High-risk hypertensive patients should probably be treated initially with combination therapy, one of which should be a diuretic. The use of diuretics and beta-blockers as well as ACE-inhibitors alone or with a diuretic should be considered as initial therapy (a change from JNC VI). alpha-blockers should be reserved for special situations, i.e. prostatic hypertrophy (in contrast to WHO-ISH recommendations). An ACE-inhibitor or ARB, usually along with a diuretic, can be considered as preferred therapy in hypertensive diabetic patients. Some data suggest equal or greater reduction in strokes with a calcium channel blocker than other medications. J Hypertens 20 (suppl 1):S3-S10 (C) 2002 Lippincott Williams Wilkins. C1 Yale Univ, Sch Med, Scarsdale, NY 10583 USA. NHLBI, Natl High Blood Pressure Educ Program, Bethesda, MD USA. RP Moser, M (reprint author), Yale Univ, Sch Med, 13 Murray Hill Rd, Scarsdale, NY 10583 USA. NR 32 TC 15 Z9 15 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD FEB PY 2002 VL 20 SU 1 BP S3 EP S10 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 532FK UT WOS:000174460800002 PM 11996197 ER PT J AU Olasz, EB Lang, LX Seidel, J Green, MV Eckelman, WC Katz, SI AF Olasz, EB Lang, LX Seidel, J Green, MV Eckelman, WC Katz, SI TI Fluorine-18 labeled mouse bone marrow-derived dendritic cells can be detected in vivo by high resolution projection imaging SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE dendritic cell; migration; positron emission tomography ID IN-VIVO; MIGRATION PATTERNS; HUMAN-LYMPHOCYTES; IN-111 OXINE; LYMPH-NODES; T-CELLS; INDUCTION; INJECTION; IMMUNITY; IMMATURE AB Immunization with ex vivo generated dendritic cells has become a focus for many clinical applications. The optimal site of injection and the migration pattern of these cells remain to be elucidated. We therefore developed a novel method for labeling mouse bone marrow-derived dendritic cells (BMDC) with the positron emitting radioisotope F-18 using N-succinimidyl-4-[F-18]fluorobenzoate,which covalently binds to the lysine residues of cell surface proteins. When we determined the stability of F-18 labeled BMDC, we found that at 4 h only 44 +/- 10% of the initial cell-bound activity was retained at 37 degreesC, whereas considerably more (91 +/- 3%) was retained at 4 degreesC. Labeled cells did not exhibit any significant alteration in cell viability or phenotype as determined by trypan blue exclusion and FACS analysis 24 h after radiolabeling. Furthermore, F-18-labeled BMDC stimulated allogeneic T cells in a mixed leukocyte reaction as potently as did sham-treated BMDC and migrated towards secondary lymphoid tissue chemokine (SLC) in a chemotaxis assay in vitro with the same efficiency as sham-treated BMDC. Migration of F-18-labeled BMDC was studied after footpad injection by (1) ex. vivo counting of dissected tissues using a gamma counter and (2) in vivo by imaging mice with PiPET, a 2-mm resolution positron projection imager. After 4 h, the ratio between measured activity in draining vs. contralateral (D/C) lymph nodes (LN) was 166 +/- 96 (n = 7) in the case of live cell injections, whereas if we injected heat-killed F-18-labeled BMDC or F-18-labeled macrophages the D/C ratios were 17 +/- 2 (n = 2) and 14 +/- 4 (n = 2), respectively. Injection of cell-free activity in the form of F-18-labeled 4-fluorobenzoic acid resulted in a D/C ratio of 7 +/- 2 (n = 3), suggesting that the activity measured in the draining lymph node was associated with migrated F-18-labeled BMDC. When F-18-labeled live cells were injected into the footpad, 0.18 +/- 0.04% (n = 7) of footpad activity was found in the draining LN within 4 h, whereas none was found in the contralateral LN. Quantitative assessment of cell migration by PET projection imaging of mice confirmed the ex-vivo counting results. These studies indicate that PET imaging offers a new approach for in vivo studies of dendritic cell biodistribution and migration. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NIH, PET Dept, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD USA. RP Katz, SI (reprint author), NCI, Dermatol Branch, NIH, Bldg 10,Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. NR 34 TC 49 Z9 50 U1 2 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD FEB 1 PY 2002 VL 260 IS 1-2 BP 137 EP 148 DI 10.1016/S0022-1759(01)00528-2 PG 12 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 515MH UT WOS:000173499300014 PM 11792384 ER PT J AU Mehlhop, E Villamide, LA Frank, I Gettie, A Santisteban, C Messmer, D Ignatius, R Lifson, JD Pope, M AF Mehlhop, E Villamide, LA Frank, I Gettie, A Santisteban, C Messmer, D Ignatius, R Lifson, JD Pope, M TI Enhanced in vitro stimulation of rhesus macaque dendritic cells for activation of SIV-specific T cell responses SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE nonhuman primate; dendritic cells (DCs); antigen presentations; cellular activation ID CLASS-II COMPARTMENT; MATURATION; ANTIGEN; RECEPTOR; CYTOKINES; BLOOD; CD40; DIFFERENTIATION; INTERLEUKIN-12; ENDOCYTOSIS AB The macaque-simian immunodeficiency virus (SIV) system is one of the best animal models available to study the role of dendritic cells (DCs) in transmission and pathogenesis of HIV, as well as to test DC-based vaccine and therapeutic strategies. To better define and optimize this system, the responsiveness of macaque monocyte-derived DCs to a variety of maturation stimuli was examined. Characteristic immunophenotypic and functional DC maturation induced by standard monocyte conditioned medium (MCM) was compared to the activation induced by a panel of stimuli including soluble CD40L, LPS, Poly I:C, PGE(2)/TNFalpha and a cocktail mixture of PGE(2)/TNFalpha/IL-1beta/IL-6. Immumophenotypic analysis confirmed that all stimuli induced stable up-regulation of CD25, CD40, CD80, CD83, CD96, HLA-DR, DC-LAMP (CD208), and DEC-205 (CD205). In general, macaque DCs exhibited weaker responses to LPS and Poly I:C than human DCs, and soluble CD40L stimulation induced variable expression of CD25. Interestingly, while the endocytic capacity of CD40L-matured cells was down-modulated comparably to DCs matured with MCM or the cocktail, the T cell stimulatory activity was not enhanced to the same extent. The particularly reproducible and potent T cell stimulatory capacity of cocktail-treated DCs correlated with a more homogenous mature DC phenotype, consistently high levels of IL-12 production, and better viability upon reculture compared to DCs activated by other stimuli. Furthermore, cocktail-matured DCs efficiently captured and presented inactivated SIV to SIV-primed T cells in vitro. Thus, the cocktail represents a particularly potent and useful stimulus for the generation of efficacious immunostimulatory macaque DCs. (C) 2002 Elsevier Science B,V. All rights reserved. C1 Rockefeller Univ, Cellular Physiol & Immunol Lab, New York, NY 10021 USA. Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. Tulane Reg Primate Res Ctr, Covington, LA 70433 USA. NCI, AIDS Vaccine Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Pope, M (reprint author), Populat Council, Ctr Biomed Res, 1230 York Ave, New York, NY 10021 USA. FU NCI NIH HHS [N01-CO-56000]; NIAID NIH HHS [AI40877, AI47681] NR 42 TC 55 Z9 55 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD FEB 1 PY 2002 VL 260 IS 1-2 BP 219 EP 234 DI 10.1016/S0022-1759(01)00544-0 PG 16 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 515MH UT WOS:000173499300021 PM 11792391 ER PT J AU Hu, LN Rezanka, LJ Mi, QS Lustig, A Taub, DD Longo, DL Kenny, JJ AF Hu, LN Rezanka, LJ Mi, QS Lustig, A Taub, DD Longo, DL Kenny, JJ TI T15-idiotype-negative B cells dominate the phosphocholine binding cells in the preimmune repertoire of t15i knockin mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTI-PHOSPHORYLCHOLINE ANTIBODIES; IMMUNE-DEFICIENT MICE; HEAVY-CHAIN GENE; STREPTOCOCCUS-PNEUMONIAE; PROTEUS-MORGANII; TRANSGENIC MICE; JUNCTIONAL DIVERSITY; SOMATIC MUTATION; FINE SPECIFICITY; STRUCTURAL BASIS AB T15i knockin (KI) mice express a H chain that is encoded by a rearranged T15 VDJ transgene which has been inserted into the J(H) region of chromosome 12. This T15H chain combines with a kappa22-33 L chain to produce a T15-Id(+) Ab having specificity for phosphocholine (PC). Inasmuch as T15-Id(+) Abs dominate the primary immune response to PC in normal mice, it was surprising to find that 80% of the PC-dextran-binding B cells in unimmunized homozygous T15i KI mice were T15-Id(-). Analysis of L chains expressed in these T15-Id(-), PC-specific B cells revealed that two L chains, kappa8-28 and kappa19-15, were expressed in this population. The V-kappa region of these L chains was recombined to J(k)5, which is typical of L chains present in PC-specific Abs. When T15i KI mice were immunized with PC Ag, T15-Id(+) B cells expanded 6-fold and differentiated into Ab-secreting cells. There was no indication that the T15-Id(-) B cells either proliferated or differentiated into Ab-secreting cells following immunization. Thus, T15-Id(-) B cells dominate the PC-binding population, but they fail to compete with T15-Id(+) B cells during a functional immune response. Structural analysis of T15H:kappa8-28L and T15H:kappa19-15L Abs revealed L chain differences from the kappa22-33 L chain which could account for the lower affinity and/or avidity of these Abs for PC or PC carrier compared with the T15-Id(+) T15H: kappa22-33L Ab. C1 NIA, Immunol Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. JP Robarts Res Inst, Autoimmune & Diabet Grp, London, ON, Canada. RP Hu, LN (reprint author), NIA, Immunol Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 54 TC 6 Z9 6 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2002 VL 168 IS 3 BP 1273 EP 1280 PG 8 WC Immunology SC Immunology GA 514FY UT WOS:000173429300039 PM 11801665 ER PT J AU Hoffmann, TK Loftus, DJ Nakano, K Maeurer, MJ Chikamatsu, K Appella, E Whiteside, TL DeLeo, AB AF Hoffmann, TK Loftus, DJ Nakano, K Maeurer, MJ Chikamatsu, K Appella, E Whiteside, TL DeLeo, AB TI The ability of variant peptides to reverse the nonresponsiveness of T lymphocytes to the wild-type sequence p53(264-272) epitope SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SQUAMOUS-CELL CARCINOMAS; DENDRITIC CELLS; TUMOR-CELLS; P53 PROTEIN; IN-VITRO; GENERATION; RECOGNIZE; ANTIGEN; MUTANT; IDENTIFICATION AB Recently, we observed that CTL specific for the wild-type (wt) sequence p53(264-272) peptide could only be expanded ex vivo from PBMC of a subset of the HLA-A2.1(+) normal donors or cancer patients tested. Surprisingly, the tumors of the responsive patients expressed normal levels of wt p53 and could be considered unlikely to present this epitope. In contrast, tumors of nonresponsive patients accumulated mutant p53 and were more likely to present this epitope. We sought to increase the responsive rate to the wt p53(264-272) peptide of PBMC obtained from normal donors and patients by identifying more immunogenic variants of this peptide. Two such variants were generated by amino acid exchanges at positions 6 (6T) and 7 (7W) of the peptide. These variants were capable of inducing T cells from PBMC of nonresponsive donors that recognized the parental peptide either pulsed onto target cells or naturally presented by tumors. TCR Vbeta analysis of two T cell lines isolated from bulk populations of effectors reactive against the wt p53(264-272) peptide, using either the parental or the 7W variant peptide, indicated that these T cells were expressing identical TCR Vbeta13.6/complementarity-determining region 3/J region sequences. This finding confirms the heteroclitic nature of at least one of the variant peptides identified in this study. The use of variant peptides of the wt p53(264-272) epitope represents a promising approach to overcoming the nonresponsiveness of certain cancer patients to this self epitope, thereby enhancing its potential use in tumor vaccines for appropriately selected cancer patients. C1 Univ Pittsburgh, Sch Med, Pittsburgh Canc Inst, Div Basic Res, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Dept Otolaryngol, Pittsburgh, PA 15213 USA. NCI, Bethesda, MD 20892 USA. Univ Mainz, Dept Med Microbiol, D-6500 Mainz, Germany. RP DeLeo, AB (reprint author), Univ Pittsburgh, Sch Med, Pittsburgh Canc Inst, Div Basic Res, Biomed Sci Tower W956,211 Lothrop St, Pittsburgh, PA 15213 USA. FU NIDCR NIH HHS [P01 DE 12321] NR 34 TC 43 Z9 43 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2002 VL 168 IS 3 BP 1338 EP 1347 PG 10 WC Immunology SC Immunology GA 514FY UT WOS:000173429300048 PM 11801674 ER PT J AU Yang, XP Freeman, LA Knapper, CL Amar, MJA Remaley, A Brewer, HB Santamarina-Fojo, S AF Yang, XP Freeman, LA Knapper, CL Amar, MJA Remaley, A Brewer, HB Santamarina-Fojo, S TI The E-box motif in the proximal ABCA1 promoter mediates transcriptional repression of the ABCA1 gene SO JOURNAL OF LIPID RESEARCH LA English DT Article DE high density lipoproteins; ATP-binding cassette transporter; E-box ID ATP-BINDING-CASSETTE; UPSTREAM STIMULATORY FACTOR; CELLULAR CHOLESTEROL EFFLUX; FATTY-ACID SYNTHASE; HELIX-ZIPPER PROTEIN; TANGIER-DISEASE; DOWN-REGULATION; LIPOPROTEIN-LIPASE; MOLECULAR-CLONING; IN-VIVO AB To identify regulatory elements in the proximal human ATP-binding cassette transporter Al (hABCAl) gene promoter we transfected RAW cells with plasmids containing mutations in the E-box, APl, and liver X receptor (LXR) elements as well as the two Spl motifs. Point mutations in either Spl site or in the APl site had only a minor effect whereas mutation of the LXR element decreased promoter activity. In contrast, mutation or deletion of the E-box motif caused a 3-fold increase in transcriptional activity under basal conditions. Gel shift and DNasel footprint analysis showed binding of a protein or protein complex to this region. Preincubation of nuclear extracts with antibodies established that USF1, USF2, and fos related antigen (Fra) 2 bind to DNA sequences in the human ABCAl promoter that contains the intact E-box but not the mutant or deleted E-box. Co-transfection of USF1 and USF2 enhanced, but Fra2 repressed, ABCAl promoter activity. Thus, a complex consisting of USF1, USF2, and Fra2 binds the E-box motif 147 bp upstream of the transcriptional start site and facilitates repression of the human ABCAl promoter. These combined studies identify a novel site in the human ABCAl promoter involved in the regulation of ABCAl gene expression.-Yang, X-R, L. A. Freeman, C. L. Knapper, NI. J. A. Amar, A. Remaley, H. B. Brewer, Jr., and S. Santamarina-Fojo. The E-box motif in the proximal ABCAl promoter mediates transcriptional repression of the ABCAl gene. C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. RP Santamarina-Fojo, S (reprint author), NHLBI, Mol Dis Branch, NIH, Bldg 10,Room 7N115,10 Ctr Dr, Bethesda, MD 20892 USA. NR 70 TC 49 Z9 52 U1 0 U2 2 PU LIPID RESEARCH INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD FEB PY 2002 VL 43 IS 2 BP 297 EP 306 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 525ZA UT WOS:000174102900014 PM 11861672 ER PT J AU Yamada, KI Murugesan, R Devasahayam, N Cook, JA Mitchell, JB Subramanian, S Krishna, MC AF Yamada, KI Murugesan, R Devasahayam, N Cook, JA Mitchell, JB Subramanian, S Krishna, MC TI Evaluation and comparison of pulsed and continuous wave Radiofrequency electron paramagnetic resonance techniques for in vivo detection and imaging of free radicals SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article ID MAGNETIC-RESONANCE; LOW-FREQUENCY; EPR SPECTROMETER; ESR SPECTROMETER; NITRIC-OXIDE; TIME; SPECTROSCOPY; OXYGENATION; MICE; RESONATORS AB The performance of two electron paramagnetic resonance (EPR) spectrometers/imagers, one configured in pulsed mode and the other in continuous wave (CW) mode, at an operating frequency of 300 MHz is compared. Using the same resonator (except for altered Q-factors), identical samples and filling factors in the two techniques have been evaluated for their potentials and limitations for in vivo spectroscopic and imaging applications. The assessment is based on metrics such as sensitivity, spatial and temporal resolution, field of view, image artifacts, viable spin probes, and subjects of study. The spectrometer dead time limits the pulsed technique to samples with long phase memories (>275 ns). Nevertheless, for viable narrow-line spin probes, the pulsed technique offers better sensitivity and temporal resolution. The CW technique, on the other hand, does not restrict the choice at spin probes. In addition, the phase-sensitive narrow-band detection of the CW technique gives artifact-free images even for large objects. Selected examples illustrating the performance of the CW and pulsed techniques are presented to put the capabilities of the two techniques in perspective. C1 NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bldg 10,Room B3 B69, Bethesda, MD 20892 USA. RI Yamada, Ken-ichi/E-6318-2012 NR 54 TC 46 Z9 46 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD FEB PY 2002 VL 154 IS 2 BP 287 EP 297 DI 10.1006/jmre.2001.2487 PG 11 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 527MF UT WOS:000174189300014 PM 11846586 ER PT J AU Clore, GM Bewley, CA AF Clore, GM Bewley, CA TI Using conjoined rigid body/torsion angle simulated annealing to determine the relative orientation of covalently linked protein domains from dipolar couplings SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article ID PHOSPHORYL TRANSFER COMPLEX; HIV-INACTIVATING PROTEIN; LIQUID-CRYSTALLINE PHASE; NMR STRUCTURES; CYANOVIRIN-N; BODY MINIMIZATION; GLOBAL STRUCTURE; MACROMOLECULES; REFINEMENT; ALIGNMENT AB A simple and robust method for determining the relative orientations of covalently linked protein domains using conjoined rigid body/torsion angle dynamics simulated annealing on the basis of residual dipolar couplings is presented. In this approach each domain is treated as a rigid body and the relevant degrees of conformational freedom are restricted to the backbone torsion angles (phi, psi) of the linker between the domains. By this means translational information afforded by the presence of an intact linker is preserved. We illustrate this approach using the domain-swapped dimer of the HIV-inactivating protein cyanovirin-N as an example. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 32 TC 53 Z9 53 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD FEB PY 2002 VL 154 IS 2 BP 329 EP 335 DI 10.1006/jmre.2001.2489 PG 7 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 527MF UT WOS:000174189300020 PM 11846592 ER PT J AU Sotiriou, C Khanna, C Jazaeri, AA Petersen, D Liu, ET AF Sotiriou, C Khanna, C Jazaeri, AA Petersen, D Liu, ET TI Core biopsies can be used to distinguish differences in expression profiling by cDNA microarrays SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID FINE-NEEDLE ASPIRATION; GENE-EXPRESSION; EWINGS-SARCOMA; HUMAN CANCER; CELL-LINES; PATTERNS; TUMORS; LESIONS; MYC AB The primary focus of this work was to determine the feasibility of obtaining representative expression array profiles from clinical core biopsies. For this purpose we performed six 16-gauge needle core biopsies and an excision biopsy on each of two different human xenografts, one from an Ewing's sarcoma cell line and the second from neuroblastoma cell fine grown in Beige-Scid mice. Three of the six core biopsies were processed separately and the remaining three were pooled and processed together. As the initial RNA material isolated from the core biopsies was not sufficient for microarray analysis, an amplification procedure using a modified Eberwine protocol was performed, and the amplified products applied onto a 6000-feature human cDNA microarray. Comparisons of the array results from core biopsies (amplified RNA) and surgical specimens (non-amplified RNA) showed maintenance of the expression profile as assessed by hierarchical clustering. Gene expression profiles obtained from microarray analysis clearly differentiated the Ewing's sarcoma from the neuroblastoma with both core and excisional biopsies as starting material. Pooling the core biopsies did not improve the concordance with excisional. biopsies. in conclusion, our results suggest that core biopsies can be used as a suitable and reliable material for the determination of tumor genetic profiles. C1 NCI, Med Branch, Div Clin Sci, NIH, Gaithersburg, MD USA. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Liu, ET (reprint author), Genome Inst Singapore, 1 Res Link,IMA Bldg 04-01, Singapore 117604, Singapore. RI Jazaeri, Amir/A-2400-2008; Liu, Edison/C-4141-2008; Jazaeri, Amir/I-3458-2015 OI Jazaeri, Amir/0000-0003-4335-4151 NR 23 TC 34 Z9 34 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD FEB PY 2002 VL 4 IS 1 BP 30 EP 36 DI 10.1016/S1525-1578(10)60677-0 PG 7 WC Pathology SC Pathology GA 561LC UT WOS:000176141300003 PM 11826185 ER PT J AU Moody, TW Jensen, RT Fridkin, M Gozes, I AF Moody, TW Jensen, RT Fridkin, M Gozes, I TI (N-stearyl, Norleucine(17))VIPhybrid is a broad spectrum vasoactive intestinal peptide receptor antagonist SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE VIP receptors; antagonist; PACAP receptors; binding; cyclic AMP (cAMP) ID ACTIVATING POLYPEPTIDE PACAP; HIGH-AFFINITY; CANCER CELLS; IN-VITRO; FUNCTIONAL EXPRESSION; SIGNAL-TRANSDUCTION; VIP1 RECEPTOR; GROWTH; LUNG; IDENTIFICATION AB The effects of a (N-stearyl, Norleucine(17)) vasoactive intestinal peptide hybrid ((SN)VIPhybrid) on cells stably transfected with VPAC(1), VPAC(2), or PAC(1) receptors were investigated. (SN)VIPhybrid inhibited specific I-125-VIP binding to membranes derived from CHO cells transfected with VPAC(1) or VPAC(2) receptors with high affinity (IC50 = 30 and 50 nM). (SN)VIPhyb inhibited specific I-125-PACAP-27 binding to membranes derived from NIH/3T3 cells transfected with PAC(1) receptors with high affinity (IC50 = 65 nM). PACAP-27 caused cAMP elevation in NIH/3T3 cells transfected with PAC(1) receptors and the increase cAMP caused by pituitary adenylated cyclase (PACAP) was inhibited by (SN)VIPhyb. Also, the increase in cAMP caused by VIP using CHO cells transfected with VPAC(1) or VPAC(2) receptors was antagonized by (SN)VIPhyb. These results indicate that (SN)VIPhyb is an antagonist for VPAC(1), VPAC(2), and PAC(1) receptors. C1 NCI, Med Branch, Rockville, MD 20850 USA. NIDDKD, Digest Dis Branch, Bethesda, MD 20892 USA. Weizmann Inst Sci, Dept Organ Chem, IL-76100 Rehovot, Israel. Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. RP Moody, TW (reprint author), NCI, Med Branch, Rockville, MD 20850 USA. NR 44 TC 20 Z9 22 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD FEB-APR PY 2002 VL 18 IS 1-2 BP 29 EP 35 DI 10.1385/JMN:18:1-2:29 PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 533FR UT WOS:000174519200004 PM 11931347 ER PT J AU Romano, J Beni-Adani, L Nissenbaum, OL Brenneman, DE Shohami, E Gozes, I AF Romano, J Beni-Adani, L Nissenbaum, OL Brenneman, DE Shohami, E Gozes, I TI A single administration of the peptide NAP induces long-term protective changes against the consequences of head injury - Gene atlas array analysis SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE NAP; Mac-1; atlas array; head trauma; ADNP; VIP ID TRAUMATIC BRAIN INJURY; VASOACTIVE-INTESTINAL-PEPTIDE; CEREBRAL-ARTERY OCCLUSION; NECROSIS-FACTOR-ALPHA; RAT-BRAIN; INFLAMMATORY RESPONSE; MONOCLONAL-ANTIBODIES; CEREBROSPINAL-FLUID; ALZHEIMERS-DISEASE; TNF-ALPHA AB The femtomolar-acting eight-amino-acid peptide (NAP), derived from activity-dependent neuroprotective protein (ADNP), provides long-term protection against the deleterious effects of closed head injury (CHI) in mice. Fifteen minutes after injury, mice were divided into two groups, control and NAP-treated and a single subcutaneous injection of NAP or vehicle was administered. A third group served as sham-treated (not subjected to head trauma). Each mouse was assessed for its clinical function, using neurological severity score, at various time intervals following CHI, up to 30-45 d. Total cerebral cortex RNA was prepared from the site of injury of CHI mice, and from parallel regions in peptide-treated and sham brains. RNA was then reversed transcribed to yield radioactive cDNA preparations that were hybridized to Atlas array membranes containing 1200 cDNAs spots. Comparison of sham-treated individual mice showed differential expression levels of at least 15 mRNA species. Furthermore, results indicated that one of the genes that did not change among individuals but specifically increased after CHI and decreased after NAP treatment was the cell surface glycoprotein Mac-1 (CD11B antigen). Thus, Mac-1 is suggested as a marker for the long-term outcome of head injury and as a potential target for NAP protective actions. C1 Tel Aviv Univ, Sackler Fac Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, IL-69978 Tel Aviv, Israel. NICHHD, Sect Dev & Mol Pharmacol, LDN, NIH, Bethesda, MD 20892 USA. Hebrew Univ Jerusalem, Sch Pharm, IL-91120 Jerusalem, Israel. RP Gozes, I (reprint author), Tel Aviv Univ, Sackler Fac Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. NR 41 TC 26 Z9 27 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD FEB-APR PY 2002 VL 18 IS 1-2 BP 37 EP 45 DI 10.1385/JMN:18:1-2:37 PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 533FR UT WOS:000174519200005 PM 11931348 ER PT J AU Holmes, A Yang, RJ Crawley, JN AF Holmes, A Yang, RJ Crawley, JN TI Evaluation of an anxiety-related phenotype in galanin overexpressing transgenic mice SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Review DE galanin; anxiety; stress; multitiered strategy; transgenic mice; norepinephrine; yohimbine; chlordiazepoxide; elevated plus-maze; light <-> dark exploration test ID CORTICOTROPIN-RELEASING FACTOR; CENTRAL-NERVOUS-SYSTEM; LOCUS-COERULEUS NEURONS; RECEPTOR MESSENGER-RNA; IMPAIRED STRESS-RESPONSE; ELEVATED PLUS-MAZE; NEUROPEPTIDE-Y; BASAL FOREBRAIN; NOREPINEPHRINE RELEASE; TYROSINE-HYDROXYLASE AB Understanding the role of neuropeptides in mediating emotional behaviors is an important avenue for discovering novel drug targets for anxiety disorders. A role for galanin in mediating anxiety-related behavior is suggested by the pattern of distribution in the CNS and the coexistence of galanin with norepinephrine in the locus coeruleus. Studies in rats have shown that central administration of galanin modulates anxiety-related behaviors, and galanin release blocks the proanxiety effects of noradrenergic activation in prestressed rats. To further investigate the role of galanin in anxiety behaviors, we conducted a comprehensive behavioral phenotyping of galanin overexpressing transgenic mice (GAL-tg). GAL-tg mice were normal on measures of general health, neurological reflexes, home cage social behaviors, sensory functions, motor coordination, and exploratory locomotor activity. In three separate tests for anxiety-related behaviors, the elevated plus-maze, light <----> dark exploration, and open field center time, GAL-tg mice showed no anxiety-like phenotype. GAL-tg mice and wildtype littermate controls were equally responsive to the anxiolytic effects of chlordiazepoxide (10 mg/kg) in the light <----> dark exploration test, indicating normal benzodiazepine receptor function in GAL-tg mice. Stimulation of noradrenergic cells via administration with an alpha2 adrenoreceptor antagonist, yohimbine (2.5 mg/kg), produced proanxiety effects in wild type mice in the light <----> dark exploration test, but not in the GAL-tg mice. These data suggest that galanin contributes to the modulation of anxiety states induced by high levels of noradrenergic activation, but is silent under less challenging situations. A specific role for galanin in extreme anxiety states represents an attractive target for the development of novel anxiolytic treatments. C1 NIMH, Sect Behav Neuropharmacol, NIH, Bethesda, MD 20892 USA. RP Holmes, A (reprint author), NIMH, Sect Behav Neuropharmacol, NIH, Bethesda, MD 20892 USA. NR 115 TC 93 Z9 95 U1 1 U2 10 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD FEB-APR PY 2002 VL 18 IS 1-2 BP 151 EP 165 DI 10.1385/JMN:18:1-2:151 PG 15 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 533FR UT WOS:000174519200017 PM 11931346 ER PT J AU Haak, LL Grimaldi, M Smaili, SS Russell, JT AF Haak, LL Grimaldi, M Smaili, SS Russell, JT TI Mitochondria regulate Ca2+ wave initiation and inositol trisphosphate signal transduction in oligodendrocyte progenitors SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE calcium wave; gelsolin; inositol trisphosphate; mitochondria; oligodendrocyte progenitor; PIP2 ID ENDOPLASMIC-RETICULUM PROTEINS; K-ATP CHANNELS; CALCIUM SIGNALS; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; CYCLOSPORINE-A; IP3 RECEPTOR; KINASE-C; CELLS; GELSOLIN; BINDING AB Mitochondria in oligodendrocyte progenitor cells (OPs) Dtake up and release cytosolic Ca2+ during agonist-evoked Ca2+ waves, but it is not clear whether or how they regulate Ca2+ signaling in OPs. We asked whether mitochondria. play an active role during agonist-evoked Ca2+ release from intracellular stores. Ca2+ puffs, wave initiation, and wave propagation were measured in fluo-4 loaded OP processes using linescan confocal microscopy. Mitochondrial depolarization, measured by tetramethyl rhodamine ethyl ester (TMRE) fluorescence, accompanied Ca2+ puffs and waves. In addition, waves initiated only where mitochondria were localized. To determine whether energized mitochondria were necessary for wave generation, we blocked mitochondrial function with the electron transport chain inhibitor antimycin A (AA) in combination with oligomycin. AA decreased wave speed and puff probability. These effects were not due to global changes in ATP. We found that AA increased cytosolic Ca2+ markedly reduced agonist-evoked inositol trisphosphate (IP3) production, and also enhanced phosphatidylinositol 4,5-bisphosphate (PIP2) binding to the Ca2+ dependent protein gelsolin. Thus, the reduction in puff probability and wave speed after AA treatment may be explained by competition for PIP2 between phospholipase C and gelsolin. Energized mitochondria and low cytosolic Ca2+ concentration may be required to maintain PIP2, a substrate for IP3 signal transcluction. C1 NICHHD, LCSN, NIH, Bethesda, MD 20892 USA. Univ Fed Sao Paulo, Dept Farmacol, Sao Paulo, Brazil. RP Haak, LL (reprint author), NICHHD, LCSN, NIH, Bldg 49,Rm 5A22,49 Convent Dr, Bethesda, MD 20892 USA. RI Haak, Laurel/C-4986-2008; OI Haak, Laurel/0000-0001-5109-3700; Grimaldi, Maurizio/0000-0002-7331-7055 NR 69 TC 20 Z9 20 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2002 VL 80 IS 3 BP 405 EP 415 DI 10.1046/j.0022-3042.2001.00727.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 517PE UT WOS:000173618500005 PM 11905989 ER PT J AU Lee, J Seroogy, KB Mattson, MP AF Lee, J Seroogy, KB Mattson, MP TI Dietary restriction enhances neurotrophin expression and neurogenesis in the hippocampus of adult mice SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE brain-derived neurotrophic factor; caloric restriction; neurotrophin-3; stem cells; trkB; tyrosine kinase ID NERVE GROWTH-FACTOR; DENTATE GYRUS; MESSENGER-RNA; DIFFERENTIAL REGULATION; DOPAMINERGIC-NEURONS; ENRICHED ENVIRONMENT; CALORIC RESTRICTION; PARKINSONS-DISEASE; FOOD RESTRICTION; PRECURSOR CELLS AB The adult brain contains small populations of neural precursor cells (NPC) that can give rise to new neurons and glia, and may play important roles in learning and memory, and recovery from injury. Growth factors can influence the proliferation, differentiation and survival of NPC, and may mediate responses of NPC to injury and environmental stimuli such as enriched environments and physical activity. We now report that neurotrophin expression and neurogenesis can be modified by a change in diet. When adult mice are maintained on a dietary restriction (DR) feeding regimen, numbers of newly generated cells in the dentate gyrus of the hippocampus are increased, apparently as the result of increased cell survival. The new cells exhibit phenotypes of neurons and astrocytes. Levels of expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are increased by DR, while levels of expression of high-affinity receptors for these neurotrophins (trkB and trkC) are unchanged. In addition, DR increases the ratio of full-length trkB to truncated trkB in the hippocampus. The ability of a change in diet to stimulate neurotrophin expression and enhance neurogenesis has important implications for, dietary, modification of neuroplasticity and responses of the brain to injury and disease. C1 NIA, Neurosci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. Univ Kentucky, Dept Anat & Neurobiol, Lexington, KY 40536 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Gerontol Res Ctr, 4F01,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012; Lee, Jaewon/N-9064-2013 FU NINDS NIH HHS [NS39128] NR 61 TC 243 Z9 254 U1 2 U2 15 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2002 VL 80 IS 3 BP 539 EP 547 DI 10.1046/j.0022-3042.2001.00747.x PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 517PE UT WOS:000173618500018 PM 11905999 ER PT J AU Van Ess, PJ Pedersen, WA Culmsee, C Mattson, MP Blouin, RA AF Van Ess, PJ Pedersen, WA Culmsee, C Mattson, MP Blouin, RA TI Elevated hepatic and depressed renal cytochrome P450 activity in the Tg2576 transgenic mouse model of Alzheimer's disease SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Alzheimer's disease; amyloid precursor protein; cytochrome P450; metabolism ID TESTOSTERONE 16-ALPHA-HYDROXYLASE C-P-45016-ALPHA; AMYLOID PRECURSOR PROTEIN; DRUG-METABOLIZING-ENZYMES; LIVER-MICROSOMES; CEREBROSPINAL-FLUID; GENE FAMILY; RAT-LIVER; MICE; DEXAMETHASONE; INSULIN AB Recent studies indicate that the Tg2576 transgenic mouse model of Alzheimer's disease [tg(hAPP)] demonstrates disturbances in plasma glucose and neuroendocrine function reminiscent of Alzheimer's disease (AD). Alterations in any one of these systems can have a profound effect on hepatic cytochrome P450 (CYP) expression. Additionally, the recent discovery that amyloid beta 1-42 can induce the expression of CYP reductase in neuronal cultures further suggests that hepatic CYP-related metabolism may be affected by the expression of mutant human amyloid precursor protein in these tg(hAPP) mice. Therefore, the current study was conducted to investigate the activity and protein content of several CYP isoforms in the livers and kidneys of aged (20-month-old) tg(hAPP) mice. [g(hAPP)] mice exhibit significant elevations in hepatic CYP2B, CYP2E1-, CYP3A- and CYP4A-associated activities and CYP4A immunoreactive protein compared with wild-type. In contrast to the liver, a significant depression in renal CYP2E1- and CYP4A-associated activities were demonstrated in tg(hAPP) mice. The presence of the mutant hAPP protein was detected in the brain, kidney and livers of tg(hAPP) mice. C1 Univ Kentucky, Div Pharmaceut Sci, Coll Pharm, Lexington, KY 40536 USA. Univ Kentucky, Sanders Brown Res Ctr Aging, Lexington, KY USA. NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Blouin, RA (reprint author), Univ Kentucky, Div Pharmaceut Sci, Coll Pharm, 907 Rose St, Lexington, KY 40536 USA. RI Mattson, Mark/F-6038-2012 FU NIA NIH HHS [AG14554]; NINDS NIH HHS [NS29001, NS35253] NR 44 TC 2 Z9 2 U1 1 U2 4 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2002 VL 80 IS 4 BP 571 EP 578 DI 10.1046/j.0022-3042.2001.00724.x PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 522NQ UT WOS:000173903800003 PM 11841564 ER PT J AU Hashimoto, R Hough, C Nakazawa, T Yamamoto, T Chuang, DM AF Hashimoto, R Hough, C Nakazawa, T Yamamoto, T Chuang, DM TI Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE bipolar disorder; excitotoxicity; lithium; neuroprotection; NMDA receptor; phosphorylation ID CEREBELLAR GRANULE CELLS; LONG-TERM POTENTIATION; D-ASPARTATE RECEPTOR; GLYCOGEN-SYNTHASE KINASE-3-BETA; CALCIUM INFLUX; HUMAN BRAIN; 2B SUBUNIT; APOPTOSIS; CORTEX; SYSTEM AB The therapeutic mechanisms of lithium for treating bipolar mood disorder remain poorly understood. Recent studies demonstrate that lithium has neuroprotective actions against a variety of insults. Here, we studied neuroprotective effects: of lithium against excitotoxicity in cultured cerebral cortical neurons. Glutamate-induced excitotoxicity in cortical neurons was exclusively mediated by NMDA receptors. Pre-treatment of cortical neurons with LiCl time-dependently suppressed excitotoxicity with maximal protection after 6 days of pretreatment. Significant protection was observed at the therapeutic and subtherapeutic concentration of 0.2-1.6 mm LiCl with almost complete protection at I mm. Neuroprotection was also elicited by valproate, another major mood-stabilizer. The neuroprotective effects of lithium coincided with inhibition of NMDA receptor-mediated calcium influx. Lithium pre-treatment did not alter total protein levels, of NR1, NR2A and NR2B subunits of NMDA receptors. However, it did markedly reduce the level of NR2B phosphorylation at Tyr1472 and this was temporally associated with its neuroprotective effect. Because NR2B tyrosine phosphorylation has been positively correlated with NMDA receptor-mediated synaptic activity and excitotoxicity, the suppression of NR2B phosphorylation by lithium is likely to result in the inactivation of NMDA receptors and contributes to neuroprotection against excitotoxicity. This action could also be relevant to its clinical efficacy for bipolar 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. Univ Tokyo, Inst Med Sci, Dept Oncol, Tokyo 108, Japan. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, Mood & Anxiety Disorder Program, NIH, Bldg 10,Rm 4C-206,10 Ctr Dr,MSC 1363, Bethesda, MD 20892 USA. RI Nakazawa, Takanobu/E-1012-2014; Hashimoto, Ryota/P-8572-2014 OI Nakazawa, Takanobu/0000-0002-5049-9140; Hashimoto, Ryota/0000-0002-5941-4238 NR 45 TC 198 Z9 210 U1 1 U2 5 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2002 VL 80 IS 4 BP 589 EP 597 DI 10.1046/j.0022-3042.2001.00728.x PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 522NQ UT WOS:000173903800005 PM 11841566 ER PT J AU Humphries, A Klein, D Baler, R Carter, DA AF Humphries, A Klein, D Baler, R Carter, DA TI cDNA array analysis of pineal gene expression reveals circadian rhythmicity of the dominant negative helix-loop-helix protein-encoding gene, Id-1 SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Article DE circadian rhythm; HLH protein; transcription factor; clock gene; melatonin ID SEROTONIN N-ACETYLTRANSFERASE; DNA-BINDING PROTEINS; RAT PINEAL; MESSENGER-RNA; GLAND; ID1; DIFFERENTIATION; QUANTITATION; CELLS AB The pineal gland is a major output of the endogenous vertebrate circadian clock, with melatonin serving as the output signal. In many species, elevated nocturnal melatonin production is associated with changes in pineal gene expression. In the current study, cDNA array analysis was used in an attempt to identify additional genes that exhibit day/night differential expression in the rat pineal gland. This revealed 38 candidate genes, including Id-1 (inhibitor of DNA binding and differentiation). Id-1 encodes a helix-loop-helix (HLH) protein that lacks a basic DNA binding domain and could affect pineal physiology via a dominant negative trans-acting regulatory activity. For this reason Id-1 was selected for further analysis. Id-1 was expressed in a major population of pineal cells and the Id-1 protein was associated with a nuclear complex. The levels of Id-1 mRNA and protein exhibit approximately six-fold day/night rhythms. In contrast, the related genes Id-2 and Id-3 do not exhibit marked day/night differences in pineal expression. Rhythmic Id-1 expression is primarily limited to a C-terminally extended splice variant of Id-1, which would restrict the functional output of the rhythm to protein binding partners of this isoform of Id-1. Our findings add to the body of evidence indicating that transcriptional regulators play a role in neuroendocrine rhythms, and extend this by introducing the concept of a dominant negative HLH involvement. The rhythm in Id-1 in the pineal gland provides an experimental opportunity to identify Id-l-binding partners which may also be involved in Id-1 activity in other functional contexts. C1 Cardiff Univ, Sch Biosci, Cardiff, S Glam, Wales. NICHHD, Sect Neuroendocrinol, Dev Neurobiol Lab, Bethesda, MD 20892 USA. NIMH, Unit Temporal Gene Express, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Carter, DA (reprint author), Cardiff Univ, Sch Biosci, POB 911,Museum Ave, Cardiff, S Glam, Wales. RI Carter, David/A-4479-2010 OI Carter, David/0000-0002-8419-3975 NR 42 TC 47 Z9 48 U1 1 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD FEB PY 2002 VL 14 IS 2 BP 101 EP 108 DI 10.1046/j.0007-1331.2001.00738.x PG 8 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 513MJ UT WOS:000173382100003 PM 11849369 ER PT J AU Ferraina, S Pare, M Wurtz, RH AF Ferraina, S Pare, M Wurtz, RH TI Comparison of cortico-cortical and cortico-collicular signals for the generation of saccadic eye movements SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID POSTERIOR PARIETAL CORTEX; SPATIAL WORKING-MEMORY; LATERAL INTRAPARIETAL AREA; 3 MOTOR AREAS; SUPERIOR COLLICULUS; RHESUS-MONKEY; REVERSIBLE INACTIVATION; DISPARITY SENSITIVITY; PREFRONTAL CORTEX; GUIDED SACCADES AB Many neurons in the frontal eye field (FEF) and lateral intraparietal (LIP) areas of cerebral cortex are active during the visual-motor events preceding the initiation of saccadic eye movements: they respond to visual targets, increase their activity before saccades, and maintain their activity during intervening delay periods. Previous experiments have shown that the output neurons from both LIP and FEF convey the full range of these activities to the superior colliculus (SC) in the brain stem. These areas of cerebral cortex also have strong interconnections, but what signals they convey remains unknown. To determine what these cortico-cortical signals are, we identified the LIP neurons that project to FEF by antidromic activation, and we studied their activity during a delayed-saccade task. We then compared these cortico-cortical signals to those sent subcortically by also identifying the LIP neurons that project to the intermediate layers of the SC. Of 329 FEF projection neurons and 120 SC projection neurons, none were co-activated by both FEF and SC stimulation. FEF projection neurons were encountered more superficially in LIP than SC projection neurons, which is consistent with the anatomical projection of many cortical layer III neurons to other cortical areas and of layer V neurons to subcortical structures. The estimated conduction velocities of FEF projection neurons (16.7 m/s) were significantly slower that those of SC projection neurons (21.7 m/s), indicating that FEF projection neurons have smaller axons. We identified three main differences in the discharge properties of FEF and SC projection neurons: only 44% of the FEF projection neurons changed their activity during the delayed-saccade task compared with 69% of the SC projection neurons; only 17% of the task-related FEF projection neurons showed saccadic activity, whereas 42% of the SC projection neurons showed such increases; 78% of the FEF projection neurons had a visual response but no saccadic activity, whereas only 55% of the SC projection neurons had similar activity. The FEF and SC projection neurons had three similarities: both had visual, delay, and saccadic activity, both had stronger delay and saccadic activity with visually guided than with memory-guided saccades, and both had broadly tuned responses for disparity stimuli, suggesting that their visual receptive fields have a three-dimensional configuration. These observations indicate that the activity carried between parietal and frontal cortical areas conveys a spectrum of signals but that the preponderance of activity conveyed might be more closely related to earlier visual processing than to the later saccadic stages that are directed to the SC. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Wurtz, RH (reprint author), NEI, Sensorimotor Res Lab, NIH, 9000 Rockville Pike,Bldg 49,Rm 2A50, Bethesda, MD 20892 USA. NR 75 TC 96 Z9 97 U1 0 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD FEB PY 2002 VL 87 IS 2 BP 845 EP 858 DI 10.1152/jn.00317.2001 PG 14 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 537AV UT WOS:000174735100019 PM 11826051 ER PT J AU Allers, KA Ruskin, DN Bergstrom, DA Freeman, LE Ghazi, LJ Tierney, PL Walters, JR AF Allers, KA Ruskin, DN Bergstrom, DA Freeman, LE Ghazi, LJ Tierney, PL Walters, JR TI Multisecond periodicities in basal ganglia firing rates correlate with theta bursts in transcortical and hippocampal EEG SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID SUBTHALAMIC NUCLEUS; OSCILLATION AB Multisecond oscillations in firing rate with periods in the range of 2-60 s (mean, 20-35 s) are present in 50-90% of spike trains from basal ganglia neurons recorded from locally anesthetized, immobilized rats. To determine whether these periodic oscillations are associated with similar periodicities in cortical activity, transcortical electroencephalographic (EEG) activity was recorded in conjunction with single- or dual-unit neuronal activity in the subthalamic nucleus (STN) or the globus pallidus (GP), and the data were analyzed with spectral and wavelet analyses. Multisecond oscillations in firing rates of 31% of the STN neurons and 46% of the GP neurons with periodicities significantly correlated with bursts of theta (4-7 Hz) activity in transcortical EEG. Further recordings of localized field potentials in the hippocampus and frontal or parietal cortices simultaneously with GP unit activity showed field potentials from the hippocampus, but not from the frontal or parietal cortices, exhibited bursts of theta rhythm that were correlated with GP firing rate oscillations. These results demonstrate a functional connectivity between basal ganglia neuronal activity and theta band activity in the hippocampus. C1 NINCDS, Expt Therapeut Branch, Neurophysiol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RP Allers, KA (reprint author), Univ Oxford, Dept Pharmacol, Mansfield Rd, Oxford OX1 3QT, England. RI Tierney, Patrick/E-5860-2010 NR 16 TC 38 Z9 39 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD FEB PY 2002 VL 87 IS 2 BP 1118 EP 1122 DI 10.1152/jn.00234.2001 PG 5 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 537AV UT WOS:000174735100043 PM 11826075 ER PT J AU Gao, HM Hong, JS Zhang, WQ Liu, B AF Gao, HM Hong, JS Zhang, WQ Liu, B TI Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE pesticides; microglia; superoxide; dopamine; Parkinson's disease; neurotoxicity ID PARKINSONS-DISEASE; NADPH OXIDASE; NITRIC-OXIDE; ACTIVATION; NEUTROPHILS; BRAIN; INHIBITION; GENERATION; MEDIATORS; EXPOSURE AB Increasing evidence has suggested an important role for environmental factors such as exposure to pesticides in the pathogenesis of Parkinson's disease. In experimental animals the exposure to a common herbicide, rotenone, induces features of parkinsonism; mechanistically, rotenone-induced destruction of dopaminergic neurons has been attributed to its inhibition of the activity of neuronal mitochondrial complex I. However, the role of microglia, the resident brain immune cells in rotenone-induced neurodegeneration, has not been reported. Using primary neuron-enriched and neuron/glia cultures from the rat mesencephalon, we discovered an extraordinary feature for rotenone-induced degeneration of cultured dopaminergic neurons. Although little neurotoxicity was detected in neuron-enriched cultures after treatment for 8 d with up to 20 nM rotenone, significant and selective dopaminergic neurodegeneration was observed in neuron/glia cultures 2 d after treatment with 20 nM rotenone or 8 d after treatment with 1 nM rotenone. The greatly enhanced neurodegenerative ability of rotenone was attributed to the presence of glia, especially microglia, because the addition of microglia to neuron-enriched cultures markedly increased their susceptibility to rotenone. Mechanistically, rotenone stimulated the release of superoxide from microglia that was attenuated by inhibitors of NADPH oxidase. Furthermore, inhibition of NADPH oxidase or scavenging of superoxide significantly reduced the rotenone-induced neurotoxicity. This is the first report demonstrating that microglia play a pivotal role in rotenone-induced degeneration of dopaminergic neurons. The results of this study should advance our understanding of the mechanism of action for pesticides in the pathogenesis of Parkinson's disease. C1 NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Dalian Med Univ, Dept Physiol, Dalian 116027, Peoples R China. RP Liu, B (reprint author), NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, F1-01,POB 12233, Res Triangle Pk, NC 27709 USA. RI gao, huiming/C-8454-2012; liu, Bin/A-7695-2009 NR 44 TC 286 Z9 301 U1 2 U2 12 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 1 PY 2002 VL 22 IS 3 BP 782 EP 790 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 518HB UT WOS:000173660800028 PM 11826108 ER PT J AU Szklarczyk, A Lapinska, J Rylski, M McKay, RDG Kaczmarek, L AF Szklarczyk, A Lapinska, J Rylski, M McKay, RDG Kaczmarek, L TI Matrix metalloproteinase-9 undergoes expression and activation during dendritic remodeling in adult hippocampus SO JOURNAL OF NEUROSCIENCE LA English DT Article DE brain MMP-9 and MMP-2; matrix metalloproteinases; extracellular proteolysis; dendritic remodeling; hippocampus; mRNA translocation; brain extracellular matrix; kainic acid; neuronal activity-dependent gene expression ID CHONDROITIN SULFATE PROTEOGLYCAN; LESION-INDUCED SYNAPTOGENESIS; MESSENGER-RNA EXPRESSION; DENTATE GYRUS; TISSUE INHIBITOR; KAINIC ACID; MOSSY FIBERS; SPINAL-CORD; RAT-BRAIN; NEURONS AB Neurons of adult brain are able to remodel their synaptic connections in response to various stimuli. Modifications of the peridendritic environment, including the extracellular matrix, are likely to play a role during synapse remodeling. Proteolytic disassembly of ECM is a complex process using the regulated actions of specific extracellular proteinases. One of best-characterized families of matrix-modifying enzymes is the matrix metalloproteinase (MMP) family. Here, we describe changes in the expression and function of two well known MMPs, MMP-9 and MMP-2, in adult rat brain before and after systemic administration of the glutamate receptor agonist kainate. Kainate application results in enhanced synaptic transmission and seizures followed by selective tissue remodeling, primarily in hippocampal dentate gyrus. MMP-9 but not MMP-2 was highly expressed by neurons in normal adult rat brain. MMP-9 protein was localized in neuronal cell bodies and dendrites. Kainate upregulated the level of MMP-9 mRNA and protein within hours after drug administration. This was followed several hours later by MMP-9 enzymatic activation. Within hippocampus, MMP-9 mRNA and activity were increased selectively in dentate gyrus, including its dendritic layer. In addition, MMP-9 mRNA levels decreased in areas undergoing neuronal cell loss. This unique spatiotemporal pattern of MMP-9 expression suggests its involvement in activity-dependent remodeling of dendritic architecture with possible effects on synaptic physiology. C1 NINCDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Nencki Inst, Mol Neurobiol Lab, PL-02093 Warsaw, Poland. Warmia Masuria Univ, Fac Biol, Dept Genet, PL-10719 Olsztyn, Poland. RP Szklarczyk, A (reprint author), NINCDS, Mol Biol Lab, NIH, 36 Convent Dr,Bldg 36,Room 3C09, Bethesda, MD 20892 USA. RI Kaczmarek, Leszek/B-6171-2008 OI Kaczmarek, Leszek/0000-0002-7207-3490 NR 44 TC 248 Z9 254 U1 1 U2 21 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 1 PY 2002 VL 22 IS 3 BP 920 EP 930 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 518HB UT WOS:000173660800041 PM 11826121 ER EF