FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Qin, M Kang, J Smith, CB AF Qin, M Kang, J Smith, CB TI Increased local rates of cerebral protein synthesis in fragile X knockout mice. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 NIMH, Neurobiol Unit, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 390 BP 528 EP 529 PG 2 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300350 ER PT J AU Huang, CC Lawson, N Weinstein, B Johnson, S AF Huang, CC Lawson, N Weinstein, B Johnson, S TI reg6 is required for branching morphogenesis during blood vessel regeneration in zebrafish caudal fins. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. NIH, Unit Vertebrate Organogenesis, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 414 BP 534 EP 534 PG 1 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300371 ER PT J AU Perantoni, AO Timofeeva, O Richman, C Pajni-Underwood, S Lewandoski, M AF Perantoni, AO Timofeeva, O Richman, C Pajni-Underwood, S Lewandoski, M TI Fgf8 plays a fundamental role in kidney development. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 NCI, LCC, NIH, Frederick, MD 21701 USA. NCI, CDBL, NIH, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 466 BP 546 EP 546 PG 1 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300421 ER PT J AU Kwan, KM Li, AG Mishina, Y Wang, XJ Roop, DR Wurst, W Behringer, RR AF Kwan, KM Li, AG Mishina, Y Wang, XJ Roop, DR Wurst, W Behringer, RR TI BMPR-IA signaling is required for differentiation and growth of hair during postnatal hair follicle morphogenesis. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX USA. Baylor Coll Med, Dept Dermatol, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. NIEHS, Reprod & Dev Toxicol Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 480 BP 549 EP 550 PG 2 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300433 ER PT J AU Mathers, P Voroninal, V Wilson, C Kozlov, S Lewandoski, M AF Mathers, P Voroninal, V Wilson, C Kozlov, S Lewandoski, M TI Rx is required both for optic vesicle formation and maintenance of retinal cell fate. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 W Virginia Univ, Sensory Neurosci Res Ctr, Morgantown, WV 26506 USA. Natl Canc Inst, Canc & Dev Bio Lab, Frederick, MD USA. NR 0 TC 0 Z9 0 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 495 BP 552 EP 553 PG 2 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300445 ER PT J AU Fritz, A Solomon, KS Kudoh, T Mackereth, MD Dawid, IB AF Fritz, A Solomon, KS Kudoh, T Mackereth, MD Dawid, IB TI Early development of the otic placode in zebrafish. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 Emory Univ, Dept Biol, Atlanta, GA 30322 USA. NICHD, Genet Mol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 499 BP 553 EP 554 PG 2 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300449 ER PT J AU Mishina, Y Ye, L Huang, HY Chen, D Dallas, S Kunieda, T Tsutsui, TW Lu, YB Ke, HZ Bonewald, LF Feng, JQ AF Mishina, Y Ye, L Huang, HY Chen, D Dallas, S Kunieda, T Tsutsui, TW Lu, YB Ke, HZ Bonewald, LF Feng, JQ TI Deficiency for dentin matrix protein 1, a specific gene for mineralized tissues, causes osteochondrodysplasia, osteoarthritis, and rickets/osteomalacia during postnatal development. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Univ Missouri, Sch Dent, Kansas City, MO USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. NR 0 TC 0 Z9 0 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 517 BP 557 EP 557 PG 1 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300463 ER PT J AU Keller, M Jiang, D Chitnis, A AF Keller, M Jiang, D Chitnis, A TI Zic2 and Zic3 proteins together regulate proneural and neural crest domains in zebrafish. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 NICHHD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 528 BP 560 EP 560 PG 1 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300473 ER PT J AU Hallsson, JH Haflidado, S Stivers, C Odenwald, W Pignoni, F Arnheiter, H Steingrimsson, E AF Hallsson, JH Haflidado, S Stivers, C Odenwald, W Pignoni, F Arnheiter, H Steingrimsson, E TI The bHLH-zip transcription factor Mitf is conserved in drosophila and is expressed in the developing eye SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. NINDS, Lab Dev Neurogenet, NIH, Baltimore, MD USA. Harvard Univ, Sch Med, MEEI, Cambridge, MA 02138 USA. NINDS, Neurochem Lab, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 549 BP 564 EP 565 PG 2 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300492 ER PT J AU Chen, YT Knezevic, V Ervin, V Mackem, S AF Chen, YT Knezevic, V Ervin, V Mackem, S TI Direct interaction between Gli3 and Hoxd proteins alters the Sonic hedgehog pathway and skeletal patterning during limb development. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 566 BP 569 EP 569 PG 1 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300509 ER PT J AU Ma, X Kawamoto, S Adelstein, RS AF Ma, X Kawamoto, S Adelstein, RS TI Hypomorphic and normal expression of a point mutated NMHC II-B results in distinct phenotypes in mice. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 NHLBI, LMC, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 664 BP 591 EP 591 PG 1 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300597 ER PT J AU van den IJssel, P Wheelock, R Prescott, A Russell, P Quinlan, RA AF van den IJssel, P Wheelock, R Prescott, A Russell, P Quinlan, RA TI Nuclear speckle localisation of the small heat shock protein alpha B-crystallin and its inhibition by the R120G cardiomyopathy-linked mutation SO EXPERIMENTAL CELL RESEARCH LA English DT Review DE chaperone; cardiomyopathy; alpha B-crystallin; nuclear speckles; interchromatin granules ID ARTEMIA-FRANCISCANA EMBRYOS; DESMIN-RELATED MYOPATHY; MISSENSE MUTATION; STRESS-PROTEIN; COILED BODIES; IN-VITRO; INTRACELLULAR-LOCALIZATION; NEURONAL DIFFERENTIATION; ACTIN POLYMERIZATION; IMMUNOREACTIVE ALPHA AB In this study, the small heat shock protein (sHSP) chaperones, alphaB-crystallin and HSP27, are identified as nuclear speckle components in unstressed cells in tissue culture. This new finding suggests a constitutive function for these sHSP chaperones in the nucleus and suggests a new perspective on the cardiomyopathy-causing mutation for alphaB-crystallin that could involve transcriptional splicing effects. Both alphaB-crystallin and HSP27 were immunolocalised to nuclear speckles (interchromatin granule clusters). While alphaB-crystallin was preferentially localised to speckles as shown by colocalisation with non-snRNP, SC35, as well as the snRNP components Sm and U1A, HSP27 was also seen associated with the nucleolar compartment, indicating a subtle difference between these closely related sHSPs. Actinomycin D treatment caused the relocalisation of alphaB-crystallin along with Sm and SC35 to a smaller number of more distinct spots, suggesting a link between speckle localisation and the transcriptional status of the cells. We then examined several transformed, immortalised, and primary cells expressing endogenous alphaB-crystallin as well as some cells with ectopic alphaB-crystallin expression. All consistently showed alphaB-crystallin in nuclear speckles. The nuclear localisation of the sHSPs was also confirmed biochemically and 2D gel electrophoresis revealed that there was only one major nuclear alphaB-crystallin isoform. This suggested that phosphorylation was not required for nuclear localisation of alphaB-crystallin. This was confirmed by the transient transfection of HeLa cells with a phosphorylation-defective alphaB-crystallin. In contrast, the transfection of R120G alphaB-crystallin, the mutation that causes cardiomyopathy, inhibited the nuclear speckle localisation of alphaB-crystallin. These data suggest that the cardiomyopathy-causing mutation for alphaB-crystallin has nuclear as well as cytoplasmic consequences, suggesting an explanation for the difference in severity of the desmin and alphaB-crystallin transgenic models of their respective cardiomyopathies. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Univ Durham, Sch Biol & Biomed Sci, Durham DH1 3LE, England. NEI, Bethesda, MD 20892 USA. Univ Dundee, Inst Med Sci, Sch Life Sci, Dundee DD1 5EH, Scotland. RP Quinlan, RA (reprint author), Univ Durham, Sch Biol & Biomed Sci, S Rd, Durham DH1 3LE, England. RI Quinlan, Roy/A-1348-2012; OI Quinlan, Roy/0000-0003-0644-4123; Prescott, Alan/0000-0002-0747-7317 NR 105 TC 43 Z9 44 U1 2 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 JUL 15 PY 2003 VL 287 IS 2 BP 249 EP 261 DI 10.1016/S0014-4827(03)00092-2 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 699JG UT WOS:000184052800006 PM 12837281 ER PT J AU Mulholland, NM Snyder, SK Kolla, SS Smith, CL AF Mulholland, NM Snyder, SK Kolla, SS Smith, CL TI Chromatin-dependent regulation of the MMTV promoter by cAMP signaling is mediated through distinct pathways SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE mouse mammary tumor virus promoter; transcription; cAMP signaling; chromatin; repression; glucocorticoid receptor ID TUMOR VIRUS PROMOTER; LONG TERMINAL REPEAT; CREB-BINDING-PROTEIN; CYCLIC-AMP; HISTONE H3; IN-VIVO; TRANSCRIPTIONAL ACTIVATION; GENE-EXPRESSION; NUCLEAR RECEPTOR; C-FOS AB The nucleoprotein structure of the mouse mammary tumor virus (MMTV) promoter defines its response to cAMP signaling. A stably replicating MMTV template in highly organized chromatin is repressed in the presence of cAMP, whereas a transiently transfected template with a disorganized structure is activated. In this study, we investigate the nature of the cAMP-induced signal(s) by which these opposing responses occur to gain insight into their mechanism. We demonstrate that the transcriptional changes observed at both templates are mediated through cAMP-dependent protein kinase A (PKA). In addition, the MMTV promoter lacks a consensus cAMP response element (CRE) and neither template requires cAMP response element-binding protein (CREB) to elicit a response to cAMP signaling. However, the responses of the two templates differ mechanistically in that the CREB-binding protein p300 potentiates activation from the transient template in a manner dependent on its Cys/His-rich region 3, but does not appear to affect the repression of the replicating chromatin template. Chromatin immunoprecipitation assays show that cAMP treatment results in a decrease in acetylation of histone H4, and in multiple modifications of histone H3 at specific nucleosomes in the promoter region of the stable MMTV template. These findings suggest novel CREB-independent, chromatin-dependent pathways for transcriptional regulation by cAMP. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NCI, Lab Receptor Biol & Gene Express, Signal Transduct Grp, NIH, Bethesda, MD 20892 USA. George Washington Univ, Dept Genet, Washington, DC 20052 USA. RP Smith, CL (reprint author), NCI, Lab Receptor Biol & Gene Express, Signal Transduct Grp, NIH, Bldg 41,Room B608,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA. NR 75 TC 5 Z9 5 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 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD JUL 15 PY 2003 VL 287 IS 2 BP 361 EP 373 DI 10.1016/S0014-4827(03)00153-8 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 699JG UT WOS:000184052800016 PM 12837291 ER PT J AU Lurie, Z Offer, T Russo, A Samuni, A Nitzan, D AF Lurie, Z Offer, T Russo, A Samuni, A Nitzan, D TI Do stable nitroxide radicals catalyze or inhibit the degradation of hyaluronic acid? SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE antioxidants; superoxide; SOD mimics; ionizing radiation; viscosity; free radicals ID SYNOVIAL-FLUID; MYELOPEROXIDASE SYSTEM; SELECTIVE OXIDATION; HYDROXYL RADICALS; PULSE-RADIOLYSIS; SOD MIMICS; METAL-IONS; KINETICS; DESFERRIOXAMINE; SUPEROXIDE AB Reactive oxygen-derived species and particularly OH radicals can degrade hyaluronic acid (HA), resulting in a loss of viscosity and a subsequent decrease in its effectiveness as a joint-lubricating agent. The production of OH in the vicinity of HA can be catalyzed by bound redox-active metals, which participate in the Haber-Weiss reaction. Damage to HA can also occur as a result of hypochlorite formed by myeloperoxidase (MPO). The protective reagents commonly used to inhibit oxidative stress-induced degradation of HA include antioxidative enzymes, such as SOD and catalase, chelators that coordinate metal ions rendering them redox-inactive, and scavengers of radicals, such as OH, as well as nonradical reactive species. In recent years, stable cyclic nitroxides have also been widely used as effective antioxidants. In many cases, nitroxide antioxidants operate catalytically and mediate their protective effect through an exchange between their oxidized and reduced forms. It was anticipated, therefore, that nitroxides would protect HA from oxidative degradation as well. On the other hand, nitroxides serve as catalysts in many oxidation reactions of alcohols, sugars and polysaccharides, including hyalouronan. Such opposite effects of nitroxides on oxidative degradation are particularly intriguing and the aim of the present study was to examine their effect on HA when subjected to diverse forms of oxidative stress. The results indicate that nitroxides protect HA from OH radicals generated enzymatically or radiolytically. The protective effect is attributable neither to the scavenging of OH nor to the oxidation of reduced metal, but to the reaction of nitroxides with secondary carbohydrate radicals-most likely peroxyl radicals. (C) 2003 Elsevier Inc. C1 Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Mol Biol, IL-91120 Jerusalem, Israel. Natl Canc Inst, NIH, Dept Radiat Biol, Bethesda, MD USA. Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Oral & Maxillofacial Surg, IL-91120 Jerusalem, Israel. RP Samuni, A (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Mol Biol, IL-91120 Jerusalem, Israel. NR 38 TC 13 Z9 14 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL 15 PY 2003 VL 35 IS 2 BP 169 EP 178 DI 10.1016/S0891-5849(03)00270-3 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 701BL UT WOS:000184145600006 PM 12853073 ER PT J AU Holt, I Ostlund, C Stewart, CL Man, NT Worman, HJ Morris, GE AF Holt, I Ostlund, C Stewart, CL Man, NT Worman, HJ Morris, GE TI Effect of pathogenic mis-sense mutations in lamin A on its interaction with emerin in vivo SO JOURNAL OF CELL SCIENCE LA English DT Article DE nuclear lamina; mouse knockout; nuclear envelope; Emery-Dreifuss muscular dystrophy; lipodystrophy ID DREIFUSS MUSCULAR-DYSTROPHY; PARTIAL LIPODYSTROPHY; NUCLEAR-ENVELOPE; DILATED CARDIOMYOPATHY; ROD DOMAIN; A/C; GENE; MEMBRANE; PROTEIN; LMNA AB Mutations in lamin A/C can cause Emery-Dreifuss muscular dystrophy (EDMD) or a related cardiomyopathy (CMD1A). Using transfection of lamin-A/C-deficient fibroblasts, we have studied the effects of nine pathogenic mutations on the ability of lamin A to assemble normally and to localize emerin normally at the nuclear rim. Five mutations in the rod domain (L85R, N195K, E358K, M371K and R386K) affected the assembly of the lamina. With the exception of mutant L85R, all rod domain mutants induced the formation of large nucleoplasmic foci in about 10% of all nuclei. The presence of emerin in these foci suggests that the interaction of lamin A with emerin is not directly affected by the rod domain mutations. Three mutations in the tail region, R453W, W520S and R527P, might directly affect emerin binding by disrupting the structure of the putative emerin-binding site, because mutant lamin A localized normally to the nuclear rim but its ability to trap emerin was impaired. Nucleoplasmic foci rarely formed in these three cases (<2%) but, when they did so, emerin was absent, consistent with a direct effect of the mutations on emerin binding. The lipodystrophy mutation R482Q, which causes a different phenotype and is believed to act through an emerin-independent mechanism, was indistinguishable from wild-type in its localization and its ability to trap emerin at the nuclear rim. The novel hypothesis suggested by the data is that EDMD/CMD1A mutations in the tail domain of lamin A/C work by direct impairment of emerin interaction, whereas mutations in the rod region cause defective lamina assembly that might or might not impair emerin capture at the nuclear rim. Subtle effects on the function of the lamina-emerin complex in EDMD/CMD1A patients might be responsible for the skeletal and/or cardiac muscle phenotype. C1 NE Wales Inst, Biochem Grp, Wrexham LL11 2AW, Wales. Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Dept Anat & Cell Biol, New York, NY 10032 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Canc & Dev Biol, Frederick, MD 21702 USA. RP Morris, GE (reprint author), NE Wales Inst, Biochem Grp, Wrexham LL11 2AW, Wales. NR 32 TC 51 Z9 54 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JUL 15 PY 2003 VL 116 IS 14 BP 3027 EP 3035 DI 10.1242/jcs.00599 PG 9 WC Cell Biology SC Cell Biology GA 704XZ UT WOS:000184368100022 PM 12783988 ER PT J AU Takimoto, CH Remick, SC Sharma, S Mani, S Ramanathan, RK Doroshow, J Hamilton, A Mulkerin, D Graham, M Lockwood, GF Ivy, P Egorin, M Schuler, B Greenslade, D Goetz, A Knight, R Thomas, R Monahan, BP Dahut, W Grem, JL AF Takimoto, CH Remick, SC Sharma, S Mani, S Ramanathan, RK Doroshow, J Hamilton, A Mulkerin, D Graham, M Lockwood, GF Ivy, P Egorin, M Schuler, B Greenslade, D Goetz, A Knight, R Thomas, R Monahan, BP Dahut, W Grem, JL TI Dose-escalating and pharmacological study of oxaliplatin in adult cancer patients with impaired renal function: A National Cancer Institute Organ Dysfunction Working Group Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BODY-SURFACE AREA; CELL-LINES; OVARIAN-CANCER; SINGLE-AGENT; PHASE-II; PLATINUM; CISPLATIN; PHARMACOKINETICS; CARBOPLATIN; RESISTANCE AB Purpose: This study was undertaken to determine the toxicities, phormacokinetics, and maximum tolerated doses of oxaliplatin in patients with renal impairment and to develop formal guidelines for oxaliplatin dosing in this patient population. Patients and Methods: Thirty-seven adult cancer patients with variable renal function received intravenous oxaliplatin at 60 to 130 mg/m(2) every 3 weeks. Patients were stratified by 24-hour creatinine clearance (CrCL) into four cohorts: group A (controls, CrCL greater than or equal to60 mL/min), group B (mild dysfunction, CrCL 40 to 59 mL/min), group C (moderate dysfunction, CrCl. 20 to 39 mL/min), and group D (severe dysfunction, CrCl. <20 mL/min). Doses were escalated in cohorts of three patients, and urine and plasma ultrafiltrates were assayed for platinum concentrations. Results: No dose-limiting toxicities were observed in any patient group during the first cycle of therapy. Escalation of oxaliplatin to the maximum dose of 130 mg/m(2) was well tolerated in all patient groups with a CrCl greater than or equal to20 mL/min (groups A, B, and C). Pharmacokinetic analysis showed that patients with decreased CrCl. had a corresponding decrease in the clearance of plasma ultrafiltrable platinum (r(2) = 0.765). However, oxaliplatin-induced side effects were not more common or severe in patients with mild to moderate renal dysfunction, despite the decrease in ultrafiltrable platinum clearance. Conclusion: Oxaliplatin at 130 mg/m(2) every 3 weeks is well tolerated by patients with mild to moderate degrees of renal dysfunction. These data strongly support the recommendation that dose reductions of single-agent oxaliplatin are not necessary in patients with a CrCl. greater than 20 mL/min. (C) 2003 by American Society of Clinical Oncology. C1 Univ Texas, Hlth Sci Ctr, Canc Therapy & Res Ctr, Inst Drug Dev, San Antonio, TX 78229 USA. USN, Med Branch, Natl Naval Med Ctr, Bethesda, MD USA. NCI, Investigat Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Ctr, Bethesda, MD USA. Univ Hosp Cleveland, Ctr Comprehens Canc, Cleveland, OH USA. Case Western Reserve Univ, Cleveland, OH USA. Mem Sloan Kettering Canc Ctr, New York, NY USA. NYU, New York, NY USA. Albert Einstein Coll Med, Montefiore Hosp, Bronx, NY USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. City Hope Natl Med Ctr, Duarte, CA USA. Univ Wisconsin, Madison, WI USA. Sanofi Synthelabo Inc, Dept Clin Metab & Pharmacokinet, Malvern, PA USA. NCI, Bethesda, MD USA. RP Takimoto, CH (reprint author), Univ Texas, Hlth Sci Ctr, Canc Therapy & Res Ctr, Inst Drug Dev, 7979 Wurzbach Rd,Rm Z415, San Antonio, TX 78229 USA. FU NCI NIH HHS [U01CA062502, U01 CA062491, U01CA062491, U01CA062505, U01CA069853, U01CA069855, U01CA076642] NR 30 TC 54 Z9 56 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 15 PY 2003 VL 21 IS 14 BP 2664 EP 2672 DI 10.1200/JCO.2003.11.015 PG 9 WC Oncology SC Oncology GA 702JB UT WOS:000184219800008 PM 12860942 ER PT J AU Sparreboom, A Verweij, J AF Sparreboom, A Verweij, J TI Paclitaxel pharmacokinetics, threshold models, and dosing strategies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID BODY-SURFACE AREA; TIME-COURSE; MYELOSUPPRESSION; LEUKOPENIA; DRUGS C1 NCI, Bethesda, MD 20892 USA. Dr Daniel Den Hoed Canc Ctr, Eramus MC, NL-3008 AE Rotterdam, Netherlands. RP Sparreboom, A (reprint author), NCI, Bethesda, MD 20892 USA. RI Sparreboom, Alex/B-3247-2008 NR 12 TC 12 Z9 13 U1 0 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 15 PY 2003 VL 21 IS 14 BP 2803 EP 2804 DI 10.1200/JCO.2003.99.038 PG 2 WC Oncology SC Oncology GA 702JB UT WOS:000184219800028 PM 12860961 ER PT J AU Perczel, A Farkas, O Jakli, I Topol, IA Csizmadia, IG AF Perczel, A Farkas, O Jakli, I Topol, IA Csizmadia, IG TI Peptide models. XXXIII. Extrapolation of low-level Hartree-Fock data of peptide conformation to large basis set SCF, MP2, DFT, and CCSD(T) results. The Ramachandran surface of alanine dipeptide computed at various levels of theory SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE peptides; ab inito and DFT computation; MP and CCSD(T); structure and stability; Ramachandran surface; X-ray structure ID POTENTIAL-ENERGY SURFACES; PROTEIN CHAIN CONFORMATIONS; MULTIPOLE METHOD GVFMM; AMINO-ACID-RESIDUES; AB-INITIO; ELECTRON CORRELATION; CONVERGENCE ACCELERATION; STEREOCHEMICAL CRITERIA; ALLOWED CONFORMATIONS; SIDE-CHAIN AB At the dawn of the new, millenium, new concepts are required for a more profound understanding of protein structures. Together with NMR and X-ray-based 3D-stucture determinations in silico methods are now widely accepted. Homology-based modeling studies, molecular dynamics methods, and quantum mechanical approaches are more commonly used. Despite the steady and exponential increase in computational power, high level ab initio methods will not be in common use for studying the structure and dynamics of large peptides and proteins in the near future. We are presenting here a novel approach, in which low- and medium-level ab initio energy results are scaled, thus extrapolating to a higher level of information. This scaling is of special significance, because we observed previously on molecular properties such as energy, chemical shielding data, etc., determined at a higher theoretical le vel, do correlate better with experimental data, than those originating from lower theoretical treatments. The Ramachandran surface of an alanine dipeptide now determined at six different levels of theory [RHF and B3LYP 3-21G, 6-31 +G(d) and 6-311 + +G(d,p)] serves as a suitable test. Minima, first-order critical points and partially optimized structures, determined at different levels of theory (SCF, DFT), were completed with high level energy calculations such as MP2, MP4D, and CCSD(T). For the first time three different CCSD(T) sets of energies were determined for all stable B3LYP/6-311+ +G(d,p) minima of an alanine dipeptide. From the simplest ab initio data (e.g., RHF/3-21G) to more complex results [CCSD(T)/6-311 +G(d,p)//B3LYP/6-311 + +G(d,p)] all data sets were compared, analyzed in a comprehensive manner, and evaluated by means of statistics. (C) 2003 Wiley Periodicals, Inc. J Comput Chem 24: 1026-1042, 2003. C1 Eotvos Lorand Univ, Dept Organ Chem, H-1518 Budapest 112, Hungary. NCI, Adv Biomed Comp Ctr, SAIC Frederick, Frederick, MD 21702 USA. Univ Toronto, Dept Chem, Toronto, ON M5S 1A1, Canada. RP Perczel, A (reprint author), Eotvos Lorand Univ, Dept Organ Chem, POB 32, H-1518 Budapest 112, Hungary. EM perczel@para.chem.elte.hu RI Farkas, Odon/F-9180-2012 NR 43 TC 50 Z9 51 U1 0 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0192-8651 J9 J COMPUT CHEM JI J. Comput. Chem. PD JUL 15 PY 2003 VL 24 IS 9 BP 1026 EP 1042 DI 10.1002/jcc.10267 PG 17 WC Chemistry, Multidisciplinary SC Chemistry GA 687DA UT WOS:000183359600003 PM 12759903 ER PT J AU Lafont, BAP Buckler-White, A Plishka, R Buckler, C Martin, MA AF Lafont, BAP Buckler-White, A Plishka, R Buckler, C Martin, MA TI Characterization of pig-tailed macaque classical MHC class I genes: Implications for MHC evolution and antigen presentation in macaques SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; SIMIAN IMMUNODEFICIENCY VIRUS; PEPTIDE BINDING MOTIF; MOLECULE MAMU-A-ASTERISK-01; RHESUS MACAQUES; ANKYLOSING-SPONDYLITIS; DISEASE PROGRESSION; HLA; INFECTION; ALLELES AB MHC-dependent CD8(+) T cell responses have been associated with control of viral replication and slower disease progression during lentiviral infections. Pig-tailed macaques (Macaca nemestrina) and rhesus monkeys (Macaca mulatta), two nonhuman primate species commonly used to model HIV infection, can exhibit distinct clinical courses after infection with different primate lentiviruses. As an initial step in assessing the role of MHC class I restricted immune responses to these infections, we have cloned and characterized classical MHC class I genes of pig-tailed macaques and have identified 19 MHC class I alleles (Mane) orthologous to rhesus macaque MHC-A, -B, and -I genes. Both Mane-A and Mane-B loci were found to be duplicated, and no MHC-C locus was detected. Pig-tailed and rhesus macaque MHC-A alleles form two groups, as defined by 14 polymorphisms affecting mainly their B peptide-binding pockets. Furthermore, an analysis of multiple pig-tailed monkeys revealed the existence of three MHC-A haplotypes. The distribution of these haplotypes in various Old World monkeys provides new insights about MHC-A evolution in nonhuman primates. An examination of B and F peptide-binding pockets in rhesus and pig-tailed macaques suggests that their MHC-B molecules present few common peptides to their respective CTLs. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Martin, MA (reprint author), NIAID, Mol Microbiol Lab, NIH, 4 Ctr Dr, Bethesda, MD 20892 USA. RI Lafont, Bernard/B-7236-2014 NR 61 TC 26 Z9 26 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2003 VL 171 IS 2 BP 875 EP 885 PG 11 WC Immunology SC Immunology GA 700BY UT WOS:000184093800048 PM 12847257 ER PT J AU Taggart, CC Greene, CM Smith, SG Levine, RL McCray, PB O'Neill, S McElvaney, NG AF Taggart, CC Greene, CM Smith, SG Levine, RL McCray, PB O'Neill, S McElvaney, NG TI Inactivation of human beta-defensins 2, and 3 by elastolytic cathepsins SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BRONCHOALVEOLAR LAVAGE FLUID; BETA-DEFENSINS; PSEUDOMONAS-AERUGINOSA; ANTIMICROBIAL PEPTIDES; CYSTIC-FIBROSIS; HUMAN AIRWAY; LUNG; MACROPHAGES; EXPRESSION; EPITHELIA AB beta-Defensins are antimicrobial peptides that contribute to the innate immune responses of eukaryotes. At least three defensins, human beta-defensins 1, 2, and 3 (HBD-1, -2, and -3), are produced by epithelial cells lining the respiratory tract and are active toward Gram-positive (HBD-3) and Gram-negative (HBD-1, -2, and -3) bacteria. It has been postulated that the antimicrobial activity of defensins is compromised by changes in airway surface liquid composition in lungs of patients with cystic fibrosis (CF), therefore contributing to the bacterial colonization of the lung by Pseudomonas and other bacteria in CF. In this report we demonstrate that HBD-2 and HBD-3 are susceptible to degradation and inactivation by the cysteine proteases cathepsins B, L, and S. In addition, we show that all three cathepsins are present and active in CF bronchoalveolar lavage. Incubation of HBD-2 and -3 with CF bronchoalveolar lavage leads to their degradation, which can be completely (HBD-2) or partially (HBD-3) inhibited by a cathepsin inhibitor. These results suggest that beta-defensins are susceptible to degradation and inactivation by host proteases, which may be important in the regulation of beta-defensin activity. In chronic lung diseases associated with infection, overexpression of cathepsins may lead to increased degradation of HBD-2 and -3, thereby favoring bacterial infection and colonization. C1 Beaumont Hosp, Royal Coll Surg Ireland, Educ & Res Ctr, Dept Med,Pulm Res Div, Dublin 9, Ireland. Univ Dublin Trinity Coll, Moyne Inst, Dept Microbiol, Dublin 2, Ireland. NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Univ Iowa, Coll Med, Dept Pediat, Iowa City, IA 52242 USA. RP Taggart, CC (reprint author), Beaumont Hosp, Royal Coll Surg Ireland, Educ & Res Ctr, Dept Med,Pulm Res Div, Dublin 9, Ireland. RI McElvaney, Noel/A-6809-2010; Greene, Catherine/D-3513-2012; Smith, Stephen/C-8523-2014; Taggart, Clifford/G-4492-2014; Levine, Rodney/D-9885-2011 OI Greene, Catherine/0000-0003-2549-2569; Smith, Stephen/0000-0001-7807-2176; NR 36 TC 110 Z9 122 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2003 VL 171 IS 2 BP 931 EP 937 PG 7 WC Immunology SC Immunology GA 700BY UT WOS:000184093800055 PM 12847264 ER PT J AU An, P Vlahov, D Margolick, JB Phair, J O'Brien, TR Lautenberger, J O'Brien, SJ Winkler, CA AF An, P Vlahov, D Margolick, JB Phair, J O'Brien, TR Lautenberger, J O'Brien, SJ Winkler, CA TI A tumor necrosis factor-alpha-inducible promoter variant of interferon-gamma accelerates CD4(+) T cell depletion in human immunodeficiency virus-1-infected individuals SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 52nd Annual Meeting oof the American-Society-of-Human-Genetics CY OCT 15-19, 2002 CL BALTIMORE, MARYLAND SP American Soc Human Genet ID IMMUNODEFICIENCY-VIRUS TYPE-1; VIRAL LOAD; AIDS; INFECTION; MOLECULES; DEATH; COUNT AB A polymorphism, - 179G/T, in the promoter of the interferon (IFN)-gamma gene (IFNG) confers differential tumor necrosis factor-alpha (TNF-alpha) inducibility to the IFNG promoter. The rarer allele, -179T, but not -179G, is inducible by TNF-alpha. We investigated the effects of IFNG - 179G/T on AIDS pathogenesis. In 298 African American human immunodeficiency virus (HIV)-1 seroconverters, the IFNG - 179G/T genotype was associated with accelerated progression to CD4 < 200 and AIDS-1993, a finding suggesting that IFNG - 179T is a risk factor for AIDS progression, as measured by CD4 cell count. It is possible that increased IFN-γ production induced by TNF-α when - 179T is present causes CD4 cell depletion by apoptosis. C1 NCI, Frederick Canc Res & Dev Ctr, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. NCI, Lab Genom Divers, Frederick, MD 21702 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. NCI, Viral Epidemiol Branch, DCEG, Bethesda, MD 20892 USA. Northwestern Univ, Sch Med, Comprehens AIDS Ctr, Chicago, IL USA. RP Winkler, CA (reprint author), NCI, Frederick Canc Res & Dev Ctr, Basic Res Program, SAIC Frederick Inc, Bldg 560, Frederick, MD 21702 USA. FU NCI NIH HHS [N01 CO 124000] NR 15 TC 27 Z9 31 U1 0 U2 1 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 JUL 15 PY 2003 VL 188 IS 2 BP 228 EP 231 DI 10.1086/376455 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 699HT UT WOS:000184051500006 PM 12854077 ER PT J AU Hanekom, WA Mendillo, M Manca, C Haslett, PAJ Siddiqui, MR Barry, C Kaplan, G AF Hanekom, WA Mendillo, M Manca, C Haslett, PAJ Siddiqui, MR Barry, C Kaplan, G TI Mycobacterium tuberculosis inhibits maturation of human monocyte-derived dendritic cells in vitro SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 7t International Symposium on Dendritic Cells CY SEP 19-24, 2002 CL BAMBERG, GERMANY ID BACILLUS-CALMETTE-GUERIN; REGULATORY CELLS; T-CELLS; DC-SIGN; INFECTION; ANTIGEN; VIRUS; IMMUNOLOGY; ACTIVATION; CYTOKINES AB To induce effector immunity, dendritic cells (DCs) must differentiate into fully mature cells. We show that, after human monocyte-derived DCs were infected with virulent Mycobacterium tuberculosis, up-regulation of cellular-surface maturation markers was minimal and reversible. In the presence of a potent stimulus for maturation (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, and prostaglandin E-2 [PGE(2)]), M. tuberculosis inhibited phenotypic DC maturation. M. tuberculosis - infected DCs had an impaired ability to induce allogeneic lymphoproliferation and activated autologous memory CD4(+) and CD8(+) T cells optimally only in the presence of TNF-alpha, IL-1beta, and PGE(2). Thus, virulent M. tuberculosis inhibits phenotypic and functional maturation of human monocyte-derived DCs. This mechanism, which has been described elsewhere for various viruses and for the virulent mycobacterium M. leprae, may be a novel mechanism that this pathogen uses to evade the host's immune response. C1 Univ Miami, Sch Med, Dept Pediat, Div Infect Dis & Immunol, Miami, FL 33136 USA. Univ Miami, Sch Med, Dept Microbiol & Immunol, Miami, FL 33136 USA. Int Ctr Publ Hlth, Publ Hlth Res Inst, Lab Mycobacterial Immun & Pathogenesis, Newark, NJ USA. Rockefeller Univ, Cellular Physiol & Immunol Lab, New York, NY 10021 USA. NIAID, TB Res Sect, Host Def Lab, NIH, Rockville, MD USA. RP Hanekom, WA (reprint author), Univ Miami, Sch Med, Dept Pediat, Div Infect Dis & Immunol, 1550 NW 10th Ave,Ste 211 D4-4, Miami, FL 33136 USA. RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000783-11]; NIAID NIH HHS [AI 22616, AI 54361, R01 AI054338] NR 33 TC 63 Z9 65 U1 0 U2 0 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 JUL 15 PY 2003 VL 188 IS 2 BP 257 EP 266 DI 10.1086/376451 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 699HT UT WOS:000184051500010 PM 12854081 ER PT J AU Lin, FYC Weisman, LE Troendle, J Adams, K AF Lin, FYC Weisman, LE Troendle, J Adams, K TI Prematurity is the major risk factor for late-onset group B streptococcus disease SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Annual Meeting of the Pediatric-Academic-Societies CY MAY 04-07, 2002 CL BALTIMORE, MARYLAND SP Pediat Acad Soc ID BREAST-MILK TRANSMISSION; NOSOCOMIAL TRANSMISSION; NEWBORN NURSERY; COLONIZATION; INFECTION; EPIDEMIOLOGY; ANTIBODY; INFANT; WOMEN; POLYSACCHARIDE AB A case-control study was conducted in the greater Houston area to determine risk factors for late-onset group B streptococcus (GBS) disease ( onset of disease or first positive culture between 7 and 180 days after birth). Characteristics of 122 case patients diagnosed during 1995 - 2000 were compared with control subjects matched for birth hospital and date of birth. Half the case patients were preterm infants, 84% of whom were born at < 34 weeks of gestation. The risk for late-onset GBS disease increased by a factor of 1.34 (95% confidence interval [CI], 1.15 - 1.56) for each week of decreasing gestation, by 3.70 ( 95% CI, 1.35 - 10.1) for infants of black mothers, and by 4.15 ( 95% CI, 1.27 - 13.60) for infants of mothers with a positive GBS screening. These risk factors are similar to that of early-onset GBS disease. However, prematurity is the major risk factor for late-onset GBS disease. C1 NICHHD, NIH, US Dept HHS, Bethesda, MD 20892 USA. Baylor Coll Med, Houston, TX 77030 USA. RP Lin, FYC (reprint author), NICHHD, NIH, US Dept HHS, 6100 Execut Blvd,Rm 7B03, Bethesda, MD 20892 USA. FU NICHD NIH HHS [HD 43214] NR 37 TC 37 Z9 38 U1 1 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 15 PY 2003 VL 188 IS 2 BP 267 EP 271 DI 10.1086/376457 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 699HT UT WOS:000184051500011 PM 12854082 ER PT J AU Walsh, TJ Petraitis, V Petraitiene, R Field-Ridley, A Sutton, D Ghannoum, M Sein, T Schaufele, R Peter, J Bacher, J Casler, H Armstrong, D Espinel-Ingroff, A Rinaldi, MG Lyman, CA AF Walsh, TJ Petraitis, V Petraitiene, R Field-Ridley, A Sutton, D Ghannoum, M Sein, T Schaufele, R Peter, J Bacher, J Casler, H Armstrong, D Espinel-Ingroff, A Rinaldi, MG Lyman, CA TI Experimental pulmonary aspergillosis due to Aspergillus terreus: Pathogenesis and treatment of an emerging fungal pathogen resistant to amphotericin B SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS; PERSISTENTLY GRANULOCYTOPENIC RABBITS; GAS-LIQUID CHROMATOGRAPHY; COLONY-STIMULATING FACTOR; NONPOLAR PACKED COLUMNS; IN-VITRO; INVASIVE ASPERGILLOSIS; PSEUDALLESCHERIA-BOYDII; DISSEMINATED INFECTION; ANTIFUNGAL ACTIVITY AB Aspergillus terreus is an uncommon but emerging fungal pathogen, which causes lethal infections that are often refractory to amphotericin B (AmB). In comparison to Aspergillus fumigatus, A. terreus was resistant to the in vitro fungicidal effects of safely achievable concentrations of AmB. These in vitro findings correlated directly with resistance of A. terreus to AmB in experimental invasive pulmonary aspergillosis. Residual fungal pulmonary burden and galactomannan antigenemia demonstrated persistent infection, despite therapy with deoxycholate AmB or liposomal AmB. By comparison, posaconazole and itraconazole resolved GM antigenemia, reduced residual fungal burden, and improved survival. There were no differences in phagocytic host response to A. terreus versus A. fumigatus; however, the rate of conidial germination of A. terreus was slower. The strain of A. terreus with the highest minimum inhibitory and minimum lethal concentration of AmB also had the lowest membrane ergosterol content. The hyphae of A. terreus in vivo displayed distinctive aleurioconidia, which may be a practical microscopic feature for rapid preliminary diagnosis. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. NIH, Surg Serv, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. Univ Texas, Fungus Testing Lab, San Antonio, TX USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bldg 10,Rm 13N240, Bethesda, MD 20892 USA. NR 59 TC 142 Z9 146 U1 0 U2 5 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 JUL 15 PY 2003 VL 188 IS 2 BP 305 EP 319 DI 10.1086/377210 PG 15 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 699HT UT WOS:000184051500017 PM 12854088 ER PT J AU Pinto, LA Edwards, J Castle, PE Harro, CD Lowy, DR Schiller, JT Wallace, D Kopp, W Adelsberger, JW Baseler, MW Berzofsky, JA Hildesheim, A AF Pinto, LA Edwards, J Castle, PE Harro, CD Lowy, DR Schiller, JT Wallace, D Kopp, W Adelsberger, JW Baseler, MW Berzofsky, JA Hildesheim, A TI Cellular immune responses to human papillomavirus (HPV)-16 L1 in healthy volunteers immunized with recombinant HPV-16 L1 virus-like particles SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID COTTONTAIL RABBIT PAPILLOMAVIRUS; CERVICAL-CANCER; MEDIATED-IMMUNITY; ADULT VOLUNTEERS; VACCINE; INFECTION; CHALLENGE; PROTECTION; WORLDWIDE AB The causal association between papillomavirus (HPV) infection and cervical cancer has been demonstrated; the development of a prophylactic vaccine to protect against HPV infection may therefore reduce the incidence of this cancer worldwide. Noninfectious HPV-like particles (VLPs), composed of the L1 major capsid protein, are current candidate vaccines for prevention of HPV infection and cervical neoplasia. Although neutralizing antibodies have a pivotal role in the prevention of initial infection, cellular immune responses to HPV antigens may have an important role in viral clearance. A phase II trial was conducted to further evaluate the immunogenicity of a recombinant HPV-16 L1 VLP vaccine administered intramuscularly, without adjuvant, at 0, 1, and 6 months. Cell-mediated immune responses (lymphoproliferation and cytokine production) to HPV-16 L1 VLPs were evaluated in peripheral blood mononuclear cells (PBMCs) from 43 individuals receiving the L1 VLP vaccine and from 10 individuals receiving placebo. Vaccination resulted, at months 2 and 7 (i.e., 1 month after the second immunization and 1 month after third immunization, respectively), in increases in T cell - proliferative response to HPV-16 L1 VLPs (P < .001). In addition, significant increases in cytokine (interferon-γ, interleukin [IL]-5 and IL-10) responses to L1 VLPs were observed after vaccination (P < .001). The strongest cytokine responses at month 7 were observed in individuals with high antibody titers at month 2, suggesting that neutralizing antibodies generated by initial vaccination may augment T cell responses to subsequent booster vaccinations. No significant increases in lymphoproliferative or cytokine responses to L1 VLPs were observed in individuals receiving placebo. In summary, the HPV-16 L1 vaccine induces not only robust B cell responses but also L1-specific T cell responses detectable by proliferation of both CD4(+) and CD8(+) T cells and in vitro production of both Th1- and Th2-type cytokines. Future efficacy studies are needed to evaluate whether and/or how VLP vaccines confer protection against genital HPV infection and associated disease. C1 NCI Frederick, SAIC Frederick Inc, Frederick, MD 21702 USA. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD USA. RP Pinto, LA (reprint author), NCI Frederick, SAIC Frederick Inc, Bldg 469,Rm 120, Frederick, MD 21702 USA. FU NCI NIH HHS [N01 CO 12400] NR 29 TC 96 Z9 104 U1 1 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 15 PY 2003 VL 188 IS 2 BP 327 EP 338 DI 10.1086/376505 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 699HT UT WOS:000184051500019 PM 12854090 ER PT J AU Wink, DA Espey, MG Thomas, DD Miranda, KM Paolocci, N AF Wink, DA Espey, MG Thomas, DD Miranda, KM Paolocci, N TI The chemical biology of NO. Insights into potential therapeutic strategies of NO. SO JOURNAL OF INORGANIC BIOCHEMISTRY LA English DT Meeting Abstract CT 11th International Conference on Biological Inorganic Chemistry CY JUL 19-23, 2003 CL CAIMS, AUSTRALIA C1 NIH, Bethesda, MD 20892 USA. Univ Arizona, Tucson, AZ 85721 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. RI Miranda, Katrina/B-7823-2009 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0162-0134 J9 J INORG BIOCHEM JI J. Inorg. Biochem. PD JUL 15 PY 2003 VL 96 IS 1 BP 41 EP 41 DI 10.1016/S0162-0134(03)80474-9 PG 1 WC Biochemistry & Molecular Biology; Chemistry, Inorganic & Nuclear SC Biochemistry & Molecular Biology; Chemistry GA 698QG UT WOS:000184009800063 ER PT J AU Miranda, KM Paolocci, N Katori, T Thomas, DD Wink, DA AF Miranda, KM Paolocci, N Katori, T Thomas, DD Wink, DA TI A biochemical rationale for the orthogonal behavior of nitroxyl (HNO) and nitric oxide (NO) in the cardiovascular system SO JOURNAL OF INORGANIC BIOCHEMISTRY LA English DT Meeting Abstract CT 11th International Conference on Biological Inorganic Chemistry CY JUL 19-23, 2003 CL CAIMS, AUSTRALIA C1 Univ Arizona, Tucson, AZ 85721 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. NIH, Bethesda, MD 20892 USA. RI Miranda, Katrina/B-7823-2009 NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0162-0134 J9 J INORG BIOCHEM JI J. Inorg. Biochem. PD JUL 15 PY 2003 VL 96 IS 1 BP 49 EP 49 DI 10.1016/S0162-0134(03)80487-7 PG 1 WC Biochemistry & Molecular Biology; Chemistry, Inorganic & Nuclear SC Biochemistry & Molecular Biology; Chemistry GA 698QG UT WOS:000184009800076 ER PT J AU Murakami, H Borde, V Shibata, T Lichten, M Ohta, K AF Murakami, H Borde, V Shibata, T Lichten, M Ohta, K TI Correlation between premeiotic DNA replication and chromatin transition at yeast recombination initiation sites SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DOUBLE-STRAND BREAKS; MEIOTIC RECOMBINATION; SACCHAROMYCES-CEREVISIAE; FUNCTIONAL INTERACTIONS; CHROMOSOME-III; HOT-SPOT; MEIOSIS; CONFIGURATION; CELLS; MRE11 AB The DNA double-strand breaks (DSBs) that initiate meiotic recombination in Saccharomyces cerevisiae are preceded first by DNA replication and then by a chromatin transition at DSB sites. This chromatin transition, detected as a quantitative increase in micrococcal nuclease (MNase) sensitivity, occurs specifically at DSB sites and not at other MNase-sensitive sites. Replication and DSB formation are directly linked: breaks do not form if replication is blocked, and delaying replication of a region also delays DSB formation in that region. We report here experiments that examine the relationship between replication, the DSB-specific chromatin transition and DSB formation. Deleting replication origins (and thus delaying replication) on the left arm of one of the two parental chromosomes III affects DSBs specifically on that replication-delayed arm and not those on the normally replicating arm. Thus, replication timing determines DSB timing in cis. Delaying replication on the left arm of chromosome III also delays the chromatin transition at DSB sites on that arm but not on the normally replicating right arm. Since the chromatin transition precedes DSB formation and requires the function of many genes necessary for DSB formation, these results suggest that initial events for DSB formation in chromatin are coupled with premeiotic DNA replication. C1 RIKEN, Inst Phys & Chem Res, Genet Dynam Res Unit Lab, Wako, Saitama 3510198, Japan. Saitama Univ, Grad Sch Sci & Engn, Saitama 3388570, Japan. NCI, Biochem Lab, Div Basic Sci, Bethesda, MD 20892 USA. RIKEN, Inst Phys & Chem Res, Mol & Cellular Biol Lab, Wako, Saitama 3510198, Japan. RP Ohta, K (reprint author), RIKEN, Inst Phys & Chem Res, Genet Dynam Res Unit Lab, Wako, Saitama 3510198, Japan. RI Borde, Valerie/G-5228-2012; Lichten, Michael/C-5795-2013 OI Lichten, Michael/0000-0001-9707-2956 NR 26 TC 35 Z9 38 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 15 PY 2003 VL 31 IS 14 BP 4085 EP 4090 DI 10.1093/nar/gkg441 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 700HN UT WOS:000184106700032 PM 12853625 ER PT J AU Matveeva, OV Shabalina, SA Nemtsov, VA Tsodikov, AD Gesteland, RF Atkins, JF AF Matveeva, OV Shabalina, SA Nemtsov, VA Tsodikov, AD Gesteland, RF Atkins, JF TI Thermodynamic calculations and statistical correlations for oligo-probes design SO NUCLEIC ACIDS RESEARCH LA English DT Article ID NEAREST-NEIGHBOR THERMODYNAMICS; DOT-T MISMATCHES; COMPLEMENTARY OLIGONUCLEOTIDES; SCANNING ARRAYS; DNA; HYBRIDIZATION; PARAMETERS; RNA; MICROARRAYS; SELECTION AB Optimization of probe design for array-based experiments requires improved predictability of oligonucleotide hybridization behavior. Currently, designing oligonucleotides capable of interacting efficiently and specifically with the relevant target is not a routine procedure. Multiple examples demonstrate that oligonucleotides targeting different regions of the same RNA differ in their hybridization ability. The present work shows how thermodynamic evaluations of oligo-target duplex or oligo self-structure stabilities can facilitate probe design. Statistical analysis of large sets of hybridization data reveals that thermodynamic evaluation of oligonucleotide properties can be used to avoid poor RNA binders. Thermodynamic criteria for the selection of 20 and 21mers, which, with high probability, interact efficiently and specifically with their targets, are suggested. The design of longer oligonucleotides can also be facilitated by the same calculations of DeltaGdegrees(T) values for oligo-target duplex or oligo self-structure stabilities and similar selection schemes. C1 Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20814 USA. MGGT, Moscow 125502, Russia. Univ Utah, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT 84112 USA. RP Matveeva, OV (reprint author), Univ Utah, Dept Human Genet, 15N 2030E Room 7410, Salt Lake City, UT 84112 USA. RI Shabalina, Svetlana/N-8939-2013 OI Shabalina, Svetlana/0000-0003-2272-7473 FU NIGMS NIH HHS [R01 GM048152, GM48152, R01-GM61200] NR 21 TC 70 Z9 76 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 15 PY 2003 VL 31 IS 14 BP 4211 EP 4217 DI 10.1093/nar/gkg476 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 700HN UT WOS:000184106700046 PM 12853639 ER PT J AU Bonne, O Brandes, D Segman, R Pitman, RK Yehuda, R Shalev, AY AF Bonne, O Brandes, D Segman, R Pitman, RK Yehuda, R Shalev, AY TI Prospective evaluation of plasma cortisol in recent trauma survivors with posttraumatic stress disorder SO PSYCHIATRY RESEARCH LA English DT Article DE hypothalamic-pituitary-adrenal axis; prognosis; longitudinal ID MOTOR-VEHICLE ACCIDENTS; ADRENOCORTICAL ACTIVITY; SALIVARY CORTISOL; PTSD; INDIVIDUALS; SYMPTOMS; HEALTH; CYCLE; PHASE AB Hypothalamic pituitary adrenal axis abnormalities have been described in posttraumatic stress disorder (PTSD), and among the recently traumatized. Plasma cortisol and continuous measures of PTSD symptoms were obtained from 21 survivors, at 1 week and 6 months after traumatic events. Eight survivors met Clinician Administered PTSD Scale criteria for PTSD at 6 months. Cortisol levels at 1 week did not predict subsequent PTSD. Survivors with and without PTSD had similar mean levels of cortisol at both time points. Cortisol levels at 6 months negatively correlated with self-reported PTSD symptoms within PTSD subjects. (C) 2003 Elsevier Ireland Ltd. All rights reserved. C1 Hadassah Univ Hosp, Ctr Traumat Stress, IL-91120 Jerusalem, Israel. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. Dept Vet Affairs Med Ctr, Dept Psychiat, Posttraumat Stress Disorder Program, Bronx, NY 10468 USA. RP Bonne, O (reprint author), NIMH, Mood & Anxiety Disorders Program, 15K N Dr,Room 200, Bethesda, MD 20892 USA. FU NIMH NIH HHS [MH 50379] NR 24 TC 36 Z9 36 U1 3 U2 5 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD JUL 15 PY 2003 VL 119 IS 1-2 BP 171 EP 175 DI 10.1016/S0165-1781(03)00098-2 PG 5 WC Psychiatry SC Psychiatry GA 704FX UT WOS:000184329300018 PM 12860372 ER PT J AU Doyle, ME Theodorakis, MJ Holloway, HW Bernier, M Greig, NH Egan, JM AF Doyle, ME Theodorakis, MJ Holloway, HW Bernier, M Greig, NH Egan, JM TI The importance of the nine-amino acid C-terminal sequence of exendin-4 for binding to the GLP-1 receptor and for biological activity SO REGULATORY PEPTIDES LA English DT Article DE insulinotropic compounds; peptide structure/function ID GLUCAGON-LIKE PEPTIDE-1; GLUCOSE; IV; PANCREAS; EXPRESSION; ANALOG; CELLS; AMIDE; MICE; RATS AB Exendin-4. a 39-amino acid (AA) peptide, is a long-acting agonist at the glucagon-like peptide-1 (GLP-1) receptor. Consequently, it may be preferable to GLP-1 as a long-term treatment for type 2 diabetes mellitus. Exendin-4 (Ex-4), unlike GLP-1, is not degraded by dipeptidyl peptidase IV (DPP IV), is less susceptible to degradation by neutral endopeptidase, and possesses a nine-AA C-terminal sequence absent from GLP-1. Here we examine the importance of these nine AAs for biological activity of Ex-4, a sequence of truncated Ex-4 analogs, and native GLP-1 and GLP-1 analogs to which all or parts of the C-terminal sequence have been added. We found that removing these AAs from Ex-4 to produce Ex (1-30) reduced the affinity for the GLP-1 receptor (GLP-1R) relative to Ex-4 (IC50: Ex-4, 3.22 +/- 0.9 nM; Ex (1-30), 32 5.8 nM) but made it comparable to that of GLP-1 (IC50: 44.9 +/- 3.2 nM). The addition of this nine-AA sequence to GLP-1 improved the affinity of both GLP-1 and the DPP IV resistant analog GLP-1 8-glycine for the GLP-1 receptor (IC50: GLP-1 Gly(8) [GG], 220 +/- 23 nM; GLP-1 Gly(8) Ex (31-39) 74 +/- 11 nM). Observations of the cAMP response in an insulinoma cell line show a similar trend for biological activity. Published by Elsevier Science B.V. C1 NIA, Diabet Sect 23, NIH, Baltimore, MD 21224 USA. NIA, Drug Design & Dev Sect, NIH, Baltimore, MD 21224 USA. RP Egan, JM (reprint author), NIA, Diabet Sect 23, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Bernier, Michel/0000-0002-5948-368X NR 20 TC 41 Z9 45 U1 2 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD JUL 15 PY 2003 VL 114 IS 2-3 BP 153 EP 158 DI 10.1016/S0167-0115(03)00120-4 PG 6 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 701WV UT WOS:000184192700012 PM 12832104 ER PT J AU Patterson, RM Stachlewitz, R Germolec, D AF Patterson, RM Stachlewitz, R Germolec, D TI Induction of apoptosis by 2,3,7,8-tetrachlorodibenzo-p-dioxin following endotoxin exposure SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; INDUCED LIVER-INJURY; TNF-ALPHA; CASPASE ACTIVATION; CELL-DEATH; FAS LIGAND; (TCDD)-INDUCED IMMUNOTOXICITY; HUMAN KERATINOCYTES; FACTOR INVOLVEMENT; HEPATIC-INJURY AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent and persistent environmental toxin that induces hepatotoxicity and increases endotoxin-induced liver injury. The objective of this study was to evaluate whether TCDD could modulate apoptosis and cytokine-controlled apoptotic signaling pathways following lipopolysaccharide (LPS) exposure in female B6C3F1 mice. The effects of TCDD treatment were most dramatic late in the time course (10-14 days posttreatment). Serum enzyme activities were elevated at day 10 (100 mug TCDD/40 mug LPS treatment) and day 14 (100 mug TCDD/saline treatment), indicating peak liver damage occurred at those times. Histological examination of perfused livers showed an increase in apoptotic cells at day 14 in animals treated with 10 mug TCDD. Caspase-1 activity was suppressed at 14 days in mice treated with 100 mug TCDD/40 mug LPS and 100 mug TCDD/4 mug LPS compared to the respective corn oil (CO)/LPS-treated controls. Caspase-3 activity was suppressed at 14 days in 100 mug TCDD/saline-100 mug TCDD/40 mug LPS- and 100 mug TCDD/4 mug LPS-treated mice compared to respective CO/saline- or CO/LPS-treated control mice. At 40 mug LPS, caspase activity was stimulated in TCDD (100 mug)-exposed mice at 3 and 7 days and then suppressed at 10 and 14 days. Western blot analysis, electrophoretic mobility shift assay, and ELISA did not show any effect by TCDD (100 mug) on IkappaB-beta and IkappaB-alpha protein expression or on DNA binding activity of the nuclear NFkappaB protein. These data indicate that TCDD induces apoptosis 14 days posttreatment; however, we found no evidence of suppression of the antiapoptotic transcription factor NFkappaB. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIEHS, Environm Immunol Lab, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. Abbott Biores Ctr, Worcester, MA 01605 USA. RP Germolec, D (reprint author), NIEHS, Environm Immunol Lab, Mol Toxicol Lab, 3 Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. NR 72 TC 12 Z9 15 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUL 15 PY 2003 VL 190 IS 2 BP 120 EP 134 DI 10.1016/S0041-008X(03)00186-8 PG 15 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 707XA UT WOS:000184534100004 PM 12878042 ER PT J AU Anna, CH Iida, M Sills, RC Devereux, TR AF Anna, CH Iida, M Sills, RC Devereux, TR TI Expression of potential beta-catenin targets, cyclin D1, c-Jun, c-Myc, E-cadherin, and EGFR in chemically induced hepatocellular neoplasms from B6C3F1 mice SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE mouse liver; chemical carcinogenesis; beta-Catenin/Wnt targets; cyclin D1; E-cadherin/beta-catenin complex ID RAS PROTOONCOGENE ACTIVATION; MOUSE-LIVER TUMORS; METHYLENE-CHLORIDE; TRANSGENIC MICE; GENE; D1; MUTATIONS; CARCINOMAS; PATHWAY; HEPATOBLASTOMAS AB In this study we used liver neoplasms induced by several chemical carcinogens to investigate potential nuclear targets associated with beta-catenin/Wnt signaling and potential membrane-associated beta-catenin binding partners. Strong expression of cyclin D1, in a pattern similar to that observed previously for beta-catenin, was observed by Western analysis for all five hepatoblastomas examined regardless of treatment. Increased expression of cyclin D1 was also detected in 12 of 35 (34%) hepatocellular neoplasms. Ten of 15 tumors (67%) that had mutations in the Catnb gene had upregulation of cyclin D1, while only 2 of 20 tumors (10%) without Catnb mutations had increased cyclin D1 expression. Immunohistochemical analysis confirmed strong expression of cyclin D1 in most nuclei of hepatoblastomas and scattered nuclear staining in hepatocellular tumors that had Catnb mutations. Increased c-Jun expression was observed in 19 of 30 (63%) hepatocellular tumors and all hepatoblastomas, although upregulation was not completely correlated with Catnb mutation. C-Myc expression was not increased in the tumors. Reduced expression of E-cadherin, which interacts with beta-catenin at the membrane, was observed in some tumors, but this did not correlate with Catnb mutation, Expression of the epidermal growth factor receptor, which may have a role in beta-catenin tyrosine phosphorylation, was lower in some tumors than in normal tissue depending on chemical treatment. The results provide evidence that increased expression of cyclin D1 and c-Jun may provide an advantage during tumor progression and in the transition from hepatocellular neoplasms to hepatoblastomas. Moreover, it is likely increased cyclin D1 expression results at least in part from Catnb mutation, beta-catenin accumulation, and increased Wnt signaling. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathobiol, NIH, Res Triangle Pk, NC 27709 USA. RP Devereux, TR (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, MD D4-04,POB 12233, Res Triangle Pk, NC 27709 USA. NR 32 TC 39 Z9 39 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 JUL 15 PY 2003 VL 190 IS 2 BP 135 EP 145 DI 10.1016/S0041-008X(03)00170-4 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 707XA UT WOS:000184534100005 PM 12878043 ER PT J AU Hirshberg, B Preston, EH Xu, H Tal, MG Neeman, Z Bunnell, D Soleimanpour, S Hale, DA Kirk, AD Harlan, DM AF Hirshberg, B Preston, EH Xu, H Tal, MG Neeman, Z Bunnell, D Soleimanpour, S Hale, DA Kirk, AD Harlan, DM TI Rabbit antithymocyte globulin induction and sirolimus monotherapy supports prolonged islet allograft function in a nonhuman primate islet transplantation model SO TRANSPLANTATION LA English DT Article ID DEPENDENT DIABETES-MELLITUS; PROTOCOL; REVERSAL; THYMOGLOBULIN; MECHANISMS; DISEASE; ATGAM AB Background. We reported that rabbit anti-thymocyte globulin (RATG) induction followed by maintenance immunosuppression with sirolimus supports human kidney allograft survival and asked if this combination would promote islet allograft survival in our primate model. Methods. Using intra-arterial streptozotocin infusion, we rendered four cynomolgus primates diabetic with undetectable C-peptide levels. Animals were maintained on insulin therapy for at least 1 month, and then islets from mixed lymphocyte reaction mismatched primates were infused into the portal vein. Immediately before the islet allotransplant and for 6 additional days, primates were infused with RATG (20 mg/kg) and given a sirolimus dose to achieve a 24-hr trough level of 8 to 14 ng/mL. Results. The regimen resulted in profound peripheral and lymph node lymphocyte depletion for up to 1 month. Repopulation was gradual thereafter. One primate remained insulin-independent for 169 days and rejected after a sirolimus-dose reduction. Two primates died on day 23 while insulin independent because of wound dehiscence, and a third died on day 30 with high sirolimus levels. Liver sections revealed well-vascularized islets with no signs of inflammation. Conclusion. Using a nonhuman primate islet transplant model, RATG plus sirolimus supports islet survival as long as proper sirolimus levels are maintained, but the therapy is limited by sirolimus toxicity. Our findings suggest that RATG is not toxic for islets and thus may be considered in future clinical trails while recognizing that sirolimus monotherapy, with its difficult-to-achieve therapeutic dosing, may not be sufficient to maintain long-term islet allograft function in an autoimmune environment. C1 NIDDK, Transplantat & Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Hirshberg, B (reprint author), NIDDK, Transplantat & Autoimmun Branch, NIH, 10 Ctr Dr,Bldg 10,Room 11 S 219, Bethesda, MD 20892 USA. RI Kirk, Allan/B-6905-2012 NR 24 TC 11 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2003 VL 76 IS 1 BP 55 EP 60 DI 10.1097/01.TP.0000068899.48252.1D PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 703BW UT WOS:000184261000010 PM 12865786 ER PT J AU Kirk, AD Hale, DA Mannon, RB Kleiner, DE Hoffmann, SC Kampen, RL Cendales, LK Tadaki, DK Harlan, DM Swanson, SJ AF Kirk, AD Hale, DA Mannon, RB Kleiner, DE Hoffmann, SC Kampen, RL Cendales, LK Tadaki, DK Harlan, DM Swanson, SJ TI Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (Campath-1H) SO TRANSPLANTATION LA English DT Article ID TRANSPLANTATION TOLERANCE; INDUCTION THERAPY; T-CELLS; KIDNEY; EXPRESSION; RECIPIENTS; SURVIVAL; REPERFUSION; APOPTOSIS; REJECTION AB Background. Profound T-cell depletion before allotransplantation with gradual posttransplant T-cell repopulation induces a state of donor-specific immune hyporesponsiveness or tolerance in some animal models. Alemtuzumab (Campath-1H, Millennium Pharmaceuticals, Cambridge, MA) is a humanized CD52-specific monoclonal antibody that produces profound T-cell depletion in humans and reduces the need for maintenance immunosuppression after renal transplantation. We therefore performed a study to determine if pretransplant T-cell depletion with alemtuzumab would induce tolerance in human renal allografts and to evaluate the nature of the alloimmune response in the setting of T-cell depletion. Methods. Seven nonsensitized recipients of living-donor kidneys were treated perioperatively with alemtuzumab and followed postoperatively without maintenance immunosuppression. Patients were evaluated clinically by peripheral flow cytometry, protocol biopsies evaluated immunohistochemically, and real-time polymerase chain reaction-based transcriptional analysis. Results. Lymphocyte depletion was profound in the periphery and secondary lymphoid tissues. All patients developed reversible rejection episodes within the first month that were characterized by predominantly monocytic (not lymphocytic) infiltrates with only rare T cells in the peripheral blood or allograft. These episodes were responsive to treatment with steroids or sirolimus or both. After therapy, patients remained rejection-free on reduced immunosuppression, generally monotherapy sirolimus, despite the recovery of lymphocytes to normal levels. Conclusions. T-cell depletion alone does not induce tolerance in humans. These data underscore a prominent role for early responding monocytes in human allograft rejection. C1 NIDDKD, Transplantat & Autoimmun Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Organ Transplant Serv, Washington, DC 20307 USA. RP Kirk, AD (reprint author), Room 11S-219,Bldg 10,Ctr Dr, Bethesda, MD 20892 USA. RI Kirk, Allan/B-6905-2012; OI Kleiner, David/0000-0003-3442-4453 NR 30 TC 295 Z9 306 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2003 VL 76 IS 1 BP 120 EP 129 DI 10.1097/01.TP.0000071362.99021.D9 PG 10 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 703BW UT WOS:000184261000021 PM 12865797 ER PT J AU Creevy, KE Bauer, TR Tuschong, LM Embree, LJ Colenda, L Cogan, K Starost, MF Haskins, ME Hickstein, DD AF Creevy, KE Bauer, TR Tuschong, LM Embree, LJ Colenda, L Cogan, K Starost, MF Haskins, ME Hickstein, DD TI Canine leukocyte adhesion deficiency colony for investigation of novel hematopoietic therapies SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article DE canine; adhesion; leukocyte ID TOTAL-BODY IRRADIATION; PHARMACOLOGICAL IMMUNOSUPPRESSION; HYPERTROPHIC OSTEODYSTROPHY; GRANULOCYTOPATHY SYNDROME; MARROW TRANSPLANTATION; P150,95 GLYCOPROTEINS; WHITE SETTERS; IRISH RED; LFA-1; DOGS AB The genetic immunodeficiency disease canine leukocyte adhesion deficiency (CLAD) was originally described in juvenile Irish Setters with severe, recurrent bacterial infections. CLAD was subsequently shown to result from a mutation in the leukocyte integrin CD18 subunit which prevents leukocyte surface expression of the CD11/CD18 complex. We describe the development of a mixed-breed CLAD colony with clinical features that closely parallel those described in Irish Setters. We demonstrate that the early identification of CLAD heterozygotes and CLAD-affected dogs by a combination of flow cytometry and DNA sequencing allows the CLAD-affected animals to receive life-saving antibiotic therapy. The distinct clinical phenotype in CLAD, the ability to detect CD18 on the leukocyte surface by flow cytometry, and the history of the canine model in marrow transplantation, enable CLAD to serve as an attractive large-animal model for the investigation of novel hematopoietic stem cell and gene therapy strategies. Published by Elsevier B.V. C1 NCI, Canc Res Ctr, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. NIH, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. RP Hickstein, DD (reprint author), NCI, Canc Res Ctr, Expt Transplantat & Immunol Branch, NIH, Bldg 10,Rm 12C-116,10 Ctr Dr, Bethesda, MD 20892 USA. FU NCRR NIH HHS [RR 02512] NR 25 TC 18 Z9 18 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD JUL 15 PY 2003 VL 94 IS 1-2 BP 11 EP 22 DI 10.1016/S0165-2427(03)00057-6 PG 12 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA 702CU UT WOS:000184208400002 PM 12842608 ER PT J AU Peters, U Askling, J Gridley, G Ekbom, A Linet, M AF Peters, U Askling, J Gridley, G Ekbom, A Linet, M TI Causes of death in patients with celiac disease in a population-based Swedish cohort SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID DEPENDENT DIABETES-MELLITUS; FATAL PNEUMOCOCCAL SEPTICEMIA; GLUTEN-FREE DIET; DERMATITIS-HERPETIFORMIS; HIGH PREVALENCE; UNITED-STATES; LIVER-DISEASE; MALIGNANCY; MORTALITY; RISK AB Background: Patients with celiac disease have an increased risk of death from gastrointestinal malignancies and lymphomas, but little is known about mortality from other causes and few studies have assessed long-term outcomes. Methods: Nationwide data on 10032 Swedish patients hospitalized from January 1, 1964, through December 3 1, 1993, with celiac disease and surviving at least 12 months were linked with the national mortality register. Mortality risks were computed as standardized mortality ratios (SMRs), comparing mortality rates of patients with celiac disease with rates in the general Swedish population. Results: A total of 828 patients with celiac disease died during the follow-up period (1965-1994). For all causes of death combined, mortality risks were significantly elevated: 2.0-fold (95% confidence interval [CI], 1.8-2.1) among all patients with celiac disease and 1.4-fold (95% Cl, 1.2-1.6) among patients with celiac disease with no other discharge diagnoses at initial hospitalization. The overall SMR did not differ by sex or calendar year of initial hospitalization, whereas mortality risk in patients hospitalized with celiac disease before the age of 2 years was significantly lower by 60% (95% Cl, 0.2-0.8) compared with the same age group of the general population. Mortality risks were elevated for a wide array of diseases, including non-Hodgkin lymphoma (SMR, 11.4), cancer of the small intestine (SMR, 17.3), autoimmune diseases (including rheumatoid arthritis [ SMR, 7.3] and diffuse diseases of connective tissue [SMR, 17.0]), allergic disorders (such as asthma [SMR, 2.8]), inflammatory bowel diseases (including ulcerative colitis and Crohn disease [SMR, 70.9]), diabetes mellitus (SMR, 3.0), disorders of immune deficiency (SMR, 20.9), tuberculosis (SMR, 5.9), pneumonia (SMR, 2.9), and nephritis (SMR, 5.4). Conclusion: The elevated mortality risk for all causes of death combined reflected, for the most part, disorders characterized by immune dysfunction. C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Karolinska Inst, Dept Med Epidemiol, Stockholm, Sweden. RP Peters, U (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, 6120 Execut Blvd,EPS 3024, Bethesda, MD 20892 USA. NR 79 TC 147 Z9 154 U1 2 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 14 PY 2003 VL 163 IS 13 BP 1566 EP 1572 DI 10.1001/archinte.163.13.1566 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 701HL UT WOS:000184162100009 PM 12860579 ER PT J AU Backman, C You, ZB Perlmann, T Hoffer, BJ AF Backman, C You, ZB Perlmann, T Hoffer, BJ TI Elevated locomotor activity without altered striatal dopamine contents in Nurr1 heterozygous mice after acute exposure to methamphetamine SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Nurr1; dopamine; methamphetamine; behavior ID NUCLEAR RECEPTORS; SUBSTANTIA-NIGRA; BRAIN-REGIONS; MOUSE-BRAIN; NGFI-B; NEURONS; TRANSCRIPTION; EXPRESSION; INCREASES; GENE AB Gene targeting experiments, in which both alleles of the Nurr1 gene were deleted, have shown that this molecule plays an essential role in the development of midbrain dopaminergic neurons, as shown by the loss of dopaminergic markers and the neurotransmitter dopamine (DA) in the ventral mesencephalon of Nurr1 null mutant mice. Nurr1-deficient mice die within a few hours of birth. Herein, we investigated whether adult mice (12-15-month-old), heterozygous for the Nurr1 mutation (Nurr1(+/-)), show alterations in locomotor function and in the nigrostriatal dopaminergic system after acute exposure to methamphetamine. We first evaluated spontaneous and amphetamine-induced (5 mg/kg) locomotor response of >12-month-old wildtype (Nurr1(+/+)) and Nurr1(+/-) mice. Both, spontaneous and methamphetamine-induced locomotor behavior was significantly increased in the Nurr1(+/-) animals as compared to Nurr1(+/+) mice. Striatal DA and DA metabolite levels were measured in untreated animals and methamphetamine-treated animals. No significant differences in striatal dopamine levels or its metabolites DOPAC and HVA were found in the Nurr1(+/-) as compared to Nurr1(+/+) mice in untreated or methamphetamine-treated animals. These data show that deletion of a single allele of the Nurr1 gene alters the locomotor activity of 12-15-month-old Nurr1(+/-) animals. While total dopamine levels were not altered in the striatum of Nurr1(+/-) mice, future studies will be necessary to determine if processes involved with the dynamics of DA release/clearance within the nigrostriatal system may be altered in Nurr1(+/-) mutant mice. (C) 2003 Elsevier Science B.V. All rights reserved. C1 NIDA, Cellular Neurobiol Branch, Baltimore, MD 21221 USA. NIDA, Behav Neurosci Branch, NIH, Baltimore, MD 21224 USA. Karolinska Inst, Ludwig Inst Canc Res, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden. RP Backman, C (reprint author), NIDA, Cellular Neurobiol Branch, 5500 Nathan Shock Dr, Baltimore, MD 21221 USA. RI backman, cristina/C-1276-2013 NR 17 TC 23 Z9 23 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JUL 14 PY 2003 VL 143 IS 1 BP 95 EP 100 DI 10.1016/S0166-4328(03)00029-9 PG 6 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 702TR UT WOS:000184240500011 PM 12842300 ER PT J AU Koitz, B AF Koitz, B TI Traveling on a light budget SO SCIENTIST LA English DT Editorial Material C1 NIH, Off Financial Management Travel, Bethesda, MD 20892 USA. RP Koitz, B (reprint author), NIH, Off Financial Management Travel, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SCIENTIST INC PI PHILADELPHIA PA 3535 MARKET ST, SUITE 200, PHILADELPHIA, PA 19104-3385 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD JUL 14 PY 2003 VL 17 IS 14 BP 51 EP 51 PG 1 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 709ZL UT WOS:000184656400030 ER PT J AU Wiebers, D Whisnant, JP Huston, J Meissner, I Brown, RD Piepgras, DG Forbes, GS Thielen, K Nichols, D O'Fallon, WM Peacock, J Jaeger, L Kassell, NF Kongable-Beckman, GL Torner, JC Naleway, A Yoo, B Sorensen, B Wiebers, DO Whisnant, JP Huston, J Meissner, I Brown, RD Piepgras, DG Forbes, GS Thielen, K Nichols, D O'Fallon, WM Peacock, J Jaeger, L Kassell, NF Kongable-Beckman, GL Torner, JC Wiebers, DO Whisnant, JP Huston, J Meissner, I Brown, RD Piepgras, DG Forbes, GS Nichols, D O'Fallon, WM Peacock, J Jaeger, L Kassell, NF Kongable-Beckman, GL Torner, JC Naleway, A Drake, CG Ferguson, GG Kurtzke, J Andreoli, A Edner, G Sengupta, R Castel, JP Molyneux, A Marler, JR AF Wiebers, D Whisnant, JP Huston, J Meissner, I Brown, RD Piepgras, DG Forbes, GS Thielen, K Nichols, D O'Fallon, WM Peacock, J Jaeger, L Kassell, NF Kongable-Beckman, GL Torner, JC Naleway, A Yoo, B Sorensen, B Wiebers, DO Whisnant, JP Huston, J Meissner, I Brown, RD Piepgras, DG Forbes, GS Thielen, K Nichols, D O'Fallon, WM Peacock, J Jaeger, L Kassell, NF Kongable-Beckman, GL Torner, JC Wiebers, DO Whisnant, JP Huston, J Meissner, I Brown, RD Piepgras, DG Forbes, GS Nichols, D O'Fallon, WM Peacock, J Jaeger, L Kassell, NF Kongable-Beckman, GL Torner, JC Naleway, A Drake, CG Ferguson, GG Kurtzke, J Andreoli, A Edner, G Sengupta, R Castel, JP Molyneux, A Marler, JR CA Int Study Unruptured Intracranial TI Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment SO LANCET LA English DT Article ID RUPTURE; MANAGEMENT; COILING AB Background The management of unruptured intracranial aneurysms is controversial. Investigators from the International Study of Unruptured Intracranial Aneurysms aimed to assess the natural history of unruptured intracranial aneurysms and to measure the risk associated with their repair. Methods Centres in the USA, Canada, and Europe enrolled patients for prospective assessment of unruptured aneurysms. Investigators recorded the natural history in patients who did not have surgery, and assessed morbidity and mortality associated with repair of unruptured aneurysms by either open surgery or endovascular procedures. Findings 4060 patients were assessed-1692 did not have aneurysmal repair, 1917 had open surgery, and 451 had endovascular procedures. 5-year cumulative rupture rates for patients who did not have a history of subarachnoid haemorrhage with aneurysms located in internal carotid artery, anterior communicating or anterior cerebral artery, or middle cerebral artery were 0%, 2.6%, 14.5%, and 40% for aneurysms less than 7 mm, 7-12 mm, 13-24 mm, and 25 mm or greater, respectively, compared with rates of 2.5%, 14.5%, 18.4%, and 50%, respectively, for the same size categories involving posterior circulation and posterior communicating artery aneurysms. These rates were often equalled or exceeded by the risks associated with surgical or endovascular repair of comparable lesions. Patients' age was a strong predictor of surgical outcome, and the size and location of an aneurysm predict both surgical and endovascular outcomes. Interpretation. Many factors are involved in management of patients with unruptured intracranial aneurysms. Site, size, and group specific risks of the natural history should be compared with site, size, and age-specific risks of repair for each patient. C1 Mayo Clin & Mayo Fdn, ISUIA Coordinating Ctr, Rochester, MN 55905 USA. Univ Virginia, Charlottesville, VA USA. Univ Iowa, Iowa City, IA USA. NINDS, Bethesda, MD 20892 USA. RP Wiebers, D (reprint author), Mayo Clin & Mayo Fdn, ISUIA Coordinating Ctr, 200 1st St SW, Rochester, MN 55905 USA. FU NINDS NIH HHS [R01-NS-28492] NR 15 TC 1378 Z9 1450 U1 8 U2 53 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUL 12 PY 2003 VL 362 IS 9378 BP 103 EP 110 DI 10.1016/S0140-6736(03)13860-3 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 699ZY UT WOS:000184089200008 PM 12867109 ER PT J AU Brandel, JP Preece, M Brown, P Croes, E Laplanche, JL Agid, Y Will, R Alperovitch, A AF Brandel, JP Preece, M Brown, P Croes, E Laplanche, JL Agid, Y Will, R Alperovitch, A TI Distribution of codon 129 genotype in human growth hormone-treated CJD patients in France and the UK SO LANCET LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE AB Since homozygosity MM at codon 129 of the prion protein gene is a recognised risk factor in all forms of Creutzfeldt-Jakob disease (CJD), we studied the distribution of codon 129 polymorphism in patients in France and in the UK with CJD transmitted iatrogenically by human growth hormone. The overall frequencies of codon 1.29 genotypes in these patients differed from those in the population unaffected by CJD. An excess of VV homozygotes was noted among those with iatrogenic CJD compared with sporadic CJD cases. The proportion of MM genotype in UK patients was surprisingly low (4%) compared with that in French patients (62%). There is no evident explanation for this different distribution, which might be due to infection with different strains of prion in human growth hormone. C1 Salpetriere Hosp, Natl Reference Ctr Latrogen CJD, F-75651 Paris 13, France. Salpetriere Hosp, INSERM, U360, F-75651 Paris, France. Inst Child Hlth, London, England. NIH, Lab CNS Studies, Bethesda, MD 20892 USA. Erasmus Univ, Sch Med, Rotterdam, Netherlands. Lariboisiere Hosp, Cent Lab Biochem, Paris, France. Western Gen Hosp, CJD Surveillance Unit, Edinburgh EH4 2XU, Midlothian, Scotland. RP Brandel, JP (reprint author), Salpetriere Hosp, Natl Reference Ctr Latrogen CJD, F-75651 Paris 13, France. RI LAPLANCHE, Jean-Louis/S-8707-2016 NR 5 TC 53 Z9 54 U1 0 U2 6 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUL 12 PY 2003 VL 362 IS 9378 BP 128 EP 130 DI 10.1016/S0140-6736(03)13867-6 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 699ZY UT WOS:000184089200015 PM 12867116 ER PT J AU Kim, M Choi, J Carlson, BA Han, JK Rhee, K Sargent, T Hatfield, DL Lee, BJ AF Kim, M Choi, J Carlson, BA Han, JK Rhee, K Sargent, T Hatfield, DL Lee, BJ TI A novel TBP-interacting zinc finger protein functions in early development of Xenopus laevis SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE embryogenesis; FAX; development; Xenopus laevis; zinc finger protein; RNA interference ID TRNA(SEC) GENE; TRANSCRIPTION; EXPRESSION; EMBRYOS; RNA; INTERFERENCE AB A zinc finger protein that interacts with Xenopus TATA-binding protein was previously isolated by a yeast two-bybrid screen and found to serve as a transcriptional repressor. The gene was designated the negatively regulating zinc finger protein gene (NZFP). Herein, NZFP was found to be expressed maternally. After gastrulation, the level of NZFP mRNA decreased significantly throughout the neurula stage. However, mRNA levels increased at stage 35 and then began to decrease at stage 48. Eventually, no NZFP mRNA was observed in adult tissues except in the ovary. NZFP mRNA was detected in the animal hemisphere during gastrulation and observed in the neural ectoderm at the neurula stage. At the tailbud stage, NZFP was highly expressed in the head tissues such as brain, eyes, otic vesicles, lateral line placodes, and branchial arches, but weakly in somites. Depletion of NZFP in the embryos using RNA interference caused premature death at the gastrula stage or induced secondary partial axis after gastrulation. These results strongly suggest that NZFP is an essential transcription factor involved in the cell movement during gastrulation and the formation of the dorsal axis during early development in Xenopus. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Seoul Natl Univ, Inst Mol Biol & Genet, Genet Mol Lab, Seoul 151742, South Korea. NCI, Sect Mol Biol Selenium, Basic Res Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Pohang Univ Sci & Technol, Div Mol & Life Sci, Pohang 790784, Kyungbuk, South Korea. Seoul Natl Univ, Sch Biol Sci, Seoul 151742, South Korea. NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Lee, BJ (reprint author), Seoul Natl Univ, Inst Mol Biol & Genet, Genet Mol Lab, Seoul 151742, South Korea. NR 14 TC 3 Z9 3 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 JUL 11 PY 2003 VL 306 IS 4 BP 1106 EP 1111 DI 10.1016/S0006-291X(03)01069-6 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 698HF UT WOS:000183992400046 PM 12821157 ER PT J AU Gallo, SA Finnegan, CM Viard, M Raviv, Y Dimitrov, A Rawat, SS Puri, A Durell, S Blumenthal, R AF Gallo, SA Finnegan, CM Viard, M Raviv, Y Dimitrov, A Rawat, SS Puri, A Durell, S Blumenthal, R TI The HIV Env-mediated fusion reaction SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Review DE HIV; fusion; Env; SIV; virus; CD4; gp120; gp41; CXCR4; CCR5; six-helix bundle ID HUMAN-IMMUNODEFICIENCY-VIRUS; CELL-CELL FUSION; TYPE-1 ENVELOPE GLYCOPROTEIN; PROTEIN TYROSINE KINASE; INDUCED MEMBRANE-FUSION; INFLUENZA HEMAGGLUTININ; SOLUBLE CD4; CONFORMATIONAL-CHANGES; INITIAL-STAGES; LIPID RAFTS AB The current general model of HIV viral entry involves the binding of the trimeric viral envelope glycoprotein gp120/gp41 to cell surface receptor CD4 and chemokine co-receptor CXCR4 or CCR5, which triggers conformational changes in the envelope proteins. Gp 120 then dissociates from gp41, allowing for the fusion peptide to be inserted into the target membrane and the pre-hairpin configuration of the ectodomain to form. The C-terminal heptad repeat region and the leucine/isoleucine zipper region then form the thermostable six-helix coiled-coil, which drives the membrane merger and eventual fusion. This model needs updating, as there has been a wealth of data produced in the last few years concerning HIV entry, including target cell dependencies, fusion kinetic data, and conformational intermediates. A more complete model must include the involvement of membrane microdomains, actin polymerization, glycosphingolipids, and possibly CD4 and chemokine signaling in entry. In addition, kinetic experiments involving the addition of fusion inhibitors have revealed some of the rate-limiting steps in this process, adding a temporal component to the model. A review of these data that may require an updated version of the original model is presented here. (C) 2003 Elsevier B.V. All rights reserved. C1 NCI, Lab Expt & Computat Biol, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Blumenthal, R (reprint author), NCI, Lab Expt & Computat Biol, Ctr Canc Res, NIH, Miller Dr, Frederick, MD 21702 USA. OI Gallo, Stephen/0000-0001-6043-2153 NR 168 TC 292 Z9 342 U1 4 U2 38 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD JUL 11 PY 2003 VL 1614 IS 1 BP 36 EP 50 DI 10.1016/S0005-2736(03)00161-5 PG 15 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 706ZA UT WOS:000184483900005 PM 12873764 ER PT J AU Phogat, SK Dimitrov, DS AF Phogat, SK Dimitrov, DS TI Cell biology of virus entry: a review of selected topics from the 3rd International Frederick meeting SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Review AB Following the first two Frederick meetings on virus entry in 1997 [Cell 91 (1997) 721]1 and in 2000 [Cell 101 (2000) 697]2, further developments in our understanding of the multifactorial and multistage process of virus entry, and possible biomedical implications were presented and discussed in a lively fashion by leading scientists from around the world at the third Frederick meeting on the Cell Biology of Viral Entry (May 7-10, Frederick, MD) organized by R. Blumenthal (NCI-Frederick, NIH, Frederick) and E. Hunter (University of Alabama, Birmingham). Unlike the previous two meetings, non-enveloped viruses were not discussed this time, and the focus was how envelope glycoproteins (Envs) mediate entry into cells. Major topics included Env structure, virus receptors, entry intermediates, membrane fusion, fusion kinetics, and rafts. Virus envelope structures will be described in more detail here because the other topics are extensively discussed in the other chapters of this volume. (C) 2003 Elsevier B.V. All rights reserved. C1 NCI, Lab Expt & Computat Biol, CCR, NIH, Frederick, MD 21702 USA. RP Dimitrov, DS (reprint author), NCI, Lab Expt & Computat Biol, CCR, NIH, Bldg 469,Room 216,POB B,Miller Dr, Frederick, MD 21702 USA. NR 2 TC 5 Z9 6 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD JUL 11 PY 2003 VL 1614 IS 1 BP 85 EP 88 DI 10.1016/S0005-2736(03)00165-2 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 706ZA UT WOS:000184483900009 PM 12873768 ER PT J AU Masumi, A Yamakawa, Y Fukazawa, H Ozato, K Komuro, K AF Masumi, A Yamakawa, Y Fukazawa, H Ozato, K Komuro, K TI Interferon regulatory factor-2 regulates cell growth through its acetylation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTIONAL COACTIVATORS P300; ADENOVIRAL ONCOPROTEIN E1A; CREB-BINDING PROTEIN/P300; HIV-1 TAT; HISTONE ACETYLTRANSFERASES; IN-VIVO; P300-MEDIATED ACETYLATION; FACTOR GATA-1; FACTOR IRF-2; DNA-BINDING AB We have previously shown that interferon regulatory factor-2 (IRF-2) is acetylated by p300 and PCAF in vivo and in vitro. In this study we identified, by mass spectrometry, two lysine residues in the DNA binding domain (DBD), Lys-75 and Lys-78, to be the major acetylation sites in IRF-2. Although acetylation of IRF-2 did not alter DNA binding activity in vitro, mutation of Lys-75 diminished the IRF-2-dependent activation of histone H4 promoter activity. Acetylation of IRF-2 and IRF-2-stimulated H4 promoter activity were inhibited by the adenovirus E1A, indicating the involvement of p300/ CBP. Mutation of Lys-78, a residue conserved throughout the IRF family members, led to the abrogation of DNA binding activity independently of acetylation. H4 is transcribed only in rapidly growing cells and its promoter activity is dependent on cell growth. Consistent with a role for acetylated IRF-2 in cell growth control, IRF-2 was acetylated only in growing NIH 3T3 cells, but not in growth-arrested counterparts. Chromatin immunoprecipitation assays showed that IRF-2 interacted with p300 and bound to the endogenous H4 promoter only in growing cells, although the levels of total IRF-2 were comparable in both growing and growth-arrested cells. These results indicate that IRF-2 is acetylated in a cell growth-dependent manner, which enables it to contribute to transcription of cell growth-regulated promoters. C1 Natl Inst Infect Dis, Dept Safety Res Biol, Musashimurayama, Tokyo, Japan. Natl Inst Infect Dis, Dept Biochem & Cell Biol, Musashimurayama, Tokyo, Japan. Natl Inst Infect Dis, Dept Bioact Mol, Musashimurayama, Tokyo, Japan. NICHD, Lab Mol Growth & Regulat, NIH, Bethesda, MD 20892 USA. RP Masumi, A (reprint author), Natl Inst Infect Dis, Dept Safety Res Biol, 4-7-1 Gakuen, Musashimurayama, Tokyo, Japan. NR 55 TC 34 Z9 36 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 JUL 11 PY 2003 VL 278 IS 28 BP 25401 EP 25407 DI 10.1074/jbc.M213037200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 697AN UT WOS:000183920200019 PM 12738767 ER PT J AU Kino, T Souvatzoglou, E De Martino, MU Tsopanomihalu, M Wan, YH Chrousos, GP AF Kino, T Souvatzoglou, E De Martino, MU Tsopanomihalu, M Wan, YH Chrousos, GP TI Protein 14-3-3 sigma interacts with and favors cytoplasmic subcellular localization of the glucocorticoid receptor, acting as a negative regulator of the glucocorticoid signaling pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LIGAND-BINDING DOMAIN; NUCLEAR EXPORT; 14-3-3 PROTEIN; BETA-ISOFORM; DNA-BINDING; PHOSPHORYLATION; 14-3-3-PROTEINS; TRAFFICKING; RAF-1; CALRETICULIN AB The glucocorticoid receptor (GR) alpha interacts with the highly conserved 14-3-3 family proteins. The latter bind phosphorylated serine/threonine residues of "partner" molecules and influence many signal transduction events by altering their subcellular localization and/or protecting them from proteolysis. To examine the physiologic role of 14-3-3 on the glucocorticoid-signaling pathway, we studied the nucleocytoplasmic shuttling and transactivation properties of GRalpha in a cell line replete with or devoid of 14-3-3sigma. We found that endogenous 14-3-3sigma helped localize green fluorescent protein-fused GRalpha in the cytoplasm in the absence of ligand and potentiated its nuclear export after ligand withdrawal. 14-3-3sigma also suppressed the transcriptional activity of GRalpha on a glucocorticoid-responsive promoter. Disruption of the classic nuclear export signal of 14-3-3sigma inactivated its ability to influence the nucleocytoplasmic trafficking and transactivation activity of GRalpha, whereas introduction of a mutation inactivating the binding activity of 14-3-3sigma to some of its partner proteins did not. 14-3-3sigma bound the ligand-binding domain of GRalpha through its COOH-terminal portion, in a partially ligand-dependent fashion, while it did not interact with "ligand-binding domain" of GRbeta at all. These results suggest that 14-3-3sigma functions as a negative regulator in the glucocorticoid signaling pathway, possibly by shifting the subcellular localization/circulation of this receptor toward the cytoplasm through its nuclear export signal. Since 14-3-3 proteins play significant roles in numerous cellular activities, such as cell cycle progression, growth, differentiation, and apoptosis, these actions might indirectly influence the transcriptional activity of GRalpha. Conversely, through its 14-3-3 protein interactions, GRalpha may influence these processes. C1 NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NCI, Human Retrovirus Sect, Ctr Canc Res, NIH, Frederick, MD 21702 USA. Univ Colorado, Hlth Sci Ctr, Dept Pathol, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Program Mol Biol, Denver, CO 80262 USA. RP Kino, T (reprint author), NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Rm 9D42,10 Ctr Dr,MSC 1583, Bethesda, MD 20892 USA. NR 41 TC 54 Z9 59 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 JUL 11 PY 2003 VL 278 IS 28 BP 25651 EP 25656 DI 10.1074/jbc.M302818200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 697AN UT WOS:000183920200048 PM 12730237 ER PT J AU Wedel, BJ Vazquez, G McKay, RR Bird, GS Putney, JW AF Wedel, BJ Vazquez, G McKay, RR Bird, GS Putney, JW TI A calmodulin/inositol 1,4,5-trisphosphate (IP3) receptor-binding region targets TRPC3 to the plasma membrane in a calmodulin/IP3 receptor-independent process SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RETICULUM RETENTION SIGNAL; OPERATED HTRP3 CHANNELS; ENDOPLASMIC-RETICULUM; C-TERMINUS; CATION CHANNELS; SPLICE VARIANTS; MOLECULAR-BASIS; CA2+ ENTRY; TRAFFICKING; PROTEIN AB Conformational coupling with the inositol 1,4,5-trisphosphate (IP3) receptor has been suggested as a possible mechanism of activation of TRPC3 channels and a region in the C terminus of TRPC3 has been shown to interact with the IP3 receptor as well as calmodulin (calmodulin/IP3 receptor-binding (CIRB) region). Here we show that internal deletion of 20 amino acids corresponding to the highly conserved CIRB region results in the loss of diacylglycerol and agonist-mediated channel activation in HEK293 cells. By using confocal microscopy to examine the cellular localization of Topaz fluorescent protein fusion constructs, we demonstrate that this loss in activity is caused by faulty targeting of CIRB-deleted mutants to intracellular compartments. Wild type TRPC3 and mutants lacking a C-terminal predicted coiled coil region downstream of CIRB were targeted to the plasma membrane correctly in HEK293 cells and exhibited TRPC3-mediated calcium entry in response to agonist activation. Mutation of conserved YQ and MKR motifs to alanine within the CIRB region in TRPC3-Topaz, which would be expected to interfere with IP3 receptor and/or calmodulin binding, had no effect on channel function or targeting. Additionally, TRPC3 targets to the plasma membrane of DT40 cells lacking all three IP3 receptors and forms functional ion channels. These findings indicate that the previously identified CIRB region of TRPC3 is involved in its targeting to the plasma membrane by a mechanism that does not involve interaction with IP3 receptors. C1 NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. NR 46 TC 54 Z9 59 U1 2 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 JUL 11 PY 2003 VL 278 IS 28 BP 25758 EP 25765 DI 10.1074/jbc.M303890200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 697AN UT WOS:000183920200062 PM 12730194 ER PT J AU Bottone, FG Martinez, JM Collins, JB Afshari, CA Eling, TE AF Bottone, FG Martinez, JM Collins, JB Afshari, CA Eling, TE TI Gene modulation by the cyclooxygenase inhibitor, sulindac sulfide, in human colorectal carcinoma cells - Possible link to apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; COLON-CANCER CELLS; FAMILIAL ADENOMATOUS POLYPOSIS; NSAID-ACTIVATED GENE; TARGET GENES; ADENOCARCINOMA CELLS; INDUCE APOPTOSIS; DNA-DAMAGE; EXPRESSION; GROWTH AB The mechanisms underlying the anti-tumorigenic properties of cyclooxygenase inhibitors are not well understood. One novel hypothesis is alterations in gene expression. To test this hypothesis sulindac sulfide, which is used to treat familial adenomatous polyposis, was selected to detect gene modulation in human colorectal cells at physiological concentrations with microarray analysis. At micromolar concentrations, sulindac sulfide stimulated apoptosis and inhibited the growth of colorectal cancer cells on soft agar. Sulindac sulfide ( 10 muM) altered the expression of 65 genes in SW-480 colorectal cancer cells, which express cyclooxygenase-1 but little cyclooxygenase-2. A more detailed study of 11 genes revealed that their expression was altered in a time- and dose-dependent manner as measured by real-time RT-PCR. Northern analysis confirmed the expression of 9 of these genes, and Western analysis supported the conclusion that sulindac sulfide altered the expression of these proteins. Cyclooxygenase-deficient HCT-116 cells were more responsive to sulindac sulfide-induced gene expression than SW-480 cells. However, this response was diminished in HCT-116 cells overexpressing cyclooxygenase-1 compared with normal HCT-116 cells suggesting the presence of cyclooxygenase attenuates this response. However, prostaglandin E-2, the main product of cyclooxygenase, only suppressed the sulindac sulfide-induced expression of two genes, with little known biological function while it modulated the expression of two more. The most likely explanation for this finding is the metabolism of sulindac sulfide to inactive metabolites by the peroxidase activity of cyclooxygenase. In conclusion, this is the first report showing sulindac sulfide, independent of cyclooxygenase, altered the expression of several genes possibly linked to its anti-tumorigenic and pro-apoptotic activity. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Computat Biol & Risk Anal, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Natl Ctr Toxicogenom, NIH, Res Triangle Pk, NC 27709 USA. RP Eling, TE (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, POB 12233,Mail Drop E4-09,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 58 TC 47 Z9 50 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 11 PY 2003 VL 278 IS 28 BP 25790 EP 25801 DI 10.1074/jbc.M301002200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 697AN UT WOS:000183920200066 PM 12734198 ER PT J AU Matsuda, T Berg, BJV Bebenek, K Osheroff, WP Wilson, SH Kunkel, TA AF Matsuda, T Berg, BJV Bebenek, K Osheroff, WP Wilson, SH Kunkel, TA TI The base substitution fidelity of DNA polymerase beta-dependent single nucleotide base excision repair SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHATE LYASE ACTIVITY; CELL-EXTRACTS/; IN-VITRO; IOTA; IDENTIFICATION; ENZYME; SPECIFICITY; CORRECT; LAMBDA; GAMMA AB Damaged DNA bases are removed from mammalian genomes by base excision repair (BER). Single nucleotide BER requires several enzymatic activities, including DNA polymerase and 5',2'-deoxyribose-5-phosphate lyase. Both activities are intrinsic to four human DNA polymerases whose base substitution error rate during gap-filling DNA synthesis varies by more than 10,000-fold. This suggests that BER fidelity could vary over a wide range in an enzyme dependent manner. To investigate this possibility, here we describe an assay to measure the fidelity of BER reactions reconstituted with purified enzymes. When human uracil DNA glycosylase, AP endonuclease, DNA polymerase beta, and DNA ligase 1 replace uracil opposite template A or G, base substitution error rates are less than or equal to0.3 to less than or equal to2.8 x 10(-4). BER error rates are higher when excess incorrect dNTPs are included in the reaction or when wild type DNA polymerase beta is replaced by DNA polymerase beta variants that fill single nucleotide gaps with lower fidelity. Under these conditions, the base substitution fidelity of polymerase beta-dependent BER is 3-8-fold higher than is single nucleotide gap filling by polymerase beta alone. Thus other proteins in the BER reaction may enhance the base substitution fidelity of DNA polymerase beta during single nucleotide BER. C1 NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, DHHS, POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 30 TC 28 Z9 33 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 JUL 11 PY 2003 VL 278 IS 28 BP 25947 EP 25951 DI 10.1074/jbc.C300170200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 697AN UT WOS:000183920200087 PM 12734201 ER PT J AU Santoro, F Greenstone, HL Insinga, A Liszewski, MK Atkinson, JP Lusso, P Berger, EA AF Santoro, F Greenstone, HL Insinga, A Liszewski, MK Atkinson, JP Lusso, P Berger, EA TI Interaction of glycoprotein H of human herpesvirus 6 with the cellular receptor CD46 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SIMPLEX-VIRUS GLYCOPROTEIN; HERPESVIRUS ENTRY MEDIATOR; COFACTOR PROTEIN CD46; HLA CLASS-II; MEASLES-VIRUS; MONOCLONAL-ANTIBODIES; NEUTRALIZING EPITOPE; VARIANT-A; FUNCTIONAL DOMAINS; SEQUENCE ANALYSES AB Human herpesvirus 6 (HHV-6) employs the complement regulator CD46 (membrane cofactor protein) as a receptor for fusion and entry into target cells. Like other known herpesviruses, HHV-6 encodes multiple glycoproteins, several of which have been implicated in the entry process. In this report, we present evidence that glycoprotein H (gH) is the viral component responsible for binding to CD46. Antibodies to CD46 co-immunoprecipitated an similar to110-kDa protein band specifically associated with HHV-6-infected cells. This protein was identified as gH by selective depletion with an anti-gH monoclonal antibody, as well as by immunoblot analysis with a rabbit hyperimmune serum directed against a gH synthetic peptide. In reciprocal experiments, a monoclonal antibody against HHV-6 gH was found to co-immunoprecipitate CD46. Studies using monoclonal antibodies directed against specific CD46 domains, as well as engineered constructs lacking defined CD46 regions, demonstrated a close correspondence between the CD46 domains involved in the interaction with gH and those previously shown to be critical for HHV-6 fusion (i.e. short consensus repeats 2 and 3). C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. San Raffaele Sci Inst, Dept Biol & tech Res, Unit Human Virol, I-20132 Milan, Italy. Washington Univ, Sch Med, Dept Med, Div Rheumatol, St Louis, MO 63110 USA. Univ Cagliari, Sch Med, Dept Med Sci, I-09100 Cagliari, Italy. RP Berger, EA (reprint author), NIAID, Viral Dis Lab, NIH, Bldg 4,Rm 237, Bethesda, MD 20892 USA. FU NIAID NIH HHS [R01 AI37618] NR 53 TC 47 Z9 49 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 11 PY 2003 VL 278 IS 28 BP 25964 EP 25969 DI 10.1074/jbc.M302373200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 697AN UT WOS:000183920200090 PM 12724329 ER PT J AU Chattopadhyay, R Rathore, D Fujioka, H Kumar, S de la Vega, P Haynes, D Moch, K Fryauff, D Wang, RB Carucci, DJ Hoffman, SL AF Chattopadhyay, R Rathore, D Fujioka, H Kumar, S de la Vega, P Haynes, D Moch, K Fryauff, D Wang, RB Carucci, DJ Hoffman, SL TI PfSPATR, a Plasmodium falciparum protein containing an altered thrombospondin type I repeat domain is expressed at several stages of the parasite life cycle and is the target of inhibitory antibodies SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN MALARIA PARASITE; CIRCUMSPOROZOITE PROTEIN; SPOROZOITES; VACCINE; GENE; SEQUENCE; IMMUNOGENICITY; SAFETY; GLYCOPROTEIN; MOSQUITOS AB The annotated sequence of chromosome 2 of Plasmodium falciparum was examined for genes encoding proteins that may be of interest for vaccine development. We describe here the characterization of a protein with an altered thrombospondin Type I repeat domain (PfSPATR) that is expressed in the sporozoite, asexual, and sexual erythrocytic stages of the parasite life cycle. Immunoelectron microscopy indicated that this protein was expressed on the surface of the sporozoites and around the rhoptries in the asexual erythrocytic stage. An Escherichia coli-produced recombinant form of the protein bound to HepG2 cells in a dose-dependent manner and antibodies raised against this protein blocked the invasion of sporozoites into a transformed hepatoma cell line. Sera from Ghanaian adults and from a volunteer who had been immunized with radiation-attenuated P. falciparum sporozoites specifically recognized the expression of this protein on transfected COS-7 cells. These data support the evaluation of this protein as a vaccine candidate. C1 USN, Med Res Ctr, Malaria Program, Silver Spring, MD 20910 USA. NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Inst Pathol, Cleveland, OH 44106 USA. RP Hoffman, SL (reprint author), Sanaria, 308 Argosy Dr, Gaithersburg, MD 20878 USA. NR 37 TC 35 Z9 35 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 11 PY 2003 VL 278 IS 28 BP 25977 EP 25981 DI 10.1074/jbc.M300865200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 697AN UT WOS:000183920200092 PM 12716913 ER PT J AU Perrot, V Rechler, MM AF Perrot, V Rechler, MM TI Characterization of insulin inhibition of transactivation by a C-terminal fragment of the forkhead transcription factor Foxo1 in rat hepatoma cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-B; GENE-EXPRESSION; FACTOR FKHR; PHOSPHATIDYLINOSITOL 3-KINASE; GLUCOSE-TRANSPORT; CAENORHABDITIS-ELEGANS; PHOSPHORYLATION SITES; RESPONSE SEQUENCE; NUCLEAR EXCLUSION; FAMILY-MEMBER AB The transcription factor Foxo1 controls the expression of genes involved in fundamental cellular processes. In keeping with its important physiological roles, Foxo1 activity is negatively regulated in response to growth factors and cytokines that activate a phosphatidylinositol 3-kinase (PI 3-kinase) protein kinase B (PKB)/Akt pathway. PKB/Akt-mediated phosphorylation of Foxo1 has been shown to result in the inhibition of target gene transcription and to trigger the export of Foxo1 from the nucleus, which is generally believed to explain the subsequent decrease of transcription. In the present study, using a chimeric protein in which a C-terminal fragment of Foxo1 (amino acids 208-652) containing the transactivation domain is fused to the yeast Gal4 DNA binding domain, we present evidence showing that insulin can directly regulate transactivation by Foxo1 in H4IIE rat hepatoma cells. Insulin inhibition of Foxo1-(208-652)-stimulated transactivation is mediated by PI 3-kinase but in contrast to full-length Foxo1, does not require either of the two PKB/Akt phosphorylation sites (Ser(253) and Ser(316)) present in the protein fragment. Using mutational and deletion studies, we identify two potential phosphorylation sites, Ser(319) and Ser(499), as well as a 15-amino acid region located between residues 350 and 364 that are critical for insulin inhibition of transactivation by Foxo1-(208-652). We conclude that the transcriptional activity of Foxo1 is regulated at different levels by insulin: transactivation, as well as DNA binding and nuclear exclusion. These different regulatory mechanisms allow the precise control of transcription of Foxo1 target genes by insulin. C1 NIDDK, Growth & Dev Sect, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Perrot, V (reprint author), NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bldg 30,Rm 207,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 81 TC 16 Z9 16 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 11 PY 2003 VL 278 IS 28 BP 26111 EP 26119 DI 10.1074/jbc.M212750200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 697AN UT WOS:000183920200109 PM 12724332 ER PT J AU Tian, JH Das, S Sheng, ZH AF Tian, JH Das, S Sheng, ZH TI Ca2+- dependent phosphorylation of syntaxin-1A by the death-associated protein (DAP) kinase regulates its interaction with Munc18 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LONG-TERM POTENTIATION; SYNAPTOSOME-ASSOCIATED PROTEIN; SYNAPTIC VESICLE FUSION; II MUTANT MICE; MEMBRANE-FUSION; NEUROTRANSMITTER RELEASE; CORE COMPLEX; 3-DIMENSIONAL STRUCTURE; CALCIUM-DEPENDENCE; CHROMAFFIN CELLS AB Syntaxin-1 is a key component of the synaptic vesicle docking/fusion machinery that binds with VAMP/synaptobrevin and SNAP-25 to form the SNARE complex. Modulation of syntaxin binding properties by protein kinases could be critical to control of neurotransmitter release. Using yeast two-hybrid selection with syntaxin-1A as bait, we have isolated a cDNA encoding the C-terminal domain of death-associated protein (DAP) kinase, a calcium/calmodulin-dependent serine/threonine protein kinase. Expression of DAP kinase in adult rat brain is restricted to particular neuronal subpopulations, including the hippocampus and cerebral cortex. Biochemical studies demonstrate that DAP kinase binds to and phosphorylates syntaxin-1 at serine 188. This phosphorylation event occurs both in vitro and in vivo in a Ca2+-dependent manner. Syntaxin-1A phosphorylation by DAP kinase or its S188D mutant, which mimics a state of complete phosphorylation, significantly decreases syntaxin binding to Munc18-1, a syntaxin-binding protein that regulates SNARE complex formation and is required for synaptic vesicle docking. Our results suggest that syntaxin is a DAP kinase substrate and provide a novel signal transduction pathway by which syntaxin function could be regulated in response to intracellular [Ca2+] and synaptic activity. C1 NINDS, Synapt Funct Unit, NIH, Bethesda, MD 20892 USA. RP Sheng, ZH (reprint author), NINDS, Synapt Funct Unit, NIH, Bldg 36,Rm 5A23,36 Convent Dr, Bethesda, MD 20892 USA. NR 79 TC 47 Z9 50 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 JUL 11 PY 2003 VL 278 IS 28 BP 26265 EP 26274 DI 10.1074/jbc.M300492200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 697AN UT WOS:000183920200126 PM 12730201 ER PT J AU Shinomiya, K Kabasawa, Y Yanagidaira, K Sasaki, H Muto, M Okada, T Ito, Y AF Shinomiya, K Kabasawa, Y Yanagidaira, K Sasaki, H Muto, M Okada, T Ito, Y TI Protein separation by nonsynchronous coil planet centrifuge with aqueous-aqueous polymer phase systems SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE counter-current chromatography; instrumentation; proteins ID COUNTERCURRENT CHROMATOGRAPHIC-SEPARATION; CELL-SEPARATION; ROTATING SEALS; ASSEMBLIES; COLUMNS AB Counter-current chromatographic separation of proteins was performed using a rotary-seal-free nonsynchronous coil planet centrifuge (CPC) fabricated in our laboratory. This apparatus has a unique feature that allows a freely adjustable rotational rate of the coiled separation column at a given revolution speed. The separation was performed using a set of stable proteins including cytochrome c, myoglobin and lysozyme with two different types of aqueous-aqueous polymer phase systems, i.e., PEG (polyethylene glycol) 1000-dibasic potassium phosphate, and PEG 8000-dextran T500 in 5 mM potassium phosphate buffer. Using a set of multilayer coiled columns prepared from 0.8 mm I.D. PTFE tubing with different volumes (11, 24, 39 ml), the effect of the column capacity on the partition efficiency was investigated under a given set of experimental conditions. Among these experiments, the best separation of proteins was attained using the 39 ml capacity column with a 12.5% (w/w) PEG 1000-12.5% (w/w) dibasic potassium phosphate system at 10 rpm of coil rotation under 800 rpm. With lower phase mobile at 0.2 ml/min in the head-to-tail elution, the resolution between cytochrome c and myoglobin was 1.6 and that between myoglobin and lysozyme, 1.9. With upper phase mobile in the head-to-tail elution, the resolution between lysozyme and myoglobin peaks was 1.5. In these two separations, the stationary phase retention was 35.0 and 33.3%, respectively. Further studies were carried out using a pair of eccentric coil assemblies with 0.8 mm I.D. PTFE tubing at a total capacity of 20 ml. A comparable resolution was obtained using both lower and upper phases as a mobile phase in a head-to-tail elution. The results of our studies demonstrate that the nonsynchronous CPC is useful for protein separation with aqueous-aqueous polymer phase systems. (C) 2003 Elsevier B.V. All rights reserved. C1 Nihon Univ, Coll Pharm, Funabashi, Chiba 2748555, Japan. Nihon Univ, Coll Sci & Technol, Machining Technol Ctr, Funabashi, Chiba 2748501, Japan. Aichi Med Univ, Dept Physiol, Nagakute, Aichi 4801195, Japan. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Shinomiya, K (reprint author), Nihon Univ, Coll Pharm, 7-7-1 Narashinodai, Funabashi, Chiba 2748555, Japan. NR 23 TC 17 Z9 19 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD JUL 11 PY 2003 VL 1005 IS 1-2 BP 103 EP 112 DI 10.1016/S0021-9673(03)00915-4 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 703TJ UT WOS:000184296800008 PM 12924785 ER PT J AU Priola, SA Caughey, B Chesebro, B AF Priola, SA Caughey, B Chesebro, B TI Toxicity and protection in prions - Response SO SCIENCE LA English DT Letter ID PRP C1 NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Priola, SA (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 11 PY 2003 VL 301 IS 5630 BP 169 EP 169 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 699KN UT WOS:000184056200021 ER PT J AU Richmond, BJ Liu, Z Shidara, M AF Richmond, BJ Liu, Z Shidara, M TI Predicting future rewards SO SCIENCE LA English DT Editorial Material ID PREFRONTAL CORTEX; ANTERIOR CINGULATE; NEURONAL SIGNALS; SELECTION; MACAQUE; MOTOR C1 NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. AIST, Neurosci Res Inst, Syst Neurosci Grp, Tsukuba, Ibaraki, Japan. RP Richmond, BJ (reprint author), NIMH, Neuropsychol Lab, Bldg 9, Bethesda, MD 20892 USA. NR 18 TC 23 Z9 24 U1 0 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 11 PY 2003 VL 301 IS 5630 BP 179 EP 180 DI 10.1126/science.1087383 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 699KN UT WOS:000184056200029 PM 12855797 ER PT J AU Volodin, AA Smirnova, EA Bocharova, TN Camerini-Otero, RD AF Volodin, AA Smirnova, EA Bocharova, TN Camerini-Otero, RD TI Phasing of RecA monomers on quasi-random DNA sequences SO FEBS LETTERS LA English DT Article DE RecA protein; presynaptic complex; RecA monomer positioning; homologous recombination; DNA strand exchange ID ESCHERICHIA-COLI GENOME; HOMOLOGOUS RECOMBINATION; PAIRING SEQUENCES; CHI-SITES; PROTEIN; ISLANDS; BINDING; COMPLEXES; EXCHANGE AB We show that some arbitrarily chosen DNA sequences the ability to influence the positioning of RecA monomers in RecA-DNA complexes. The preferential phase of binding of RecA monomers is shown to depend on the DNA sequence and its nucleotide composition. A simple rearrangement of bases in a limited DNA stretch influences the phasing of RecA monomers. On the other hand, that some features of DNA sites demonstrates the existence of mechanisms for both positive and negative regulation of phasing on natural DNAs. The possible role of phasing of RecA monomers on DNA is discussed. (C) 2003 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies. C1 Russian Acad Sci, Inst Mol Genet, Moscow 123182, Russia. NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Volodin, AA (reprint author), Russian Acad Sci, Inst Mol Genet, Kurchatov Sq 2, Moscow 123182, Russia. RI Volodin, Alexander/B-9656-2012 NR 19 TC 2 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUL 10 PY 2003 VL 546 IS 2-3 BP 203 EP 208 DI 10.1016/S0014-5793(03)00572-6 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 697VM UT WOS:000183964000007 PM 12832040 ER PT J AU Hillier, LW Fulton, RS Fulton, LA Graves, TA Pepin, KH Wagner-McPherson, C Layman, D Maas, J Jaeger, S Walker, R Wylie, K Sekhon, M Becker, MC O'Laughlin, MD Schaller, ME Fewell, GA Delehaunty, KD Miner, TL Nash, WE Cordes, M Du, H Sun, H Edwards, J Bradshaw-Cordum, H Ali, J Andrews, S Isak, A VanBrunt, A Nguyen, C Du, FY Lamar, B Courtney, L Kalicki, J Ozersky, P Bielicki, L Scott, K Holmes, A Harkins, R Harris, A Strong, CM Hou, SF Tomlinson, C Dauphin-Kohlberg, S Kozlowicz-Reilly, A Leonard, S Rohlfing, T Rock, SM Tin-Wollam, AM Abbott, A Minx, P Maupin, R Strowmatt, C Latreille, P Miller, N Johnson, D Murray, J Woessner, JP Wendl, MC Yang, SP Schultz, BR Wallis, JW Spieth, J Bieri, TA Nelson, JO Berkowicz, N Wohldmann, PE Cook, LL Hickenbotham, MT Eldred, J Williams, D Bedell, JA Mardis, ER Clifton, SW Chissoe, SL Marra, MA Raymond, C Haugen, E Gillett, W Zhou, Y James, R Phelps, K Iadanoto, S Bubb, K Simms, E Levy, R Clendenning, J Kaul, R Kent, WJ Furey, TS Baertsch, RA Brent, MR Keibler, E Flicek, P Bork, P Suyama, M Bailey, JA Portnoy, ME Torrents, D Chinwalla, AT Gish, WR Eddy, SR McPherson, JD Olson, MV Eichler, EE Green, ED Waterston, RH Wilson, RK AF Hillier, LW Fulton, RS Fulton, LA Graves, TA Pepin, KH Wagner-McPherson, C Layman, D Maas, J Jaeger, S Walker, R Wylie, K Sekhon, M Becker, MC O'Laughlin, MD Schaller, ME Fewell, GA Delehaunty, KD Miner, TL Nash, WE Cordes, M Du, H Sun, H Edwards, J Bradshaw-Cordum, H Ali, J Andrews, S Isak, A VanBrunt, A Nguyen, C Du, FY Lamar, B Courtney, L Kalicki, J Ozersky, P Bielicki, L Scott, K Holmes, A Harkins, R Harris, A Strong, CM Hou, SF Tomlinson, C Dauphin-Kohlberg, S Kozlowicz-Reilly, A Leonard, S Rohlfing, T Rock, SM Tin-Wollam, AM Abbott, A Minx, P Maupin, R Strowmatt, C Latreille, P Miller, N Johnson, D Murray, J Woessner, JP Wendl, MC Yang, SP Schultz, BR Wallis, JW Spieth, J Bieri, TA Nelson, JO Berkowicz, N Wohldmann, PE Cook, LL Hickenbotham, MT Eldred, J Williams, D Bedell, JA Mardis, ER Clifton, SW Chissoe, SL Marra, MA Raymond, C Haugen, E Gillett, W Zhou, Y James, R Phelps, K Iadanoto, S Bubb, K Simms, E Levy, R Clendenning, J Kaul, R Kent, WJ Furey, TS Baertsch, RA Brent, MR Keibler, E Flicek, P Bork, P Suyama, M Bailey, JA Portnoy, ME Torrents, D Chinwalla, AT Gish, WR Eddy, SR McPherson, JD Olson, MV Eichler, EE Green, ED Waterston, RH Wilson, RK TI The DNA sequence of human chromosome 7 SO NATURE LA English DT Article ID HUMAN GENOME SEQUENCE; HUMAN-CHROMOSOME 7; WILLIAMS-SYNDROME; PHYSICAL MAP; MOUSE GENOME; GENE; DUPLICATION; IDENTIFICATION; INTEGRATION; ANNOTATION AB Human chromosome 7 has historically received prominent attention in the human genetics community, primarily related to the search for the cystic fibrosis gene and the frequent cytogenetic changes associated with various forms of cancer. Here we present more than 153 million base pairs representing 99.4% of the euchromatic sequence of chromosome 7, the first metacentric chromosome completed so far. The sequence has excellent concordance with previously established physical and genetic maps, and it exhibits an unusual amount of segmentally duplicated sequence (8.2%), with marked differences between the two arms. Our initial analyses have identified 1,150 protein-coding genes, 605 of which have been confirmed by complementary DNA sequences, and an additional 941 pseudogenes. Of genes confirmed by transcript sequences, some are polymorphic for mutations that disrupt the reading frame. C1 Washington Univ, Sch Med, Genome Sequencing Ctr, St Louis, MO 63108 USA. Univ Washington, Genome Ctr, Seattle, WA 98195 USA. Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. Washington Univ, Dept Comp Sci, St Louis, MO 63130 USA. European Mol Biol Lab, D-69117 Heidelberg, Germany. Case Western Reserve Univ, Sch Med, Ctr Computat Genome, Dept Genet, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Ctr Human Genet, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. Washington Univ, Sch Med, Howard Hughes Med Inst, St Louis, MO 63110 USA. RP Wilson, RK (reprint author), Washington Univ, Sch Med, Genome Sequencing Ctr, Campus Box 8501,4444 Forest Pk Ave, St Louis, MO 63108 USA. EM rwilson@watson.wustl.edu RI Wendl, Michael/A-2741-2008; Bork, Peer/F-1813-2013; Tang, Macy/B-9798-2014; Marra, Marco/B-5987-2008; Torrents, David/G-5785-2015; OI Bork, Peer/0000-0002-2627-833X; Furey, Terry/0000-0001-5546-9672; Torrents, David/0000-0002-6086-9037; Schultz, Brian/0000-0003-4964-976X; Haugen, Eric/0000-0001-7444-8981; Flicek, Paul/0000-0002-3897-7955; Eddy, Sean/0000-0001-6676-4706 NR 49 TC 153 Z9 840 U1 1 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 10 PY 2003 VL 424 IS 6945 BP 157 EP U2 DI 10.1038/nature01782 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 699AA UT WOS:000184032700033 PM 12853948 ER PT J AU Miller-Butterworth, CM Jacobs, DS Harley, EH AF Miller-Butterworth, CM Jacobs, DS Harley, EH TI Strong population substructure is correlated with morphology and ecology in a migratory bat SO NATURE LA English DT Article ID LONG-FINGERED BAT; MITOCHONDRIAL-DNA; MINIOPTERUS-SCHREIBERSII; GENETIC-STRUCTURE; MICROSATELLITE DATA; PHILOPATRY; DISPERSAL; MTDNA AB Examining patterns of inter-population genetic diversity can provide valuable information about both historical and current evolutionary processes affecting a species. Population genetic studies of flying and migratory species such as bats and birds have traditionally shown minimal population substructure, characterized by high levels of gene flow between populations(1,2). In general, strongly substructured mammalian populations either are separated by non-traversable barriers or belong to terrestrial species with low dispersal abilities(3). Species with female philopatry ( the tendency to remain in or consistently return to the natal territory) might show strong substructure when examined with maternally inherited mitochondrial DNA, but this substructure generally disappears when biparentally inherited markers are used, owing to male-mediated gene flow(4). Male-biased dispersal is considered typical for mammals(5), and philopatry in both sexes is rare. Here we show strong population substructure in a migratory bat species, and philopatry in both sexes, as indicated by concordance of nuclear and mtDNA findings. Furthermore, the genetic structure correlates with local biomes and differentiation in wing morphology. There is therefore a close correlation of genetic and morphological differentiation in sympatric subspecific populations of this mammalian species. C1 Univ Cape Town, Dept Zool, ZA-7701 Rondebosch, South Africa. Univ Cape Town, Div Chem Pathol, Wildlife Genet Unit, ZA-7925 Cape Town, South Africa. RP Miller-Butterworth, CM (reprint author), NCI, Lab Genom Divers, POB B, Frederick, MD 21702 USA. EM cbutterworth@mail.ncifcrf.gov RI Miller-Butterworth, Cassandra/H-5994-2013; Jacobs, David/L-9118-2013 NR 30 TC 69 Z9 70 U1 2 U2 30 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 10 PY 2003 VL 424 IS 6945 BP 187 EP 191 DI 10.1038/nature01742 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 699AA UT WOS:000184032700040 PM 12853955 ER PT J AU Edland, SD Vriese, FWD Compton, D Smith, GE Ivnik, R Boeve, BF Tangalos, EG Petersen, RC AF Edland, SD Vriese, FWD Compton, D Smith, GE Ivnik, R Boeve, BF Tangalos, EG Petersen, RC TI Insulin degrading enzyme (IDE) genetic variants and risk of Alzheimer's disease: evidence of effect modification by apolipoprotein E (APOE) SO NEUROSCIENCE LETTERS LA English DT Article DE insulin degrading enzyme; Alzheimer's disease; amyloid beta; protease; genetic epidemiology ID LINKAGE DISEQUILIBRIUM MEASURES; AMYLOID BETA-PROTEIN; DEGRADATION; ASSOCIATION; LOCUS; CHROMOSOME-10; PEPTIDE; BRAINS; SAMPLE AB Insulin degrading enzyme (IDE) is a protease that degrades insulin and the beta-amyloid peptide implicated in Alzheimer's disease (AD). We reexamined data on five previously reported IDE polymorphisms stratifying the analysis by the presence or absence of an apolipoprotein E (APOE) epsilon4 allele. Three IDE variants were associated with AD within epsilon4-negative subjects (genotype exact test P-values less than or equal to0.02). A haplotype containing the minor variant at each of these sites represented an estimated 4.2% of case haplotypes versus 12.3% of control haplotypes among epsilon4-negative subjects. Lack of this minor haplotype may be predictive of AD, potentially explaining some fraction of disease within subjects without the APOE epsilon4 risk allele. Confirmation of this finding with a larger sample of cases and controls is warranted. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. C1 Mayo Clin & Mayo Fdn, Div Clin Epidemiol, Rochester, MN 55905 USA. NIA, Neurogenet Lab, Bethesda, MD 20892 USA. Mayo Clin, Dept Psychol, Rochester, MN 55905 USA. Mayo Clin, Dept Neurol, Rochester, MN 55905 USA. Mayo Clin, Div Community Internal Med, Rochester, MN 55905 USA. RP Edland, SD (reprint author), Mayo Clin & Mayo Fdn, Div Clin Epidemiol, 200 1st St SW, Rochester, MN 55905 USA. OI Smith, Glenn/0000-0003-1506-9484 NR 23 TC 44 Z9 45 U1 1 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUL 10 PY 2003 VL 345 IS 1 BP 21 EP 24 DI 10.1016/S0304-3940(03)00488-9 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 692ZW UT WOS:000183691000006 PM 12809979 ER PT J AU Itokawa, M Yamada, K Iwayama-Shigeno, Y Ishitsuka, Y Detera-Wadleigh, S Yoshikawa, T AF Itokawa, M Yamada, K Iwayama-Shigeno, Y Ishitsuka, Y Detera-Wadleigh, S Yoshikawa, T TI Genetic analysis of a functional GRIN2A promoter (GT)n repeat in bipolar disorder pedigrees in humans SO NEUROSCIENCE LETTERS LA English DT Article DE N-methyl-D-aspartate receptor 2A subunit; short tandem repeat; pedigree disequilibrium test; family-based association; linkage; schizophrenia ID DISEQUILIBRIUM TEST; ASSOCIATION; GLUTAMATE; ILLNESS; CORTEX; BRAIN AB Hypofunction of glutamatergic neurotransmission has been hypothesized to underlie the pathophysiology of bipolar affective disorder, as well as schizophrenia. We examined the role of the N-methyl-D-aspartate receptor 2A subunit (GRIN2A) gene on 16p13.3, a region thought to be linked to bipolar disorder, (1) because in a prior study we identified a functional and polymorphic (GT)n repeat in the 5' regulatory region of the gene, with longer alleles showing lower transcriptional activity and an over representation in schizophrenia, and (2) because of the suggestion of a genetic overlap between affective disorder and schizophrenia. Family-based association tests detected a nominally significant preferential transmission of longer alleles in a panel of 96 multiplex bipolar pedigrees. These results support the hypothesis that a hypoglutamatergic state is involved in the pathogenesis of bipolar affective disorder. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. C1 RIKEN, Brain Sci Inst, Lab Mol Psychiat, Wako, Saitama 3510198, Japan. Tokyo Inst Psychiat, Dept Schizophrenia Res, Tokyo 1568585, Japan. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Yoshikawa, T (reprint author), RIKEN, Brain Sci Inst, Lab Mol Psychiat, 2-1 Hirosawa, Wako, Saitama 3510198, Japan. NR 17 TC 48 Z9 48 U1 3 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUL 10 PY 2003 VL 345 IS 1 BP 53 EP 56 DI 10.1016/S0304-3940(03)00501-9 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 692ZW UT WOS:000183691000014 PM 12809987 ER PT J AU Miller, FG Rosenstein, DL AF Miller, FG Rosenstein, DL TI Protection of research subjects - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID CLINICAL-RESEARCH C1 NIH, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 2 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 JUL 10 PY 2003 VL 349 IS 2 BP 190 EP 191 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 698XH UT WOS:000184024400023 ER PT J AU Nussbaum, R Ellis, C AF Nussbaum, R Ellis, C TI Genetics of neurodegenerative disorders - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID ALZHEIMER-DISEASE; ALPHA-2-MACROGLOBULIN; POLYMORPHISM; ASSOCIATION C1 NHGRI, Bethesda, MD 20892 USA. RP Nussbaum, R (reprint author), NHGRI, Bethesda, MD 20892 USA. NR 5 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 JUL 10 PY 2003 VL 349 IS 2 BP 194 EP 194 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 698XH UT WOS:000184024400031 ER PT J AU Rutter, JL Goldstein, AM Davila, MR Tucker, MA Struewing, JP AF Rutter, JL Goldstein, AM Davila, MR Tucker, MA Struewing, JP TI CDKN2A point mutations D153spl(c.457G > T) and IVS2+1G > T result in aberrant splice products affecting both p16(INK4a) and p14(ARF) SO ONCOGENE LA English DT Article DE melanoma; RT-PCR; alternate reading frame; cryptic splice site ID CELL-CYCLE ARREST; PRONE FAMILIES; MELANOMA; P19(ARF); GENE; INHIBITION; LOCUS; MDM2; P53 AB The CDKN2A gene, which encodes the proteins p16(INK4a) and p14(ARF), is located on chromosome 9p21. Germline mutations at this locus increase susceptibility to cutaneous malignant melanoma (CMM). In general, missense and nonsense mutations are primarily responsible for defective p16(INK4a) and possibly p14(ARF) protein function and account for similar to20% of inherited CMM cases. We report a G>T transversion mutation in the last nucleotide of exon 2, affecting the aspartic acid residue at position 153 of CDKN2A-p16(INK4a) in a proband with melanoma. If splicing were unaffected, this mutation would change Asp to Tyr. RT-PCR analysis, however, revealed that this mutation, which we have termed D153spl(c.457G>T), and a previously described mutation at the next nucleotide, IVS2 + 1G > T, result in identical aberrant splicing affecting both p16(INK4a) and p14(ARF). The two main alternate splice products for each of the two normal transcripts includes a 74 bp deletion in exon 2, revealing a cryptic splice site, and the complete skipping of exon 2. The dual inactivation of p16(INK4a), and p14(ARF) may contribute to the CMM in these families. C1 NCI, Lab Populat Genet, NIH, DHHS,Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. RP Struewing, JP (reprint author), NCI, Lab Populat Genet, NIH, DHHS,Ctr Canc Res, Bldg 41,Room D702,41 Library Dr,MSC 5060, Bethesda, MD 20892 USA. RI Struewing, Jeffery/C-3221-2008; Tucker, Margaret/B-4297-2015; Struewing, Jeffery/I-7502-2013; OI Struewing, Jeffery/0000-0002-4848-3334; Rutter, Joni/0000-0002-6502-2361 NR 21 TC 17 Z9 20 U1 1 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 JUL 10 PY 2003 VL 22 IS 28 BP 4444 EP 4448 DI 10.1038/sj.onc.1206564 PG 5 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 698BZ UT WOS:000183978900014 PM 12853981 ER PT J AU Young, NS Rosenfeld, S AF Young, NS Rosenfeld, S TI Aplastic anemia and immunosuppression - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID CELLS C1 NHLBI, Hematol Branch, Bethesda, MD 20892 USA. RP Young, NS (reprint author), NHLBI, Hematol Branch, Bethesda, MD 20892 USA. NR 5 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 JUL 9 PY 2003 VL 290 IS 2 BP 193 EP 193 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 698GH UT WOS:000183989800018 ER PT J AU Goldstein, S Samuni, A Russo, A AF Goldstein, S Samuni, A Russo, A TI Reaction of cyclic nitroxides with nitrogen dioxide: The intermediacy of the oxoammonium cations SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NITRIC-OXIDE; LIPID-PEROXIDATION; HYDROGEN-PEROXIDE; ELECTRON-TRANSFER; PEROXYNITRITE DECOMPOSITION; PULSE RADIOLYSIS; PHYSIOLOGICAL PH; DNA SCISSION; KINETICS; RADICALS AB Piperidine and pyrrolidine nitroxides, such as 2,2,6,6-tetramethylpiperidinoxyl (TPO) and 3-carbamoylproxyl (3-CP), respectively, are cell-permeable stable radicals, which effectively protect cells, tissues, isolated organs, and laboratory animals from radical-induced damage. The kinetics and mechanism of their reactions with OH, superoxide, and carbon-centered radicals have been extensively studied, but not with NO2, although the latter is a key intermediate in cellular nitrosative stress. In this research, NO2 was generated by pulse radiolysis, and its reactions with TPO, 4-OH-TPO, 4-oxo-TPO, and 3-CP were studied by fast kinetic spectroscopy, either directly or by using ferrocyanide or 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate), which effectively scavenge the product of this reaction, the oxoammonium cation. The rate constants for the reactions of NO2 With these nitroxides were determined to be (7-8) x 10(8) M-1 s(-1), independent of the pH over the range 3.9-10.2. These are among the highest rate constants measured for NO2 and are close to that of the reaction of NO2 with NO, that is, 1.1 x 10(9) M-1 s(-1). The hydroxylamines TPO-H and 4-OH-TPO-H are less reactive toward NO2, and an upper limit for the rate constant for these reactions was estimated to be 1 x 10(5) M-1 s(-1). The kinetics results demonstrate that the reaction of nitroxides with NO2 proceeds via an inner-sphere electron-transfer mechanism to form the respective oxoammonium cation, which is reduced back to the nitroxide through the oxidation of nitrite to NO2. Hence, the nitroxide slows down the decomposition of NO2 into nitrite and nitrate and could serve as a reservoir of NO2 unless the respective oxoammonium is rapidly scavenged by other reductant. This mechanism can contribute toward the protective effect of nitroxides against reactive nitrogen-derived species, although the oxoammonium cations themselves might oxidize essential cellular targets if they are not scavenged by common biological reductants, such as thiols. C1 Hebrew Univ Jerusalem, Dept Phys Chem, IL-91904 Jerusalem, Israel. Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Biol Mol, IL-91120 Jerusalem, Israel. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Goldstein, S (reprint author), Hebrew Univ Jerusalem, Dept Phys Chem, IL-91904 Jerusalem, Israel. NR 45 TC 48 Z9 48 U1 1 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUL 9 PY 2003 VL 125 IS 27 BP 8364 EP 8370 DI 10.1021/ja035286x PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA 697JJ UT WOS:000183938900055 PM 12837108 ER PT J AU Sukhodolets, MV Garges, S AF Sukhodolets, MV Garges, S TI Interaction of Escherichia coli RNA polymerase with the ribosomal protein S1 and the Sm-like ATPase Hfq SO BIOCHEMISTRY LA English DT Article ID PHAGE Q-BETA; MESSENGER-RNA; HOST FACTOR; TRANSLATIONAL INITIATION; BACTERIAL HOMOLOG; QBETA-REPLICASE; TRANSCRIPTION; SUBUNIT; RECOGNITION; BINDING AB We report evidence that ribosomal protein S1 and nucleic acid-binding protein Hfq copurify in molar ratios with RNA polymerase (RNAP). Purified SI associates independently with RNAP, and Hfq binding to polymerase occurs in the presence of SI. Looking for a functional role of the RNAP-S1-Hfq association, we studied the effects of S I and Hfq on transcription and coupled transcription-translation. S I was capable of significant stimulation of the RNAP transcriptional activity from a number of promoters; the stimulatory effect was observed on linear as well as supercoiled DNA templates. In addition, we present biochemical and genetic evidence of ATPase activity associated with the Sm-like hexameric nucleic acid-binding protein Hfq. The limited sequence homology between Hfq and known ATP-utilizing enzymes suggests a new class of ATPases. C1 NCI, Math Biol Lab, NIH, Bethesda, MD 20892 USA. RP Sukhodolets, MV (reprint author), NCI, Math Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 44 TC 74 Z9 76 U1 1 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 JUL 8 PY 2003 VL 42 IS 26 BP 8022 EP 8034 DI 10.1021/bi020638i PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 697RW UT WOS:000183957900017 PM 12834354 ER PT J AU Wang, TJ Larson, MG Levy, D Benjamin, EJ Corey, D Leip, EP Vasan, RS AF Wang, TJ Larson, MG Levy, D Benjamin, EJ Corey, D Leip, EP Vasan, RS TI Heritability and genetic linkage of plasma natriuretic peptide levels SO CIRCULATION LA English DT Article DE natriuretic peptides; genetics; epidemiology; atrial natriuretic factor ID BLOOD-PRESSURE; HYPERTENSION; PHENOTYPES; DISEASE AB Background-Natriuretic peptides play a critical role in the maintenance of salt and water homeostasis and regulation of vascular tone. Thus, interindividual variation in plasma natriuretic peptide levels may contribute to variation in susceptibility to volume overload and hypertension. It is unknown to what extent genetic factors contribute to variation in plasma natriuretic peptide levels. Methods and Results-We studied 1914 Framingham Study participants (mean age 57 years, 53% women) who underwent routine echocardiography and testing for plasma N-terminal proatrial natriuretic peptide (N-ANP) and brain natriuretic peptide (BNP). We estimated sex-specific multivariable models and used variance-components methods, implemented in SOLAR (Sequential Oligogenic Linkage Analysis Routines), to estimate heritability. Multipoint linkage analyses were performed using data from a 10-cM-density genome scan. Age, clinical, and echocardiographic variables accounted for 42% and 40% of the variation in log N-ANP and log BNP levels, respectively, in men. Corresponding values in women were 27% and 21%. Multivariable-adjusted heritabilities were 0.44 for log N-ANP and 0.35 for log BNP (P<0.0001). Genome-wide linkage analyses, based on 1142 participants from the 314 largest families, revealed 2 regions of suggestive linkage for log N-ANP and log BNP on chromosomes 2p25 (log-of-odds score 2.40) and 12p13 (log-of-odds score 2.13), respectively. Conclusions-In this community-based sample, a substantial proportion of the unexplained variation in plasma natriuretic peptide levels was attributable to additive genetic effects. Additional studies using candidate gene approaches may provide insight into the genetic loci that regulate plasma natriuretic peptide levels in humans. C1 Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [1U01-HL-66582, K24-HL-04334, N01-HC-25195] NR 19 TC 59 Z9 63 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 8 PY 2003 VL 108 IS 1 BP 13 EP 16 DI 10.1161/01.CIR.0000081657.83724.A7 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 698GZ UT WOS:000183991600015 PM 12821537 ER PT J AU Podgornik, R Hansen, PL Parsegian, VA AF Podgornik, R Hansen, PL Parsegian, VA TI On a reformulation of the theory of Lifshitz-van der Waals interactions in multilayered systems SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID VAPOR-PRESSURE PARADOX AB In order to investigate the form of the van der Waals interaction in different multilayer geometries we reformulate the Lifshitz theory in terms of an algebra of 2x2 matrices. This device allows us to derive a closed form solution for the secular determinant of the modes in terms of simple quadratures with explicit N dependence. We specifically investigate (i) the van der Waals interactions between a substrate and a multilayer system as a function of the separation between the substrate and the multilayer system and (ii) the interaction between two multilayer systems over a medium of variable separation. (C) 2003 American Institute of Physics. C1 NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. Univ Ljubljana, Fac Math & Phys, SI-1000 Ljubljana, Slovenia. Univ So Denmark, Dept Chem, MEMPHYS Ctr Biomembrane Phys, DK-5230 Odense, Denmark. RP Podgornik, R (reprint author), NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RI Podgornik, Rudolf/C-6209-2008 OI Podgornik, Rudolf/0000-0002-3855-4637 NR 9 TC 19 Z9 19 U1 0 U2 5 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 JUL 8 PY 2003 VL 119 IS 2 BP 1070 EP 1077 DI 10.1063/1.1578613 PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 695QV UT WOS:000183842500047 ER PT J AU Yaffe, K Lindquist, K Penninx, BW Simonsick, EM Pahor, M Kritchevsky, S Launer, L Kuller, L Rubin, S Harris, T AF Yaffe, K Lindquist, K Penninx, BW Simonsick, EM Pahor, M Kritchevsky, S Launer, L Kuller, L Rubin, S Harris, T TI Inflammatory markers and cognition in well-functioning African-American and white elders SO NEUROLOGY LA English DT Article ID C-REACTIVE PROTEIN; ALZHEIMERS-DISEASE; BRAIN; INTERLEUKIN-6; VARIABILITY; DEMENTIA; THERAPY; RISK AB Background: Several lines of evidence suggest that inflammatory mechanisms contribute to AD. Objective: To examine whether several markers of inflammation are associated with cognitive decline in African-American and white well-functioning elders. Methods: The authors studied 3,031 African-American and white men and women (mean age 74 years) enrolled in the Health, Aging, and Body Composition Study. Serum levels of interleukin-6 (IL-6) and C-reactive protein (CRP) and plasma levels of tumor necrosis factor-alpha (TNFalpha) were measured at baseline; cognition was assessed with the Modified Mini-Mental State Examination (3MS) at baseline and at follow-up. Cognitive decline was defined as a decline of >5 points. Results: In age-adjusted analyses, participants in the highest tertile of IL-6 or CRP performed nearly 2 points lower (worse) on baseline and follow-up 3MS (p < 0.001 for all) and declined by almost 1 point over the >2 years (p = 0.01 for IL-6 and p = 0.04 for CRP) compared with those in the lowest tertile. After multivariate adjustment, 3MS scores among participants in the highest tertile of IL-6 and CRP were similar at baseline but remained significantly lower at follow-up (p less than or equal to 0.05 for both). Those in the highest inflammatory marker tertile were also more likely to have cognitive decline compared with the lowest tertile for IL-6 (26 vs 20%; age-adjusted odds ratio [OR] = 1.34; 95% CI 1.06 to 1.69) and for CRP (24 vs 19%; OR = 1.41; 95% CI 1.10 to 1.79) but not for TNFalpha (23 vs 21%; OR = 1.12; 95% CI 0.88 to 1.43). There was no significant interaction between race and inflammatory marker or between nonsteroidal anti-inflammatory drug use and inflammatory marker on cognition. Conclusions: Serum markers of inflammation, especially IL-6 and CRP, are prospectively associated with cognitive decline in well-functioning elders. These findings support the hypothesis that inflammation contributes to cognitive decline in the elderly. C1 Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Geriatr, San Francisco, CA 94121 USA. Univ Calif San Francisco, Prevent Sci Grp, San Francisco, CA 94121 USA. Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. NIA, Intramural Res Program, Bethesda, MD 20892 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN USA. Univ Pittsburgh, Sch Med, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Dept Psychiat, 4150 Clement St,Box 111G, San Francisco, CA 94121 USA. FU NIA NIH HHS [K23-AG00888, N01-AG-2103, N01-AG-2106, N01-AG-6-2101] NR 25 TC 363 Z9 373 U1 2 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 8 PY 2003 VL 61 IS 1 BP 76 EP 80 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 698BY UT WOS:000183978800016 PM 12847160 ER PT J AU Bembi, B Marsala, SZ Sidransky, E Ciana, G Carrozzi, M Zorzon, M Martini, C Gioulis, M Pittis, MG Capus, L AF Bembi, B Marsala, SZ Sidransky, E Ciana, G Carrozzi, M Zorzon, M Martini, C Gioulis, M Pittis, MG Capus, L TI Gaucher's disease with Parkinson's disease - Clinical and pathological aspects SO NEUROLOGY LA English DT Article ID APOPTOSIS; NEURONS AB The association between type 1 Gaucher disease and PD has been reported in the literature. The clinical picture is characterized by the predominance of bilateral akinetic-rigid signs and poor response to levodopa therapy. The authors describe four patients (two siblings) with type 1 Gaucher disease presenting with the following signs of typical PD: asymmetric onset of rigidity, resting tremor, bradykinesia, and a favorable response to Parkinson therapies. C1 IRCCS Burlo Garofolo, Unita Operat Dipartimentale Malattie Metab, I-34137 Trieste, Italy. IRCCS Burlo Garofolo, Unita Operat Neuropsichiatria Infantile, I-34137 Trieste, Italy. Univ Trieste, Dipartimento Med Clin & Neurol, I-34127 Trieste, Italy. NIMH, Clin Neurosci Branch, Bethesda, MD 20892 USA. RP Bembi, B (reprint author), IRCCS Burlo Garofolo, Unita Operat Dipartimentale Malattie Metab, Via Istria 65-1, I-34137 Trieste, Italy. NR 10 TC 83 Z9 87 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 8 PY 2003 VL 61 IS 1 BP 99 EP 101 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 698BY UT WOS:000183978800021 PM 12847165 ER PT J AU Vereb, G Szollosi, J Matko, J Nagy, P Farkas, T Vigh, L Matyus, L Waldmann, TA Damjanovich, S AF Vereb, G Szollosi, J Matko, J Nagy, P Farkas, T Vigh, L Matyus, L Waldmann, TA Damjanovich, S TI Dynamic, yet structured: The cell membrane three decades after the Singer-Nicolson model SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Review ID FLUORESCENCE CORRELATION SPECTROSCOPY; RESONANCE ENERGY-TRANSFER; GPI-ANCHORED PROTEINS; CLASS-I MOLECULES; MHC CLASS-I; HLA CLASS-I; SCANNING OPTICAL MICROSCOPY; HUMAN LYMPHOBLASTOID-CELLS; LIPID RAFT COMPONENTS; FLUID MOSAIC MODEL AB The fluid mosaic membrane model proved to be a very useful hypothesis in explaining many, but certainly not all, phenomena taking place in biological membranes. New experimental data show that the compartmentalization of membrane components can be as important for effective signal transduction as is the fluidity of the membrane. In this work, we pay tribute to the Singer-Nicolson model, which is near its 30th anniversary, honoring its basic features, "mosaicism" and "diffusion," which predict the interspersion of proteins and lipids and their ability to undergo dynamic rearrangement via Brownian motion. At the same time, modifications based on quantitative data are proposed, highlighting the often genetically predestined, yet flexible, multilevel structure implementing a vast complexity of cellular functions. This new "dynamically structured mosaic model" bears the following characteristics: emphasis is shifted from fluidity to mosaicism, which, in our interpretation, means nonrandom codistribution patterns of specific kinds of membrane proteins forming small-scale clusters at the molecular level and large-scale clusters (groups of clusters, islands) at the submicrometer level. The cohesive forces, which maintain these assemblies as principal elements of the membranes, originate from within a microdomain structure, where lipid-lipid, protein-protein, and protein-lipid interactions, as well as sub- and supramembrane (cytoskeletal, extracellular matrix, other cell) effectors, many of them genetically predestined, play equally important roles. The concept of fluidity in the original model now is interpreted as permissiveness of the architecture to continuous, dynamic restructuring of the molecular- and higher-level clusters according to the needs of the cell and as evoked by the environment. C1 Univ Debrecen, Hungarian Acad Sci, Med & Hlth Sci Ctr, Res Ctr Mol Med,Dept Biophys & Cell Biol, H-4012 Debrecen, Hungary. Univ Debrecen, Hungarian Acad Sci, Med & Hlth Sci Ctr, Res Ctr Mol Med,Cell Biophys Res Grp, H-4012 Debrecen, Hungary. Eotvos Lorand Univ, Dept Immunol, H-1117 Budapest, Hungary. Hungarian Acad Sci, Biol Res Ctr, Inst Biochem, H-6701 Szeged, Hungary. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Damjanovich, S (reprint author), Univ Debrecen, Hungarian Acad Sci, Med & Hlth Sci Ctr, Res Ctr Mol Med,Dept Biophys & Cell Biol, H-4012 Debrecen, Hungary. EM dami@jaguar.dote.hu RI Damjanovich, Sandor/A-9284-2011; Matko, Janos/C-9008-2013; Nagy, Peter/D-2188-2013; Vereb, Gyorgy/A-4241-2008 OI Matko, Janos/0000-0001-9434-934X; Nagy, Peter/0000-0002-7466-805X; Vereb, Gyorgy/0000-0003-2157-3265 NR 110 TC 318 Z9 327 U1 11 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 JUL 8 PY 2003 VL 100 IS 14 BP 8053 EP 8058 DI 10.1073/pnas.1332550100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 702KF UT WOS:000184222500005 PM 12832616 ER PT J AU Hanbauer, I Boja, ES Moskovitz, J AF Hanbauer, I Boja, ES Moskovitz, J TI A homologue of elongation factor 1 gamma regulates methionine sulfoxide reductase A gene expression in Saccharomyces cerevisiae SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID OXIDATIVE DAMAGE; SUBSTRATE STEREOSPECIFICITY; DROSOPHILA-MELANOGASTER; LIFE-SPAN; STRESS; RESISTANCE; YEAST; OVEREXPRESSION; ALZHEIMERS; PROTEIN AB Methionine sulfoxide reductase A (MsrA) maintains the function of many proteins by reversing oxidation of methionine residues. Lack of this repair mechanism very likely increases aging-related disease susceptibility. In Saccharomyces cerevisiae, disruption of the msrA gene increases free and protein-bound methionine sulfoxide and decreases cell viability. Although the underlying mechanisms in the induction of the msrA gene are still unknown, a transcriptional regulation may be involved. Hence, a search of nuclear proteins regulating the msrA gene is a major target of the experiments reported in this article. Using protein purification combined with MS, we discovered that calcium phospholipid-binding protein (CPBP), a homologue of elongation factor-1gamma, is a component of a complex that binds to the msrA promoter. By measuring CPBP cooperative binding to the msrA promoter, we have mapped the CPBP binding site to a 39-bp sequence at the 3' end of the promoter. In a mutant yeast strain lacking the CPBP-encoding gene, the ability to overexpress msrA mRNA and MsrA protein was impaired and MsrA catalytic activity was greatly reduced, suggesting that CPBP may enhance msrA gene expression. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Moskovitz, J (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3, Bethesda, MD 20892 USA. NR 20 TC 19 Z9 20 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 8 PY 2003 VL 100 IS 14 BP 8199 EP 8204 DI 10.1073/pnas.1432898100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 702KF UT WOS:000184222500031 PM 12824466 ER PT J AU Mazan-Mamczarz, K Galban, S de Silanes, IL Martindale, JL Atasoy, U Keene, JD Gorospe, M AF Mazan-Mamczarz, K Galban, S de Silanes, IL Martindale, JL Atasoy, U Keene, JD Gorospe, M TI RNA-binding protein HuR enhances p53 translation in response to ultraviolet light irradiation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE UV light; embryonic lethal abnormal vision ID TUMOR-SUPPRESSOR PROTEIN; MESSENGER-RNA; RICH ELEMENT; CELLS; EXPRESSION; STABILIZATION; ACTIVATION; STABILITY; SUBSETS; REGION AB Exposure to short-wavelength UV light (UVC) strongly induces p53 expression. In human RKO colorectal carcinoma cells, this increase was not due to elevated p53 mRNA abundance, cytoplasmic export of p53 mRNA or UVC-triggered stabilization of the p53 protein. Instead, p53 translation was potently enhanced after UVC irradiation. The 3' UTR of p53 was found to be a target of the RNA-binding protein HuR in a UVC-dependent manner in vitro and in vivo. HuR-overexpressing RKO cells displayed elevated p53 levels, whereas cells expressing reduced HuR showed markedly diminished p53 abundance and p53 translation. Our results demonstrate a role for HuR in binding to the p53 mRNA and enhancing its translation. C1 NIA, Intramural Res Program, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. Duke Univ, Sch Med, Durham, NC 27710 USA. RP Gorospe, M (reprint author), NIA, Intramural Res Program, Cellular & Mol Biol Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Lopez de Silanes, Isabel/K-4962-2015 OI Lopez de Silanes, Isabel/0000-0001-6762-9792 NR 29 TC 279 Z9 283 U1 2 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 8 PY 2003 VL 100 IS 14 BP 8354 EP 8359 DI 10.1073/pnas.1432104100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 702KF UT WOS:000184222500058 PM 12821781 ER PT J AU Phan, GQ Yang, JC Sherry, RM Hwu, P Topalian, SL Schwartzentruber, DJ Restifo, NP Haworth, LR Seipp, CA Freezer, LJ Morton, KE Mavroukakis, SA Duray, PH Steinberg, SM Allison, JP Davis, TA Rosenberg, SA AF Phan, GQ Yang, JC Sherry, RM Hwu, P Topalian, SL Schwartzentruber, DJ Restifo, NP Haworth, LR Seipp, CA Freezer, LJ Morton, KE Mavroukakis, SA Duray, PH Steinberg, SM Allison, JP Davis, TA Rosenberg, SA TI Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CELL-CYCLE PROGRESSION; CTLA-4 BLOCKADE; COMBINATION IMMUNOTHERAPY; DENDRITIC CELLS; IN-VITRO; ACTIVATION; PROLIFERATION; CD28; INTERLEUKIN-10; IMMUNIZATION AB Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical immunoregulatory molecule (expressed on activated T cells and a subset of regulatory T cells) capable of down-regulating T cell activation. Blockade of CTLA-4 has been shown in animal models to improve the effectiveness of cancer immunotherapy. We thus treated 14 patients with metastatic melanoma by using serial i.v. administration of a fully human anti-CTLA-4 antibody (MDX-010) in conjunction with s.c. vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209-217(210M) and gp100:280-288(288V). This blockade of CTLA-4 induced grade III/IV autoimmune manifestations in six patients (43%), including dermatitis, enterocolitis, hepatitis, and hypophysitis, and mediated objective cancer regression in three patients (21%; two complete and one partial responses). This study establishes CTLA-4 as an important molecule regulating tolerance to "self" antigens in humans and suggests a role for CTLA-4 blockade in breaking tolerance to human cancer antigens for cancer immunotherapy. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. Univ Calif Berkeley, Dept Mol & Cell Biol, Howard Hughes Med Inst, Berkeley, CA 94720 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 37 TC 918 Z9 967 U1 7 U2 41 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 8 PY 2003 VL 100 IS 14 BP 8372 EP 8377 DI 10.1073/pnas.1533209100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 702KF UT WOS:000184222500061 PM 12826605 ER PT J AU Kawamura, T Gulden, FO Sugaya, M McNamara, DT Borris, DL Lederman, MM Orenstein, JM Zimmerman, PA Blauvelt, A AF Kawamura, T Gulden, FO Sugaya, M McNamara, DT Borris, DL Lederman, MM Orenstein, JM Zimmerman, PA Blauvelt, A TI R5 HIV productively infects Langerhans cells, and infection levels are regulated by compound CCR5 polymorphisms SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CHEMOKINE RECEPTOR 5; DISEASE PROGRESSION; DENDRITIC CELLS; DC-SIGN; INTRAVAGINAL INOCULATION; TYPE-1 INFECTION; AIDS PROGRESSION; TRANSMISSION; GENE AB Langerhans cells (LCs) are suspected to be initial targets for HIV after sexual exposure (by becoming infected or by capturing virus). Here, productive R5 HIV infection of LC ex vivo and I-C-mediated transmission of virus to CD4(+) T cells were both found to depend on CCR5. By contrast, infection of monocyte-derived dendritic cells and transfer of infection from monocyte-derived dendritic cells to CD4+ T cells were mediated by CCR5-dependent as well as DC-specific ICAM-3-grabbing nonintegrin-dependent pathways. Furthermore, in 62 healthy individuals, R5 HIV infection levels in LCs ex vivo were associated with CCR5 genotype. Specifically, genotyping for ORFDelta32 revealed that LCs isolated from ORFDelta32/wt individuals were significantly less susceptible to HIV when compared with LCs isolated from ORFwt/wt individuals (P = 0.016). Strikingly, further genetic analyses of the A-2459G CCR5 promoter polymorphism in ORFDelta32/wt heterozygous individuals revealed that LCs isolated from -2459A/G + ORFDelta32/wt individuals were markedly less susceptible to HIV than were LCs from -2459A/A + ORFDelta32/wt individuals (P = 0.012). Interestingly, these genetic susceptibility data in LCs parallel those of genetic susceptibility studies performed in cohorts of HIV-infected individuals. Thus, we suggest that CCR5-mediated infection of LCs, and not capture of virus by LCs, provides a biologic basis for understanding certain aspects of host genetic susceptibility to initial HIV infection. C1 Case Western Reserve Univ, AIDS Res Ctr, Dept Med, Cleveland, OH 44195 USA. Univ Hosp Cleveland, Cleveland, OH 44195 USA. NCI, Canc Res Ctr, Dermatol Branch, Bethesda, MD 20892 USA. George Washington Univ, Dept Pathol, Washington, DC 20037 USA. RP Zimmerman, PA (reprint author), W147D,2109 Adelbert Rd, Cleveland, OH 44106 USA. FU NIAID NIH HHS [AI51649, AI43645, P01 AI051649] NR 48 TC 130 Z9 135 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 JUL 8 PY 2003 VL 100 IS 14 BP 8401 EP 8406 DI 10.1073/pnas.1432450100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 702KF UT WOS:000184222500066 PM 12815099 ER PT J AU Belland, RJ Zhong, GM Crane, DD Hogan, D Sturdevant, D Sharma, J Beatty, WL Caldwell, HD AF Belland, RJ Zhong, GM Crane, DD Hogan, D Sturdevant, D Sharma, J Beatty, WL Caldwell, HD TI Genomic transcriptional profiling of the developmental cycle of Chlamydia trachomatis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID OUTER-MEMBRANE PROTEIN; ENVELOPE PROTEINS; SEQUENCE-ANALYSIS; GENE-EXPRESSION; IN-VITRO; EEA1; IDENTIFICATION; INCLUSION; PSITTACI; FUSION AB Chlamydia trachomatis is one of the most common bacterial pathogens and is the etiological agent of debilitating sexually transmitted and ocular diseases in humans. The organism is an obligate intracellular prokaryote characterized by a highly specialized biphasic developmental cycle. We have performed genomic transcriptional analysis of the chlamydial developmental cycle. This approach has led to the identification of a small subset of genes that control the primary (immediate-early genes) and secondary (late genes) differentiation stages of the cycle. Immediate-early gene products initiate bacterial metabolism and potentially modify the bacterial phagosome to escape fusion with lysosomes. One immediate early gene (CT147) is a homolog of the human early endosomal antigen-1 that is localized to the chlamydial phagosome; suggesting a functional role for CT147 in establishing the parasitophorous vacuole in a nonfusogenic pathway. Late gene products terminate bacterial cell division and constitute structural components and remodeling activities involved in the formation of the highly disulfide cross-linked outer-membrane complex that functions in attachment and invasion of new host cells. Many of the genes expressed during the immediate-early and late differentiation stages are Chlamydia-specific and have evolutionary origins in eukaryotic lineages. C1 NIAID, Rocky Mt Labs, Labs Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. NIAID, Rocky Mt Labs, Labs Intracellular Parasites, NIH, Hamilton, MT 59840 USA. Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. Univ Texas, Hlth Sci Ctr, Dept Microbiol, San Antonio, TX 78229 USA. RP Belland, RJ (reprint author), NIAID, Rocky Mt Labs, Labs Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. NR 46 TC 265 Z9 268 U1 1 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 8 PY 2003 VL 100 IS 14 BP 8478 EP 8483 DI 10.1073/pnas.1331135100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 702KF UT WOS:000184222500079 PM 12815105 ER PT J AU Feng, XR Carlton, JM Joy, DA Mu, JB Furuya, T Suh, BB Wang, YF Barnwell, JW Su, XZ AF Feng, XR Carlton, JM Joy, DA Mu, JB Furuya, T Suh, BB Wang, YF Barnwell, JW Su, XZ TI Single-nucleotide polymorphisms and genome diversity in Plasmodium vivax SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN MALARIA PARASITE; FALCIPARUM; SEQUENCE; GENES; MAP; CHLOROQUINE; STRAIN; CHIMPANZEES; SELECTION; EVOLUTION AB The study of genetic variation in malaria parasites has practical significance for developing strategies to control the disease. Vaccines based on highly polymorphic antigens may be confounded by allelic restriction of the host immune response. In response to drug pressure, a highly plastic genome may generate resistant mutants more easily than a monomorphic one. Additionally, the study of the distribution of genomic polymorphisms may provide information leading to the identification of genes associated with traits such as parasite development and drug resistance. Indeed, the age and diversity of the human malaria parasite Plasmodium falciparum has been the subject of recent debate, because an ancient parasite with a complex genome is expected to present greater challenges for drug and vaccine development. The genome diversity of the important human pathogen Plasmodium vivax, however, remains essentially unknown. Here we analyze an approximate to100-kb contiguous chromosome segment from five isolates, revealing 191 single-nucleotide polymorphisms (SNPs) and 44 size polymorphisms. The SNPs are not evenly distributed across the segment with blocks of high and low diversity. Whereas the majority (approximate to63%) of the SNPs are in intergenic regions, introns contain significantly less SNPs than intergenic sequences. Polymorphic tandem repeats are abundant and are more uniformly distributed at a frequency of about one polymorphic tandem repeat per 3 kb. These data show that A vivax has a highly diverse genome, and provide useful information for further understanding the genome diversity of the parasite. C1 NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. Inst Genomic Res, Parasite Genomic Grp, Rockville, MD 20850 USA. Amer Type Culture Collect, Dept Bioinformat, Manassas, VA 20110 USA. Ctr Dis Control & Prevent, Div Parasit Dis, Atlanta, GA 30341 USA. RP Su, XZ (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI feng, xiaorong/G-4811-2010; Furuya, Tetsuya/J-5916-2013; Furuya, Tetsuya/H-2412-2013; OI feng, xiaorong/0000-0001-8410-3020; Furuya, Tetsuya/0000-0003-3979-7072; Su, Xinzhuan/0000-0003-3246-3248 NR 48 TC 69 Z9 71 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 8 PY 2003 VL 100 IS 14 BP 8502 EP 8507 DI 10.1073/pnas.1232502100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 702KF UT WOS:000184222500083 PM 12799466 ER PT J AU Wilkemeyer, MF Chen, SY Menkari, CE Brenneman, DE Sulik, KK Charness, ME AF Wilkemeyer, MF Chen, SY Menkari, CE Brenneman, DE Sulik, KK Charness, ME TI Differential effects of ethanol antagonism and neuroprotection in peptide fragment NAPVSIPQ prevention of ethanol-induced developmental toxicity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FETAL ALCOHOL SYNDROME; DEPENDENT NEUROTROPHIC FACTOR; VASOACTIVE-INTESTINAL-PEPTIDE; CELL-CELL ADHESION; FEMTOMOLAR-ACTING PEPTIDES; DEVELOPING NERVOUS-SYSTEM; NEURONAL CULTURES; OXIDATIVE STRESS; CEREBRAL-CORTEX; MOUSE MODEL AB NAPVSIPQ (NAP), an active fragment of the glial-derived activity-dependent neuroprotective protein, is protective at femtomolar concentrations against a wide array of neural insults and prevents ethanol-induced fetal wastage and growth retardation in mice. NAP also antagonizes ethanol inhibition of L1-mediated cell adhesion (ethanol antagonism). We performed an Ala scanning substitution of NAP to determine the role of ethanol antagonism and neuroprotection in NAP prevention of ethanol embryotoxicity. The Ser-Ile-Pro region of NAP was crucial for both ethanol antagonism and protection of cortical neurons from tetrodotoxin toxicity (neuroprotection). Ala replacement of either Ser-5 or Pro-7 (P7A-NAP) abolished NAP neuroprotection but minimally changed the efficacy of NAP ethanol antagonism. In contrast, Ala replacement of Ile-6 (16A-NAP) caused a decrease in potency (>2 logarithmic orders) with only a small reduction (<10%) in the efficacy of NAP neuroprotection but markedly reduced the efficacy (50%) and the potency (5 logarithmic orders) of NAP ethanol antagonism. Ethanol significantly reduced the number of paired somites in mouse whole-embryo culture; this effect was prevented significantly by 100 pM NAP or by 100 pM P7A-NAP, but not by 100 pM 16A-NAP. The structure-activity relation for NAP prevention of ethanol embryotoxicity was similar to that for NAP ethanol antagonism and different from that for NAP neuroprotection. These findings support the hypothesis that NAP antagonism of ethanol inhibition of L1 adhesion plays a central role in NAP prevention of ethanol embryotoxicity and highlight the potential importance of ethanol effects on L1 in the pathophysiology of fetal alcohol syndrome. C1 Harvard Univ, Sch Med, Vet Affairs Boston Healthcare Syst, Dept Neurol 127,Nuerol Serv, W Roxbury, MA 02132 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Cell & Dev Biol, Chapel Hill, NC 27599 USA. NICHHD, Sect Dev & Mol Pharmacol, NIH, Bethesda, MD 20892 USA. RP Charness, ME (reprint author), Harvard Univ, Sch Med, Vet Affairs Boston Healthcare Syst, Dept Neurol 127,Nuerol Serv, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. OI Charness, Michael/0000-0002-3301-8966 FU NIAAA NIH HHS [R37 AA012974, P60 AA011605, AA12974, AA11605, P50 AA011605, R01 AA012974] NR 46 TC 71 Z9 72 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 8 PY 2003 VL 100 IS 14 BP 8543 EP 8548 DI 10.1073/pnas.1331636100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 702KF UT WOS:000184222500090 PM 12808140 ER PT J AU Li, P Zhang, MC Long, YQ Peach, ML Liu, HP Yang, DJ Nicklaus, M Roller, PP AF Li, P Zhang, MC Long, YQ Peach, ML Liu, HP Yang, DJ Nicklaus, M Roller, PP TI Potent Grb2-SH2 domain antagonists not relying on phosphotyrosine mimics SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID NONPHOSPHORYLATED INHIBITOR; ABSOLUTE-CONFIGURATION; BREAST-CANCER; SRC; SPARSOMYCIN; SPECIFICITY; AFFINITY; BINDING AB Development of Grb2-SH2 domain antagonists is an effective approach to inhibit the growth of malignant cells by modulating Grb2-related Ras signaling. We report here potent Grb2-SH2 domain antagonists that do not rely on phosphotyrosine or its mimics. These non-phosphorylated antagonists were developed and further modified by constraining the backbone conformation and optimizing amino acid side chains of a phage library-derived peptide, G1TE. After extensive SAR studies and structural optimization, non-phosphorylated peptide 12 was discovered with an IC50 of 75 nM. This potent peptidomimetic provides a novel template for the development of non-pTyr containing Grb2-SH2 domain antagonists and acts as a chemotherapeutic lead for the treatment of erbB2-related cancer. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. RP Roller, PP (reprint author), NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. OI Nicklaus, Marc/0000-0002-4775-7030 NR 17 TC 21 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 JUL 7 PY 2003 VL 13 IS 13 BP 2173 EP 2177 DI 10.1016/S0960-894X(03)00385-8 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 691DV UT WOS:000183590300018 PM 12798329 ER PT J AU Newman, AH Cao, JJ Bennett, CJ Robarge, MJ Freeeman, RA Luedtke, RR AF Newman, AH Cao, JJ Bennett, CJ Robarge, MJ Freeeman, RA Luedtke, RR TI N-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl, butenyl and butynyl}arylcarboxamides as novel dopamine D-3 receptor antagonists SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID PARTIAL AGONIST; D3 RECEPTOR; COCAINE-SEEKING; LIGANDS; POTENT; BP-897; INHIBITION; AFFINITY; DESIGN; RAT AB The dopamine D-3 receptor subtype has been targeted as a potential neurochemical modulator of the behavioral actions of psychomotor stimulants, such as cocaine. Previous synthetic studies provided structural requirements for high affinity binding to D-3 receptors which included a 2,3-dichloro-phenylpiperazine linked to an arylamido function via a butyl chain. To reduce lipo-philicity of these agents and further investigate optimal conformation, a second series of 15 novel ligands was designed that included heteroaromatic substitution and unsaturated alkyl linkers. These compounds were synthesized and evaluated for binding at rat D-3 and D-2 receptors stably expressed in Sf9 cells. D-3 binding affinities ranged from K-i = 0.6-1080 nM, with a broad range of D-3/D-2 selectivities (2-97). The discovery of potent, selective and bioavailable D-3 receptor ligands will provide essential molecular probes to elucidate the role D-3 receptors play in the psychomotor stimulant and reinforcing effects of cocaine. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 NIDA, Med Chem Sect, Intramural Res Program, Baltimore, MD 21224 USA. Univ N Texas, Hlth Sci Ctr, Dept Pharmacol & Neurosci, Ft Worth, TX 76107 USA. RP Newman, AH (reprint author), NIDA, Med Chem Sect, Intramural Res Program, Baltimore, MD 21224 USA. NR 22 TC 52 Z9 52 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 JUL 7 PY 2003 VL 13 IS 13 BP 2179 EP 2183 DI 10.1016/S0960-894X(03)00389-5 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 691DV UT WOS:000183590300019 PM 12798330 ER PT J AU Kelly, JA Spolski, R Kovanen, PE Suzuki, T Bollenbacher, J Pise-Masison, CA Radonovich, MF Lee, S Jenkins, NA Copeland, NG Morse, HC Leonard, WJ AF Kelly, JA Spolski, R Kovanen, PE Suzuki, T Bollenbacher, J Pise-Masison, CA Radonovich, MF Lee, S Jenkins, NA Copeland, NG Morse, HC Leonard, WJ TI Stat5 synergizes with T cell receptor/antigen stimulation in the development of lymphoblastic lymphoma SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE Stat5; TCR; lymphoma; DNA microarray; CD8(+)T cell ID PROTEIN-TYROSINE-PHOSPHATASE; CONSTITUTIVE ACTIVATION; GENE-EXPRESSION; IL-2 RECEPTOR; SIGNALING PATHWAYS; FUSION PROTEIN; ABL ONCOGENE; PROLIFERATION; MICE; DIFFERENTIATION AB Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors. We now report the development of thymic T cell lymphoblastic lymphomas in transgenic mice in which Stat5a or Stat5b is overexpressed within the lymphoid compartment. The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes. Remarkably, the Stat5 transgene potently induced development of CD8(+) T cells, even in mice expressing a class II-restricted TCR transgene, with resulting CD8(+) T cell lymphomas. These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NCI, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, Mouse Canc Genet Program, Frederick, MD 21702 USA. NIAID, Immunopathol Lab, NIH, Rockville, MD 20852 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10,Rm 7N252, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov OI Morse, Herbert/0000-0002-9331-3705 NR 42 TC 55 Z9 56 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 7 PY 2003 VL 198 IS 1 BP 79 EP 89 DI 10.1084/jem.20021548 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 700VP UT WOS:000184132100009 PM 12835478 ER PT J AU Fronicke, L Wienberg, J Stone, G Adams, L Stanyon, R AF Fronicke, L Wienberg, J Stone, G Adams, L Stanyon, R TI Towards the delineation of the ancestral eutherian genome organization: comparative genome maps of human and the African elephant (Loxodonta africana) generated by chromosome painting SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE chromosomal homology; Zoo-FISH; synteny conservation; phylogeny; Afrotheria ID ZOO-FISH ANALYSIS; PLACENTAL MAMMAL RADIATION; CYTOGENETIC ANALYSIS; KARYOTYPE; HOMOLOGIES; SEGMENTS; REVEALS; HYBRIDIZATION; EVOLUTION; TREE AB This study presents a whole-genome comparison of human and a representative of the Afrotherian clade, the African elephant, generated by reciprocal Zoo-FISH. An analysis of Afrotheria genomes is of special interest, because recent DNA sequence comparisons identify them as the oldest placental mammalian clade. Complete sets of whole-chromosome specific painting probes for the African elephant and human were constructed by degenerate oligonucleotide-primed PCR amplification of flow-sorted chromosomes. Comparative genome maps are presented based on their hybridization patterns. These maps show that the elephant has a moderately rearranged chromosome complement when compared to humans. The human paint probes identified 53 evolutionary conserved segments on the 27 autosomal elephant chromosomes and the X chromosome. Reciprocal experiments with elephant probes delineated 68 conserved segments in the human genome. The comparison with a recent aardvark and elephant Zoo-FISH study delineates new chromosomal traits which link the two Afrotherian species phylogenetically. In the absence of any morphological evidence the chromosome painting data offer the first non-DNA sequence support for an Afrotherian clade. The comparative human and elephant genome maps provide new insights into the karyotype organization of the proto-afrotherian, the ancestor of extant placental mammals, which most probably consisted of 2n = 46 chromosomes. C1 NCI, Comparat Mol Cytogenet Sect, Genet Branch, Frederick, MD 21702 USA. GSF Forschungszentrum Umwelt & Gesundheit, D-85764 Neuherberg, Germany. Univ Munich, Dept Biol 2, D-80333 Munich, Germany. RP Fronicke, L (reprint author), NCI, Comparat Mol Cytogenet Sect, Genet Branch, Bldg 560,Room 11-75, Frederick, MD 21702 USA. EM froenickel@gmx.net OI Stanyon, Roscoe/0000-0002-7229-1092 NR 56 TC 50 Z9 51 U1 0 U2 8 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD JUL 7 PY 2003 VL 270 IS 1522 BP 1331 EP 1340 DI 10.1098/rspb.2003.2383 PG 10 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 701HF UT WOS:000184161600002 PM 12965023 ER PT J AU Hurst, SA Mauron, A AF Hurst, SA Mauron, A TI Assisted suicide and euthanasia in Switzerland - Reply SO BRITISH MEDICAL JOURNAL LA English DT Letter C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. Univ Geneva, Fac Med, Unite Rech & Enseignement Bioeth, CH-1211 Geneva 4, Switzerland. RP Hurst, SA (reprint author), NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RI Hurst, Samia/A-9661-2008 OI Hurst, Samia/0000-0002-1980-5226 NR 3 TC 0 Z9 0 U1 0 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD JUL 5 PY 2003 VL 327 IS 7405 BP 52 EP 53 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 699NK UT WOS:000184062700039 ER PT J AU Dancey, JE Freidlin, B AF Dancey, JE Freidlin, B TI Targeting epidermal growth factor receptor - are we missing the mark? SO LANCET LA English DT Review ID TYROSINE KINASE INHIBITOR; MONOCLONAL-ANTIBODY; CANCER; ZD1839; IRESSA; AGENTS; TRIAL AB Context Aberrant signalling through the epidermal growth factor receptor (EGFR) is associated with neoplastic cell proliferation; migration; stromal invasion, resistance to apoptosis, and angiogenesis. The high frequency of abnormalities in EGFR signalling in human carcinomas and gliomas and laboratory studies showing that inhibition of EGFR can impair tumour growth means that EGFR is an attractive target for the development of cancer therapeutics. Among the classes of agents targeting EGFR in clinical development are monoclonal antibodies against the extracellular ligand-binding domain of the receptor, and small molecules that inhibit activation of the receptor tyrosine kinase. Although there are pharmacological and mechanistic differences between the two classes of inhibitor, preclinical studies suggest they both inhibit cell proliferation and have additive or synergistic cytotoxicity with standard therapies: Results from early clinical trials indicate that these agents are well tolerated and have antitumour activity. Starting point In May, 2003, the Australian Therapeutic Goods Administration and the US Food and Drug Administration. approved the EGFR inhibitor geftinib (ZD1839, Iressa) for, the. treatment of patients with advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. The US approval was based on results of a phase 2 study of 216 patients with NSCLC; including 142 patients with refractory disease. In this subgroup, the response rate was about 10%. The approval of the drug was granted despite negative results from two randomised controlled trials in over 2000 previously untreated patients with NSCLC; which showed no benefit in survival, objective tumour response, or time to progression. when gefitinib was added to chemotherapy. Where next? Research is needed to identify and validate predictive factors that can be used to select patients with disease likely to respond to EGFR inhibitors, and to elucidate the mechanism of interaction of these agents with standard therapies and other molecularly targeted agents. Appropriately designed clinical trials are required to define the optimum dose; schedule; and sequence for these agents in combination with conventional therapies and other targeted agents. C1 NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Dancey, JE (reprint author), NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Execut Plaza N,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 20 TC 146 Z9 150 U1 0 U2 9 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUL 5 PY 2003 VL 362 IS 9377 BP 62 EP 64 DI 10.1016/S0140-6736(03)13810-X PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 699KW UT WOS:000184056900025 PM 12853203 ER PT J AU Williams, RK Yeager, CL Holmes, KV AF Williams, RK Yeager, CL Holmes, KV TI Potential for receptor-based antiviral drugs against SAPS SO LANCET LA English DT Letter ID AMINOPEPTIDASE-N; VIRUS C1 NIAID, Off Technol Dev, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Madigan Army Med Ctr, Dept Clin Invest, Tacoma, WA 98431 USA. Univ Colorado, Hlth Sci Ctr, Dept Microbiol, Denver, CO USA. RP Williams, RK (reprint author), NIAID, Off Technol Dev, NIH, Dept Hlth & Human Serv, 6610 Rockledge Dr, Bethesda, MD 20892 USA. NR 5 TC 3 Z9 4 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUL 5 PY 2003 VL 362 IS 9377 BP 77 EP 77 DI 10.1016/S0140-6736(03)13818-4 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 699KW UT WOS:000184056900033 PM 12853208 ER PT J AU Hutchinson, SL Wooldridge, L Tafuro, S Laugel, B Glick, M Boulter, JM Jakobsen, BK Price, DA Sewell, AK AF Hutchinson, SL Wooldridge, L Tafuro, S Laugel, B Glick, M Boulter, JM Jakobsen, BK Price, DA Sewell, AK TI The CD8 T cell coreceptor exhibits disproportionate biological activity at extremely low binding affinities SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MHC CLASS-I; RECEPTOR-LIGAND INTERACTIONS; NEGATIVE SELECTION; LYMPHOCYTES-T; MEMBRANE COMPARTMENTATION; CD8-ALPHA-BETA CORECEPTOR; SIGNAL-TRANSDUCTION; CRYSTAL-STRUCTURE; ANTIGEN RECEPTOR; TYROSINE KINASE AB T lymphocytes recognize peptides presented in the context of major histocompatibility complex (MHC) molecules on the surface of antigen presenting cells. Recognition specificity is determined by the alphabeta T cell receptor (TCR). The T lymphocyte surface glycoproteins CD8 and CD4 enhance T cell antigen recognition by binding to MHC class I and class II molecules, respectively. Biophysical measurements have determined that equilibrium binding of the TCR with natural agonist peptide-MHC (pMHC) complexes occurs with K-D values of 1-50 muM. The pMHCI/CD8 and pMHCII/CD4 interactions are significantly weaker than this (K-D >100 muM), and the relative roles of TCR/pMHC and pMHC/coreceptor affinity in T cell activation remain controversial. Here, we engineer mutations in the MHCI heavy chain and beta(2)-microglobulin that further reduce or abolish the pMHCI/CD8 interaction to probe the significance of pMHC/coreceptor affinity in T cell activation. We demonstrate that the pMHCI/CD8 coreceptor interaction retains the vast majority of its biological activity at affinities that are reduced by over 15-fold (K-D >2 mM). In contrast to previous reports, we observe that the weak interaction between HLA A68 and CD8, which falls within this spectrum of reduced affinities, retains substantial functional activity. These findings are discussed in the context of current concepts of coreceptor dependence and the mechanism by which TCR coreceptors facilitate T cell activation. C1 T Cell Modulat Grp, Oxford OX1 3SY, England. John Radcliffe Hosp, MRC, Human Immunol Unit, Weatherall Inst Mol Med, Oxford OX3 9DS, England. Univ Oxford, Oxfrod Ctr Mol Sci, Oxford OX1 3QZ, England. Avidex Ltd, Abingdon OX14 4RX, Oxon, England. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Sewell, AK (reprint author), T Cell Modulat Grp, Peter Medawar Bldg Pathogen Res,S Parks Rd, Oxford OX1 3SY, England. RI Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Sewell, Andrew/0000-0003-3194-3135 NR 68 TC 70 Z9 71 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 4 PY 2003 VL 278 IS 27 BP 24285 EP 24293 DI 10.1074/jbc.M300633200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 695HJ UT WOS:000183824800008 PM 12697765 ER PT J AU Sreenath, T Thyagarajan, T Hall, B Longenecker, G D'Souza, R Hong, S Wright, JT MacDougall, M Sauk, J Kulkarni, AB AF Sreenath, T Thyagarajan, T Hall, B Longenecker, G D'Souza, R Hong, S Wright, JT MacDougall, M Sauk, J Kulkarni, AB TI Dentin sialophosphoprotein knockout mouse teeth display widened predentin zone and develop defective dentin mineralization similar to human dentinogenesis imperfecta type III SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID COLLAGEN FIBRILS; TRANSFORMING GROWTH-FACTOR-BETA-1; RAT INCISOR; DSPP GENE; PROTEOGLYCANS; EXPRESSION; MATRIX; PHOSPHOPROTEIN; DECORIN; SIALOPROTEIN AB Dentin sialophosphoprotein (Dspp) is mainly expressed in teeth by the odontoblasts and preameloblasts. The Dspp mRNA is translated into a single protein, Dspp, and cleaved into two peptides, dentin sialoprotein and dentin phosphoprotein, that are localized within the dentin matrix. Recently, mutations in this gene were identified in human dentinogenesis imperfecta II (Online Mendelian Inheritance in Man (OMIM) accession number 125490) and in dentin dysplasia II (OMIM accession number 125420) syndromes. Herein, we report the generation of Dspp-null mice that develop tooth defects similar to human dentinogenesis imperfecta III with enlarged pulp chambers, increased width of predentin zone, hypomineralization, and pulp exposure. Electron microscopy revealed an irregular mineralization front and a lack of calcospherites coalescence in the dentin. Interestingly, the levels of biglycan and decorin, small leucine-rich proteoglycans, were increased in the widened predentin zone and in void spaces among the calcospherites in the dentin of null teeth. These enhanced levels correlate well with the defective regions in mineralization and further indicate that these molecules may adversely affect the dentin mineralization process by interfering with coalescence of calcospherites. Overall, our results identify a crucial role for Dspp in orchestrating the events essential during dentin mineralization, including potential regulation of proteoglycan levels. C1 NIDCR, Funct Genom Unit, NIH, Bethesda, MD 20892 USA. NIDCR, Gene Targeting Facil, NIH, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Houston, TX 77030 USA. Univ N Carolina, Chapel Hill, NC 27599 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX 78229 USA. Univ Baltimore, Baltimore, MD 21201 USA. RP Sreenath, T (reprint author), 30 Convent Dr,Room 527, Bethesda, MD 20892 USA. OI D'Souza, Rena/0000-0002-1505-5173 NR 47 TC 220 Z9 229 U1 1 U2 15 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 4 PY 2003 VL 278 IS 27 BP 24874 EP 24880 DI 10.1074/jbc.M303908200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 695HJ UT WOS:000183824800076 PM 12721295 ER PT J AU Gao, ZG Zuberi, A Quon, MJ Dong, ZG Ye, JP AF Gao, ZG Zuberi, A Quon, MJ Dong, ZG Ye, JP TI Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID KAPPA-B KINASE; INDUCED TYROSINE PHOSPHORYLATION; IRS-SIGNALING SYSTEM; N-TERMINAL KINASE; PROTEIN-KINASE; FACTOR-ALPHA; TNF-ALPHA; 3T3-L1 ADIPOCYTES; PHOSPHATIDYLINOSITOL 3-KINASE; TRANSGENIC MICE AB The hypoglycemic effects of high dose salicylates in the treatment of diabetes were documented before the advent of insulin. However, the molecular mechanisms by which salicylates exert these anti-diabetic effects are not well understood. In this study, we analyzed the effects of aspirin (acetylsalicylic acid) on serine phosphorylation of insulin receptor substrate 1 (IRS-1) in cells treated with tumor necrosis factor (TNF)-alpha. Phosphorylation of IRS-1 at Ser(307), Ser(267), and Ser(612) was monitored by immunoblotting with phospho-specific IRS-1 antibodies. In 3T3-L1 and Hep G2 cells, phosphorylation of IRS-1 at Ser(307) in response to TNF-alpha treatment correlated with phosphorylation of JNK, c-Jun, and degradation of IkappaBalpha. Moreover, phosphorylation of IRS-1 at Ser(307) in embryo fibroblasts derived from either JNK or IKK knockout mice was reduced when compared with that in the wild-type controls. Taken together, these data suggest that serine phosphorylation of IRS-1 in response to TNF-alpha is mediated, in part, by JNK and IKK. Interestingly, aspirin treatment inhibited the phosphorylation of IRS-1 at Ser(307) as well as the phosphorylation of JNK, c-Jun, and degradation of IkappaBalpha. Furthermore, other serine kinases including Akt, extracellular regulated kinase, mammalian target of rapamycin, and PKCzeta were also activated by TNF-alpha (as assessed by phospho-specific antibodies). Phosphorylation of IRS-1 at Ser(267) and Ser(612) correlated with the activation of these kinases. Phosphorylation of Akt and the mammalian target of rapamycin ( but not extracellular regulated kinase or PKCzeta) in response to TNF-alpha was inhibited by aspirin treatment. Finally, aspirin rescued insulin-induced glucose uptake in 3T3-L1 adipocytes pretreated with TNF-alpha. We conclude that aspirin may enhance insulin sensitivity by protecting IRS proteins from serine phosphorylation catalyzed by multiple kinases. C1 Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. NIH, Diabet Unit, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. RP Ye, JP (reprint author), Louisiana State Univ, Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. RI Quon, Michael/B-1970-2008; OI Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 NR 67 TC 174 Z9 189 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 4 PY 2003 VL 278 IS 27 BP 24944 EP 24950 DI 10.1074/jbc.M300423200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 695HJ UT WOS:000183824800085 PM 12714600 ER PT J AU Haughn, L Hawley, RG Morrison, DK von Boehmer, H Hockenbery, DM AF Haughn, L Hawley, RG Morrison, DK von Boehmer, H Hockenbery, DM TI BCL-2 and BCL-X-L restrict lineage choice during hematopoietic differentiation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECEPTOR-DEFICIENT MICE; CELL-DEATH; MEDIATED ACTIVATION; GROWTH-FACTORS; EXPRESSION; APOPTOSIS; PROTEIN; FAMILY; INHIBITION; RAF-1 AB Differentiation of hematopoietic cells from multipotential progenitors is regulated by multiple growth factors and cytokines. A prominent feature of these soluble factors is promotion of cell survival, in part mediated by expression of either of the anti-apoptotic proteins, BCL-2 and BCL-X-L. The complex expression pattern of these frequently redundant survival factors during hematopoiesis may indicate a role in lineage determination. To investigate the latter possibility, we analyzed factor-dependent cell-Patersen (FDCP)-Mix multipotent progenitor cells in which we stably expressed BCL-2 or BCL-X-L. Each factor maintained complete survival of interleukin-3 (IL-3)-deprived FDCP-Mix cells but, unexpectedly, directed FDCP-Mix cells along restricted and divergent differentiation pathways. Thus, IL-3-deprived FDCP-Mix BCL-2 cells differentiated exclusively to granulocytes and monocytes/macrophages, whereas FDCP-Mix BCL-X-L cells became erythroid. FDCP-Mix BCL-2 cells grown in IL-3 were distinguished from FDCP-Mix and FDCP-Mix BCL-X-L cells by a striking reduction in cellular levels of Raf-1 protein. Replacement of the BCL-2 BH4 domain with the related BCL-X-L BH4 sequence resulted in a switch of FDCP-Mix BCL-2 cells to erythroid fate accompanied by persistence of Raf-1 protein expression. Moreover, enforced expression of Raf-1 redirected FDCP-Mix BCL-2 cells to an erythroid fate, and prohibited generation of myeloid cells. These results identify novel roles for BCL-2 and BCL-X-L in cell fate decisions beyond cell survival. These effects are associated with differential regulation of Raf-1 expression, perhaps involving the previously identified interaction between BCL-2-BH4 and the catalytic domain of Raf-1. C1 Fred Hutchinson Canc Res Ctr, Div Human Biol & Clin Res, Seattle, WA 98109 USA. Amer Red Cross, Hematopoiesis Dept, Jerome H Holland Lab, Rockville, MD 20855 USA. NCI, Cellular Growth Mechanisms Sect, Frederick Canc Res & Dev Ctr, NIH, Ft Detrick, MD 21702 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Hockenbery, DM (reprint author), Fred Hutchinson Canc Res Ctr, Div Human Biol & Clin Res, Mailstop D2-190,1100 Fairview Ave N, Seattle, WA 98109 USA. FU NHLBI NIH HHS [IP50HL54881] NR 48 TC 34 Z9 35 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 4 PY 2003 VL 278 IS 27 BP 25158 EP 25165 DI 10.1074/jbc.M212849200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 695HJ UT WOS:000183824800110 PM 12721288 ER PT J AU Cai, ML Williams, DC Wang, GS Lee, BR Peterkofsky, A Clore, GM AF Cai, ML Williams, DC Wang, GS Lee, BR Peterkofsky, A Clore, GM TI Solution structure of the phosphoryl transfer complex between the signal-transducing protein IIA(Glucose) and the cytoplasmic domain of the glucose transporter IICBGlucose of the Escherichia coli glucose phosphotransferase system SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RESIDUAL DIPOLAR COUPLINGS; N-TERMINAL DOMAIN; GLOBAL REPRESSOR MLC; TYROSINE-PHOSPHATASE; BACTERIAL PHOSPHOENOLPYRUVATE; PHOSPHOCARRIER PROTEIN; STRUCTURE REFINEMENT; NMR STRUCTURES; ENZYME-I; CARBOHYDRATE TRANSPORTERS AB The solution structure of the final phosphoryl transfer complex in the glucose-specific arm of the Escherichia coli phosphotransferase system, between enzyme IIA(Glucose) (IIA(Glc)) and the cytoplasmic B domain (IIBGlc) of the glucose transporter IICBGlc, has been solved by NMR. The interface (similar to1200-Angstrom(2) buried surface) is formed by the interaction of a concave depression on IIA(Glc) with a convex protrusion on IIBGlc. The phosphoryl donor and acceptor residues, His-90 of IIA(Glc) and Cys-35 of IIBGlc ( residues of IIBGlc are denoted in italics) are in close proximity and buried at the center of the interface. Cys-35 is primed for nucleophilic attack on the phosphorus atom by stabilization of the thiolate anion (pK(a) similar to6.5) through intramolecular hydrogen bonding interactions with several adjacent backbone amide groups. Hydrophobic intermolecular contacts are supplemented by peripheral electrostatic interactions involving an alternating distribution of positively and negatively charged residues on the interaction surfaces of both proteins. Salt bridges between the Asp-38/Asp-94 pair of IIA(Glc) and the Arg-38/Arg-40 pair of IIBGlc neutralize the accumulation of negative charge in the vicinity of both the Sgamma atom of Cys-35 and the phosphoryl group in the complex. A pentacoordinate phosphoryl transition state is readily accommodated without any change in backbone conformation, and the structure of the complex accounts for the preferred directionality of phosphoryl transfer between IIA(Glc) and IIBGlc. The structures of IIA(Glc).IIBGlc and the two upstream complexes of the glucose phosphotransferase system (EI.HPr and IIA(Glc).HPr) reveal a cascade in which highly overlapping binding sites on HPr and IIA(Glc) recognize structurally diverse proteins. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg ,Rm B1-30I, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 79 TC 57 Z9 57 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 4 PY 2003 VL 278 IS 27 BP 25191 EP 25206 DI 10.1074/jbc.M302677200 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 695HJ UT WOS:000183824800114 PM 12716891 ER PT J AU Kadyrov, FA Drake, JW AF Kadyrov, FA Drake, JW TI Properties of bacteriophage T4 proteins deficient in replication repair SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA BINDING-PROTEIN; CRYSTAL-STRUCTURE; MAMMALIAN-CELLS; RECOMBINATION; HELICASE; DAMAGE; GENE-41; MUTANTS; PATHWAY; BYPASS AB An epistasis group of mutations engendering increased sensitivity to diverse DNA-damaging agents was described previously in bacteriophage T4. These mutations are alleles of genes 32 and 41, which, respectively, encode a single-stranded DNA-binding protein (gp32) and the replicative DNA helicase (gp41). The mechanism by which the lethality of DNA damage is mitigated is unknown but seems not to involve the direct reversal of damage, excision repair, conventional recombination repair, or translesion synthesis. Here we explore the hypothesis that the mechanism involves a switch in DNA primer extension from the cognate template to an alternative template, the just-synthesized daughter strand of the other parental strand. The activities of the mutant proteins are reduced about 2-fold (for gp32) or 4-fold (for gp41) in replication complexes catalyzing coordinated synthesis of leading and lagging strands, in binding single-stranded DNA, promoting DNA annealing, and promoting branch migration. In striking contrast, the mutant proteins are strongly impaired in promoting template switching, thus supporting the hypothesis of survival by template switching. C1 NIEHS, Lab Mol Genet E3 01, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Drake, JW (reprint author), NIEHS, Lab Mol Genet E3 01, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. NR 27 TC 11 Z9 11 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 4 PY 2003 VL 278 IS 27 BP 25247 EP 25255 DI 10.1074/jbc.M302564200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 695HJ UT WOS:000183824800119 PM 12697750 ER PT J AU Arakawa, T Tsuboi, T Kishimoto, A Sattabongkot, J Suwanabun, N Rungruang, T Matsumoto, Y Tsuji, N Hisaeda, H Stowers, A Shimabukuro, I Sato, Y Torii, M AF Arakawa, T Tsuboi, T Kishimoto, A Sattabongkot, J Suwanabun, N Rungruang, T Matsumoto, Y Tsuji, N Hisaeda, H Stowers, A Shimabukuro, I Sato, Y Torii, M TI Serum antibodies induced by intranasal immunization of mice with Plasmodium vivax Pvs25 co-administered with cholera toxin completely block parasite transmission to mosquitoes SO VACCINE LA English DT Article DE vaccine; malaria; mucosal ID B-SUBUNIT; VACCINE CANDIDATES; MUCOSAL ADJUVANT; TARGET ANTIGEN; MALARIA; FALCIPARUM; PFS25; EXPRESSION; EPITOPES; PROTEINS AB Transmission-bloc king vaccines (TBVs) targeting ookinete surface proteins expressed on sexual-stage malaria parasites are considered one promising strategy for malaria control. To evaluate the prospect of developing non-invasive and easy-to-administer mucosal malaria transmission-blocking vaccines, mice were immunized intranasally with a Plasmodium vivax ookinete surface protein, Pvs25 with a mucosal adjuvant cholera toxin (CT). Immunization induced significant serum IgG with high IgG1IgG2a ratio (indicative of Th-2 type immune response). Feeding Anopheles dirus mosquitoes with mixtures of immune sera and gametocyternic blood derived from vivax-infected volunteer patients in Thailand significantly reduced both the number of midgut oocysts as well as the percentage of infected mosquitoes. The observed transmission-blocking effect was dependent on immune sera dilution. This study demonstrates for the first time that the mucosally induced mouse immune sera against a human malaria ookinete surface protein can completely block parasite transmission to vector mosquitoes, suggesting the possibility of non-invasive mucosal vaccines against mucosa-unrelated important pathogens like malaria. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Univ Ryukyus, Div Mol Microbiol, Ctr Mol Biosci, Nishihara, Okinawa 9030213, Japan. Ehime Univ, Dept Mol Parasitol, Sch Med, Shigenobu, Ehime 7910295, Japan. Ryukoku Univ, Dept Bioprod, Sch Agr, Nishihara, Okinawa 9030213, Japan. Armed Forces Res Inst Med Sci, Dept Entomol, Bangkok 10400, Thailand. Univ Tokyo, Lab Global Anim Resource Sci, Grad Sch Agr & Life Sci, Bunkyo Ku, Tokyo 1138657, Japan. Natl Agr Res Org, Lab Parasit Dis, Natl Inst Anim Hlth, Tsukuba, Ibaraki 3050856, Japan. Univ Tokushima, Dept Immunol & Parasitol, Sch Med, Tokushima 7708503, Japan. NIAID, Parasit Dis Lab, Malaria Vaccine Dev Unit, NIH, Rockville, MD 20852 USA. Univ Ryukyus, Dept Parasitol, Sch Med, Nishihara, Okinawa 9030215, Japan. RP Tsuboi, T (reprint author), Ehime Univ, Cell Free Sci & Technol Res Ctr, 3 Bunkyo Cho, Matsuyama, Ehime 7908577, Japan. NR 24 TC 35 Z9 37 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUL 4 PY 2003 VL 21 IS 23 BP 3143 EP 3148 DI 10.1016/S02640410X(03)00258-5 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 699EP UT WOS:000184043200008 PM 12804841 ER PT J AU Da Silva, DA Schiller, JT Kast, WM AF Da Silva, DA Schiller, JT Kast, WM TI Heterologous boosting increases immunogenicity of chimeric papillomavirus virus-like particle vaccines SO VACCINE LA English DT Article DE papillomavirus; virus-like particle; neutralization; HPV16; BPV; CRPV ID COTTONTAIL RABBIT PAPILLOMAVIRUS; ANTITUMOR IMMUNE-RESPONSE; MUCOSAL VACCINATION; TYPE-16 L1; IMMUNIZATION; INFECTION; MICE; ANTIBODIES; CELLS; NEUTRALIZATION AB Chimeric human papillomavirus virus-like particles (HPV cVLPs), containing the HPV 16 non-structural protein E7, are potent vaccines for inducing antigen-specific protective immunity against HPV-transformed tumors in animal models. Previous data demonstrated that the effectiveness of cytotoxic T lymphocyte (CTL) induction after repetitive vaccination with the same cVLP, and thus vaccine efficacy, is limited by the presence of neutralizing antibodies induced after the first application. Here, we determined if altering the route of vaccine delivery or incorporation of the target antigen into VLPs of a heterologous papillomavirus type could overcome inhibition of MHC class I antigen presentation by neutralizing antibodies, resulting in a boosting of CD8(+) T-cell responses against the incorporated antigen, HPV 16 ET Mucosal delivery of cVLPs resulted in detection of systemic E7-specific CD8(+) T cells, however, these routes were not able to bypass the inhibitory effect of circulating antibodies against homologous VLP types. In contrast, mice immunized and boosted with heterologous cVLPs containing HPV 16 E7 showed a higher frequency of E7-specific T cells in vitro and displayed reduced tumor growth in a therapeutic setting compared to mice treated with homologous cVLPs. The data indicate that the use of different cVLP types for prime/boost regimens is a promising strategy to increase the efficacy and usefulness of cVLP-based vaccines for the treatment of cervical neoplasia. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Loyola Univ, Cardinal Bernardin Canc Ctr, Dept Microbiol & Immunol, Canc Immunol Program, Maywood, IL 60153 USA. NIH, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Kast, WM (reprint author), Loyola Univ, Cardinal Bernardin Canc Ctr, Dept Microbiol & Immunol, Canc Immunol Program, 2160 S 1st Ave, Maywood, IL 60153 USA. FU NCI NIH HHS [P01CA97296, R01CA74397] NR 42 TC 42 Z9 45 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUL 4 PY 2003 VL 21 IS 23 BP 3219 EP 3227 DI 10.1016/S0264-410X(03)00237-8 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 699EP UT WOS:000184043200018 PM 12804851 ER PT J AU Karramkam, M Hinnen, F Berrehouma, M Hlavacek, C Vaufrey, F Halldin, C McCarron, JA Pike, VW Dolle, F AF Karramkam, M Hinnen, F Berrehouma, M Hlavacek, C Vaufrey, F Halldin, C McCarron, JA Pike, VW Dolle, F TI Synthesis of a [6-pyridinyl-F-18]-labelled fluoro derivative of WAY-100635 as a candidate radioligand for brain 5-HT1A receptor imaging with PET SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID NICOTINIC ACETYLCHOLINE-RECEPTORS; POSITRON-EMISSION-TOMOGRAPHY; F-18 P-MPPF; IN-VIVO; BINDING; ANTAGONISTS; ANALOG; P-MPPF; SEROTONIN; OCCUPANCY AB In recent years, considerable effort has been spent on the design, synthesis and pharmacological characterization of radiofluorinated derivatives of the 5-HT1A receptor antagonist, WAY-100635, for the in vivo study of these receptors in human brain with PET. (Pyridinyl-6)-fluoro- and (pyridinyl-5)-fluoro-analogues of WAY-100635 (6-fluoro and 5-fluoro-WAY-100635, 5a/6a) were synthesized as well as the corresponding chloro-, bromo- and nitro-derivatives as precursors for labelling (5b-d and 6b-d). Comparative radiolabelling of these precursors with fluorine-18 (positron-emitting isotope, 109.8 min half-life) clearly demonstrated that only ortho-fluorination in this pyridine series, and not meta-fluorination, is of interest for the preparation of a radioligand by nucleophilic heteroaromatic substitution. 6-[F-18]Fluoro-WAY-100635 ([F-18]5a) can be efficiently synthesized in one step, either from the corresponding 6-bromo precursor (using conventional heating at 145degreesC for 10min) or from the corresponding 6-nitro precursor (using microwave activation at 100 W for 1 min). Typically, 15-25 mCi (0.55-0.92 GBq) of 6-[F-18]fluoro-WAY-100635 ([F-18]5a, 1-2Ci/mumol or 37-72GBq/mumol) were obtained in 50-70min starting from a 100mCi (3.7GBq) aliquot of a batch of cyclotron-produced [F-18]fluoride. This F-18-labelled radioligand is now being evaluated in PET studies. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 CEA, Serv Hosp Frederic Joliot, Dept Rech Med, F-91401 Orsay, France. Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, Karolinska Hosp, S-17176 Stockholm, Sweden. NIMH, Mol Imaging Branch, PET, Radiopharmaceut Sci Sect, Bethesda, MD 20892 USA. RP Dolle, F (reprint author), CEA, Serv Hosp Frederic Joliot, Dept Rech Med, 4 Pl Gen Leclerc, F-91401 Orsay, France. NR 60 TC 36 Z9 39 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUL 3 PY 2003 VL 11 IS 13 BP 2769 EP 2782 DI 10.1016/S0968-0896(03)00225-5 PG 14 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 691DT UT WOS:000183590100012 PM 12788351 ER PT J AU Stergiopoulos, SG Stratakis, CA AF Stergiopoulos, SG Stratakis, CA TI Human tumors associated with Carney complex and germline PRKAR1A mutations: a protein kinase A disease! SO FEBS LETTERS LA English DT Review DE protein kinase A; regulatory subunit; Carney complex; chromosome 17; deletion; tumor suppressor gene ID SPOTTY SKIN PIGMENTATION; PSAMMOMATOUS MELANOTIC SCHWANNOMA; NODULAR ADRENOCORTICAL DISEASE; ENDOCRINE OVERACTIVITY; GENETIC-HETEROGENEITY; REGULATORY SUBUNIT; DUCTAL ADENOMA; CARDIAC MYXOMA; ATRIAL-MYXOMA; I-ALPHA AB Carney complex (CNC) is a multiple neoplasia syndrome that consists of endocrine (thyroid, pituitary, adrenocortical and gonadal), non-endocrine (myxomas, nevi and other cutaneous pigmented lesions), and neural (schwannomas) tumors. Primary pigmented nodular adrenocortical disease (PPNAD) is the most common endocrine manifestation of CNC and the only inherited form of Cushing syndrome known to date. In the search of genes responsible for CNC, two chromosomal loci were identified; one (17q22-24) harbored the gene encoding the type I-alpha regulatory subunit (RIalpha) of protein kinase A (PKA), PRKAR1A, a critical component of the cAMP signaling pathway. Here we review CNC and the implications of this discovery for the cAMP and/or PKA's involvement in human tumorigenesis. (C) 2003 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. C1 NICHD, DEP, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHD, DEP, Sect Endocrinol & Genet, NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC1862, Bethesda, MD 20892 USA. NR 29 TC 51 Z9 53 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUL 3 PY 2003 VL 546 IS 1 BP 59 EP 64 DI 10.1016/S0014-5793(03)00452-6 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 697YH UT WOS:000183970500010 PM 12829237 ER PT J AU Zou, MF Kopajtic, T Katz, JL Newman, AH AF Zou, MF Kopajtic, T Katz, JL Newman, AH TI Structure-activity relationship comparison of (S)-2 beta-substituted 3 alpha-(Bis[4-fluorophenyllmethoxy)tropanes and (R)-2 beta-substituted 3 alpha-(3,4-dichlorophenyl)tropanes at the Dopamine transporter SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID COCAINE RECOGNITION SITES; 3-PHENYLTROPANE ANALOGS; UPTAKE INHIBITORS; LIGAND-BINDING; BENZTROPINE; ADDICTION; RECEPTORS; BRAIN; RAT AB Extensive structure-activity relationships at the dopamine transporter (DAT) have been developed around two classes of tropane-based ligands. Opposing stereoselectivity and divergent structural requirements for optimal DAT binding suggest that these tropane-based DAT inhibitors may not access identical binding domains. To further investigate this hypothesis, a series of (S)-2beta-carboalkoxy-3alpha-(bis[4-fluorophenyl]methoxy)tropanes (11a-f, 13-16) and their identically (R)-2beta-substituted 3beta-(3,4-dichlorophenyl)tropanes (3, 5a-d) were prepared and evaluated for binding at the DAT and for inhibition of [H-3]dopamine uptake in rat brain. These studies showed that most of the identically 2-carboalkoxy-substituted analogues, within the two classes of compounds, bind with high affinity to DAT (K-i = 5.5 - 100 nM), albeit with opposite stereochemistry. However, the larger azido- (15) and isothiocyanato- (16) (S)-2beta-carbophenylethoxy-3alpha-(bis [4-fluorophenyl] methoxy)tropanes demonstrated a significant decrease in DAT binding potency (IC50 = 210 and 537 nM, respectively), suggesting that the DAT does not tolerate 2-position steric bulk in the benztropine class, as it does with the 2-substituted 3-aryltropanes. In addition, binding affinities at the serotonin transporter, norepinephrine transporter, and muscarinic receptors were evaluated and compared for compounds 2, 3, 11a-e, and 13. Together, the binding profiles across these systems demonstrated significant differences between these two classes of tropane-based ligands, which may be exploited toward the discovery of a cocaine-abuse pharmacotherapeutic. C1 NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NIDA, Psychobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Newman, AH (reprint author), NIDA, Med Chem Sect, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM anewman@intra.nida.nih.gov NR 29 TC 21 Z9 21 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 JUL 3 PY 2003 VL 46 IS 14 BP 2908 EP 2916 DI 10.1021/jm0300375 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 695HF UT WOS:000183824500011 PM 12825932 ER PT J AU Lee, J Lee, J Kang, M Shin, M Kim, JM Kang, SU Lim, JO Choi, HK Suh, YG Park, HG Oh, U Kim, HD Park, YH Ha, HJ Kim, YH Toth, A Wang, Y Tran, R Pearce, LV Lundberg, DJ Blumberg, PM AF Lee, J Lee, J Kang, M Shin, M Kim, JM Kang, SU Lim, JO Choi, HK Suh, YG Park, HG Oh, U Kim, HD Park, YH Ha, HJ Kim, YH Toth, A Wang, Y Tran, R Pearce, LV Lundberg, DJ Blumberg, PM TI N-(3-acyloxy-2-benzylpropyl)-N '-[4-(methylsulfonylamino)benzyl]thiourea analogues: Novel potent and high affinity antagonists and partial antagonists of the vanilloid receptor SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ROOT GANGLION NEURONS; IODO-RESINIFERATOXIN; CAPSAICIN-RECEPTOR; ANALGESIC AGENTS; AGONIST ACTIVITY; RAT; CAPSAZEPINE; PHARMACOLOGY; CHANNELS; HEAT AB Isosteric replacement of the phenolic hydroxyl group in potent vanilloid receptor (VR1) agonists with the alkylsulfonamido group provides a series of compounds which are effective antagonists to the action of the capsaicin on rat VR1 heterologously expressed in Chinese hamster ovary (CHO) cells. In particular, compound 61, N-[2-(3,4-dimethylbenzyl)-3-pivaloyloxypropyl]-N[3-fluoro-4-(methylsulfonylamino)benzyl] thiourea was a full antagonist against capsaicin, displayed a K-i value of 7.8 nM (compared to 520 nM for capsazepine and 4 nM for 5-iodoRTX), and showed excellent analgesic activity in mice. Structure-activity analysis of the influence of modifications in the A- and C-regions of 4-methylsulfonamide ligands on VR1 agonism/antagonism indicated that 3-fluoro substitution in the A-region and a 4-tert-butylbenzyl moiety in the C-region favored antagonism, whereas a 3-methoxy group in the A-region and 3-acyloxy-2-benzylpropyl moieties in the C-region favored agonism. C1 Seoul Natl Univ, Coll Pharm, Res Inst Pharmaceut Sci, Kwanak Ku, Seoul 151742, South Korea. Sookmyung Womens Univ, Coll Pharm, Seoul 140742, South Korea. AmorePacific R&D Ctr, Yongin Si 449900, Kyounggi Do, South Korea. Digital Biotech, Ansan 425839, Kyounggi Do, South Korea. NCI, Ctr Canc Res, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. RP Lee, J (reprint author), Seoul Natl Univ, Coll Pharm, Res Inst Pharmaceut Sci, Kwanak Ku, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr RI Toth, Attila/F-4859-2010; Kang, Myungshim /K-5331-2014; OI Toth, Attila/0000-0001-6503-3653; Kang, Myungshim /0000-0002-4778-8240; Lee, Jiyoun/0000-0003-3819-5889 NR 32 TC 98 Z9 100 U1 1 U2 13 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 JUL 3 PY 2003 VL 46 IS 14 BP 3116 EP 3126 DI 10.1021/jm030089u PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 695HF UT WOS:000183824500029 PM 12825950 ER PT J AU Thomas, JB Atkinson, RN Vinson, NA Catanzaro, JL Perretta, CL Fix, SE Mascarella, SW Rothman, RB Xu, H Dersch, CM Cantrell, BE Zimmerman, DM Carroll, FI AF Thomas, JB Atkinson, RN Vinson, NA Catanzaro, JL Perretta, CL Fix, SE Mascarella, SW Rothman, RB Xu, H Dersch, CM Cantrell, BE Zimmerman, DM Carroll, FI TI Identification of (3R)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-pi peridinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarbo xamide as a novel potent and selective opioid kappa receptor antagonist SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PHARMACOLOGICAL CHARACTERIZATION; FUNCTIONAL EXPRESSION; OPIATE RECEPTOR; N-SUBSTITUENT; CLONING; LIGANDS; CDNA; BINDING; (+)-(3R,4R)-DIMETHYL-4-(3-HYDROXYPHENYL)PIPERIDINE; AFFINITY AB (3R)-7-Hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic) was identified as a potent and selective kappa opioid receptor antagonist. Structure-activity relationship (SAR) studies on JDTic analogues revealed that the 3R,4R stereochemistry of the 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine core structure, the 3R attachment of the 7-hydroxy-1,2,3,4-tetrahydroisoquinoline group, and the 1S configuration of the 2-methylpropyl (isopropyl) group were all important to its kappa potency and selectivity. The results suggest that, like other kappa opioid antagonists such as nor-BNI and GNTI, JDTic requires a second basic amino group to express potent and selective kappa antagonist activity in the [35 SIGTPgammaS functional assay. However, unlike previously reported kappa antagonists, JDTic also requires a second phenol group in rigid proximity to this second basic amino group. The potent and selective kappa antagonist properties of JDTic can be rationalized using the "message-address" concept wherein the (3R,4R)-3,4-dimethyl4-(hydroxyphenyl)piperidinyl group represents the message, and the basic amino and phenol group in the N substituent constitutes the address. It is interesting to note the structural commonality (an amino and phenol groups) in both the message and address components of JDTic. The unique structural features of JDTic will make this compound highly useful in further characterization of the kappa receptor. C1 Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Natl Inst Drug Abuse, Intramural Res Program, Clin Psychopharmacol Sect, NIH, Baltimore, MD 21224 USA. Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Carroll, FI (reprint author), Res Triangle Inst, 3040 Cornwallis Rd, Res Triangle Pk, NC 27709 USA. EM fic@rti.org FU NIDA NIH HHS [DA 09045] NR 30 TC 56 Z9 58 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 JUL 3 PY 2003 VL 46 IS 14 BP 3127 EP 3137 DI 10.1021/jm030094y PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 695HF UT WOS:000183824500030 PM 12825951 ER PT J AU Langford, CA AF Langford, CA TI Treatment of ANCA-associated vasculitis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NIAID, Immunol Dis Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Langford, CA (reprint author), NIAID, Immunol Dis Sect, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 22 Z9 26 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 JUL 3 PY 2003 VL 349 IS 1 BP 3 EP 4 DI 10.1056/NEJMp030047 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 696PW UT WOS:000183896100001 PM 12840085 ER PT J AU Nabel, EG AF Nabel, EG TI Cardiovascular disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID ACTIVATED PROTEIN-C; LEFT-VENTRICULAR HYPERTROPHY; CONVERTING ENZYME GENE; LONG-QT SYNDROME; INHERITED CARDIAC-ARRHYTHMIA; RANDOMIZED CONTROLLED-TRIAL; EPITHELIAL SODIUM-CHANNEL; CONGESTIVE-HEART-FAILURE; MYOCARDIAL-INFARCTION; HUMAN HYPERTENSION C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Nabel, EG (reprint author), NHLBI, NIH, Bldg 10-8C103,10 Ctr Dr, Bethesda, MD 20892 USA. NR 94 TC 195 Z9 210 U1 3 U2 6 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 3 PY 2003 VL 349 IS 1 BP 60 EP 72 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 696PW UT WOS:000183896100011 PM 12840094 ER PT J AU Davis, BR Wright, JT Cutler, JA AF Davis, BR Wright, JT Cutler, JA TI Angiotensin-converting-enzyme inhibitors and diuretics for hypertension SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Univ Texas, Hlth Sci Ctr, Houston, TX 77030 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. NHLBI, Bethesda, MD 20892 USA. RP Davis, BR (reprint author), Univ Texas, Hlth Sci Ctr, Houston, TX 77030 USA. NR 1 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 JUL 3 PY 2003 VL 349 IS 1 BP 91 EP 92 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 696PW UT WOS:000183896100023 ER PT J AU Schoen, RE Pinsky, PF Weissfeld, JL Bresalier, RS Church, T Prorok, P Gohagan, JK AF Schoen, RE Pinsky, PF Weissfeld, JL Bresalier, RS Church, T Prorok, P Gohagan, JK CA Prostate Lung Colorectal Ovarian C TI Results of repeat sigmoidoscopy 3 years after a negative examination SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID SCREENING FLEXIBLE SIGMOIDOSCOPY; AVERAGE-RISK PERSONS; COLORECTAL-CANCER; ASYMPTOMATIC ADULTS; NURSE ENDOSCOPISTS; COLONOSCOPY; ADENOMAS; POLYPS; YIELD; TRIAL AB Context The necessary frequency of endoscopic colorectal cancer screening after a negative examination is uncertain. Objective To examine the yield of adenomas and cancer in the distal colon found by repeat flexible sigmoidoscopy (FSG) 3 years after a negative examination. Design, Setting, and Participants Participants were drawn from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), a randomized, controlled community-based study of cancer screening. The mean (SD) age was 65.7 (4.0) years at study entry (1993-1995) and 61.6% were men. individuals underwent screening FSG at baseline and at 3 years as part of the protocol and were referred to their personal physicians for further evaluation of screen-detected abnormalities. Results from subsequent diagnostic evaluations were tracked in a standardized fashion. Of 11583 eligible for repeat screening FSG 3 years after an initial negative examination, 9317 (80.4%) returned. Main Outcome Measures Polyp or mass detection in distal colon at year 3 repeat FSG; incidence of adenoma or cancer in distal colon at year 3 examination; determination of reason for detection (increased depth of insertion or improved preparation at the year 3 examination or detection in a previously examined area). Results A total of 1292 returning participants (13.9%) had a polyp or mass detected by FSG 3 years after the initial examination. In the distal colon, 3.1% (292/ 9317) were found to have an adenoma or cancer. The incidence of advanced adenoma (n=72) or cancer (n=6) in the distal colon was 78 (0.8%)of 9317. Of individuals with advanced distal adenomas detected at the year 3 examination, 80.6% (58/72) had lesions found in a portion of the colon that had been adequately examined at the initial sigmoidoscopy. Conclusions Repeat FSG 3 years after a negative examination will detect advanced adenomas and distal colon cancer. Although the overall percentage with detected abnormalities is modest, these data raise concern about the impact of a prolonged screening interval after a negative examination. C1 Univ Pittsburgh, Pittsburgh Canc Inst, Pittsburgh, PA USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Div Gastrointestinal Med & Nutr, Houston, TX 77030 USA. Univ Minnesota, Div Environm & Occupat Hlth, Minneapolis, MN USA. RP Schoen, RE (reprint author), Presbyterian Univ Hosp, Div Gastroenterol & Hepatol, Mezzanine Level,C Wing,200 Lothrop St, Pittsburgh, PA 15213 USA. OI Church, Timothy R./0000-0003-3292-5035 FU NCI NIH HHS [N01-CN2551] NR 35 TC 69 Z9 70 U1 0 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 2 PY 2003 VL 290 IS 1 BP 41 EP 48 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 696CR UT WOS:000183868600018 PM 12837710 ER PT J AU Chudasama, Y Baunez, C Robbins, TW AF Chudasama, Y Baunez, C Robbins, TW TI Functional disconnection of the medial prefrontal cortex and subthalamic nucleus in attentional performance: Evidence for corticosubthalamic interaction SO JOURNAL OF NEUROSCIENCE LA English DT Article DE disconnection; attention; medial prefrontal cortex; subthalamic nucleus; behavior; basal ganglia ID SPATIAL WORKING MEMORY; REACTION-TIME-TASK; PARKINSONS-DISEASE; BASAL GANGLIA; CEREBRAL-CORTEX; RESPONSE CHARACTERISTICS; EXTERNAL PALLIDUM; LESIONS; RAT; STIMULATION AB The present study used a disconnection procedure to test whether the medial prefrontal cortex (mPFC) and the subthalamic nucleus (STN) were functional components in a common neural system that controlled continuous performance in a test of sustained and divided visual attention. Animals with disconnected lesions of the mPFC and STN in contralateral hemispheres were severely impaired in several aspects of performance, including discriminative accuracy, increased perseveration, and slowed response latencies during postoperative testing. These deficits persisted throughout the entire experimental test period. Increasing the stimulus duration alleviated the accuracy deficit but failed to improve speed of responding or reduce perseverative responses. These deficits were in marked contrast to animals with combined mPFC and STN lesions made on the ipsilateral side, which produced behavior not different from that of sham controls. Rats with unilateral lesions of either structure alone were also impaired in terms of accuracy and perseveration. These data suggest that some of the deficits observed after bilateral STN lesions ( attention and perseveration) may be attributable to a disrupted corticosubthalamic projection. This study provides direct evidence that performance in tasks that require optimal attentional and executive control relies on a corticosubthalamic interaction within the neural circuitry of the basal ganglia. C1 Univ Cambridge, Dept Expt Psychol, Cambridge CB2 3EB, England. CNRS, Lab Neurobiol Cognit, F-13402 Marseille 20, France. RP Chudasama, Y (reprint author), NIMH, Neuropsychol Lab, 49 convent Dr,Bldg 49,Room 1B80, Bethesda, MD 20892 USA. EM yogita@ln.nimh.nih.gov RI BAUNEZ, Christelle/B-2255-2008 NR 44 TC 77 Z9 80 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 2 PY 2003 VL 23 IS 13 BP 5477 EP 5485 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 697CF UT WOS:000183924100010 PM 12843247 ER PT J AU Bachis, A Major, EO Mocchetti, I AF Bachis, A Major, EO Mocchetti, I TI Brain-derived neurotrophic factor inhibits human immunodeficiency virus-1/gp120-mediated cerebellar granule cell death by preventing gp120 internalization SO JOURNAL OF NEUROSCIENCE LA English DT Article DE apoptosis; BDNF; caspase-3; CXCR4; CCR5; SDF-1 alpha ID CHEMOKINE RECEPTOR CXCR4; NERVE GROWTH-FACTOR; VIRUS TYPE-1; COAT PROTEIN; GP120-INDUCED NEUROTOXICITY; GLYCOPROTEIN GP120; NEURONAL APOPTOSIS; HIV GLYCOPROTEIN; NITRIC-OXIDE; RAT AB The human immunodeficiency virus type 1 (HIV-1) envelope protein gp120 has been implicated in the pathogenesis of HIV-1 dementia. Thus, inhibition of gp120 activity could reduce HIV toxicity in the brain. We have used primary cultures of rat cerebellar granule cells to examine mechanisms whereby gp120 causes cell death and to characterize neuroprotective agents. gp120 induced a time- and concentration-dependent apoptotic cell death, which was caspase-3-mediated but caspase-1 independent, and was totally blocked by the irreversible caspase-3-like protease inhibitor N-acetyl-Asp-Glu-Val-Asp-chloromethylketone. Caspase-3 activation was observed only in neurons that internalize gp120, indicating that internalization is key to gp120 toxicity. Because brain-derived neurotrophic factor (BDNF) prevents caspase-3-mediated neuronal cell death, we examined whether BDNF could prevent gp120-mediated apoptosis. Preincubation of neurons with BDNF before the addition of gp120 reduced caspase-3 activation, and consequently rescued 80% of neurons from apoptosis. Most importantly, BDNF reduced the levels of CXC chemokine receptor-4 (CXCR4), a receptor that mediates HIV-1 gp120-induced apoptosis. This effect correlated with the ability of BDNF to reduce gp120 internalization and apoptosis. Moreover, BDNF blocked the neurotoxic effect of stromal-derived factor-1alpha, a natural ligand for CXCR4, further establishing a correlation between neuroprotection and downregulation of CXCR4. We propose that BDNF may be a valid therapy to slow down the progression of HIV/gp120-mediated neurotoxicity. C1 NINDS, Lab Mol Med & Neurosci, Bethesda, MD 20814 USA. RP Mocchetti, I (reprint author), Georgetown Univ, Med Ctr, Dept Neurosci, Res Bldg,Room EP04,Box 571464, Washington, DC 20057 USA. FU NINDS NIH HHS [NS40670] NR 46 TC 85 Z9 88 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 2 PY 2003 VL 23 IS 13 BP 5715 EP 5722 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 697CF UT WOS:000183924100038 PM 12843275 ER PT J AU Abraham, IM Han, SK Todman, MG Korach, KS Herbison, AE AF Abraham, IM Han, SK Todman, MG Korach, KS Herbison, AE TI Estrogen receptor beta mediates rapid estrogen actions on gonadotropin-releasing hormone neurons in vivo SO JOURNAL OF NEUROSCIENCE LA English DT Article DE CREB; estrogen; estrogen receptor beta; GnRH; LHRH; nongenomic; rapid; transgenics ID ELEMENT-BINDING PROTEIN; CENTRAL-NERVOUS-SYSTEM; RAT-BRAIN; COUPLED RECEPTORS; MEMBRANE-RECEPTOR; NEGATIVE FEEDBACK; KINASE PATHWAY; GNRH NEURONS; ACTIVATION; ESTRADIOL AB The gonadal steroid estrogen exerts an important modulatory influence on the activity of multiple neuronal networks. In addition to classical genomic mechanisms of action, estrogen also exerts poorly understood rapid, nongenomic effects on neurons. To examine whether estrogen may exert rapid actions on intracellular signaling within gonadotropin-releasing hormone (GnRH) neurons in vivo, we examined the phosphorylation status of cAMP response element-binding protein (CREB) in these cells after the administration of 17-beta-estradiol to ovariectomized (OVX) mice. The percentage of GnRH neurons expressing phosphorylated CREB was increased more than sixfold (p < 0.05) in a time- and dose-dependent manner by estrogen, with the increase first observed 15 min after estrogen administration. A series of in vitro studies demonstrated that estrogen acted directly on native GnRH neurons to phosphorylate CREB, but that estrogen conjugated to bovine serum albumin was without effect. The role of classical estrogen receptors (ERs) was evaluated using ER knock-out mice in vivo. The effect of estrogen on CREB phosphorylation in GnRH neurons was normal in ERα knock-out mice but completely absent in ERβ knock-out mice. Finally, studies in intact female mice revealed levels of CREB phosphorylation within GnRH neurons that were equivalent to those of estrogen-treated OVX mice. These observations demonstrate that ERβ mediates the rapid, direct effects of estrogen on the GnRH neuronal phenotype, and that these actions persist under physiological conditions. They also provide the first evidence for a role of ERβ in nongenomic estrogen signaling within the brain in vivo. C1 Univ Otago, Sch Med Sci, Dept Physiol, Ctr Neuroendocrinol, Dunedin, New Zealand. Babraham Inst, Neuroendocrinol Lab, Cambridge CB2 4AT, England. NIEHS, Reprod & Dev Toxicol Lab, Recptor Biol Sect, Res Triangle Pk, NC 27709 USA. RP Herbison, AE (reprint author), Univ Otago, Sch Med Sci, Dept Physiol, Ctr Neuroendocrinol, POB 913, Dunedin, New Zealand. OI Korach, Kenneth/0000-0002-7765-418X NR 52 TC 168 Z9 170 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 2 PY 2003 VL 23 IS 13 BP 5771 EP 5777 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 697CF UT WOS:000183924100044 PM 12843281 ER PT J AU Gakh, AA Romanovich, AY Bax, A AF Gakh, AA Romanovich, AY Bax, A TI Thermodynamic rearrangement synthesis and NMR structures of C-1, C-3, and T isomers of C60H36 SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID TRANSFER HYDROGENATION; SENSITIVITY; C60F36; 9,10-DIHYDROANTHRACENE; BUCKMINSTERFULLERENE; SPECTROSCOPY; C-60 AB The structures of three C60H36 isomers, produced by high-temperature transfer hydrogenation of C-60 in a 9,10-dihydroanthracene melt, was accomplished by 2D H-1-detected NMR experiments, recorded at 800 MHz. The unsymmetrical C, isomer is found to be the most abundant one (60-70%), followed by the C-3 isomer (25-30%) and the least abundant T isomer (2-5%). All three isomers are closely related in structure and have three vicinal hydrogens located on each of the 12 pentagons. Facile hydrogen migration on the fullerene surface during annealing at elevated temperatures is believed to be responsible for the preferential formation of these thermodynamically most stable C60H36 isomers. This hypothesis was further supported by thermal conversion of C60H36 isomers to a single C3(v) isomer of C60H18. C1 Oak Ridge Natl Lab, Oak Ridge, TN 37831 USA. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Oak Ridge Natl Lab, Oak Ridge, TN 37831 USA. EM gakhaa@ornl.gov NR 22 TC 33 Z9 33 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUL 2 PY 2003 VL 125 IS 26 BP 7902 EP 7906 DI 10.1021/ja0353321 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA 695CX UT WOS:000183814500047 PM 12823010 ER PT J AU Havlin, RH Park, GHJ Mazur, T Pines, A AF Havlin, RH Park, GHJ Mazur, T Pines, A TI Using switched angle spinning to simplify NMR spectra of strongly oriented samples SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MAGNETIC-RESONANCE SPECTRA; NEMATIC LIQUID-CRYSTALS; MAGIC ANGLE; C-13 NMR; DIRECTOR DYNAMICS; SHIELDING TENSORS; DIPOLAR COUPLINGS; FIELD; SPECTROSCOPY; SOLIDS AB This contribution describes a method that manipulates the alignment director of a liquid crystalline sample to obtain anisotropic magnetic interaction parameters, such as dipolar coupling, in an oriented liquid crystalline sample. By changing the axis of rotation with respect to the applied magnetic field in a spinning liquid crystalline sample, the dipolar couplings present in a normally complex strong coupling spectrum are scaled to a simple weak coupling spectrum. This simplified weak coupling spectrum is then correlated with the isotropic chemical shift in a switched angle spinning (SAS) two-dimensional (2D) experiment. This dipolar-isotropic 2D correlation was also observed for the case where the couplings are scaled to a degree where the spectrum approaches strong coupling. The SAS 2D correlation of C6F5Cl in the nematic liquid crystal I52 was obtained by first evolving at an angle close to the magic angle (54.7degrees) and then directly detecting at the magic angle. The SAS method provides a 2D correlation where the weak coupling pairs are revealed as cross-peaks in the indirect dimension separated by the isotropic chemical shifts in the direct dimension. Additionally, by using a more complex SAS method which involves three changes of the spinning axis, the solidlike spinning sideband patterns were correlated with the isotropic chemical shifts in a 2D experiment. These techniques are expected to enhance the interpretation and assignment of an isotropic. magnetic interactions including dipolar couplings for molecules dissolved in oriented liquid crystalline phases. C1 Univ Calif Berkeley, Div Mat Sci, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA. Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. RP Havlin, RH (reprint author), NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. NR 38 TC 14 Z9 14 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUL 2 PY 2003 VL 125 IS 26 BP 7998 EP 8006 DI 10.1021/ja0342244 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 695CX UT WOS:000183814500059 PM 12823022 ER PT J AU Kaye, FJ Komiya, T AF Kaye, FJ Komiya, T TI New leads suggest a clinically relevant genotype-phenotype relationship for the p53 gene SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID LUNG-CANCER; P73 FUNCTION; MUTATIONS C1 NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20889 USA. Natl Naval Med Res Inst, Bethesda, MD USA. RP Kaye, FJ (reprint author), NCI, Genet Branch, Ctr Canc Res, Bldg 8,Rm 5101, Bethesda, MD 20889 USA. EM kayef@navmed.nci.nih.gov RI kaye, frederic/E-2437-2011 NR 17 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 2 PY 2003 VL 95 IS 13 BP 926 EP 927 PG 2 WC Oncology SC Oncology GA 696XM UT WOS:000183912900001 PM 12837819 ER PT J AU Longo, DL AF Longo, DL TI Radiation therapy in the treatment of Hodgkin's disease - Do you see what I see? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID FOLLOW-UP; CHEMOTHERAPY; RISK; MOPP; ABVD; METAANALYSIS; RADIOTHERAPY; IRRADIATION; LYMPHOMA; LEUKEMIA C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Longo, DL (reprint author), NIA, Gerontol Res Ctr, Box 09,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 17 TC 15 Z9 15 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 JUL 2 PY 2003 VL 95 IS 13 BP 928 EP 929 PG 2 WC Oncology SC Oncology GA 696XM UT WOS:000183912900002 PM 12837820 ER PT J AU van Leeuwen, FE Klokman, WJ Stovall, M Dahler, EC van't Veer, MB Noordijk, EM Crommelin, MA Aleman, BMP Broeks, A Gospodarowicz, M Travis, LB Russell, NS AF van Leeuwen, FE Klokman, WJ Stovall, M Dahler, EC van't Veer, MB Noordijk, EM Crommelin, MA Aleman, BMP Broeks, A Gospodarowicz, M Travis, LB Russell, NS TI Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin's disease SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ATOMIC-BOMB SURVIVORS; 2ND MALIGNANT NEOPLASMS; LONG-TERM SURVIVORS; POOLED ANALYSIS; INCREASED RISK; WOMEN; IRRADIATION; THERAPY; RADIOTHERAPY; CHILDHOOD AB Background: Female survivors of Hodgkin's disease (HD) have a strongly elevated risk of breast cancer, but factors responsible for the increased risk are not well known. Methods: We investigated the effects of radiation dose, chemotherapy (CT), and reproductive factors on breast cancer risk in a nested case-control study in The Netherlands in a cohort of 770 female patients who had been diagnosed with HD before age 41. Detailed treatment information and data on reproductive factors were collected for 48 case patients who developed breast cancer 5 or more years after diagnosis of HD and 175 matched control subjects. The radiation dose was estimated to the area of the breast where the case patient's tumor had developed and to a comparable location in matched control subjects. Relative risks (RRs) of breast cancer were calculated by conditional logistic regression. Statistical tests were two-sided. Results: The risk of breast cancer increased statistically significantly with radiation dose (P-trend = .01); patients who received 38.5 Gy or more had an RR of 4.5 (95% confidence interval [CI] = 1.3 to 16) times that of patients who received less than 4 Gy. Patients who received both CT and radiotherapy (RT) had a statistically significantly lower risk than those treated with RT alone (RR = 0.45, 95% CI = 0.22 to 0.91). Breast cancer risk increased with increasing radiation dose among patients who received RT only (RR = 12.7, 95% CI = 1.8 to 86, for patients receiving greater than or equal to38.5 Gy) but not among patients treated with CT and RT. Sixty-nine percent of control subjects treated with RT and more than six cycles of CT, but only 9% of those who received RT alone, reached menopause before age 41. Reaching menopause before age 36 was associated with a strongly reduced risk of breast cancer (RR = 0.06, 95% CI = 0.01 to 0.45). Conclusion: Breast cancer risk increases with increasing radiation dose up to at least 40 Gy. The substantial risk reduction associated with CT may reflect its effect on menopausal age, suggesting that ovarian hormones promote tumorigenesis after radiation has produced an initiating event. C1 Netherlands Canc Inst, Dept Epidemiol, NL-1066 CX Amsterdam, Netherlands. Netherlands Canc Inst, Dept Radiotherapy, NL-1066 CX Amsterdam, Netherlands. Netherlands Canc Inst, Dept Expt Therapy, NL-1066 CX Amsterdam, Netherlands. Univ Texas, MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. Erasmus Med Ctr, Dr Daniel Den Hoed Canc Ctr, Dept Hematol, Rotterdam, Netherlands. Leiden Univ, Ctr Med, Dept Clin Oncol, Leiden, Netherlands. Catharina Hosp, Eindhoven, Netherlands. Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP van Leeuwen, FE (reprint author), Netherlands Canc Inst, Dept Epidemiol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. FU NCI NIH HHS [N01-CP-91024] NR 56 TC 233 Z9 236 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 JUL 2 PY 2003 VL 95 IS 13 BP 971 EP 980 PG 10 WC Oncology SC Oncology GA 696XM UT WOS:000183912900012 PM 12837833 ER PT J AU Leitzmann, MF Stampfer, MJ Wu, KN Colditz, GA Willett, WC Giovannucci, EL AF Leitzmann, MF Stampfer, MJ Wu, KN Colditz, GA Willett, WC Giovannucci, EL TI Zinc supplement use and risk of prostate cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID TELOMERASE ACTIVITY; CELL INVASION; INHIBITION; HEALTH; GROWTH; BREAST AB The high concentration of zinc in the prostate suggests that zinc may play a role in prostate health. We examined the association between supplemental zinc intake and prostate cancer risk among 46974 U.S. men participating in the Health Professionals Follow-Up Study. During 14 years of follow-up from 1986 through 2000, 2901 new cases of prostate cancer were ascertained, of which 434 cases were diagnosed as advanced cancer. Supplemental zinc intake at doses of up to 100 mg/day was not associated with prostate cancer risk. However, compared with nonusers, men who consumed more than 100 mg/day of supplemental zinc had a relative risk of advanced prostate cancer of 2.29 (95% confidence interval = 1.06 to 4.95; P-trend = .003), and men who took supplemental zinc for 10 or more years had a relative risk of 2.37 (95% confidence interval = 1.42 to 3.95; P-trend < .001). Although we cannot rule out residual confounding by supplemental calcium intake or some unmeasured correlate of zinc supplement use, our findings, that chronic zinc oversupply may play a role in prostate carcinogenesis, warrant further investigation. C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Channing Lab, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Leitzmann, MF (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd,EPS-MSC 7232, Bethesda, MD 20892 USA. RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NCI NIH HHS [5T32 CA09001-26, CA55075]; NHLBI NIH HHS [HL35464] NR 18 TC 124 Z9 127 U1 0 U2 8 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 JUL 2 PY 2003 VL 95 IS 13 BP 1004 EP 1007 PG 4 WC Oncology SC Oncology GA 696XM UT WOS:000183912900016 PM 12837837 ER PT J AU Gutierrez, MI Straus, SE Ibrahim, MM Dale, JK Bhatia, K AF Gutierrez, MI Straus, SE Ibrahim, MM Dale, JK Bhatia, K TI Re: Discrete alterations in the BZLF1 promoter in tumor and non-tumor-associated Epstein-Barr virus - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 King Fahad Natl Childrens Canc Ctr & Res, Riyadh, Saudi Arabia. NIAID, Div Intramural Res, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Bhatia, K (reprint author), King Faisal Specialist Hosp & Res Ctr, POB 3354,MBC 98-16, Riyadh 11211, Saudi Arabia. NR 4 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 2 PY 2003 VL 95 IS 13 BP 1009 EP 1009 PG 1 WC Oncology SC Oncology GA 696XM UT WOS:000183912900018 ER PT J AU Vannier, MW Staab, EV Clarke, LP AF Vannier, MW Staab, EV Clarke, LP TI Cancer Imaging Informatics Workshop report from the Biomedical Imaging Program of the National Cancer Institute SO ACADEMIC RADIOLOGY LA English DT Article ID RESOURCE; ARCHIVE C1 NCI, Biomed Imaging Program, NIH, Bethesda, MD 20892 USA. Univ Iowa, Dept Radiol, Iowa City, IA 52242 USA. RP Vannier, MW (reprint author), NCI, Biomed Imaging Program, NIH, Bethesda, MD 20892 USA. OI Vannier, Michael/0000-0001-9898-384X NR 19 TC 2 Z9 2 U1 0 U2 0 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD JUL PY 2003 VL 10 IS 7 BP 798 EP 802 DI 10.1016/S1076-6332(03)80126-5 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 697RM UT WOS:000183957100011 PM 12862290 ER PT J AU Asojo, OA Boulegue, C Hoover, DM Lu, WY Lubkowski, J AF Asojo, OA Boulegue, C Hoover, DM Lu, WY Lubkowski, J TI Structures of thymus and activation-regulated chemokine (TARC) SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID CC-CHEMOKINE; MOLECULAR REPLACEMENT; X-RAY; RECEPTOR; EXPRESSION; CELLS; MOLSCRIPT; CLONING; GAMMA; MICE AB Thymus and activation-regulated chemokine (TARC) is a CC chemokine that is mainly expressed in the thymus. TARC interacts primarily with the CCR4 receptor and to a lesser extent with the CCR8 receptor. The structures of TARC have been solved by molecular replacement in two space groups, triclinic (P1) and tetragonal (P4(1)), and refined to resolutions of 1.72 and 2.1 Angstrom, respectively, with R factors of 19.8% (R-free = 24.1%) and 19.8% (R-free = 27.7%), respectively. The search model originated from the crystal structure of another chemokine, RANTES, and proved to be only modestly similar to the refined structure of TARC. Whereas the tetragonal structure was easily solved using the program AMoRe, solution of the triclinic structure proved to be quite challenging and was obtained by combining the results from four different molecular-replacement programs (AMoRe, CNS, BEAST and EPMR), with subsequent extension of the gathered information. The tertiary structure of TARC is similar to that of other CC chemokines, with a three-stranded antiparallel beta-sheet flanked by a C-terminal helix. Both quaternary structures consist of dimers, which in the triclinic crystals pack further into tetramers. The TARC dimers are similar to those observed previously in the crystal structures of both MCP-1 and RANTES. C1 NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. Univ Maryland, Inst Biotechnol, Inst Human virol, Baltimore, MD 21201 USA. RP Lubkowski, J (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RI Boulegue, Cyril/A-4092-2009; Lu, Wuyuan/B-2268-2010; OI Asojo, Oluwatoyin/0000-0002-4043-2700 NR 33 TC 11 Z9 15 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JUL PY 2003 VL 59 BP 1165 EP 1173 DI 10.1107/S0907444903009454 PN 7 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 695AX UT WOS:000183809900007 PM 12832759 ER PT J AU Olive, M Goldfarb, L Dagvadorj, A Sambuughin, N Paulin, D Li, ZL Goudeau, B Vicart, P Ferrer, I AF Olive, M Goldfarb, L Dagvadorj, A Sambuughin, N Paulin, D Li, ZL Goudeau, B Vicart, P Ferrer, I TI Expression of the intermediate filament protein synemin in myofibrillar myopathies and other muscle diseases SO ACTA NEUROPATHOLOGICA LA English DT Article DE synemin; desmin; desmin-related myopathies; inclusion body myositis; oculopharyngeal muscular dystrophy ID ALPHA-B-CRYSTALLIN; MUSCULAR-DYSTROPHY; SKELETAL MYOPATHY; DESMIN POSITIVITY; GENE; MUTATIONS; PLECTIN; IDENTIFICATION; PARANEMIN; DYNAMICS AB Synemin is a member of the intermediate protein superfamily. Previous studies in avian and rodent skeletal and cardiac muscles have demonstrated that synemin localises at the Z-band, where it associates with desmin and alpha-actinin. In the present study, the distribution of synemin was examined using immunohistochemistry in muscle biopsy specimens from patients suffering from myofibrillar myopathy (MM, n=6), dermatomyositis (DM, n=3), inclusion body myositis (IBM, n=5), oculopharyngeal muscular dystrophy (OPD, n=3) and denervation atrophy (DA, n=3), to investigate the possible participation of this protein in the pathogenesis of various muscular diseases. Of patients affected by MM, two showed the presence of mutations in the desmin gene; none had mutations in the alphaB-crystallin gene; and no mutations were identified in synemin or syncoilin genes of three patients. Synemin immunohistochemistry disclosed a faint staining corresponding to the Z-bands in the cytoplasm of control muscle fibres; in contrast, focal aggregates of synemin were seen in patients with MM. Increased synemin immunoreactivity was identified diffusely or in the subsarcolemmal space of scattered fibres in patients with DM, and in vacuolated fibres of patients with IBM and OPD. Strong synemin immunoreactivity was observed in target formations and atrophic fibres of patients with denervating disorders, as well as in atrophic fibres, regardless of their origin, in all patients studied. Synemin co-localised with desmin, as seen on consecutive serial sections immunostained with anti-synemin or anti-desmin antibodies. These observations demonstrate abnormal accumulations containing both synemin and desmin in muscle fibres in patients with MM, IBM, DM, OPD and DA. Considering the important role of synemin as one of intermediate filaments of skeletal and cardiac muscle, its destruction and accumulation in the intracellular debris suggest that synemin may participate in the pathogenesis of these disorders. C1 Ciutat Sanitaria & Univ Bellvitge, Hosp Llobregat, Inst Neuropatol, Barcelona 08907, Spain. NINDS, Clin Neurogenet Unit, NIH, Bethesda, MD 20892 USA. Univ Denis Diderot, Paris, France. Univ Paris 06, Lab Cytosquelette & Dev, Paris, France. RP Olive, M (reprint author), Ciutat Sanitaria & Univ Bellvitge, Hosp Llobregat, Inst Neuropatol, C Feixa Llarga S-N, Barcelona 08907, Spain. RI Li, Zhenlin/E-3937-2016; OI Olive, Montse/0000-0001-5727-0165 NR 30 TC 11 Z9 14 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0001-6322 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD JUL PY 2003 VL 106 IS 1 BP 1 EP 7 DI 10.1007/s00401-003-0695-0 PG 7 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 695WL UT WOS:000183853300001 PM 12669240 ER PT J AU Winterer, G Enoch, MA White, KV Saylan, M Coppola, R Goldman, D AF Winterer, G Enoch, MA White, KV Saylan, M Coppola, R Goldman, D TI EEG phenotype in alcoholism: increased coherence in the depressive subtype SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Article DE alcoholism; quantitative trait; electroencephalography; cortical synchronization ID HUMAN ELECTROENCEPHALOGRAM EEG; TO-NOISE RATIO; ASSOCIATION ANALYSIS; ALPHA-EEG; DEPENDENCE; GENE; SCHIZOPHRENIA; ACTIVATION; DISORDERS; TWINS AB Objective: Electroencephalography (EEG) power and coherence changes may be trait markers for alcoholism providing clues to brain mechanisms of vulnerability. However, it is unclear whether alpha power and coherence differences reflect reversible toxic or withdrawal effects of alcohol. Method: The EEGs of 10 non-abstinent and 16 long-term abstinent alcoholics (7.7 +/- 5.8 years) and 25 controls were analyzed. Levels of anxiety and depression were assessed by questionnaire. Results: No statistically significant EEG power differences were observed between groups, although the numerical difference between alcoholics and controls was similar to that previously reported. Bilateral, intrahemispheric, posterior coherences were significantly increased in the alpha and beta frequency bands both in long-term abstinent and non-abstinent alcohol-dependent subjects - particularly when depressiveness was included as a covariate. Conclusion: These results suggest that increased EEG-coherence (cortical synchronization) may serve as endophenotype for alcoholism in conjunction with increased depressiveness and point to a possible involvement of GABAergic and/or glutamatergic neurotransmission. C1 NIMH, Unit Mol Neuroimaging, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. RP Winterer, G (reprint author), NIMH, Unit Mol Neuroimaging, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,Rm 4s235 MSC 1379, Bethesda, MD 20892 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 56 TC 34 Z9 39 U1 1 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-690X J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD JUL PY 2003 VL 108 IS 1 BP 51 EP 60 DI 10.1034/j.1600-0447.2003.00060.x PG 10 WC Psychiatry SC Psychiatry GA 689WV UT WOS:000183516700008 PM 12807377 ER PT J AU Uhl, GR AF Uhl, GR TI Are over-simplified views of addiction neuroscience providing too simplified ethical considerations? Commentary SO ADDICTION LA English DT Editorial Material C1 NIDA, Mol Neurobiol Branch, IRP, NIH, Baltimore, MD 21224 USA. RP Uhl, GR (reprint author), NIDA, Mol Neurobiol Branch, IRP, NIH, POB 5180, Baltimore, MD 21224 USA. NR 4 TC 5 Z9 5 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD JUL PY 2003 VL 98 IS 7 BP 872 EP 873 DI 10.1046/j.1360-0443.2003.00453.x PG 2 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 694ZY UT WOS:000183807300004 PM 12814491 ER PT J AU Conway, KP Swendsen, JD Merikangas, KR AF Conway, KP Swendsen, JD Merikangas, KR TI Alcohol expectancies, alcohol consumption, and problem drinking - The moderating role of family history SO ADDICTIVE BEHAVIORS LA English DT Article DE family history; alcoholism; moderator; alcohol expectancies; drinking behavior ID SUBSTANCE USE DISORDERS; PSYCHIATRIC-DISORDERS; ANXIETY DISORDERS; DRUG-ABUSE; COMORBIDITY; RISK; PSYCHOPATHOLOGY; ADOLESCENT; DEPENDENCE; BEHAVIOR AB The purpose of this investigation was to examine the moderating role of family history (FH) of alcohol use disorders on the association between positive alcohol expectancies and drinking behavior (quantity/frequency of drinking and alcohol-related problems). Lifetime DSM-III-R diagnoses of alcohol abuse/dependence in probands from the Yale Family Study were used to classify FH status of adult relatives, yielding 149 relatives of probands with alcohol abuse/dependence and 110 relatives of controls. Significant main effects were found for FH of alcoholism on problem drinking symptoms and for alcohol expectancies concerning both problem drinking symptoms and quantity/frequency of alcohol use. Regarding moderating effects, there was a significant interaction between alcohol expectancies and FH only for problem drinking symptoms. When familial density of alcoholism was examined as a moderator, significant effects were found for all drinking variables, thus demonstrating that the degree to which alcohol expectancies was associated with the drinking outcomes varied by the extent to which alcohol use disorders clustered in families. The findings arediscussed in terms of the interaction of alcohol-related risk factors and the importance of using multiple indicators of familial vulnerability. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. Univ Bordeaux, Clin Psychol Res Lab, F-33076 Bordeaux, France. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. RP Conway, KP (reprint author), NIDA, Div Epidemiol Serv & Prevent Res, 6001 Execut Blvd,Suite 5151 MSC 9589, Bethesda, MD 20892 USA. OI Conway, Kevin/0000-0002-7638-339X FU NIAAA NIH HHS [AA07080, AA09978, AA00143]; NIDA NIH HHS [DA05592, DA00089, DA00293, DA00617, DA05348, DA09241, DA09055]; NIMH NIH HHS [MH36197, K02-MH00499] NR 50 TC 31 Z9 32 U1 2 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD JUL PY 2003 VL 28 IS 5 BP 823 EP 836 DI 10.1016/S0306-4603(02)00265-4 PG 14 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 691BY UT WOS:000183586000001 PM 12788259 ER PT J AU Mattson, MP AF Mattson, MP TI Methylation and acetylation in nervous system development and neurodegenerative disorders SO AGEING RESEARCH REVIEWS LA English DT Review DE aging; Alzheimer's disease; apoptosis; oxidative stress; Parkinson's disease ID HISTONE-DEACETYLASE INHIBITORS; AMYLOID BETA-PEPTIDE; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; PLASMA HOMOCYSTEINE; S-ADENOSYLMETHIONINE; HUNTINGTONS-DISEASE; PHOSPHOLIPID METHYLATION; COGNITIVE IMPAIRMENT; PRECURSOR PROTEIN AB The cytoarchitecture and cellular signaling mechanisms of the nervous system are complex, and this complexity is reflected at the molecular level with more genes being expressed in the nervous system than in any other tissue. Gene expression and protein function in neural cells can be regulated by methylation and acetylation. Studies of mice deficient in enzymes that control DNA methylation and of animals with a dietary deficiency of folate have established critical roles for methylation in development of the nervous system. Various neuronal proteins including histones and tubulin are regulated by acetylation which appears to serve important functions in the development, stability and plasticity of neuronal networks. Some inherited neurological disorders have recently been linked to mutations in genes that regulate DNA methylation, and alterations in DNA and protein methylation and/or acetylation have been documented in studies of age-related neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Manipulations of methylation and acetylation can affect the vulnerability of neurons to degeneration and apoptosis in experimental models of neurodegenerative disorders, suggesting a contribution to altered methylation and acetylation to the disease processes. Interestingly, dietary factors that influence DNA methylation may affect the risk of neurodegenerative disorders, for example, individuals with low dietary folate intake are at increased risk of Alzheimer's and Parkinson's diseases. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 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 72 TC 74 Z9 79 U1 1 U2 16 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 JUL PY 2003 VL 2 IS 3 BP 329 EP 342 DI 10.1016/S1568-1637(03)00013-8 PG 14 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 681PW UT WOS:000183045400005 PM 12726778 ER PT J AU Barr, CS Becker, ML Suomi, SJ Higley, JD AF Barr, CS Becker, ML Suomi, SJ Higley, JD TI Relationships among CSF monoamine metabolite levels, alcohol sensitivity, and alcohol-related aggression in rhesus macaques SO AGGRESSIVE BEHAVIOR LA English DT Article DE alcohol; aggression; alcohol sensitivity; CSF; neurotransmitter metabolites ID NONHUMAN PRIMATE MODEL; 5-HYDROXYINDOLEACETIC ACID CONCENTRATIONS; ANTISOCIAL PERSONALITY-DISORDER; CEREBROSPINAL-FLUID MONOAMINE; DIMINISHED SOCIAL COMPETENCE; INDIVIDUAL-DIFFERENCES; PHYSICAL AGGRESSION; GENDER DIFFERENCES; VIOLENT BEHAVIOR; SEROTONIN AB A relationship between alcohol intake and aggressive behavior has been demonstrated in both associational and laboratory studies. Among the factors that contribute to aggression during intoxication are a history of violence and the level of alcohol-induced stimulation. In humans, excessive alcohol intake and alcoholism are predicted by decreased sensitivity, or a low level of response (LOR), to alcohol. In addition, aggressive behavior, LOR, and alcoholism have been attributed to CNS serotonergic dysfunction. Given that they are both related to diminished CNS serotonin, in this study we wanted to determine whether a low LOR to alcohol would be associated with aggression during intoxication in rhesus macaques. Adolescent rhesus macaques (N = 115) received an intravenous dose of ethanol (2.2g/kg) and were scored for their levels of response for 30 minutes. Following provocation by an investigator, animals were then scored for aggressive behaviors (lunges, open-mouth threats, stares, head-bobs, and barks) for five minutes. At the approximate age of five years, animals were entered into a free-access alcohol consumption study, during which they were allowed voluntary access for one hour/day, four days/week to aspartame-sweetened alcohol or vehicle. Alcohol intake for each subject was determined using a computerized collar, which was detected by a station system that measured individual subject consumption rates. Data were analyzed using regression analyses and t-tests. Decreased sensitivity to alcohol, alcohol-induced increases in CSF MHPG, and pre-alcohol CSF levels of 5-HIAA were associated independently with aggression during intoxication (r = -0.32, P = 0.0006, (r) under bar = - 0.299 P = 0.01, and (r) under bar = -0.21, P = 0.02, respectively). High rates of alcohol-related aggression predicted future alcohol consumption ((r) under bar = 0.27, p = 0.004), even after controlling for rearing condition and monoamine metabolite concentrations, previously shown in these animals to predict alcohol consumption. By investigating the relationships between LOR, central catecholamine reactivity and function, and alcohol-induced aggression in alcohol-naive nonhuman primates, this report provides evidence that alcohol-induced stimulation and neurotransmitter-linked predisposition to impulsive aggression independently contribute to aggression during intoxication. This paper further emphasizes the importance of the nonhuman primate model for studying susceptibility to alcohol-related aggression and alcoholism, because variables such as prior exposure to alcohol are difficult to control in human subjects. (C) 2003 Wiley-Liss, Inc. C1 NIAAA, Clin Studies Lab, Primate Unit, NIH Anim Ctr, Poolesville, MD 20837 USA. RP Higley, JD (reprint author), NIAAA, Clin Studies Lab, Primate Unit, NIH Anim Ctr, POB 529,Bldg 112, Poolesville, MD 20837 USA. NR 50 TC 10 Z9 10 U1 1 U2 7 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0096-140X J9 AGGRESSIVE BEHAV JI Aggressive Behav. PD JUL-AUG PY 2003 VL 29 IS 4 BP 288 EP 301 DI 10.1002/ab.10071 PG 14 WC Behavioral Sciences; Psychology, Multidisciplinary SC Behavioral Sciences; Psychology GA 706XH UT WOS:000184480000002 ER PT J AU Tsai, CC Emau, P Jiang, YH Tian, BP Morton, WR Gustafson, KR Boyd, MR AF Tsai, CC Emau, P Jiang, YH Tian, BP Morton, WR Gustafson, KR Boyd, MR TI Cyanovirin-N gel as a topical microbicide prevents rectal transmission of SHIV89.6P in macaques SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INACTIVATING PROTEIN; RHESUS-MONKEYS; VIRAL LOAD; AIDS; INFECTION; PLASMA; TYPE-1; DISEASE; GP120 AB Cyanovirin-N (CV-N), an 11-kDa cyanobacterial protein, potently inactivates diverse strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV) and also prevents virus-to-cell fusion, virus entry, and infection of cells in vitro. These properties make CV-N an attractive candidate for use as a topical microbicide to prevent the sexual transmission of HIV. We evaluated the efficacy of gel-formulated, recombinant CV-N gel as a topical microbicide in male macaques (Macaca fascicularis) that were rectally challenged with a chimeric SIV/HIV-1 virus known as SHIV89.6P. All of the untreated macaques were infected and experienced CD4(+) T cell depletion. In contrast, none of the macaques that received either 1 % or 2 % CV-N gel showed evidence of SHIV89.6P infection. Neither CV-N nor placebo gels produced Any adverse effects in any macaque following the rectal application. These results indicate that CV-N gel As a topical microbicide can prevent rectal transmission of SHIV in macaques. These studies encouraged clinical evaluation of CV-N as a topical microbicide to prevent sexual transmisision of HIV in humans. C1 Univ Washington, Natl Primate Res Ctr, Seattle, WA 98195 USA. NCI, Mol Targets Dev Program, Ctr Canc Res, Frederick, MD 21702 USA. Univ S Alabama, Coll Med, Canc Res Inst, Mobile, AL 36608 USA. RP Tsai, CC (reprint author), Univ Washington, Natl Primate Res Ctr, Box 357330,1705 NE Pacific St, Seattle, WA 98195 USA. FU NCRR NIH HHS [RR-00166]; NIAID NIH HHS [AI-15450, AI-65311] NR 24 TC 137 Z9 149 U1 0 U2 4 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUL PY 2003 VL 19 IS 7 BP 535 EP 541 DI 10.1089/088922203322230897 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 705NL UT WOS:000184401100001 PM 12921090 ER PT J AU Martin, MR AF Martin, MR TI Alcohol research and changes at the Center for Scientific Review SO ALCOHOL LA English DT Editorial Material C1 NCI, Ctr Sci Rev, Div Physiol & Pathol, Bethesda, MD 20892 USA. RP Martin, MR (reprint author), NCI, Ctr Sci Rev, Div Physiol & Pathol, 670 Rockledge Dr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0741-8329 J9 ALCOHOL JI Alcohol PD JUL PY 2003 VL 30 IS 3 BP 164 EP 165 PG 2 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 726CT UT WOS:000185581100008 ER PT J AU Anton, R Randall, C Latham, P Ciraulo, D LoCastro, J Donovan, D Kivlahan, D Saxon, A Johnson, B Roache, J Mason, B Salvato, F Williams, L Mattson, M Miller, W Westerberg, V Tonigan, JS O'Malley, S Petrakis, I Krystal, J Pettinati, H Flannery, B Swift, R Longabaugh, R Weiss, R Gastfriend, D Greenfield, S Zweben, A Cisler, R Fleming, M Hosking, J Garbutt, J Couper, D AF Anton, R Randall, C Latham, P Ciraulo, D LoCastro, J Donovan, D Kivlahan, D Saxon, A Johnson, B Roache, J Mason, B Salvato, F Williams, L Mattson, M Miller, W Westerberg, V Tonigan, JS O'Malley, S Petrakis, I Krystal, J Pettinati, H Flannery, B Swift, R Longabaugh, R Weiss, R Gastfriend, D Greenfield, S Zweben, A Cisler, R Fleming, M Hosking, J Garbutt, J Couper, D CA COMBINE Study Res Grp TI Testing combined pharmacotherapies and behavioral interventions in alcohol dependence: Rationale and methods SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Review DE alcohol-dependence; pharmacotherapy; behavioral-intervention; methodology ID PLACEBO-CONTROLLED TRIAL; COMPULSIVE DRINKING SCALE; DOUBLE-BLIND; ETHANOL-CONSUMPTION; DOPAMINE RELEASE; CLINICAL-TRIALS; HEAVY DRINKERS; PROJECT MATCH; USE DISORDERS; NALTREXONE AB Increasing knowledge about effective therapies for alcohol dependence calls for new research designs to examine treatment interactions between pharmacotherapies and behavioral interventions. In 1997, the National Institute on Alcohol Abuse and Alcoholism recruited 11 sites and a coordinating center for a large-scale (1,375 subjects), randomized placebo controlled trial to test 16 weeks of active treatment using naltrexone and acamprosate alone and in combination. Most participants receive 9 brief sessions delivered by medically trained providers to promote sobriety and enhance medication adherence (Medical Management, MM). Half the participants are also randomized to individualized psychotherapy (up to 20 sessions of Combined Behavioral Intervention, CBI), integrating elements of the successful behavioral interventions from Project MATCH. COMBINE seeks to evaluate the efficacy of the two most promising medications (naltrexone and acamprosate) both singly and together, when combined with different intensities of behavioral therapies. COMBINE incorporates a number of innovative design aspects, including a no-pill psychotherapy-alone condition, behavioral interventions that are both manual-guided and individualized, and pharmacotherapy dosing that is greater than in some previous, trials. Two COMBINE pilot studies demonstrate the safety and acceptability of the combination pharmacotherapy dosing, and the feasibility of implementing the manualized behavioral interventions. This paper introduces COMBINE's goals, methods and analytic strategies, and their potential to improve multimodal treatment selection. C1 Med Univ S Carolina, Charleston, SC 29425 USA. Boston Univ, Boston Univ Vet Adm Sch Med, Boston, MA 02215 USA. Univ Washington, VA Puget Sound Hlth Care Syst, Addict Treatment Ctr, Seattle, WA 98195 USA. Univ Texas, SW Texas Addict Res & Technol Ctr, San Antonio, TX 78285 USA. Univ Miami, Sch Med, Miami, FL 33101 USA. NIAAA, Bethesda, MD USA. Univ New Mexico, Ctr Alcoholism Subst Abuse & Addict, Albuquerque, NM 87131 USA. Yale Univ, Sch Med, Subst Abuse Treatment Unit, New Haven, CT 06510 USA. Univ Penn, Treatment Res Ctr, Philadelphia, PA 19104 USA. Brown Univ, Providence, RI 02912 USA. Harvard Univ, McLean Hosp, Belmont, MA 02178 USA. Harvard Univ, Massachusetts Gen Hosp, Belmont, MA 02178 USA. Univ Wisconsin, Ctr Addict & Behav Hlth Res, Milwaukee, WI 53201 USA. Univ N Carolina, Collaborat Studies Coordinating Ctr, Chapel Hill, NC 27599 USA. RP Gastfriend, D (reprint author), Massachusetts Gen Hosp Back Bay, 388 Commonwealth Ave,Lower Level, Boston, MA 02215 USA. EM dgastfriend@partners.org RI Mason, Barbara/P-6604-2016 NR 111 TC 67 Z9 69 U1 5 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUL PY 2003 VL 27 IS 7 BP 1107 EP 1122 DI 10.1097/01.alc.0000086765.46408.64 PG 16 WC Substance Abuse SC Substance Abuse GA 704RV UT WOS:000184354500010 ER PT J AU Anton, R Randall, C Latham, P Ciraulo, D LoCastro, J Donovan, D Kivlahan, D Saxon, A Johnson, B Roache, J Tiouririne, NAD Mason, B Salvato, F Williams, L Mattson, M Miller, W Westerberg, V Tonigan, JS O'Malley, S Petrakis, I Krystal, J Pettinati, H Flannery, B Swift, R Longabaugh, R Weiss, R Gastfriend, D Greenfield, S Zweben, A Cisler, R Fleming, M Hosking, J Garbutt, J Couper, D AF Anton, R Randall, C Latham, P Ciraulo, D LoCastro, J Donovan, D Kivlahan, D Saxon, A Johnson, B Roache, J Tiouririne, NAD Mason, B Salvato, F Williams, L Mattson, M Miller, W Westerberg, V Tonigan, JS O'Malley, S Petrakis, I Krystal, J Pettinati, H Flannery, B Swift, R Longabaugh, R Weiss, R Gastfriend, D Greenfield, S Zweben, A Cisler, R Fleming, M Hosking, J Garbutt, J Couper, D CA COMBINE Study Res Grp TI Testing combined pharmacotherapies and behavioral interventions for alcohol dependence (The COMBINE study): A pilot feasibility study SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE alcoholism; pharmacotherapy; behavioral therapy; naltrexone; acamprosate ID PLACEBO-CONTROLLED TRIAL; NALTREXONE; ACAMPROSATE; DRINKING; THERAPY; SAFETY AB Background: Medications (such as naltrexone and acamprosate) as well as behavioral therapies have been previously reported to be effective in the reduction of alcohol intake and to prevent relapse drinking. However, the efficacy of using several medications alone or together in combination with behavioral therapies has not been widely investigated. The purpose of this study was to evaluate the feasibility of this combined therapy approach to apply it to a larger scale multisite clinical trial. Outcome focused on recruitment, retention, adherence to study parameters and medication, physical complaints, and physiologic toxicity. Methods: At 11 sites, 108 individuals with alcohol dependence were randomized in a double blind fashion to receive placebo, naltrexone, or acamprosate alone or in combination. In addition, some individuals were randomized to receive Medical Management (MM) provided by a health care practitioner alone or in combination with an enhanced behavioral intervention, Combined Behavioral Intervention (CBI), delivered by a trained therapist. A final group received CBI alone without pills. All participants were treated and assessed for a maximum of 16 weeks. Results: The attendance at therapy and research visits, and medication adherence and tolerability were good with no statistical differences between the medication or behavioral intervention groups. Over 75% of participants completed the week-16, end of study, assessment and the average medication adherence (percent of total pills taken) was about 65%. The level and types of physical complaints were not unexpected and similar among the medication and placebo groups. There were no group differences in liver or kidney toxicity. Importantly, the combination of naltrexone and acamprosate did not present significantly more physical complaints than either alone. Conclusions: Sufficient numbers of alcohol dependent participants can be recruited and retained in a relatively sophisticated outpatient trial combining medications and behavioral interventions. Participant adherence to the trial protocol including medication regimens was at acceptable levels. Physical complaints and organ toxicity were within expected and acceptable levels. Based on these results a larger scale study utilizing these methodologies appears feasible. C1 Med Univ S Carolina, Charleston, SC 29425 USA. Boston Univ, Boston Univ Vet Adm Sch Med, Boston, MA 02215 USA. Univ Washington, VA Puget Sound Hlth Care Syst, Addict Treatment Ctr, Seattle, WA 98195 USA. Univ Texas, SW Texas Addict Res & Technol Ctr, San Antonio, TX 78285 USA. Univ Miami, Sch Med, Miami, FL USA. NIAAA, Bethesda, MD USA. Univ New Mexico, Ctr Alcoholism Subst Abuse & Addict, Albuquerque, NM 87131 USA. Yale Univ, Sch Med, Subst Abuse Treatment Unit, New Haven, CT USA. Univ Penn, Treatment Res Ctr, Philadelphia, PA 19104 USA. Brown Univ, Providence, RI 02912 USA. Harvard Univ, McLean Hosp, Belmont, MA 02178 USA. Harvard Univ, Massachusetts Gen Hosp, Belmont, MA USA. Univ Wisconsin, Ctr Addict & Behav Hlth Res, Milwaukee, WI 53201 USA. Univ N Carolina, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. RP Anton, R (reprint author), Med Univ S Carolina, 67 President St, Charleston, SC 29425 USA. EM antonr@musc.edu RI Mason, Barbara/P-6604-2016 NR 22 TC 37 Z9 37 U1 4 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUL PY 2003 VL 27 IS 7 BP 1123 EP 1131 DI 10.1097/01.ALC.0000078020.92938.0B PG 9 WC Substance Abuse SC Substance Abuse GA 704RV UT WOS:000184354500011 ER PT J AU Stolzenberg-Solomon, RZ Dodd, KW Blaser, MJ Virtamo, J Taylor, PR Albanes, D AF Stolzenberg-Solomon, RZ Dodd, KW Blaser, MJ Virtamo, J Taylor, PR Albanes, D TI Tooth loss, pancreatic cancer, and Helicobacter pylori SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE pancreatic cancer; Helicobacter pylori; tooth loss; male smokers; Finland ID MALE SMOKERS; ORAL HYGIENE; ENDOGENOUS FORMATION; PERIODONTAL-DISEASE; NATURAL DENTITION; COLORECTAL-CANCER; MEDICAL DISEASES; GASTRIC-CANCER; RISK-FACTORS; INFECTION AB Background: Poor dental health has been associated with increased risks of oral, esophageal, and gastric cancer and may also be associated with pancreatic cancer. In addition, Helicobacter pylori has been found in dental plaque and has been associated with periodontal disease and pancreatic cancer. Objective: The objective was to investigate prospectively the relation between dentition history and pancreatic cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort in Finland and the association between dentition history and H. pylori seropositivity in a cross-sectional sample of subjects without cancer (n = 475) from the same cohort. Design: Of the 29 104 male smokers aged 50-69 y in the cohort for whom there were complete data, 174 developed pancreatic cancer from 1985 to 1997. Cox proportional hazard models were used to estimate age-, smoking-, education-, urban living-, and height-adjusted hazard ratios and 95% CIs for pancreatic cancer, and logistic regression models were used to estimate age- and education-adjusted odds ratios for H. pylori carriage. Results: Tooth loss was positively associated with pancreatic cancer (edentulous compared with missing 0-10 teeth: hazard ratio = 1.63; 95% CI: 1.09, 2.46; P for trend = 0.02) but was not significantly associated with H. pylori seropositivity (edentulous compared with missing 0-10 teeth: odds ratio = 1.30; 95% Cl: 0.73, 2.32; P for trend = 0.37). Conclusion: Additional studies are needed to evaluate the association between tooth loss and pancreatic cancer, as well as cancers at other gastrointestinal sites, particularly with respect to possible biological mechanisms. C1 NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, Stat Res & Applicat Branch, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. NYU, Sch Med, Dept Med, New York, NY USA. NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. Dept Vet Affairs Med Ctr, New York, NY USA. Natl Publ Hlth Inst, Helsinki, Finland. RP NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS,Suite 320, Bethesda, MD 20892 USA. EM rs221z@nih.gov RI Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [N01CN45035, N01CN45165] NR 56 TC 46 Z9 47 U1 0 U2 7 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2003 VL 78 IS 1 BP 176 EP 181 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 692KP UT WOS:000183660500025 PM 12816788 ER PT J AU Althuis, MD Wittes, JT AF Althuis, MD Wittes, JT TI Chromium picolinate and type 2 diabetes - Reply to DS Kalman, MF McCarty, and V Juturu and JR Komorowski SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Letter ID SUPPLEMENTAL CHROMIUM; MELLITUS; GLUCOSE C1 NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Stat Collaborat Inc, Washington, DC USA. RP Althuis, MD (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. NR 11 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 JUL PY 2003 VL 78 IS 1 BP 192 EP 193 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 692KP UT WOS:000183660500030 ER PT J AU Salbe, AD Weyer, C Harper, I Lindsay, RS Ravussin, RS Ravussin, E Tataranni, PA AF Salbe, AD Weyer, C Harper, I Lindsay, RS Ravussin, RS Ravussin, E Tataranni, PA TI Relation between physical activity and obesity SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Letter C1 NIDDKD, NIH, Phoenix, AZ 85016 USA. RP Salbe, AD (reprint author), NIDDKD, NIH, 4212 N 16Th St,Room 541, Phoenix, AZ 85016 USA. NR 3 TC 2 Z9 2 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 JUL PY 2003 VL 78 IS 1 BP 193 EP 194 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 692KP UT WOS:000183660500031 PM 12816794 ER PT J AU Subar, AF Kipnis, V Troiano, RP Midthune, D Schoeller, DA Bingham, S Sharbaugh, CO Trabulsi, J Runswick, S Ballard-Barbash, R Sunshine, J Schatzkin, A AF Subar, AF Kipnis, V Troiano, RP Midthune, D Schoeller, DA Bingham, S Sharbaugh, CO Trabulsi, J Runswick, S Ballard-Barbash, R Sunshine, J Schatzkin, A TI Using intake biomarkers to evaluate the extent of dietary misreporting in a large sample of adults: The OPEN Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE biological markers; diet; diet surveys; energy intake; energy metabolism; epidemiologic methods; nutrition surveys; questionnaires ID DOUBLY LABELED WATER; FOOD FREQUENCY QUESTIONNAIRES; SOCIAL DESIRABILITY SCALE; PARA-AMINOBENZOIC ACID; ENERGY-EXPENDITURE; ASSESSMENT INSTRUMENTS; URINE COLLECTIONS; VALIDATION; COMPLETENESS; VALIDITY AB This paper describes the Observing Protein and Energy Nutrition (OPEN) Study, conducted from September 1999 to March 2000. The purpose of the study was to assess dietary measurement error using two self-reported dietary instruments-the food frequency questionnaire (FFQ) and the 24-hour dietary recall (24HR)-and unbiased biomarkers of energy and protein intakes: doubly labeled water and urinary nitrogen. Participants were 484 men and women aged 40-69 years from Montgomery County, Maryland. Nine percent of men and 7% of women were defined as underreporters of both energy and protein intake on 24HRs; for FFQs, the comparable values were 35% for men and 23% for women. On average, men underreported energy intake compared with total energy expenditure by 12-14% on 24HRs and 31-36% on FFQs and underreported protein intake compared with a protein biomarker by 11-12%, on 24HRs and 30-34% on FFQs. Women underreported energy intake on 24HRs by 16-20% and on FFQs by 34-38% and underreported protein intake by 11-15% on 24HRs and 27-32% on FFQs. There was little underreporting of the percentage of energy from protein for men or women. These findings have important implications for nutritional epidemiology and dietary surveillance. C1 NCI, DCCPS, ARP, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, Biometry Res Grp, Bethesda, MD 20892 USA. Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA. Dunn Human Nutr Unit, MRC, Cambridge, England. WESTAT Corp, Rockville, MD 20850 USA. Natl Canc Inst, Div Canc Epidemiol & Genet, Nutrit Epidemiol Branch, Bethesda, MD USA. RP Subar, AF (reprint author), NCI, DCCPS, ARP, 6130 Execut Blvd,MSC 7344,EPN 4005, Bethesda, MD 20892 USA. OI Troiano, Richard/0000-0002-6807-989X NR 38 TC 473 Z9 479 U1 5 U2 44 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 JUL 1 PY 2003 VL 158 IS 1 BP 1 EP 13 DI 10.1093/aje/kwg092 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 695ZV UT WOS:000183861000001 PM 12835280 ER PT J AU Kipnis, V Subar, AF Midthune, D Freedman, LS Ballard-Barbash, R Troiano, RP Bingham, S Schoeller, DA Schatzkin, A Carroll, RJ AF Kipnis, V Subar, AF Midthune, D Freedman, LS Ballard-Barbash, R Troiano, RP Bingham, S Schoeller, DA Schatzkin, A Carroll, RJ TI Structure of dietary measurement error: Results of the OPEN biomarker study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE bias (epidemiology); biological markers; diet; energy intake; epiderniologic methods; nutrition assessment; questionnaires; reference values ID FOOD FREQUENCY QUESTIONNAIRES; DOUBLY LABELED WATER; TOTAL-ENERGY INTAKE; BREAST-CANCER; RELATIVE RISK; WOMEN; EXPENDITURE; VALIDATION; ACCURACY; COHORT AB Multiple-day food records or 24-hour dietary recalls (24HRs) are commonly used as "reference" instruments to calibrate food frequency questionnaires (FFQs) and to adjust findings from nutritional epidemiologic studies for measurement error. Correct adjustment requires that the errors in the adopted reference instrument be independent of those in the FFQ and of true intake. The authors report data from the Observing Protein and Energy Nutrition (OPEN) Study, conducted from September 1999 to March 2000, in which valid reference biomarkers for energy (doubly labeled water) and protein (urinary nitrogen), together with a FFQ and 24HR, were observed in 484 healthy volunteers from Montgomery County, Maryland. Accounting for the reference biomarkers, the data suggest that the FFQ leads to severe attenuation in estimated disease relative risks for absolute protein or energy intake (a true relative risk of 2 would appear as 1.1 or smaller). For protein adjusted for energy intake by using either nutrient density or nutrient residuals, the attenuation is less severe (a relative risk of 2 would appear as approximately 1.3), lending weight to the use of energy adjustment. Using the 24HR as a reference instrument can seriously underestimate true attenuation (up to 60% for energy-adjusted protein). Results suggest that the interpretation of findings from FFO-based epidemiologic studies of diet-disease associations needs to be reevaluated. C1 NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD USA. Bar Ilan Univ, Dept Math Stat & Comp Sci, Ramat Gan, Israel. Gertner Inst Epidemiol & Hlth Policy Res, Tel Hashomer, Israel. MRC, Dunn Human Nutr Unit, Cambridge, England. Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA. NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD USA. Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. RP Kipnis, V (reprint author), NCI, Biometry Res Grp, Div Canc Prevent, Execut Plaza N,Room 3124,6130 Execut Blvd,MSC 735, Bethesda, MD 20892 USA. OI Troiano, Richard/0000-0002-6807-989X FU NCI NIH HHS [CA-57030]; PHS HHS [P30-E509106] NR 34 TC 403 Z9 407 U1 5 U2 32 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 JUL 1 PY 2003 VL 158 IS 1 BP 14 EP 21 DI 10.1093/aje/kwg091 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 695ZV UT WOS:000183861000002 PM 12835281 ER PT J AU Kipnis, V Subar, AF Schatzkin, A Midthune, D Troiano, RP Schoeller, DA Bingham, S Freedman, LS AF Kipnis, V Subar, AF Schatzkin, A Midthune, D Troiano, RP Schoeller, DA Bingham, S Freedman, LS TI Kipnis et al. Respond to "OPEN questions" SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID DOUBLY-LABELED WATER; INSTRUMENTS; VALIDATION; ENERGY; CANCER C1 NCI, Div Canc Prevent, Biometry Res Grp, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, Appl Res Program, Bethesda, MD USA. NCI, Div Canc Epidemiol & Genet, Nutrit Epidemiol Branch, Bethesda, MD USA. Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA. MRC, Dunn Human Nutr Unit, Cambridge, England. Bar Ilan Univ, Dept Math Stat & Comp Sci, Ramat Gan, Israel. Gertner Inst Epidemiol & Hlth Policy Res, Tel Hashomer, Israel. RP Kipnis, V (reprint author), NCI, Div Canc Prevent, Biometry Res Grp, Execut Plaza N,Room 3124,6130 Execut Blvd,MSC 735, Bethesda, MD 20892 USA. NR 10 TC 7 Z9 7 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 1 PY 2003 VL 158 IS 1 BP 25 EP 26 DI 10.1093/aje/kwg094 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 695ZV UT WOS:000183861000004 ER PT J AU Flood, A Velie, EM Sinha, R Chaterjee, N Lacey, JV Schairer, C Schatzkin, A AF Flood, A Velie, EM Sinha, R Chaterjee, N Lacey, JV Schairer, C Schatzkin, A TI Meat, fat, and their subtypes as risk factors for colorectal cancer in a prospective cohort of women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE colorectal neoplasms; dietary fats; meat; prospective studies; women ID COLON-CANCER; UNITED-STATES; RED MEAT; WELL-DONE; DIET; MEN; CONSUMPTION; ADENOMA; FIBER; ACIDS AB The authors investigated the association of intakes of meat and fat with colorectal cancer in a prospective cohort of women in the United States. Between 1987 and 1989, 45,496 women completed a 62-item National Cancer Institute/Block food frequency questionnaire, and during 386,716 person-years of follow-up, there were 487 incident cases of colorectal cancer. The authors used Cox proportional hazards regression to estimate relative risks and 95% confidence intervals for total meat, red meat, white meat, processed meat, and well-done meat intakes, as well as for total fat, saturated fat, and unsaturated fat. Relative risks for increasing quintiles of total meat and red meat consumption indicated no association with colorectal cancer (relative risk for high compared with low quintile = 1.10, 95% confidence interval: 0.83, 1.45) for red meat. For total fat, there was also no association with increasing quintiles of consumption (relative risk for high compared with low quintile = 1.14, 95% confidence interval: 0.86, 1.53). Additionally, none of the other subtypes of either meat or fat showed any association with colorectal cancer. This study provided no evidence of an association between either meat or fat (or any of their subtypes) and colorectal cancer incidence, but the authors cannot rule out the possibility of a modest association. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. RP Flood, A (reprint author), Univ Minnesota, Div Epidemiol, 1300 S 2nd St,Suite 300, Minneapolis, MN 55454 USA. RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 NR 38 TC 57 Z9 58 U1 1 U2 12 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 JUL 1 PY 2003 VL 158 IS 1 BP 59 EP 68 DI 10.1093/aje/kwg099 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 695ZV UT WOS:000183861000008 PM 12835287 ER PT J AU Masse, LC Anderson, CB AF Masse, LC Anderson, CB TI Ethnic differences among correlates of physical activity in women SO AMERICAN JOURNAL OF HEALTH PROMOTION LA English DT Article DE African American; Hispanic; determinants; cross-cultural differences ID AFRICAN-AMERICAN AB Purpose. This study investigated differences between two ethnic minority groups on five hypothesized correlates of physical activity (beliefs about the value of physical activity, normative modeling, perceived barriers, outcome expectations, and self-efficacy). Design: A cross-sectional sample consisting of 246 African American and Hispanic women 40 to 70 years of age was used. Multivariate analysis of covariance including interactions with education and income was used. Results: A three-way interaction (ethnicity by education by income) was significant for perceived barriers. In addition, a two-way interaction (education by income) was significant for normative modeling. Conclusions: Ethnic differences 15, education and income were associated with some correlates of physical activity; therefore, it is important to consider this diversity when designing physical activity interventions for minority women. C1 Univ Texas, Houston, TX USA. Baylor Coll Med, Dept Pediat, Childrens Nutr Res Ctr, Houston, TX 77030 USA. RP Masse, LC (reprint author), NCI, Div Canc Control & Populat Sci, Behav Res Program, Hlth Promot Res Branch, 6130 Execut Blvd,EPN 4076,MSC 7335, Bethesda, MD 20892 USA. FU ODCDC CDC HHS [U48/CC609653] NR 10 TC 19 Z9 19 U1 1 U2 3 PU AMER J HEALTH PROMOTION INC PI KEEGO HARBOR PA 1660 CASS LAKE RD, STE 104, KEEGO HARBOR, MI 48320 USA SN 0890-1171 J9 AM J HEALTH PROMOT JI Am. J. Health Promot. PD JUL-AUG PY 2003 VL 17 IS 6 BP 357 EP 360 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 698GW UT WOS:000183991300002 PM 12858614 ER PT J AU Lewis, CM Levinson, DF Wise, LH DeLisi, LE Straub, RE Hovatta, I Williams, NM Schwab, SG Pulver, AE Faraone, SV Brzustowicz, LM Kaufmann, CA Garver, DL Gurling, HMD Lindholm, E Coon, H Moises, HW Byerley, W Shaw, SH Mesen, A Sherrington, R O'Neill, FA Walsh, D Kendler, KS Ekelund, J Paunio, T Lonnqvist, J Peltonen, L O'Donovan, MC Owen, MJ Wildenauer, DB Maier, W Nestadt, G Blouin, JL Antonarakis, SE Mowry, BJ Silverman, JM Crowe, RR Cloninger, CR Tsuang, MT Malaspina, D Harkavy-Friedman, JM Svrakic, DM Bassett, AS Holcomb, J Kalsi, G McQuillin, A Brynjolfson, J Sigmundsson, T Petursson, H Jazin, E Zoega, T Helgason, T AF Lewis, CM Levinson, DF Wise, LH DeLisi, LE Straub, RE Hovatta, I Williams, NM Schwab, SG Pulver, AE Faraone, SV Brzustowicz, LM Kaufmann, CA Garver, DL Gurling, HMD Lindholm, E Coon, H Moises, HW Byerley, W Shaw, SH Mesen, A Sherrington, R O'Neill, FA Walsh, D Kendler, KS Ekelund, J Paunio, T Lonnqvist, J Peltonen, L O'Donovan, MC Owen, MJ Wildenauer, DB Maier, W Nestadt, G Blouin, JL Antonarakis, SE Mowry, BJ Silverman, JM Crowe, RR Cloninger, CR Tsuang, MT Malaspina, D Harkavy-Friedman, JM Svrakic, DM Bassett, AS Holcomb, J Kalsi, G McQuillin, A Brynjolfson, J Sigmundsson, T Petursson, H Jazin, E Zoega, T Helgason, T TI Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID SUSCEPTIBILITY LOCUS; LINKAGE ANALYSIS; WIDE SCAN; VULNERABILITY LOCUS; GENETIC-LINKAGE; SIBLING PAIRS; SCHIZOAFFECTIVE DISORDER; CHROMOSOME 8P; FOLLOW-UP; FAMILIES AB Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R-avg) and then weighted for sample size (rootN[affected cases]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P-AvgRnk) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P-ord). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (P-AvgRnk <.000417). Two aggregate criteria for linkage were also met ( clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P-AvgRnk and P-ord <.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations. C1 Univ Penn, Sch Med, Dept Psychiat, Ctr Neurobiol & Behav, Philadelphia, PA 19104 USA. Guys Kings & St Thomas Sch Med, Div Genet & Dev, London, England. UCL, Royal Free & Univ Coll Med Sch, Dept Psychiat & Behav Sci, London WC1E 6BT, England. NYU, Med Ctr, New York, NY 10016 USA. Columbia Univ, Dept Psychiat, New York, NY USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. NIMH, Clin Brain Disorders Branch, Intramural Res Program, Bethesda, MD 20892 USA. Natl Publ Hlth Inst, Biomedicum, Dept Mol Med, Helsinki, Finland. Natl Publ Hlth Inst, Dept Mental Hlth, Helsinki, Finland. Univ Helsinki, Dept Med Genet, Biomedicum, Helsinki, Finland. Cardiff Univ, Dept Psychol Med, Cardiff CF4 4XN, S Glam, Wales. Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany. Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Mental Hlth Ctr, Dept Psychiat, Boston, MA USA. Rutgers State Univ, Dept Genet, Piscataway, NJ USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Psychiat, Piscataway, NJ 08854 USA. Univ Louisville, Sch Med, Dept Psychiat & Behav Sci, Louisville, KY 40292 USA. Louisville Vet Affairs Med Ctr, Louisville, KY USA. Uppsala Univ, Dept Genet & Pathol, Uppsala, Sweden. Univ Utah, Salt Lake City, UT USA. Univ Hosp Schleswig Holstein, Dept Psychiat & Psychotherapy, Genet Mol Lab, Kiel, Germany. Univ Calif Irvine, Dept Psychiat, Irvine, CA 92717 USA. DNA Sci, Fremont, CA USA. Hosp Nacl Psiquitr, San Jose, Costa Rica. Xenon Genet, Burnaby, BC, Canada. Queens Univ Belfast, Belfast, Antrim, North Ireland. Hlth Res Board, Dublin, Ireland. Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA USA. Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. Univ Geneva, Sch Med, Ctr Med Univ Geneva, Dept Med Genet, CH-1211 Geneva, Switzerland. Wolston Pk Hosp, Queensland Ctr Schizophrenia Res, Wacol, Australia. Univ Queensland, Dept Psychiat, Brisbane, Qld, Australia. Univ Iowa, Coll Med, Dept Psychiat, Iowa City, IA 52242 USA. Univ Iowa, Coll Med, Mental Hlth Clin Res Ctr, Iowa City, IA 52242 USA. Washington Univ, Dept Psychiat, St Louis, MO USA. Univ Toronto, Dept Psychiat, Toronto, ON, Canada. Gen Hosp, Dept Psychiat, Reykjavik, Iceland. Natl Univ Hosp Reykjavik, Dept Psychiat, Reykjavik, Iceland. RP Levinson, DF (reprint author), Univ Penn, Sch Med, Dept Psychiat, Ctr Neurobiol & Behav, 3535 Market St,Room 4006, Philadelphia, PA 19104 USA. EM DFL@mail.med.upenn.edu RI O'Neill, Francis/C-5582-2008; Lewis, Cathryn/A-5225-2010; turton, miranda/F-4682-2011; Hovatta, Iiris/D-6871-2012; Cloninger, Claude/F-5357-2012; Ekelund, Jesper/D-6655-2013; Gurling, Hugh/A-5029-2010; Antonarakis, Stylianos/N-8866-2014; McQuillin, Andrew/C-1623-2008; OI O'Neill, Francis Anthony/0000-0002-7531-7657; Faraone, Stephen/0000-0002-9217-3982; Harkavy-Friedman, Jill/0000-0002-1449-0667; Lewis, Cathryn/0000-0002-8249-8476; Hovatta, Iiris/0000-0002-5990-7892; Cloninger, Claude/0000-0003-3096-4807; Antonarakis, Stylianos/0000-0001-8907-5823; McQuillin, Andrew/0000-0003-1567-2240; Moises, Hans/0000-0003-1522-3226; O'Donovan, Michael/0000-0001-7073-2379 FU Medical Research Council [G9309834, G9810900]; NIMH NIH HHS [R01 MH 52537, 1R01 MH 41874-01, 1R37 MH 43518, 5U01 MH 46318, K02 MH 01089, K08 MH 01392, K24 MH 64197, K24 MH064197, R01 MH 41953, R01 MH 42643, R01 MH 44245, R01 MH 45097, R01 MH 45390, R01 MH 4558, R01 MH 56098, R01 MH 61602, R01 MH 62440, R01 MH041953, R01 MH044292, R01 MH062440, R37 MH043518, U01 MH 44292, U01 MH 46276, U01 MH 46289, U01 MH046276, U01 MH046289, U01 MH046318]; PHS HHS [K02 01207] NR 62 TC 817 Z9 844 U1 5 U2 34 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL PY 2003 VL 73 IS 1 BP 34 EP 48 DI 10.1086/376549 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 696UA UT WOS:000183904900004 PM 12802786 ER PT J AU Segurado, R Detera-Wadleigh, SD Levinson, DF Lewis, CM Gill, M Nurnberg, JI Craddock, N DePaulo, JR Baron, M Gershon, ES Ekholm, J Cichon, S Turecki, G Claes, S Kelsoe, JR Schofield, PR Badenhop, RF Morissette, J Coon, H Blackwood, D McInnes, LA Foroud, T Edenberg, HJ Reich, T Rice, JP Goate, A McInnis, MG McMahon, FJ Badner, JA Goldin, LR Bennett, P Willour, VL Zandi, PP Liu, JJ Gilliam, C Juo, SH Berrettini, WH Yoshikawa, T Peltonen, L Lonnqvist, J Nothen, MM Schumacher, J Windemuth, C Rietschel, M Propping, P Maier, W Alda, M Grof, P Rouleau, GA Del-Favero, J Van Broeckhoven, C Mendlewicz, J Adolfsson, R Spence, MA Luebbert, H Adams, LJ Donald, JA Mitchell, PB Barden, N Shink, E Byerley, W Muir, W Visscher, PM Macgregor, S Gurling, H Kalsi, G McQuillin, A Escamilla, MA Reus, VI Leon, P Freimer, NB Ewald, H Kruse, TA Mors, O Radhakrishna, U Blouin, JL Antonarakis, SE Akarsu, N AF Segurado, R Detera-Wadleigh, SD Levinson, DF Lewis, CM Gill, M Nurnberg, JI Craddock, N DePaulo, JR Baron, M Gershon, ES Ekholm, J Cichon, S Turecki, G Claes, S Kelsoe, JR Schofield, PR Badenhop, RF Morissette, J Coon, H Blackwood, D McInnes, LA Foroud, T Edenberg, HJ Reich, T Rice, JP Goate, A McInnis, MG McMahon, FJ Badner, JA Goldin, LR Bennett, P Willour, VL Zandi, PP Liu, JJ Gilliam, C Juo, SH Berrettini, WH Yoshikawa, T Peltonen, L Lonnqvist, J Nothen, MM Schumacher, J Windemuth, C Rietschel, M Propping, P Maier, W Alda, M Grof, P Rouleau, GA Del-Favero, J Van Broeckhoven, C Mendlewicz, J Adolfsson, R Spence, MA Luebbert, H Adams, LJ Donald, JA Mitchell, PB Barden, N Shink, E Byerley, W Muir, W Visscher, PM Macgregor, S Gurling, H Kalsi, G McQuillin, A Escamilla, MA Reus, VI Leon, P Freimer, NB Ewald, H Kruse, TA Mors, O Radhakrishna, U Blouin, JL Antonarakis, SE Akarsu, N TI Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID OLD-ORDER AMISH; SUSCEPTIBILITY LOCUS; GENETIC-LINKAGE; WIDE SEARCH; CHROMOSOME 12Q23-Q24; CONTROLLED FAMILY; MANIC-DEPRESSION; COMPLEX TRAITS; POTENTIAL LOCI; DNA MARKERS AB Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for "very narrow" (i.e., BP-I and schizoaffective disorder - BP) and "narrow" (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample size. A "broad" model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 ( very narrow), 10q11.21-22.1 ( very narrow), and 14q24.1-32.12 ( narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region. C1 Univ Dublin Trinity Coll, Dept Genet, Neuropsychiat Genet Unit, Dublin 2, Ireland. St James Hosp, Dept Psychiat, Trinity Ctr Hlth Sci, Dublin 8, Ireland. NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Univ Penn, Dept Psychiat, Ctr Neurobiol & Behav, Philadelphia, PA 19104 USA. UCL, Royal Free & Univ Coll Med Sch, Dept Psychiat & Behav Sci,Mol Psychiat Lab, Windeyer Inst Med Sci, London WC1E 6BT, England. UCL, Guys Kings & St Thomas Sch Med, Div Genet & Dev, London WC1E 6BT, England. Indiana Univ, Dept Psychiat, Indianapolis, IN 46204 USA. Indiana Univ, Dept Med & Mol Genet, Indianapolis, IN 46204 USA. Indiana Univ, Dept Biochem & Mol Biol, Indianapolis, IN 46204 USA. Univ Birmingham, Queen Elizabeth Psychiat Hosp, Div Neurosci, Mol Psychait Grp, Birmingham, W Midlands, England. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. Columbia Univ, New York State Psychiat Inst, Dept Med Genet, Div Psychiat Genet, New York, NY USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. Mt Sinai Sch Med, Dept Human Genet, New York, NY USA. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. Univ Helsinki, Dept Med Genet, Helsinki, Finland. Natl Publ Hlth Inst, Dept Mol Med, Helsinki, Finland. Natl Publ Hlth Inst, Dept Mental Hlth, Helsinki, Finland. Flanders Interuniv Inst Biotechnol, Dept Mol Genet, Antwerp, Belgium. Univ Antwerp, Dept Med Genet, B-2020 Antwerp, Belgium. Univ Antwerp, Dept Psychiat, B-2020 Antwerp, Belgium. McGill Univ, Montreal Gen Hosp, Res Inst, Dept Psychiat, Montreal, PQ H3G 1A4, Canada. McGill Univ, Montreal Gen Hosp, Res Inst, Neurosci Res Ctr, Montreal, PQ H3G 1A4, Canada. Univ Calif San Diego, Dept Psychiat, Lab Psychiat Genom, La Jolla, CA 92093 USA. Univ New S Wales, Garvan Inst Med Res, Sydney, NSW, Australia. Univ New S Wales, Sch Psychiat, Sydney, NSW, Australia. Macquarie Univ, Sch Biol Sci, Sydney, NSW 2109, Australia. Prince Wales Hosp, Mood Disorders Unit, Sydney, NSW, Australia. Univ Laval, Quebec City, PQ, Canada. Ctr Hosp Univ Laval, Res Ctr, Ctr Neurosci, Quebec City, PQ, Canada. Univ Utah, Salt Lake City, UT USA. Univ Edinburgh, Edinburgh, Midlothian, Scotland. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. RIKEN, Inst Phys & Chem Res, Lab Mol Psychiat, Brain Sci Inst, Saitama, Japan. Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany. Univ Bonn, Inst Med Biometry Informat & Epidemiol, D-5300 Bonn, Germany. Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, D-6800 Mannheim, Germany. Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada. Univ Ottawa, Dept Psychiat, Ottawa, ON K1N 6N5, Canada. Univ Brussels, Erasme Hosp, Dept Psychiat, Brussels, Belgium. Umea Univ, Dept Clin Sci, Div Psychiat, Umea, Sweden. Univ Calif Irvine, Dept Pediat, Irvine, CA 92717 USA. Univ Calif Irvine, Dept Psychiat, Irvine, CA 92717 USA. Biofrontera Pharmaceut, Leverkusen, Germany. Univ Texas, Hlth Sci Ctr, Dept Psychiat, San Antonio, TX 78284 USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. Univ Costa Rica, Escuela Med, San Jose, Costa Rica. Univ Costa Rica, Ctr Biol Mol & Celular, San Jose, Costa Rica. Aarhus Univ Hosp, Inst Basic Psychiat Res, Risskov, Denmark. Odense Univ Hosp, Dept Clin Biochem & Genet, DK-5000 Odense, Denmark. Univ Geneva, Sch Med, Dept Med Genet, CH-1211 Geneva, Switzerland. Univ Hosp, Geneva, Switzerland. Univ Hacettepe, Dept Pediat, TR-06100 Ankara, Turkey. RP Segurado, R (reprint author), Univ Dublin Trinity Coll, Dept Genet, Neuropsychiat Genet Unit, Dublin 2, Ireland. EM seguradr@tcd.ie RI Antonarakis, Stylianos/N-8866-2014; reus, victor/I-7923-2015; Akarsu, Nurten/E-9758-2013; Schumacher, Johannes/F-4970-2015; McQuillin, Andrew/C-1623-2008; Juo, Suh-Hang/C-9545-2009; Alda, Martin/F-5812-2010; Gurling, Hugh/A-5029-2010; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Segurado, Ricardo/K-6116-2014; McMahon, Francis/A-7290-2009; Macgregor, Stuart/C-6442-2009; Lewis, Cathryn/A-5225-2010; Juo, Suh-Hang/A-1765-2010; Schofield, Peter/C-9669-2011; turton, miranda/F-4682-2011; McInnis, Melvin/F-6963-2012; OI Antonarakis, Stylianos/0000-0001-8907-5823; reus, victor/0000-0002-8193-5697; Akarsu, Nurten/0000-0001-5432-0032; Schumacher, Johannes/0000-0001-9217-6457; McQuillin, Andrew/0000-0003-1567-2240; Del Favero, jurgen/0000-0002-7427-7489; Nurnberger, John/0000-0002-7674-1767; Gill, Michael/0000-0003-0206-5337; Mitchell, Philip/0000-0002-7954-5235; McMahon, Francis/0000-0002-9469-305X; Alda, Martin/0000-0001-9544-3944; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Segurado, Ricardo/0000-0002-3547-6733; Macgregor, Stuart/0000-0001-6731-8142; Lewis, Cathryn/0000-0002-8249-8476; Schofield, Peter/0000-0003-2967-9662; McInnis, Melvin/0000-0002-0375-6247; Visscher, Peter/0000-0002-2143-8760; Edenberg, Howard/0000-0003-0344-9690 FU Medical Research Council [G9309834, G9810900]; NCRR NIH HHS [M01 RR 00827, M01 RR000827]; NHGRI NIH HHS [N01 HG 65493]; NIMH NIH HHS [1R01 MH 3448, K02 MH 01089, K24 MH 064197, K24 MH064197, MH 00176, MH 01099, MH 42243, MH 42535, MH 43979, MH 47612, MH 59553, MH 59567, MH 63876, R01 MH 042463, R01 MH 42643, R01 MH 49499, R01 MH 59545, R01 MH 62276, R01 MH042243, R01 MH049499, R01 MH059545, R01 MH059553, R01 MH059567, R01 MH062276, R01 MH063876, U01 MH 54723, U01 MH 46274, U01 MH 46280, U01 MH 46282, U01 MH 54701, U01 MH 54794]; NINDS NIH HHS [R01 NS 37484, R01 NS037484] NR 55 TC 310 Z9 315 U1 4 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL PY 2003 VL 73 IS 1 BP 49 EP 62 DI 10.1086/376547 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 696UA UT WOS:000183904900005 PM 12802785 ER PT J AU Toro, JR Nickerson, ML Wei, MH Warren, MB Glenn, GM Turner, ML Stewart, L Duray, P Tourre, O Sharma, N Choyke, P Stratton, P Merino, M Walther, MM Linehan, WM Schmidt, LS Zbar, B AF Toro, JR Nickerson, ML Wei, MH Warren, MB Glenn, GM Turner, ML Stewart, L Duray, P Tourre, O Sharma, N Choyke, P Stratton, P Merino, M Walther, MM Linehan, WM Schmidt, LS Zbar, B TI Mutations in the Fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID COLLECTING DUCT CARCINOMA; HOGG-DUBE-SYNDROME; UTERINE FIBROIDS; SPONTANEOUS PNEUMOTHORAX; CUTANEOUS LEIOMYOMATA; DEFICIENCY; ENCEPHALOPATHY; MITOCHONDRIAL; PREVALENCE; PARENCHYMA AB Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder characterized by smooth-muscle tumors of the skin and uterus and/or renal cancer. Although the identification of germline mutations in the fumarate hydratase (FH) gene in European families supports it as the susceptibility gene for HLRCC, its role in families in North America has not been studied. We screened for germline mutations in FH in 35 families with cutaneous leiomyomas. Sequence analysis revealed mutations in FH in 31 families (89%). Twenty different mutations in FH were identified, of which 18 were novel. Of these 20 mutations, 2 were insertions, 5 were small deletions that caused frameshifts leading to premature truncation of the protein, and 13 were missense mutations. Eleven unrelated families shared a common mutation: R190H. Eighty-one individuals ( 47 women and 34 men) had cutaneous leiomyomas. Ninety-eight percent (46/47) of women with cutaneous leiomyomas also had uterine leiomyomas. Eighty-nine percent (41/46) of women with cutaneous and uterine leiomyomas had a total hysterectomy, 44% at age less than or equal to 30 years. We identified 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from four families had papillary type II renal cell carcinoma, and another individual from one of these families had collecting duct carcinoma of the kidney. The present study shows that mutations in FH are associated with HLRCC in North America. HLRCC is associated with clinically significant uterine fibroids and aggressive renal tumors. The present study also expands the histologic spectrum of renal tumors and FH mutations associated with HLRCC. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. NCI, Immunobiol Lab, Ctr Canc Res, Frederick, MD 21701 USA. NCI, Basic Res Program, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. NICHHD, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Pathol Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Diagnost Radiol Serv, NIH, Bethesda, MD 20892 USA. NICHHD, Gynecol Consultat Serv, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Toro, JR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Execut Plaza S,Room 7012, Rockville, MD 20892 USA. FU NCI NIH HHS [N01 CO 12400, N01CO12400] NR 32 TC 266 Z9 270 U1 0 U2 6 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 JUL PY 2003 VL 73 IS 1 BP 95 EP 106 DI 10.1086/376435 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 696UA UT WOS:000183904900009 PM 12772087 ER PT J AU Dick, DM Foroud, T Flury, L Bowman, ES Miller, MJ Rau, NL Moe, PR Samavedy, N El-Mallakh, R Manji, H Glitz, DA Meyer, ET Smiley, C Hahn, R Widmark, C McKinney, R Sutton, L Ballas, C Grice, D Berrettini, W Byerley, W Coryell, W DePaulo, R MacKinnon, DF Gershon, ES Kelsoe, JR McMahon, FJ McInnis, M Murphy, DL Reich, T Scheftner, W Nurnberger, JI AF Dick, DM Foroud, T Flury, L Bowman, ES Miller, MJ Rau, NL Moe, PR Samavedy, N El-Mallakh, R Manji, H Glitz, DA Meyer, ET Smiley, C Hahn, R Widmark, C McKinney, R Sutton, L Ballas, C Grice, D Berrettini, W Byerley, W Coryell, W DePaulo, R MacKinnon, DF Gershon, ES Kelsoe, JR McMahon, FJ McInnis, M Murphy, DL Reich, T Scheftner, W Nurnberger, JI TI Genomewide linkage analyses of bipolar disorder: A new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MANIC-DEPRESSIVE ILLNESS; COMPLEX TRAITS; DNA MARKERS; SCREEN; SCAN; SCHIZOPHRENIA; FAMILIES; CHROMOSOME-11; REPLICATION; ALCOHOLISM AB We conducted genomewide linkage analyses on 1,152 individuals from 250 families segregating for bipolar disorder and related affective illnesses. These pedigrees were ascertained at 10 sites in the United States, through a proband with bipolar I affective disorder and a sibling with bipolar I or schizoaffective disorder, bipolar type. Uniform methods of ascertainment and assessment were used at all sites. A 9-cM screen was performed by use of 391 markers, with an average heterozygosity of 0.76. Multipoint, nonparametric linkage analyses were conducted in affected relative pairs. Additionally, simulation analyses were performed to determine genomewide significance levels for this study. Three hierarchical models of affection were analyzed. Significant evidence for linkage (genomewide P < .10) was found on chromosome 17q, with a peak maximum LOD score of 3.63, at the marker D17S928, and on chromosome 6q, with a peak maximum LOD score of 3.61, near the marker D6S1021. These loci met both standard and simulation-based criteria for genomewide significance. Suggestive evidence of linkage was observed in three other regions (genomewide P <.10), on chromosomes 2p, 3q, and 8q. This study, which is based on the largest linkage sample for bipolar disorder analyzed to date, indicates that several genes contribute to bipolar disorder. C1 Indiana Univ, Sch Med, Inst Psychiat Res, Indianapolis, IN 46202 USA. Univ Louisville, Louisville, KY 40292 USA. NIMH, Mood & Anxiety Program, NIH, US Dept HHS, Bethesda, MD 20892 USA. Wayne State Univ, Detroit, MI USA. Univ Calif Irvine, Irvine, CA USA. Univ Calif San Diego, San Diego, CA 92103 USA. San Diego Vet Affairs Healthcare Syst, San Diego, CA USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Iowa, Iowa City, IA USA. Johns Hopkins Univ, Baltimore, MD USA. Univ Chicago, Chicago, IL 60637 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. Washington Univ, St Louis, MO USA. RP Nurnberger, JI (reprint author), Indiana Univ, Sch Med, Inst Psychiat Res, 791 Union Dr, Indianapolis, IN 46202 USA. RI McMahon, Francis/A-7290-2009; Meyer, Eric/C-1029-2011; OI Meyer, Eric/0000-0002-1998-7162; Nurnberger, John/0000-0002-7674-1767; McMahon, Francis/0000-0002-9469-305X FU NHGRI NIH HHS [N01 HG 65403, N01HG65403]; NIAAA NIH HHS [AA 00285, AA 13358, F32 AA013358]; NIMH NIH HHS [MH 59567, MH 60068, R01 MH 59545, R01 MH059545, R01 MH059567, R01 MH060068]; PHS HHS [R01 59553] NR 43 TC 155 Z9 157 U1 3 U2 6 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 JUL PY 2003 VL 73 IS 1 BP 107 EP 114 DI 10.1086/376562 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 696UA UT WOS:000183904900010 PM 12772088 ER PT J AU Rice, C Heineman, EF AF Rice, C Heineman, EF TI Application of a method to evaluate the quality of work histories and document the exposure assessment process SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE work history; data quality; next-of-kin interviews; information bias; occupational case-control studies ID REFRACTORY CERAMIC FIBER; UNITED-STATES REFINERIES; MALIGNANT MESOTHELIOMA; RETROSPECTIVE MORTALITY; PETROCHEMICAL INDUSTRY; PLEURAL MESOTHELIOMA; ASBESTOS EXPOSURE; FISCHER-344 RATS; CHEMICAL-PLANTS; FIBROUS GLASS AB Background Review of work history records by industrial hygienists is an important component of many occupational epidemiologic studies. A number of factors may influence the hygienist, such as the quality of the data and his or her previous experience. Aspart of a case-control study of mesothelioma, a system was developed to capture data on several factors that can be considered in a review of work history information. Methods The overall quality of the work history record was described by noting the completeness and the consistency of the information;for any potential exposures, the reviewer experience on which the decision was based and the relative quality of the information were categorized. Because of the potential for mesothelioma cases and their next-of-kin to have undergone rigorous questioning about previous asbestos exposure an evaluation of the knowledge of the respondent was included. The frequency and intensity of exposure were also evaluated. Results Evaluation of 3,444 work records is described. The importance of data completeness in the overall evaluation of quality is shown;follow-up questions regarding specific work tasks provide information not elicited in the standard interview process. The use of the literature was an important resource to the reviewer Asbestos was reported by the respondent as an exposure on 149 work records; of these, 111 (74%) were judged to represent an unusual level of knowledge for a next-of-kin respondent. Conclusions The approach presented allows capture of information about data quality and experience of the reviewer in an epidemiologic analysis. The ratings of frequency and intensity of exposure allow exploration of differences in exposure-response analyses using various exposure metrics. (C) 2003 Wiley-Liss, Inc. C1 Univ Cincinnati, Coll Med, Dept Environm Hlth, Cincinnati, OH 45267 USA. NCI, Occupat & Environm Epidemiol Branch, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet,NIH,Dept Hlth & Human, Bethesda, MD 20892 USA. RP Rice, C (reprint author), Univ Cincinnati, Coll Med, Dept Environm Hlth, Cincinnati, OH 45267 USA. NR 76 TC 3 Z9 3 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD JUL PY 2003 VL 44 IS 1 BP 94 EP 106 DI 10.1002/ajim.10231 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 697XT UT WOS:000183969100012 PM 12822141 ER PT J AU Menon, V Wang, XL Greene, T Beck, GJ Kusek, JW Marcovina, SM Levey, AS Sarnak, MJ AF Menon, V Wang, XL Greene, T Beck, GJ Kusek, JW Marcovina, SM Levey, AS Sarnak, MJ TI Relationship between C-reactive protein, albumin, and cardiovascular disease in patients with chronic kidney disease SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE C-reactive protein (CRP); glomerular filtration rate (GFR); albumin; cardiovascular disease (CVD) ID CHRONIC-RENAL-FAILURE; PERITONEAL-DIALYSIS PATIENTS; HEMODIALYSIS-PATIENTS; NUTRITIONAL-STATUS; SERUM-ALBUMIN; RISK-FACTORS; BLOOD-PRESSURE; INFLAMMATION; MORTALITY; MARKERS AB Background C-Reactive protein (CRP) level is elevated in kidney failure and may be related to malnutrition and cardiovascular disease (CVD). Data are limited regarding relationships between CRP levels and glomerular filtration rate (GFR), nutritional indices, and CVD in patients with earlier stages of kidney disease. Methods: CRP was assayed from samples from the Modification of Diet in Renal Disease (MDRD) Study (n = 801). CRP distributions were compared between the MDRD Study and National Health and Nutrition Examination Survey (NHANES; 1999 to 2000). Associations between CRP level and GFR, nutritional indices, serum albumin levels, and CVD risk factors were examined in the MDRD Study. Results: Geometric means of CRIP, adjusted for age and sex, were similar in NHANES (0.23 mg/dL) and the MDRD Study (0.22 mg/dL). In the MDRD Study, CRP level was related directly to measures of body fat and CVD risk factors, inversely with serum albumin level and energy intake, and unrelated to GFR. In multivariable analysis adjusting for other determinants of serum albumin level, high CRP level (>0.6 mg/dL) was associated with a 0.07-g/dL (0.7-g/L; 95% confidence interval [CI], 0.03 to 0.12) lower mean serum albumin level. After adjusting for traditional CVD risk factors, the odds of CVD were 1.73 (95% CI, 1.07 to 2.78) times greater in subjects with a high CRP level. Conclusion GFR level does not appear to influence CRP level in the earlier stages of chronic kidney disease. CRP levels are independently associated with serum albumin level and CVD prevalence. Inflammation may be involved in the pathophysiological state of malnutrition and CVD in the earlier stages of predominantly nondiabetic kidney disease. (C) 2003 by the National Kidney Foundation, Inc. C1 NEMC 391, Dept Med, Div Nephrol, Boston, MA 02111 USA. Tufts New England Med Ctr, Div Nephrol, Dept Med, Boston, MA USA. Tufts New England Med Ctr, Dept Med, Div Clin Care Res, Boston, MA USA. Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. NIH, Bethesda, MD 20892 USA. Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. RP Sarnak, MJ (reprint author), NEMC 391, Dept Med, Div Nephrol, 750 Washington St, Boston, MA 02111 USA. FU NIDDK NIH HHS [1 K23 DK02904-02, UO1 DK 35073] NR 55 TC 90 Z9 105 U1 0 U2 5 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUL PY 2003 VL 42 IS 1 BP 44 EP 52 DI 10.1016/S0272-6386(03)00407-4 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 696MK UT WOS:000183890500006 PM 12830455 ER PT J AU Abbott, KC Reynolds, JC Cruess, DF Agodoa, LY AF Abbott, KC Reynolds, JC Cruess, DF Agodoa, LY TI Morning versus evening hemodialysis - In reply SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Letter C1 Walter Reed Army Med Ctr, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Washington, DC USA. NIDDK, NIH, Bethesda, MD USA. RP Abbott, KC (reprint author), Walter Reed Army Med Ctr, Washington, DC 20307 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUL PY 2003 VL 42 IS 1 BP 213 EP 213 AR E1 DI 10.1016/S0272-6386(03)00559-6 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 696MK UT WOS:000183890500029 ER PT J AU Kurpinski, KT Magyari, PA Gorlin, RJ Ng, D Biesecker, LG AF Kurpinski, KT Magyari, PA Gorlin, RJ Ng, D Biesecker, LG TI Designation of the TARP syndrome and linkage to Xp11.23-q13.3 without samples from affected patients SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Pierre Robin sequence; cleft palate; X-linked recessive; linkage analysis AB The Robin sequence is a well-known cause of cleft palate and can be sporadic or familial, isolated or syndromic. We present a four-generation family with a lethal disorder inherited in an X-linked recessive pattern that includes Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistence of the left superior vena cava. We have designated this disorder "TARP" syndrome. All affected males die in infancy of unknown causes. An X-chromosome linkage scan was performed using 14 unaffected members of a single large family and 40 STRP markers. The gene was mapped to an 11-cM region in Xp11.23-q13.3. Markers DXS1003 and DXS8092 flank the region and three-point linkage analyses revealed a maximum LOD score of 2.75 at marker DXS1039. We have designated this locus as TARP. This locus was mapped without genotyping any affecteds and demonstrates that rare, lethal disorders can be evaluated by genetic linkage, even when no affected probands are available for study. Published 2003 Wiley-Liss, Inc. C1 NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Dept Oral Pathol Genet, Minneapolis, MN USA. RP Ng, D (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bldg 49,Room 4C72, Bethesda, MD 20892 USA. NR 4 TC 5 Z9 5 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL 1 PY 2003 VL 120A IS 1 BP 1 EP 4 DI 10.1002/ajmg.a.10201 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 687FM UT WOS:000183365600001 PM 12794682 ER PT J AU Martin, RA Slaugh, R Natowicz, M Pearlman, K Orvisky, E Krasnewich, D Kleta, R Huizing, M Gahl, WA AF Martin, RA Slaugh, R Natowicz, M Pearlman, K Orvisky, E Krasnewich, D Kleta, R Huizing, M Gahl, WA TI Sialic acid storage disease of the Salla phenotype in American monozygous twin female sibs SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Salla disease; ISSD; sialic acid; sialin ID SIALURIA; FIBROBLASTS; MUTATIONS; SPECTRUM; DISORDER; EGRESS; GENE AB Salla disease, one of three disease phenotypes that manifest increased urinary excretion of unconjugated sialic acid, is an autosomal recessive condition caused by a mutation in SLC17A5. This gene encodes sialin, a lysosomal membrane transporter for sialic acid. Salla disease is rare outside of individuals of Finnish ancestry. In this report we describe the disorder in non-Finnish monozygous twin siblings, the first reported American cases of Salla disease. (C) 2003 Wiley-Liss, Inc. C1 Washington Univ, St Louis Childrens Hosp, Dept Pediat, Div Med Genet, St Louis, MO 63110 USA. Eunice Kennedy Shriver Ctr Mental Retardat Inc, Div Med Genet, Waltham, MA USA. NIMH, Clin Neurosci Branch, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Heritable Disorders Branch, Sect Human Biochem Genet, Bethesda, MD 20892 USA. RP Martin, RA (reprint author), Washington Univ, St Louis Childrens Hosp, Dept Pediat, Div Med Genet, St Louis, MO 63110 USA. NR 18 TC 10 Z9 11 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 A JI Am. J. Med. Genet. A PD JUL 1 PY 2003 VL 120A IS 1 BP 23 EP 27 DI 10.1002/ajmg.a.10246 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 687FM UT WOS:000183365600006 PM 12794687 ER PT J AU Kleta, R Aughton, DJ Rivkin, MJ Huizing, M Strovel, E Anikster, Y Orvisky, E Natowicz, M Krasnewich, D Gahl, WA AF Kleta, R Aughton, DJ Rivkin, MJ Huizing, M Strovel, E Anikster, Y Orvisky, E Natowicz, M Krasnewich, D Gahl, WA TI Biochemical and molecular analyses of infantile free sialic acid storage disease in North American children SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE sialic acid; N-acetylneuraminic acid; lysosomal storage; infantile free sialic acid storage disease (ISSD); Salla disease ID SALLA-DISEASE; KINASE GENE; SPECTRUM; SIALURIA; FIBROBLASTS; MUTATIONS; DISORDER; METABOLISM; LYSOSOMES; MYOPATHY AB The differential diagnosis of developmental delays and growth retardation in early childhood includes the allelic lysosomal sialic acid storage disorders, Salla disease and infantile free sialic acid storage disease (ISSD). These diseases, due to defective free sialic acid transport out of lysosomes, derive from mutations in the SLC17A5 gene coding for the protein sialin. We present two patients with clinical, biochemical, and molecular data indicative of lysosomal free sialic acid storage disorders. One patient, with a severe clinical course typical of ISSD, had 86-fold elevated levels of fibroblast free sialic acid, with 62% in the lysosomal fraction. His SLC17A5 mutations include a 148-bp deletion of exon 9, due to a G > A splice site mutation in position 1 of intron 9, and a 15-by deletion (del 801-815) in exon 6. Another patient, with "intermediate severe" Salla disease, had 9-fold elevated levels of free sialic acid in cultured fibroblasts, of which 87% resided in the lysosomal fraction. This girl is compound heterozygous for the SLC17A5 mutation commonly found in Finnish Salla disease patients (R39C) and a 15-by deletion found in ISSD patients (del 801-815). These observations emphasize the importance of considering free sialic acid disorders in infants with developmental delays and growth retardation, regardless of whether they are of Finnish ancestry. (C) 2003 Wiley-Liss, Inc. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Cleveland Clin Fdn, Dept Neurol, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Dept Pathol, Cleveland, OH 44195 USA. NIMH, NSB, NIH, Bethesda, MD 20892 USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. William Beaumont Hosp, Div Genet, Royal Oak, MI 48072 USA. NICHHD, Heritable Disorders Branch, Sect Human Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Gahl, WA (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Div,MSC 1851,Bldg 10,Room 10C-103, Bethesda, MD 20892 USA. NR 27 TC 19 Z9 21 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 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL 1 PY 2003 VL 120A IS 1 BP 28 EP 33 DI 10.1002/ajmg.a.20024 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 687FM UT WOS:000183365600007 PM 12794688 ER PT J AU Freedman, AN Wideroff, L Olson, L Davis, W Klabunde, C Srinath, KP Reeve, BB Croyle, RT Ballard-Barbash, R AF Freedman, AN Wideroff, L Olson, L Davis, W Klabunde, C Srinath, KP Reeve, BB Croyle, RT Ballard-Barbash, R TI US physicians' attitudes toward genetic testing for cancer susceptibility SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE physician survey; genetic testing; physician attitudes; guidelines; cancer susceptibility ID BREAST-CANCER; GENERAL-POPULATION; HEREDITARY BREAST; OVARIAN-CANCER; BRCA1; RISK; FAMILIES; RELATIVES; INSURANCE; WOMEN AB Genetic testing for an inherited susceptibility to cancer is an emerging technology in medical practice. Little information is currently available about physicians' attitudes toward these tests. To assess US physicians' opinions on unresolved issues surrounding genetic testing, a 15-min survey was administered to a stratified random sample of 1,251 physicians from 8 specialties, selected from a file of all licensed physicians in the US (response rate = 71.0%). Dependent measures included physicians' attitudes toward genetic counseling and testing qualifications, availability of guidelines, patient confidentiality and insurance discrimination issues, and clinical utility of genetic tests. More than 89% of physicians reported a need for physician guidelines, 81% thought that patients with positive genetic test results are at risk for insurance discrimination, and more than 53% thought that it was difficult to ensure the confidentiality of test results. Almost 25% indicated that genetic tests for cancer susceptibility have too many inaccurate or ambiguous results; nearly 75% thought that clear guidelines are not available for managing patients with positive test results. Only 29% of physicians reported feeling qualified to provide genetic counseling to their patients. More than 84% of oncologists considered themselves qualified to recommend genetic testing to their patients compared with 40% of primary care physicians (PCPs), and 57% of tertiary care physicians (TCPs). US physicians expressed great uncertainty about issues surrounding genetic testing for cancer susceptibility. Results of this national survey underscore the need to provide physicians with clear guidelines on the use of genetic cancer susceptibility tests and effective medical training on their appropriate implementation. Published 2003 Wiley-Liss, Inc. C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. ABT Associates Inc, Chicago, IL USA. RP Freedman, AN (reprint author), NCI, Div Canc Control & Populat Sci, EPN 405 MSC 7344,6130 Execut Blvd, Bethesda, MD 20892 USA. RI Hernandez, Jessica/G-6527-2011 NR 39 TC 98 Z9 98 U1 2 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL 1 PY 2003 VL 120A IS 1 BP 63 EP 71 DI 10.1002/ajmg.a.10192 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 687FM UT WOS:000183365600013 PM 12794694 ER PT J AU Wright, BS Nwokoro, NA Wassif, CA Porter, FD Waye, JS Eng, B Nowaczyk, MJM AF Wright, BS Nwokoro, NA Wassif, CA Porter, FD Waye, JS Eng, B Nowaczyk, MJM TI Carrier frequency of the RSH/Smith-Lemli-Opitz IVS8-1G > C mutation in African Americans SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Letter ID CHOLESTEROL-BIOSYNTHESIS; REDUCTASE GENE; ADMIXTURE; PROPORTIONS; DHCR7 C1 NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada. RP Porter, FD (reprint author), Bldg 10,Room 9D41,10 Ctr Dr, Bethesda, MD 20892 USA. NR 18 TC 16 Z9 16 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL 1 PY 2003 VL 120A IS 1 BP 139 EP 141 DI 10.1002/ajmg.a.10207 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 687FM UT WOS:000183365600026 PM 12794707 ER PT J AU Pan, ZG Shen, YL Du, C Zhou, GM Rosenwald, A Staudt, LM Greiner, TC McKeithan, TW Chan, WC AF Pan, ZG Shen, YL Du, C Zhou, GM Rosenwald, A Staudt, LM Greiner, TC McKeithan, TW Chan, WC TI Two newly characterized germinal center B-cell-associated genes, GCET1 and GCET2, have differential expression in normal and neoplastic B cells SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID CDNA ENDS; RAPID AMPLIFICATION; MEDIATED APOPTOSIS; LYMPHOMA; LINES; SURVIVAL; PATHWAYS; PROFILE; SERPIN; MOTIF AB A group of genes are highly expressed in normal germinal center (GC) B cells and GC B-cell-derived malignancies based on cDNA microarray analysis. Two new genes, GCET1 (germinal center B-cell expressed transcript 1) and GCET2, were cloned from selected expressed sequence tags (IMAGE clone 1334260 and 814622, respectively). GCET1 is located on chromosome 14q32 and has four splicing isoforms, of which the longest one is 1787 bp and encodes a 435-amino acid protein. GCET2 is located on 3q13.13, and the cloned fragment is 3270 bp, which encodes a protein of 178 an-kino acids. Blast search showed that GCET1 has a highly conserved serine proteinase inhibitor (SERPIN) domain and is located on a chromosomal locus containing seven other SERPIN family members. GCET2 is a likely homologue of the mouse gene M17, a GC-expressed transcript. Analysis of the GCET2 protein sequence indicated that it may be involved in signal transduction in the cytoplasm. Northern blot and real-time polymerase chain reaction analyses confirmed that GCET1 is highly restricted to normal GC B cells and GCB-cell-derived cell lines. Although GCET2 is also a useful marker for normal and neoplastic GC B cells, it has a wider range of expression including immature B and T cells. Real-time polymerase chain reaction assay showed that both GCET1 and GCET2 are preferentially expressed in follicular lymphoma and diffuse large B-cell lymphoma with GC B-cell differentiation, confirming previous microarray gene expression analysis, but neither one is entirely specific. Multiple markers are necessary to differentiate the GCB from the activated B-cell type of diffuse large B-cell lymphoma with a high degree of accuracy. C1 Univ Nebraska, Med Ctr, Dept Pathol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA. Univ Nebraska, Med Ctr, Dept Microbiol, Omaha, NE 68198 USA. NCI, Metab Branch, Bethesda, MD 20892 USA. RP Chan, WC (reprint author), Univ Nebraska, Med Ctr, Dept Pathol, Nebraska Med Ctr 983135, Omaha, NE 68198 USA. RI Du, Cheng/F-1569-2013 OI Du, Cheng/0000-0002-8882-2513 FU NCI NIH HHS [U01 CA084967, U01-CA84967-04] NR 30 TC 30 Z9 36 U1 0 U2 1 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 JUL PY 2003 VL 163 IS 1 BP 135 EP 144 DI 10.1016/S0002-9440(10)63637-1 PG 10 WC Pathology SC Pathology GA 695KP UT WOS:000183829900014 PM 12819018 ER PT J AU Xu, WL Comhair, SAA Zheng, S Chu, SC Marks-Konczalik, J Moss, J Haque, SJ Erzurum, SC AF Xu, WL Comhair, SAA Zheng, S Chu, SC Marks-Konczalik, J Moss, J Haque, SJ Erzurum, SC TI STAT-1 and c-Fos interaction in nitric oxide synthase-2 gene activation SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE gene regulation; signal transduction ID NF-KAPPA-B; INTERFERON-GAMMA; TARGETED DISRUPTION; SIGNAL-TRANSDUCTION; HUMAN AIRWAY; INOS GENE; JUN-FOS; TRANSCRIPTION; INDUCTION; PROMOTER AB Interferon-gamma (IFN-gamma) is required for induction of the human nitric oxide synthase-2 (NOS2) gene in lung epithelium. Although the human NOS2 promoter region contains many cytokine-responsive elements, the molecular basis of induction is only partially understood. Here, the major cis-regulatory elements that control IFN-gamma-inducible NOS2 gene transcription in human lung epithelial cells are identified as composite response elements that bind signal transducer and activator of transcription 1 (STAT-1) and activator protein 1 (AP-1), which is comprised of c-Fos, Fra-2, c-Jun, and JunD. Notably, IFN-gamma activation of the human NOS2 promoter is shown to require functional AP-1 regulatory region(s), suggesting a role for AP-1 activation/binding in the IFN-gamma induction of genes. We show that c-Fos interacts with STAT-1 after IFN-gamma activation and the c-Fos/STAT-1 complex binds to the gamma-activated site ( GAS) element in close proximity to AP-1 sites located at 4.9 kb upstream of the transcription start site. Taken together, our findings support a model in which a physical interaction between c-Fos and STAT-1 participates in NOS2 gene transcriptional activation. C1 Cleveland Clin Fdn, Lerner Res Inst, Cleveland, OH 44195 USA. NHLBI, Pulm Crit Care Med Branch, Bethesda, MD 20892 USA. RP Erzurum, SC (reprint author), Cleveland Clin Fdn, Lerner Res Inst, 9500 Euclid Ave,NB40, Cleveland, OH 44195 USA. FU NHLBI NIH HHS [HL-60917] NR 48 TC 37 Z9 39 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD JUL PY 2003 VL 285 IS 1 BP L137 EP L148 DI 10.1152/ajplung.00441.2002 PG 12 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 686HB UT WOS:000183314400016 PM 12788789 ER PT J AU Hansen, PB Hashimoto, S Briggs, J Schnermann, J AF Hansen, PB Hashimoto, S Briggs, J Schnermann, J TI Attenuated renovascular constrictor responses to angiotensin II in adenosine 1 receptor knockout mice SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE renal blood flow; ultrasonic flowmeter; renal vascular resistance; glomerular filtration rate; perfused arterioles ID RABBIT AFFERENT ARTERIOLES; RENAL VASOCONSTRICTION; PHOSPHOLIPASE-C; A(1) RECEPTOR; RAT-KIDNEY; EXPRESSION; MICROCIRCULATION; NOREPINEPHRINE; STIMULATION; REACTIVITY AB In the present experiments we examined the renovascular constrictor effects of ANG II in the chronic and complete absence of A1 adenosine receptors (A1AR) using mice with targeted deletion of the A1AR gene. Glomerular filtration rate (GFR) was not different between A1AR +/+ and A1AR -/- mice under control conditions (450.5 +/- 60 vs. 475.2 +/- 62.5 mul/min) but fell significantly less in A1AR -/- mice during infusion of ANG II at 1.5 ng/min (A1AR +/+: 242 +/- 32.5 mul/min, A1AR -/-: 371 +/- 42 mul/min; P = 0.03). Bolus injection of 1, 10, and 100 ng of ANG II reduced renal blood flow and increased renal vascular resistance significantly more in A1AR +/+ than in A1AR -/- mice. Perfused afferent arterioles isolated from A1AR -/- mice constricted in response to bath ANG II with an EC50 of 1.5 +/- 0.4 x 10(-10) mol/l, whereas a right shift in the dose-response relationship with an EC50 of 7.3 +/- 1.2 x 10(-10) mol/l (P < 0.05) was obtained in arterioles from A1AR -/- mice (P < 0.05). The expression of AT1A receptor mRNA was not different in kidney RNA from A1AR +/+ or A1AR -/- mice. We conclude that chronic A1AR deficiency diminishes the effectiveness of ANG II to constrict renal resistance vessels and to reduce GFR. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Schnermann, J (reprint author), NIDDKD, NIH, Bldg 10,Rm 4 D51,10 Ctr Dr MSC 1370, Bethesda, MD 20892 USA. NR 21 TC 32 Z9 32 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD JUL PY 2003 VL 285 IS 1 BP R44 EP R49 DI 10.1152/ajpregu.00739.2002 PG 6 WC Physiology SC Physiology GA 687AW UT WOS:000183354500011 PM 12793993 ER PT J AU Sarntinoranont, M Iadarola, MJ Lonser, RR Morrison, PF AF Sarntinoranont, M Iadarola, MJ Lonser, RR Morrison, PF TI Direct interstitial infusion of NK(1)-targeted neurotoxin into the spinal cord: a computational model SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE convection-enhanced delivery; intraparenchymal infusions; pain therapy; pharmacodynamic model; convection; finiteelement method ID SUBSTANCE-P RECEPTOR; CONVECTION-ENHANCED DELIVERY; PROTEIN-SYNTHESIS INHIBITION; DIPHTHERIA-TOXIN FRAGMENT; INDUCED INTERNALIZATION; PERSISTENT PAIN; FUSION PROTEIN; BINDING-SITES; SCIATIC-NERVE; NK1 RECEPTOR AB Convection-enhanced delivery of substance P (SP) nocitoxins to the spinal cord interstitium is under consideration for the treatment of chronic pain. To characterize treatment protocols, a three-dimensional finite-element model of infusion into the human dorsal column was developed to predict the distribution of SP-diphtheria toxin fusion protein (SP-DT') within normal and target tissue. The model incorporated anisotropic convective and diffusive transport through the interstitial space, hydrolysis by peptidases, and intracellular trafficking. For constant SP-DT' infusion (0.1 mul/min), the distribution of cytotoxicity in NK(1) receptor-expressing neurons was predicted to reach an asymptotic limit at 6-8 h in the transverse direction at the level of the infusion cannula tip (similar to60% ablation of target neurons in lamina I/II). Computations revealed that SP-DT' treatment was favored by a stable SP analog (half-life similar to60 min), high infusate concentration (385 nM), and careful catheter placement (adjacent to target lamina I/II). Sensitivity of cytotoxic regions to NK1 receptor density and white matter protease activity was also established. These data suggest that intraparenchymal infusions can be useful for treatment of localized chronic pain. C1 Natl Inst Dental & Craniofacial Res, Div Bioengn & Phys Sci, Off Res Serv, NIH, Bethesda, MD 20892 USA. Natl Inst Dental & Craniofacial Res, Pain & Neurosensory Mech Branch, NIH, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Sarntinoranont, M (reprint author), Natl Inst Dental & Craniofacial Res, Div Bioengn & Phys Sci, Off Res Serv, NIH, Bldg 13,Rm 3N17,13 South Dr, Bethesda, MD 20892 USA. EM sarntinm@mail.nih.gov NR 57 TC 12 Z9 13 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD JUL PY 2003 VL 285 IS 1 BP R243 EP R254 DI 10.1152/ajpregu.00472.2002 PG 12 WC Physiology SC Physiology GA 687AW UT WOS:000183354500035 PM 12793999 ER PT J AU Fenton, RA Chou, CL Ageloff, S Brandt, W Stokes, JB Knepper, MA AF Fenton, RA Chou, CL Ageloff, S Brandt, W Stokes, JB Knepper, MA TI Increased collecting duct urea transporter expression in Dahl salt-sensitive rats SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE UT-A; sodium-potassium-adenosine 5 '-triphosphatase; 11 beta-hydoxysteroid dehydrogenase; glucocorticoid ID THICK ASCENDING LIMBS; UT-A; NITRIC-OXIDE; MINERALOCORTICOID HORMONES; ARACHIDONIC-ACID; GENE-EXPRESSION; ANGIOTENSIN-II; RESISTANT RATS; NA+ TRANSPORT; SLC14A2 GENE AB Because abnormalities of inner medullary function have been proposed in Dahl salt-sensitive (DS) rats vs. salt-resistant (DR) rats, we performed transporter profiling by semiquantitative immunoblotting to determine whether specific solute transporter abundances are altered in inner medullas of DS rats vs. DR rats. Although none of the expressed Na transporters were upregulated in the inner medullas of DS rats compared with DR rats, there were marked increases in the protein abundances of the collecting duct urea transporters UT-A1 ( to 212% of DR) and UT-A3 ( to 223% of DR). These differences were confirmed by immunocytochemistry. Quantitative real-time RT-PCR showed higher mRNA abundance in DS rats for both UT-A1 ( to 256% of DR) and UT-A3 ( to 210% of DR). In isolated, perfused inner medullary collecting ducts, urea permeability was significantly greater in DS rats. Because both UT-A1 and UT-A3 are transcriptionally regulated by glucocorticoids, we measured both plasma corticosterone levels and inner medullary 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) abundances. Although the plasma corticosterone concentrations were not different between DS and DR rats, immunoblotting and immunocytochemistry revealed a marked elevation of 11beta-HSD2 abundance in DS rats. Consistent with the view that an elevated 11beta-HSD2 level is responsible for increased urea transporter expression in the inner medullary collecting duct, administration of the 11beta-HSD2 inhibitor carbenoxolone to DS rats decreased the abundances of UT-A1 and UT-A3 to levels similar to those seen in DR rats. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. Vet Affairs Med Ctr, Iowa City, IA 52242 USA. RP Fenton, RA (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 6N260,MSC 1603, Bethesda, MD 20892 USA. EM fentonr@nhlbi.nih.gov FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NHLBI NIH HHS [HL-55006, Z01-HL-01282-KE]; NIDDK NIH HHS [DK-52617] NR 54 TC 16 Z9 16 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JUL PY 2003 VL 285 IS 1 BP F143 EP F151 DI 10.1152/ajprenal.00073.2003 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 686HC UT WOS:000183314500016 PM 12684228 ER PT J AU Kwon, TH Nielsen, J Kim, YH Knepper, MA Frokiaer, J Nielsen, S AF Kwon, TH Nielsen, J Kim, YH Knepper, MA Frokiaer, J Nielsen, S TI Regulation of sodium transporters in the thick ascending limb of rat kidney: response to angiotensin II SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE bumetanide-sensitive sodium-potassium-2chloride cotransporter; Na-K-ATPase; type 3 sodium-hydrogen exchanger; bicarbonate transport; sodium transport ID NA+-H+ EXCHANGE; PROXIMAL TUBULE; METABOLIC-ACIDOSIS; CL COTRANSPORTER; APICAL MEMBRANE; EXPRESSION; STIMULATION; RECEPTOR; CHANNEL; NHE3 AB The effect of ANG II treatment of rats for 7 days was examined with respect to the abundance and subcellular localization of key thick ascending limb ( TAL) Na(+) transporters. Rats were on a fixed intake of Na(+) and water and treated with 0, 12.5, 25, 50 ( ANG II-50), 100 ( ANG II-100), and 200 (ANG II-200) ng . min(-1) . kg(-1) ANG II (sc). Semiquantitative immunoblotting revealed that Na(+)/H(+) exchanger 3 (NHE3) abundance in the inner stripe of the outer medulla (ISOM) of ANG II-treated rats was significantly increased: 179 +/- 28 ( ANG II-50, n = 5), 166 +/- 23 ( ANG II-100, n = 7), and 167 +/- 19% ( ANG II-200, n = 4) of control levels ( n = 6, P < 0.05), whereas lower doses of ANG II were ineffective. The abundance of the bumetanide-sensitive Na(+)-K(+)-2Cl(-) cotransporter (BSC-1) in the ISOM was also increased to 187 +/- 28 ( ANG II-50), 162 +/- 23 ( ANG II-100), and 166 +/- 19% ( ANG II-200) of control levels ( P < 0.05), but there were no changes in the abundance of Na(+)-K(+)-ATPase and the electroneutral Na(+)-HCO(3) cotransporter NBCn1. Immunocytochemistry confirmed the increase in NHE3 and BSC-1 labeling in medullary TAL ( mTAL). In the cortex and the outer strip of the outer medulla, NHE3 abundance was unchanged, whereas immunocytochemistry revealed markedly increased NHE3 labeling of the proximal tubule brush border, suggesting subcellular redistribution of NHE3 or differential protein-protein interaction. Despite this, ANG II-treated rats (50 ng . min(-1) . kg(-1) for 5 days, n = 6) had a higher urinary pH compared with controls. NH(4)Cl loading completely blocked all effects of ANG II infusion on NHE3 and BSC-1, suggesting a potential role of pH as a mediator of these effects. In conclusion, increased abundance of NHE3 and BSC-1 in mTAL cells as well as increased NHE3 in the proximal tubule brush border may contribute to enhanced renal Na(+) and HCO(3) reabsorption in response to ANG II. C1 Aarhus Univ, Water & Salt Res Ctr, DK-8000 Aarhus C, Denmark. Dongguk Univ, Dept Physiol, Sch Med, Kyungju 780714, South Korea. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Nielsen, S (reprint author), Aarhus Univ, Water & Salt Res Ctr, Bldg 233-234, DK-8000 Aarhus C, Denmark. EM sn@ana.au.dk FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 52 TC 73 Z9 77 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JUL PY 2003 VL 285 IS 1 BP F152 EP F165 DI 10.1152/ajprenal.00307.2002 PG 14 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 686HC UT WOS:000183314500017 PM 12657563 ER PT J AU Bigoni, F Stanyon, R Wimmer, R Schempp, W AF Bigoni, F Stanyon, R Wimmer, R Schempp, W TI Chromosome painting shows that the proboscis monkey (Nasalis larvatus) has a derived karyotype and is phylogenetically nested within Asian colobines SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Article DE in situ hybridization; chromosomes; primates; comparative mapping; evolution ID OLD-WORLD MONKEYS; IN-SITU HYBRIDIZATION; EVOLUTION; APES; SEQUENCES; HOMOLOGY; HUMANS; DNA AB The exceptional diploid number (2n = 48) of the proboscis monkey (Nasalis laruatus) has played a pivotal role in phylogenies that view the proboscis monkey as the most primitive colobine, and a long-isolated genus of the group. In this report we used molecular cytogenetic methods to map the chromosomal homology of the proboscis monkey in order to test these hypotheses. Our results reveal that the N. laruatus karyotype is derived and is not primitive in respect to other colobines (2n = 44) and most other Old World monkeys. The diploid number of 2n = 48 can be best explained by derived fissions of a segment of human chromosomes 14 and 6. The fragmentation and association of human chromosomes 1 and 19 as seen in other Asian colobines, but not in African colobines, is best explained as a derived reciprocal translocation linking all Asian colobines. The alternating hybridization pattern between four segments homologous to human chromosomes 1 and 19 on N. laruatus chromosome 6 is the result of the reciprocal translocation followed by a pericentric inversion. N. laruatus shares this pericentric inversion with Trachypithecus, but not with Pygathrix. This inversion apparently links Nasalis and Trachypithecus after the divergence of Pygathrix. The karyological data support the view that Asian colobines, including N. larvatus, are monophyletic. They share many linking karyological features separating them from the African colobines. The hybridization pattern also suggests that Nasalis is nested within Asian Colobines and shares a period of common descent with other Asian colobines after the divergence of Pygathrix. (C) 2003 Wiley-Liss, Inc. C1 NCI, Comparat Mol Cytogenet Core Genet Branch, Frederick, MD 21701 USA. Univ Freiburg, Inst Human Genet & Anthropol, Freiburg, Germany. RP Stanyon, R (reprint author), NCI, Comparat Mol Cytogenet Core Genet Branch, Frederick, MD 21701 USA. OI Stanyon, Roscoe/0000-0002-7229-1092 NR 35 TC 24 Z9 26 U1 3 U2 10 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD JUL PY 2003 VL 60 IS 3 BP 85 EP 93 DI 10.1002/ajp.10095 PG 9 WC Zoology SC Zoology GA 707HC UT WOS:000184504400002 PM 12874840 ER PT J AU Tohen, M Ketter, TA Zarate, CA Suppes, T Frye, M Altshuler, L Zajecka, J Schuh, LM Risser, RC Brown, E Baker, RW AF Tohen, M Ketter, TA Zarate, CA Suppes, T Frye, M Altshuler, L Zajecka, J Schuh, LM Risser, RC Brown, E Baker, RW TI Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: A 47-week study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID MAJOR AFFECTIVE-DISORDER; BIPOLAR DISORDER; WEIGHT CHANGE; RATING-SCALE; PLACEBO; ILLNESS; LITHIUM; SCHIZOPHRENIA; PSYCHOSIS; RECOVERY AB Objective: Few double-blind trials have compared longer-term efficacy and safety of medications for bipolar disorder. The authors report a 47-week comparison of olanzapine and divalproex. Method: This 47-week, randomized, double-blind study compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day) for manic or mixed episodes of bipolar disorder (N= 251). The only other psychoactive medication allowed was lorazepam for agitation. The primary efficacy instrument was the Young Mania Rating Scale; a priori protocol-defined threshold scores were greater than or equal to20 for inclusion, less than or equal to12 for remission, and greater than or equal to15 for relapse. Analytical techniques included mixed model repeated-measures analysis of variance for change from baseline, Fisher's exact test (two-tailed) for categorical comparisons, and Kaplan-Meier estimates of time to events of interest. Results: Over 47 weeks, mean improvement in Young Mania Rating Scale score was significantly greater for the olanzapine group. Median time to symptomatic mania remission was significantly shorter for olanzapine, 14 days, than for divalproex, 62 days. There were no significant differences between treatments in the rates of symptomatic mania remission over the 47 weeks (56.8% and 45.5%, respectively) and subsequent relapse into mania or depression (42.3% and 56.5%). Treatment-emergent adverse events occurring significantly more frequently during olanzapine treatment were somnolence, dry mouth, increased appetite, weight gain, akathisia, and high alanine aminotransferase levels; those for divalproex were nausea and nervousness. Conclusions: In this 47-week study of acute bipolar mania, symptomatic remission occurred sooner and overall mania improvement was greater for olanzapine than for divalproex, but rates of bipolar relapse did not differ. C1 Stanford Univ, Dept Psychiat & Behav Sci, Sch Med, Stanford, CA 94305 USA. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX USA. Univ Calif Los Angeles, Neuropsychiat Inst & Hosp, Los Angeles, CA USA. Rush Presbyterian St Lukes Med Ctr, Dept Psychiat, Chicago, IL 60612 USA. Harvard Univ, McLean Hosp, Sch Med, Lilly Res Labs, Belmont, MA 02178 USA. RP Tohen, M (reprint author), Lilly Res Labs, Indianapolis, IN 46285 USA. NR 34 TC 226 Z9 229 U1 3 U2 7 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUL PY 2003 VL 160 IS 7 BP 1263 EP 1271 DI 10.1176/appi.ajp.160.7.1263 PG 9 WC Psychiatry SC Psychiatry GA 697RN UT WOS:000183957200010 PM 12832240 ER PT J AU Weiss, RD Griffin, ML Mazurick, C Berkman, B Gastfriend, DR Frank, A Barber, JP Blaine, J Salloum, I Moras, K AF Weiss, RD Griffin, ML Mazurick, C Berkman, B Gastfriend, DR Frank, A Barber, JP Blaine, J Salloum, I Moras, K TI The relationship between cocaine craving, psychosocial treatment, and subsequent cocaine use SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 62nd Annual Meeting of the College-on-Problems-of-Drug-Dependence CY JUN 17-20, 2000 CL SAN JUAN, PUERTO RICO SP Coll Problems Drug Dependence ID COMPULSIVE DRINKING SCALE; NATIONAL-INSTITUTE; DRUG-USE; DEPENDENCE; ABSTINENCE; ALCOHOL; ABUSERS AB Objective: Regular measurement of craving during treatment for cocaine dependence can monitor patients' clinical status and potentially assess their risk for drug use in the near future. Effective treatment can reduce the correlation between craving and subsequent drug use by helping patients abstain despite high craving. This study examined the relationship between cocaine craving, psychosocial treatment, and cocaine use in the ensuing week. Method: In the National Institute on Drug Abuse Collaborative Cocaine Treatment Study, which compared four psychosocial treatments for cocaine dependence, a three-item craving questionnaire was administered weekly to 449 patients to see whether it predicted cocaine use in the ensuing week. Cocaine use was assessed with self-reports and urine screening. Results: With control for the previous week's cocaine use, a higher composite score on the craving questionnaire was associated with greater likelihood of cocaine use in the subsequent week; each 1-point increase on the composite score of the craving questionnaire increased the likelihood of cocaine use in the ensuing week by 10%. However, among patients who received individual plus group drug counseling, the treatment condition with the best overall cocaine use outcome, increased craving scores were not associated with greater likelihood of cocaine use in the subsequent week. Conclusions: A three-item cocaine craving questionnaire predicted the relative likelihood of cocaine use during the subsequent week. Moreover, the relationship between craving and subsequent cocaine use varied by treatment condition, suggesting that the most effective treatment in the study might have weakened the link between craving and subsequent use. C1 McLean Hosp, Belmont, MA 02478 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Univ Penn, Ctr Psychotherapy Res, Dept Psychiat, Philadelphia, PA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Natl Inst Drug Abuse, Bethesda, MD USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. Western Psychiat Inst & Clin, Pittsburgh, PA USA. RP Weiss, RD (reprint author), McLean Hosp, 115 Mill St, Belmont, MA 02478 USA. FU NIDA NIH HHS [DA-07693, DA-00326, DA-07085, DA-07090, DA-07663, DA-07673]; NIMH NIH HHS [MH-45178] NR 33 TC 66 Z9 68 U1 5 U2 8 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUL PY 2003 VL 160 IS 7 BP 1320 EP 1325 DI 10.1176/appi.ajp.160.7.1320 PG 6 WC Psychiatry SC Psychiatry GA 697RN UT WOS:000183957200018 PM 12832248 ER PT J AU Blumberg, HP Martin, A Kaufman, J Leung, HC Skudlarski, P Lacadie, C Fulbright, RK Gore, JC Charney, DS Krystal, JH Peterson, BS AF Blumberg, HP Martin, A Kaufman, J Leung, HC Skudlarski, P Lacadie, C Fulbright, RK Gore, JC Charney, DS Krystal, JH Peterson, BS TI Frontostriatal abnormalities in adolescents with bipolar disorder: Preliminary observations from functional MRI SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID PREFRONTAL CORTEX; CHILDREN; SCHIZOPHRENIA; MANIA AB Objective: This study investigated whether the functional abnormalities in prefrontal systems observed in adult bipolar disorder are manifested in adolescents with this illness. Method: Ten adolescents with bipolar disorder and 10 healthy comparison subjects participated in a color-naming Stroop task during event-related functional magnetic resonance imaging. Results: Signal increases in the left putamen and thalamus were significantly greater in the bipolar disorder group than in the healthy group. Age correlated positively with signal increases in the bilateral rostroventral prefrontal cortex and the striatum in the healthy group but not in the bipolar disorder group. In the bipolar disorder subjects, depressive symptoms correlated positively with signal increases in the ventral striatum. Conclusions: These findings suggest the presence of dysfunction in the subcortical portions of the frontostriatal circuits in adolescents with bipolar disorder. The absence of the prefrontal abnormalities that were observed previously in adults and the absence of the age-related increases in prefrontal activity observed in normal comparison subjects suggest that a developmental disturbance in prefrontal function may emerge in bipolar disorder over the course of adolescence. C1 Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. Yale Univ, Sch Med, Dept Diagnost Radiol, New Haven, CT USA. Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT USA. NIMH, Mood & Anxiety Res Program, Bethesda, MD USA. Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. RP Blumberg, HP (reprint author), VA Connecticut Healthcare Syst, Dept Psychiat, 950 Campbell Ave,116A, West Haven, CT 06516 USA. FU NIAAA NIH HHS [AA-00261-01]; NIMH NIH HHS [MH-01232, MH-01792, MH-59139] NR 12 TC 152 Z9 155 U1 0 U2 2 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUL PY 2003 VL 160 IS 7 BP 1345 EP 1347 DI 10.1176/appi.ajp.160.7.1345 PG 3 WC Psychiatry SC Psychiatry GA 697RN UT WOS:000183957200024 PM 12832254 ER PT J AU Atwood, A Sternberg, EM Fee, E Brown, TM AF Atwood, A Sternberg, EM Fee, E Brown, TM TI Acupuncture: Archaic or biologic? Atwood et al. responds SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Letter C1 NIMH, NIH, Bethesda, MD 20892 USA. Natl Lib Med, Hist Med Div, NIH, Bethesda, MD 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 7 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2003 VL 93 IS 7 BP 1037 EP 1038 DI 10.2105/AJPH.93.7.1037-a PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 695JK UT WOS:000183827200011 ER PT J AU Haviland, L Healton, CG Fee, E Brown, TM Toomey, BA Kastens, B AF Haviland, L Healton, CG Fee, E Brown, TM Toomey, BA Kastens, B TI Courage and dignity SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 Legacy Fdn, Washington, DC USA. Natl Lib Med, Hist Med Div, NIH, Bethesda, MD 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 3 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2003 VL 93 IS 7 BP 1045 EP 1045 DI 10.2105/AJPH.93.7.1045 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 695JK UT WOS:000183827200017 PM 12835177 ER PT J AU Singh, GK AF Singh, GK TI Area deprivation and widening inequalities in US mortality, 1969-1998 SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID HEART-DISEASE MORTALITY; COMMUNITY OCCUPATIONAL STRUCTURE; UNITED-STATES; SOCIAL-CLASS; SOCIOECONOMIC DIFFERENTIALS; CANCER MORTALITY; ALL-CAUSE; HEALTH; PATTERNS; SCOTLAND AB Objectives. This study examined age-, sex-, and race-specific gradients in US mortality by area deprivation between 1969 and 1998. Methods. A census-based area deprivation index was linked to county mortality data. Results. Area deprivation gradients in US mortality increased substantially during 1969 through 1998. The gradients were steepest for men and women aged 25 to 44 years and those younger than 25 years, with higher mortality rates observed in more deprived areas. Although area gradients were less pronounced for women in each age group, they rose sharply for women aged 25 to 44 and 45 to 64 years. Conclusions. Areal inequalities in mortality widened because of slower mortality declines in more deprived areas. Future research needs to examine population-level social, behavioral, and medical care factors that may account for the increasing gradient. C1 NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Singh, GK (reprint author), NCI, Div Canc Control & Populat Sci, NIH, 6116 Execut Blvd,Suite 504,MSC8316, Bethesda, MD 20892 USA. NR 55 TC 117 Z9 118 U1 1 U2 4 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2003 VL 93 IS 7 BP 1137 EP 1143 DI 10.2105/AJPH.93.7.1137 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 695JK UT WOS:000183827200039 PM 12835199 ER PT J AU Jison, ML Gladwin, MT AF Jison, ML Gladwin, MT TI Hemolytic anemia-associated pulmonary hypertension of sickle cell disease and the nitric oxide/arginine pathway SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID OXIDE BIOAVAILABILITY; SPHEROCYTOSIS C1 NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Jison, ML (reprint author), NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. NR 16 TC 37 Z9 37 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 1 PY 2003 VL 168 IS 1 BP 3 EP 4 DI 10.1164/rccm.2304002 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 695HH UT WOS:000183824700003 PM 12826592 ER PT J AU Mitre, E Nutman, TB AF Mitre, E Nutman, TB TI Lack of basophilia in human parasitic infections SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID FC-EPSILON-RI; NIPPOSTRONGYLUS-BRASILIENSIS; MAST-CELLS; BONE-MARROW; GUINEA-PIG; ALLERGIC SENSITIZATION; HUMAN SCHISTOSOMIASIS; QUANTITATIVE CHANGES; ACQUIRED-IMMUNITY; HISTAMINE-RELEASE AB While basophilia is often found in animal models of parasitic infection, it has not yet been established whether it occurs in parasite-infected humans. We investigated the relationship between basophilia and parasitic infections in humans by reviewing charts from 668 patients with confirmed parasitic infection (472 with only helminths, 146 with only protozoa, and 50 with both helminth and protozoan infections) and from 50 patients without parasitic infections. Basophilia (> 290 cells/mm(3)) occurred in only four of the 668 parasite-infected patients (0.6%), and there were no statistically significant differences in the percentages of patients with basophilia or in the absolute basophil counts among either the helminth-infected, protozoa-infected, or uninfected populations. Analysis with regard to relative basophil levels revealed that basophils constituted more than 3% of the peripheral white blood cell population in only four patients. Thus, basophilia occurs only rarely in human parasitic infections and is consequently not a useful clinical marker in the evaluation of suspected parasitic disease. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Nutman, TB (reprint author), NIAID, Parasit Dis Lab, NIH, 4 Ctr Dr,Room 4-126, Bethesda, MD 20892 USA. NR 34 TC 11 Z9 11 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 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUL PY 2003 VL 69 IS 1 BP 87 EP 91 PG 5 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 706WC UT WOS:000184477200019 PM 12932104 ER PT J AU He, LW Papoutsi, M Huang, RJ Tomarev, SI Christ, B Kurz, H Wilting, J AF He, LW Papoutsi, M Huang, RJ Tomarev, SI Christ, B Kurz, H Wilting, J TI Three different fates of cells migrating from somites into the limb bud SO ANATOMY AND EMBRYOLOGY LA English DT Article DE somite; myogenic cell; angiogenic endothelial cell; lymphatic endothelial cell; quail-chick chimera ID CENTRAL-NERVOUS-SYSTEM; AVIAN EMBRYOS; CHICK-EMBRYOS; GROWTH-FACTOR; ORIGIN; ANGIOGENESIS; MUSCLES; GENE; VASCULOGENESIS; MUSCULATURE AB Cells from the ventrolateral dermomyotomal lips at limb levels undergo epithelio-mesenchymal transition and migrate as individual and undifferentiated cells into the limb buds. The cells give rise to myocytes and blood vascular endothelial cells (BECs) in the limb. Using vascular endothelial growth factor receptor-3 (VEGFR-3) as a marker, it has also been shown that the somites contribute to endothelial cells of lymphatic vessels in the limbs, but it is unknown where the lymphangiogenic precursors are located within the somite. In this study we used the transcription factor Prox1 as a lymphatic marker and investigated whether cells in the dorso-lateral quarter of the somite differentiate into lymphatic endothelial cells (LECs) of the limbs. To label the migrating cells, the dorso-lateral part of an epithelial brachial somite was grafted homotopically from quail into chick embryos at HH stages 13-14. The chick hosts were incubated until day 10-11 of development. The quail cell nuclei were identified with QCPN (anti-quail) antibodies. Cell differentiation was analysed by immunohistochemical staining with QH1, anti-desmin and anti-Prox1 antibodies, and by in situ hybridisation with Prox1 probes. Our results confirm that quail cell nuclei are incorporated into the myotubes of the limb muscles. Quail cells are found in the endothelium of limb blood vessels and lymphatics, predominantly the dermal lymphatics. This indicates that superficial lymphatics develop independently from the deep ones and shows that cells migrating from the lateral somitic edge into the limb buds differentiate into three cell populations: myocytes, BECs and LECs. C1 Univ Freiburg, Inst Anat, Lehrstuhl 2, D-79104 Freiburg, Germany. NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Gottingen, Childrens Hosp, D-37075 Gottingen, Germany. RP Christ, B (reprint author), Univ Freiburg, Inst Anat, Lehrstuhl 2, Albertstr 17, D-79104 Freiburg, Germany. RI Kurz, Haymo/E-1587-2011 NR 38 TC 20 Z9 20 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-2061 J9 ANAT EMBRYOL JI Anat. Embryol. PD JUL PY 2003 VL 207 IS 1 BP 29 EP 34 DI 10.1007/s00429-003-0327-4 PG 6 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 698UY UT WOS:000184018700004 PM 12768422 ER PT J AU Svetkey, LP Harsha, DW Vollmer, WM Stevens, VJ Obarzanek, E Elmer, PJ Lin, PH Champagne, C Simons-Morton, DG Aickin, M Proschan, MA Appel, LJ AF Svetkey, LP Harsha, DW Vollmer, WM Stevens, VJ Obarzanek, E Elmer, PJ Lin, PH Champagne, C Simons-Morton, DG Aickin, M Proschan, MA Appel, LJ TI Premier: A clinical trial of comprehensive lifestyle modification for blood pressure control: Rationale, design and baseline characteristics SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE diet; blood pressure; weight loss; lifestyle ID NONPHARMACOLOGIC INTERVENTIONS; HYPERTENSION PREVENTION; SODIUM REDUCTION; DIETARY PATTERNS; NATIONAL-HEALTH; OLDER PERSONS; WEIGHT-LOSS; DASH DIET; POPULATION; PREVALENCE AB PURPOSE: To describe PREMIER, a randomized trial to determine the effects of multi-component lifestyle interventions on blood pressure (BP). METHODS: Participants with above optimal BP through stage 1 hypertension were randomized to: 1) a behavioral lifestyle (BLS) intervention that implements established recommendations, 2) a BLS intervention that implements established recommendations plus the DASH diet, or 3) an advice only standard of care group. The two BLS interventions consist of group and individual counseling sessions for 18 months. The primary outcome is systolic BP at 6 months. Additional outcomes include diastolic BP and homocysteine at 6 months; systolic and diastolic BP at 18 months; fasting lipids, glucose and insulin at 6 and 18 months; and effects in subgroup. CONCLUSION: Results from the PREMIER trial will provide scientific rationale for implementing multi-component behavioral lifestyle intervention programs to control BP and prevent CVD. Ann Epidemiol 2003; 13:462-471. (C) 2003 Elsevier Inc. All rights reserved. C1 Duke Univ, Med Ctr, Duke Hypertens Ctr, Chapel Hill, NC 27516 USA. Duke Univ, Med Ctr, Sarah W Stedman Ctr Nutr Studies, Chapel Hill, NC 27516 USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. NHLBI, DECA, NIH, Bethseda, MD USA. Johns Hopkins Med Ctr, Welch Prevent Ctr, Baltimore, MD USA. RP Svetkey, LP (reprint author), Duke Univ, Med Ctr, Duke Hypertens Ctr, 3020 Pickett Rd, Chapel Hill, NC 27516 USA. FU NHLBI NIH HHS [U01 HL60571, U01 HL60574, U01 HL62828, U01 HL60570, U01 HL60573] NR 40 TC 75 Z9 77 U1 0 U2 6 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 JUL PY 2003 VL 13 IS 6 BP 462 EP 471 DI 10.1016/S1047-2797(03)00006-1 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 704YV UT WOS:000184370300011 PM 12875806 ER PT J AU Kang, DW Latour, LL Chalela, JA Dambrosia, J Warach, S AF Kang, DW Latour, LL Chalela, JA Dambrosia, J Warach, S TI Early ischemic lesion recurrence within a week after acute ischemic stroke SO ANNALS OF NEUROLOGY LA English DT Article ID DIFFUSION-WEIGHTED MR; CARDIOPULMONARY BYPASS; CARDIOVASCULAR HEALTH; ARTERIAL TERRITORIES; CEREBRAL INFARCTION; HUMAN BRAIN; PERFUSION; PREDICTORS; DIAGNOSIS; SUBTYPE AB Previous observations suggested that multiple ischemic lesions on diffusion-weighted imaging (DWI) are. common in acute stroke patients. We hypothesized that a source of these multiple lesions was the recurrence of ischemic lesions within a week after a clinically symptomatic stroke. We analyzed 99 acute ischemic stroke patients scanned within 6 hours of onset and at subsequent times within the first week. Ischemic lesion recurrence was defined as any new lesion separate from the index lesion. Recurrent lesions occurring outside initial perfusion deficit were termed 'distant lesion recurrence'. We estimated the hazard ratio (HR) of recurrence associated with clinical and imaging characteristics using log-rank test. Any lesion recurrence was found in 34%, with distant lesion recurrence in 15%, while clinical recurrence was evident in 2%. Initial multiple DWI lesions were associated with any lesion recurrence (HR, 2.83; 95% confidence interval [CI], 1.65-10.29; p = 0.002) and with distant lesion recurrence MR, 5.99; 95% Cl, 4.05-64-07; P < 0.0001). Large-artery atherosclerosis was the most frequent stroke subtype associated with any lesion recurrence (p = 0.026). These results may indicate a prolonged state of increased ischemic risk over the first week and suggest DWI as a possible surrogate measure for recurrent stroke. C1 NINDS, Sect Stroke Diagnost & Therapeut, Stroke Branch, NIH, Bethesda, MD 20892 USA. NINDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Warach, S (reprint author), NINDS, Sect Stroke Diagnost & Therapeut, Stroke Branch, NIH, 10 Ctr Dr,Room B1D733, Bethesda, MD 20892 USA. NR 37 TC 69 Z9 73 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 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JUL PY 2003 VL 54 IS 1 BP 66 EP 74 DI 10.1002/ana.10592 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 695DC UT WOS:000183815000009 PM 12838521 ER PT J AU Stewart, PA Lees, PSJ Correa, A Breysse, P Gail, M Graubard, BI AF Stewart, PA Lees, PSJ Correa, A Breysse, P Gail, M Graubard, BI TI Evaluation of three retrospective exposure assessment methods SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE acrylonitrile; dose reconstruction; epidemiological studies; epidemiology; exposure assessment; methods validation; reproducibility; validity ID VALIDATION AB Objective: To evaluate three methods for assessing retrospective exposures of acrylonitrile workers. Methods: Three methods used to develop historical exposure estimates for a retrospective cohort mortality study of acrylonitrile workers were considered. The first method was deterministic, incorporating estimates of the impact of changes that took place in the workplace. The second method used the ratio of the mean of the measurements for three similar jobs to estimate a fourth similar job. The third method was based on the development of homogeneous exposure groups (HEG). Estimates of acrylonitrile exposure were developed using these three methods and compared with measurement means (observed means) across three categories of airborne exposure concentrations (<0.5, 0.5-0.99 and &GE;1 p.p.m.) and three categories based on the number of measurements used to develop the estimate (<10, 10-29 and greater than or equal to30). Results: The correlation between the estimates and the observed values was about 0.65 for all three methods. Estimates using the deterministic method tended to overestimate the observed means by 17%, but the number of estimates was not above or below the observed means more often than expected. There was no statistically significant relationship between the exposure estimates and the acrylonitrile concentration in the air or the number of measurements used to develop the estimates. The estimates averaged within 60% of the observed means when concentrations were above 0.5 p.p.m. and 25% regardless of the number of measurements on which the estimates were based. Estimates from the ratio method were randomly distributed above and below the observed means and averaged 70% above the observed means. The air concentration did not affect the performance of the method, although above 1 p.p.m. the estimates were within 40% of the observed means. The number of measurements comprising the estimates was related on a relative scale to the performance of the method. Exposure estimates using the HEG method were neither greater nor less than the observed means more often than what was expected. The method did better as concentration and the number of measurements increased. The estimates were within 60% of the means at >0.5 p.p.m. and for all measurement categories. Overall, there was no statistically significant difference between the estimates derived from the three estimation methods. Conclusions: All methods performed reasonably well, but the deterministic and HEG methods appeared to develop estimates closer to the observed means for concentrations >0.5 p.p.m., regardless of the number of measurements. C1 NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. RP Stewart, PA (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, 6120 Execut Blvd,MSC 7240, Bethesda, MD 20892 USA. NR 12 TC 15 Z9 15 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0003-4878 J9 ANN OCCUP HYG JI Ann. Occup. Hyg. PD JUL PY 2003 VL 47 IS 5 BP 399 EP 411 DI 10.1093/annhyg/meg060 PG 13 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA 704UZ UT WOS:000184360200005 PM 12855490 ER PT J AU Overman, GP Teter, CJ Guthrie, SK AF Overman, GP Teter, CJ Guthrie, SK TI Acamprosate for the adjunctive treatment of alcohol dependence SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE acamprosate; alcohol dependence ID CA-ACETYL HOMOTAURINATE; DOUBLE-BLIND; RELAPSE PREVENTION; MAINTAINING ABSTINENCE; ECONOMIC-EVALUATION; COST-EFFECTIVENESS; WEANED ALCOHOLICS; PLACEBO; NALTREXONE; EFFICACY AB OBJECTIVE: To review the literature related to the treatment of alcohol dependence with acamprosate, a synthetic compound structurally similar to the naturally occurring amino acid, homotaurine. DATA SOURCES: Primary literature and review articles were identified by MEDLINE search (1966-June 2003). Abstracts from recent meetings were also reviewed. DATA SYNTHESIS: Acamprosate has been marketed in 24 countries. Although the precise mechanism of acamprosate in the treatment of alcohol-dependent patients is unclear, it may restore the balance between inhibitory and excitatory neurotransmission in the central nervous system. European trials have shown consistent increases in abstinence rates compared with placebo when acamprosate use was paired with appropriate psychosocial and behavioral therapies. Decreased direct and indirect healthcare costs associated with acamprosate treatment have also been reported. CONCLUSIONS: Acamprosate is a promising medication for the treatment of alcohol dependence in the US. C1 NIMH, Ctr Clin, Dept Pharm, NIH,US Dept HHS, Bethesda, MD 20892 USA. Univ Michigan, Subst Abuse Res Ctr, Coll Pharm, Ann Arbor, MI 48109 USA. Univ Michigan, Coll Pharm, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. RP Overman, GP (reprint author), NIMH, Ctr Clin, Dept Pharm, NIH,US Dept HHS, 10 Ctr Dr,Bldg 10,Room 1N257, Bethesda, MD 20892 USA. NR 62 TC 10 Z9 11 U1 2 U2 2 PU HARVEY WHITNEY BOOKS CO PI CINCINNATI PA PO BOX 42696, CINCINNATI, OH 45242 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD JUL-AUG PY 2003 VL 37 IS 7-8 BP 1090 EP 1099 DI 10.1345/aph.1C351 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 699VC UT WOS:000184075800026 PM 12841823 ER PT J AU Park, BS AF Park, BS TI The 'Hyperbola of quantum chemistry': the changing practice and identity of a scientific discipline in the early years of electronic digital computers, 1945-65 SO ANNALS OF SCIENCE LA English DT Article; Proceedings Paper CT Annual Meeting of the History-of-Science-Society CY NOV 08-11, 2001 CL DENVER, CO SP Hist Sci Soc ID UNITED-STATES; MOLECULAR-STRUCTURE; MECHANICS; SECURITY; BENZENE; SCIENCE; SYSTEMS; WAR AB In 1965, John A. Pople presented a paper entitled 'Two-Dimensional Chart of Quantum Chemistry' to illustrate the inverse relationship between the sophistication of computational methods and the size of molecules under study. This chart, later called the 'hyperbola of quantum chemistry', succinctly summarized the growing tension between the proponents of two different approaches to computation-the ab initio method and semiempirical method-in the early years of electronic digital computers. Examining the development of quantum chemistry after World War II, 1 focus on the role of computers in shaping disciplinary identity. The availability of high-speed computers in the early 1950s attracted much attention from quantum chemists, and their community took shape through a series of conferences and personal networking. However, this emerging community soon encountered the problem of communication between groups that differed in the degree of reliance they placed on computers. I show the complexity of interactions between computing technology and a scientific discipline, in terms of both forming and splitting the community of quantum chemistry. C1 NIH, NIH Hist Off, Bethesda, MD 20892 USA. RP Park, BS (reprint author), NIH, NIH Hist Off, Bldg 31 Room 5B38,MSC 2092, Bethesda, MD 20892 USA. EM parkb@od.nih.gov RI Park, Buhm Soon/C-1681-2011 NR 112 TC 10 Z9 10 U1 0 U2 11 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0003-3790 J9 ANN SCI JI Ann. Sci. PD JUL PY 2003 VL 60 IS 3 BP 219 EP 247 DI 10.1080/00033790110117476 PG 29 WC History & Philosophy Of Science SC History & Philosophy of Science GA 700TQ UT WOS:000184127600001 ER PT J AU Zogakis, TG Gibril, F Libutti, SK Norton, JA White, DE Jensen, RT Alexander, HR AF Zogakis, TG Gibril, F Libutti, SK Norton, JA White, DE Jensen, RT Alexander, HR TI Management and outcome of patients with sporadic gastrinoma arising in the duodenum SO ANNALS OF SURGERY LA English DT Article ID ZOLLINGER-ELLISON-SYNDROME; INTRAOPERATIVE METHODS; SURGICAL-MANAGEMENT; TUMORS; LOCALIZATION; EXPERIENCE; SURGERY AB Background: Primary duodenal gastrinomas are now recognized as a common etiology for patients with sporadic Zollinger Ellison Syndrome (ZES); however, the clinical and pathologic features of this condition and long-term outcome after operation are not well characterized. Methods: Between November 1982 and September 2000, 63 patients diagnosed with sporadic ZES underwent resection of a primary duodenal gastrinoma and regional nodal metastases with curative intent. Data from a prospectively maintained database were reviewed for clinical and pathologic parameters relating to primary tumor size, location, frequency of lymph node metastases, and disease-specific and disease-free survival. Results: There were 41 males and 22 females (mean age, 48.6 years). The majority of duodenal gastrinomas were in the first or second portions of the duodenum (83%). Tumor size ranged from 0.2 to 2.0 cm with 62% measuring less than 1.0 cm. Sixty percent of individuals had regional lymph node metastases identified primarily in proximity to the primary tumor. At a median 10-year follow-up, the overall disease-specific and disease-free survivals were 100% and 60%, respectively. Actuarial 10-year disease-free survival was significantly higher for patients without lymph node metastases versus those with lymph node metastases (78% versus 48%, P = 0.0137). Conclusions: Duodenal gastrinomas in patients with sporadic ZES are frequently small, most commonly located in the proximal duodenum, and associated with regional lymph node metastases in 60%. Disease-free survival is lower for patients with regional lymph node metastases suggesting that a more systematic lymphadenectomy to extirpate occult disease may be indicated in this group. C1 NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NIDDK, Digest Dis Branch, Bethesda, MD 20892 USA. RP Alexander, HR (reprint author), NCI, Surg Branch, Ctr Canc Res, NIH, Bldg 10,Rm 2B07,10 Ctr Dr, Bethesda, MD 20892 USA. NR 24 TC 26 Z9 28 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD JUL PY 2003 VL 238 IS 1 BP 42 EP 48 DI 10.1097/01.SLA.0000074963.87688.31 PG 7 WC Surgery SC Surgery GA 730MQ UT WOS:000185834900006 PM 12832964 ER PT J AU Danforth, DN Cowan, K Altemus, R Merino, M Chow, C Berman, A Chaudhry, U Shriver, C Steinberg, SM Zujewski, J AF Danforth, DN Cowan, K Altemus, R Merino, M Chow, C Berman, A Chaudhry, U Shriver, C Steinberg, SM Zujewski, J TI Preoperative FLAC/granulocyte-colony-stimulating factor chemotherapy for stage II breast cancer: A prospective randomized trial SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article DE breast cancer; preoperative chemotherapy; neoadjuvant; breast conservation; axillary lymph nodes ID NEOADJUVANT CHEMOTHERAPY; CHEMOENDOCRINE THERAPY; LEUCOVORIN; SURVIVAL; DISEASE; SURGERY; TUMORS; WOMEN AB Background: Preoperative chemotherapy for stage II breast cancer may reduce locoregional tumors and provides initial treatment for systemic micrometastases. We conducted a prospective, randomized trial to evaluate the ability of intensive preoperative chemotherapy to enhance the outcome of this approach. Methods: Patients with clinical stage II breast cancer (T2N0, T1N1, and T2N1) were prospectively randomized to receive either preoperative or postoperative chemotherapy with five 21-day cycles of fluorouracil, leucovorin calcium, doxorubicin, and cyclophosphamide (FLAC)/granulocyte-colony-stimulating factor. Local therapy consisted of modified radical mastectomy or segmentectomy/axillary dissection/breast radiotherapy, according to patient preference. Results: Fifty-three women were randomized (26 preoperative chemotherapy and 27 postoperative chemotherapy). The objective clinical response rate of the primary tumor to preoperative chemotherapy was 80%, and the pathologic complete response rate was 20%. Preoperative chemotherapy reduced the overall incidence and number of axillary lymph node metastases. There was no difference in the use of breast-conserving local therapy between the two treatment arms. There were 20 local/regional or distant recurrences (9 preoperative and 11 postoperative). There was no difference in the overall or disease-free survival between the preoperative and postoperative chemotherapy arms. Conclusions: Preoperative FLAC/granulocyte-colony-stimulating factor chemotherapy was effective against local/regional tumors in stage II breast cancer but was otherwise comparable to postoperative chemotherapy. C1 NCI, Surg Branch, Ctr Canc Res, Bethesda, MD 20815 USA. NCI, Med Branch, Ctr Canc Res, Bethesda, MD 20815 USA. NCI, Radiat Oncol Branch, Ctr Canc Res, Bethesda, MD 20815 USA. NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20815 USA. NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20815 USA. NIH, Dept Radiol, Ctr Clin, Bethesda, MD 20892 USA. NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Dept Surg, Washington, DC 20307 USA. RP NCI, Surg Branch, Ctr Canc Res, Bldg 10,Rm 2B38, Bethesda, MD 20815 USA. EM david_danforth@nih.gov NR 29 TC 14 Z9 17 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JUL PY 2003 VL 10 IS 6 BP 635 EP 644 DI 10.1245/ASO.2003.12.008 PG 10 WC Oncology; Surgery SC Oncology; Surgery GA 698AJ UT WOS:000183975200009 PM 12839848 ER PT J AU Sternberg, E AF Sternberg, E TI Neural immune interactions in health and disease SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology CY JUN 18, 2003 CL LISBON, PORTUGAL C1 NIMH, Integrat Neural Immune Program, NIH, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2003 VL 62 SU 1 BP 3 EP 3 PG 1 WC Rheumatology SC Rheumatology GA 863HG UT WOS:000224551400008 ER PT J AU Skapenko, A Lipsky, PE Kalden, JR Schulze-Koops, H AF Skapenko, A Lipsky, PE Kalden, JR Schulze-Koops, H TI Regulatory role of Th2 cells in the pathogenesis of rheumatoid arthritis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology CY JUN 18, 2003 CL LISBON, PORTUGAL C1 Univ Erlangen Nurnberg, Nikolaus Fiebiger Ctr Mol Med, Clin Res Grp 3, D-8520 Erlangen, Germany. NIAMS, NIH, Bethesda, MD USA. Univ Erlangen Nurnberg, Dept Internal Med 3, D-8520 Erlangen, Germany. NR 0 TC 0 Z9 0 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2003 VL 62 SU 1 BP 4 EP 4 PG 1 WC Rheumatology SC Rheumatology GA 863HG UT WOS:000224551400011 ER PT J AU Oppenheim, J Yang, D Biragyn, A Kwak, L AF Oppenheim, J Yang, D Biragyn, A Kwak, L TI Many chemokines and defensins exhibit antimicrobial and immunoadjuvant activities SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology CY JUN 18, 2003 CL LISBON, PORTUGAL ID MAMMALIAN DEFENSINS; ADAPTIVE IMMUNITY; DENDRITIC CELLS; INNATE; CATHELICIDIN; ANTIGENS; IMMATURE; LL-37 C1 NCI, Lab Mol Immunoregulat, Frederick, MD 21701 USA. NCI, Expt Transplantat & Immunol Branch, Frederick, MD 21701 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2003 VL 62 SU 1 BP 32 EP 32 PG 1 WC Rheumatology SC Rheumatology GA 863HG UT WOS:000224551400103 ER PT J AU Oppenheim, J Yang, D Biragyn, A Kwak, L AF Oppenheim, J Yang, D Biragyn, A Kwak, L TI Many chemokines and defensins exhibit antimicrobial and immunoadjuvant activities SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology CY JUN 18, 2003 CL LISBON, PORTUGAL C1 Natl Canc Inst, Mol Immunoregulat Lab, Frederick, MD USA. Natl Canc Inst, Expt Transplantat & Immunol Branch, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2003 VL 62 SU 1 BP 32 EP 32 PG 1 WC Rheumatology SC Rheumatology GA 863HG UT WOS:000224551400104 ER PT J AU Sautes-Fridman, C Cohen-Solal, J Sun, P Kato, K Fridman, WH AF Sautes-Fridman, C Cohen-Solal, J Sun, P Kato, K Fridman, WH TI Structure and function of Fc gamma receptors SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology CY JUN 18, 2003 CL LISBON, PORTUGAL C1 Ctr Rech Biomed Cordeliers, U255, Paris, France. NIAID, Struct Biol Sect, NIH, Bethesda, MD 20892 USA. Nagoya City Univ, Nagoya, Aichi 467, Japan. NR 4 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2003 VL 62 SU 1 BP 40 EP 41 PG 2 WC Rheumatology SC Rheumatology GA 863HG UT WOS:000224551400129 ER PT J AU Maini, R Patel, K Baker, D Lipsky, P AF Maini, R Patel, K Baker, D Lipsky, P TI Treatment with infliximab and methotrexate leads to healing of joint erosions in patients with rheumatoid arthritis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology CY JUN 18, 2003 CL LISBON, PORTUGAL C1 Kennedy Inst Rheumatol Div, Fac Med, London, England. NIAMSD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 1 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2003 VL 62 SU 1 BP 97 EP 98 PG 2 WC Rheumatology SC Rheumatology GA 863HG UT WOS:000224551400297 ER PT J AU Skapenko, A Lipsky, PE Kalden, JR Schulze-Koops, H AF Skapenko, A Lipsky, PE Kalden, JR Schulze-Koops, H TI Regulation of human TH1 inflammation in vivo SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology CY JUN 18, 2003 CL LISBON, PORTUGAL C1 Univ Erlangen Nurnberg, Erlangen, Germany. NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2003 VL 62 SU 1 BP 141 EP 141 PG 1 WC Rheumatology SC Rheumatology GA 863HG UT WOS:000224551400446 ER PT J AU Smolen, J Kavanaugh, A Han, C Bala, M Baker, D Maini, R Lipsky, P AF Smolen, J Kavanaugh, A Han, C Bala, M Baker, D Maini, R Lipsky, P TI Fatigue is correlated with physical function and employability in patients with rheumatoid arthritis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology CY JUN 18, 2003 CL LISBON, PORTUGAL C1 Krankenhaus Dr Stadt Wien Lainz, Ctr Rheumat Dis, Vienna, Austria. Univ Calif San Diego, Div Rheumatol Allergy & Immunol, La Jolla, CA 92093 USA. Centocor Inc, Clin Res, Malvern, PA 19355 USA. Kennedy Inst, Fac Med, London W6 7DW, England. NIAMSD, Natl Inst Hlth, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2003 VL 62 SU 1 BP 151 EP 151 PG 1 WC Rheumatology SC Rheumatology GA 863HG UT WOS:000224551400479 ER PT J AU Breedveld, F Han, C Bala, M Baker, D Kavanaugh, A Maini, R Lipsky, R AF Breedveld, F Han, C Bala, M Baker, D Kavanaugh, A Maini, R Lipsky, R TI Baseline joint damage is a significant predictor of improvement in physical function in RA patients after treatment SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology CY JUN 18, 2003 CL LISBON, PORTUGAL C1 Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands. Centocor Inc, Clin Res, Malvern, PA 19355 USA. Univ Calif San Diego, Div Rheumatol Allergy & Immunol, La Jolla, CA 92093 USA. Kennedy Inst, Fac Med, London W6 7DW, England. NIAMSD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2003 VL 62 SU 1 BP 173 EP 173 PG 1 WC Rheumatology SC Rheumatology GA 863HG UT WOS:000224551400550 ER PT J AU Hansen, A Reiter, K Gosemann, M Lipsky, PE Burmester, GR Dorner, T AF Hansen, A Reiter, K Gosemann, M Lipsky, PE Burmester, GR Dorner, T TI Analysis of VHDJH rearrangements.in individual B cells of patients with primary Sjogren's syndrome SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology CY JUN 18, 2003 CL LISBON, PORTUGAL C1 Charite Univ Hosp, Outpatients Dept Med, Berlin, Germany. Charite Univ Hosp, Dept Rheumatol, Berlin, Germany. NIAMSD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2003 VL 62 SU 1 BP 236 EP 236 PG 1 WC Rheumatology SC Rheumatology GA 863HG UT WOS:000224551400768 ER PT J AU Finkelstein, SE Schrump, DS Nguyen, DM Mullick, R Summers, RM AF Finkelstein, SE Schrump, DS Nguyen, DM Mullick, R Summers, RM TI Novel thoracic imaging augments diagnosis of bronchial obstruction SO ANNALS OF THORACIC SURGERY LA English DT Editorial Material C1 NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), NIH, Dept Diagnost Radiol, Bldg 10,Room 1C660,10 Ctr Dr, Bethesda, MD 20892 USA. EM rms@nih.gov 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 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD JUL PY 2003 VL 76 IS 1 BP 296 EP 296 AR PII S0003-4975(03)03980-2 DI 10.1016/S0003-4975(02)04386-2 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 697XK UT WOS:000183968400074 PM 12842569 ER PT J AU Bocklandt, S Blumberg, PM Hamer, DH AF Bocklandt, S Blumberg, PM Hamer, DH TI Activation of latent HIV-1 expression by the potent anti-tumor promoter 12-deoxyphorbol 13-phenylacetate SO ANTIVIRAL RESEARCH LA English DT Article DE human immunodeficiency virus; phorbol ester; immunotoxin; anti-viral compounds ID HUMAN-IMMUNODEFICIENCY-VIRUS; PROTEIN-KINASE-C; ACTIVE ANTIRETROVIRAL THERAPY; T-CELL ACTIVATION; CD-1 MOUSE SKIN; NF-KAPPA-B; PHORBOL ESTER; HIV-1-INFECTED PATIENTS; SIGNAL-TRANSDUCTION; IMMUNE-ACTIVATION AB Agents that induce HIV-1 out of latency would be useful adjuvants for currently available anti-retroviral therapy. We report that nanomolar concentrations of 12-deoxyphorbol 13-phenylacetate (DPP), an anti-tumor-promoting phorbol ester originally isolated from a West African plant, induce the expression of HIV-1 in latently infected T cells and render them sensitive to killing by an immunotoxin targeted to the viral envelope glycoprotein. DPP also regulates an extensive series of genes under the control of protein kinase C, including several involved in T cell activation and cytoskeleton reorganization, and represses expression of the HIV-1 receptor CD4 and coreceptor CXCR4. DPP is 20-40-fold more potent than the related phorbol ester prostratin, probably due to its more lipophilic side chain structure. The combination of high potency and anti-tumor promoting activity make DPP an attractive candidate for the adjunctive therapy of persistent HIV-1 infection. Published by Elsevier B.V. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. RP Hamer, DH (reprint author), NCI, Biochem Lab, NIH, Bld 37 Rm 6002,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 59 TC 58 Z9 60 U1 2 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD JUL PY 2003 VL 59 IS 2 BP 89 EP 98 DI 10.1016/S0166-3542(03)00034-2 PG 10 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 714DD UT WOS:000184896300002 PM 12895692 ER PT J AU Lore, K Larsson, M AF Lore, K Larsson, M TI The role of dendritic cells in the pathogenesis of HIV-1 infection SO APMIS LA English DT Review DE dendritic cells; HIV-1 infection; pathogenesis; adaptive immunity ID IMMUNODEFICIENCY-VIRUS TYPE-1; EPIDERMAL LANGERHANS CELLS; ANTIGEN-PRESENTING CELLS; CD4(+) T-CELLS; ACTIVE ANTIRETROVIRAL THERAPY; INTERFERON-PRODUCING CELLS; IN-VITRO; DC-SIGN; PERIPHERAL-BLOOD; IMMUNE-RESPONSES AB Dendritic cells are professional antigen-presenting cells required for generation of adaptive immunity. These cells are one of the initial target cells for HIV-1 infection or capture of virions at site of transmission in the mucosa. DCs carrying HIV-1 will migrate to the lymphoid tissue where they can contribute to the dissemination of the virus to adjacent CD4(+) T cells. In addition, HIV-1-exposed DCs may have impaired antigen-presenting capacity resulting in inadequate expansion of HIV-1-specific T cell responses. Here, we review the infection of different subtypes of DCs by HIV-1 and the relevance of these cells in the transmission and establishment of HIV-1 disease. In addition, we discuss the mechanisms through which HIV-1-DC interactions could be exploited to optimise the generation and maintenance of HIV-1-specific T cell immunity. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Rockefeller Univ, Cellular Physiol & Immunol Lab, New York, NY 10021 USA. RP Lore, K (reprint author), NIAID, Vaccine Res Ctr, NIH, Blg 40,Rm 3612B, Bethesda, MD 20892 USA. NR 129 TC 24 Z9 27 U1 0 U2 3 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0903-4641 J9 APMIS JI APMIS PD JUL-AUG PY 2003 VL 111 IS 7-8 BP 776 EP 788 DI 10.1034/j.1600-0463.2003.11107809.x PG 13 WC Immunology; Microbiology; Pathology SC Immunology; Microbiology; Pathology GA 724FU UT WOS:000185478200009 PM 12974779 ER PT J AU Hunt, FY Kearsley, AJ Wan, HH AF Hunt, FY Kearsley, AJ Wan, HH TI An optimization approach to multiple sequence alignment SO APPLIED MATHEMATICS LETTERS LA English DT Article DE linear programming; sequencing; alignment AB The problem of multiple sequence alignment is recast as an optimization problem using Markov decision theory. One seeks to minimize the expected or average cost of alignment subject to data-derived constraints. In this setting, the problem is equivalent to a linear program which can be solved efficiently using modern interior-point methods. We present numerical results from an implementation of the algorithm for protein sequence alignment. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Natl Inst Stand & Technol, Math & Computat Sci Div, Gaithersburg, MD 20899 USA. NIH, Natl Ctr Genome Res, Bethesda, MD 20894 USA. RP Hunt, FY (reprint author), Natl Inst Stand & Technol, Math & Computat Sci Div, Gaithersburg, MD 20899 USA. NR 12 TC 0 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0893-9659 J9 APPL MATH LETT JI Appl. Math. Lett. PD JUL PY 2003 VL 16 IS 5 BP 785 EP 790 AR PII S0893-9659(03)00083-1 DI 10.1016/S0893-9659(03)00083-1 PG 6 WC Mathematics, Applied SC Mathematics GA 692CW UT WOS:000183643700027 ER PT J AU Charney, DS Reynolds, CF Lewis, L Lebowitz, BD Sunderland, T Alexopoulos, GS Blazer, DG Katz, IR Meyers, BS Arean, PA Borson, S Brown, C Bruce, ML Callahan, CM Charlson, ME Conwell, Y Cuthbert, BN Devanand, DP Gibson, MJ Gottlieb, GL Krishnan, KR Laden, SK Lyketsos, CG Mulsant, BH Niederehe, G Olin, JT Oslin, DW Pearson, J Persky, T Pollock, BG Raetzman, S Reynolds, M Salzman, C Schulz, R Schwenk, TL Scolnick, E Unutzer, J Weissman, MM Young, RC AF Charney, DS Reynolds, CF Lewis, L Lebowitz, BD Sunderland, T Alexopoulos, GS Blazer, DG Katz, IR Meyers, BS Arean, PA Borson, S Brown, C Bruce, ML Callahan, CM Charlson, ME Conwell, Y Cuthbert, BN Devanand, DP Gibson, MJ Gottlieb, GL Krishnan, KR Laden, SK Lyketsos, CG Mulsant, BH Niederehe, G Olin, JT Oslin, DW Pearson, J Persky, T Pollock, BG Raetzman, S Reynolds, M Salzman, C Schulz, R Schwenk, TL Scolnick, E Unutzer, J Weissman, MM Young, RC TI Depression and bipolar support alliance consensus statement on the unmet needs in diagnosis and treatment of mood disorders in late life SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Review ID PRIMARY-CARE PATIENTS; RANDOMIZED CONTROLLED TRIAL; RECURRENT MAJOR DEPRESSION; GERIATRIC DEPRESSION; ALZHEIMERS-DISEASE; ELDERLY PATIENTS; DOUBLE-BLIND; OLDER ADULTS; RISK-FACTORS; MYOCARDIAL-INFARCTION AB Objectives: To review progress made during the past decade in late-life mood disorders and to identify areas of unmet need in health care delivery and research. Participants: The Consensus Development Panel consisted of experts in late-life mood disorders, geriatrics, primary care, mental health and aging policy research, and advocacy. Evidence: (1) Literature reviews addressing risk factors, prevention, diagnosis, treatment, and delivery of services and (2) opinions and experiences of primary care and mental health care providers, policy analysts, and advocates. Consensus Process: The Consensus Development Panel listened to presentations and participated in discussions. Workgroups considered the evidence and prepared preliminary statements. Workgroup leaders presented drafts for discussion by the Consensus Development Panel. The final document was reviewed and edited to incorporate input from the entire Consensus Development Panel. Conclusions: Despite the availability of safe and efficacious treatments, mood disorders remain a significant health care issue for the elderly and are associated with disability, functional decline, diminished quality of life, mortality from comorbid medical conditions or suicide, demands on caregivers, and increased service utilization. Discriminatory coverage and reimbursement policies for mental health care are a challenge for the elderly, especially those with modest incomes, and for clinicians. Minorities are particularly underserved. Access to mental health care services for most elderly individuals is inadequate, and coordination of services is lacking. There is an immediate need for collaboration among patients, families, researchers, clinicians, governmental agencies, and third-party payers to improve diagnosis, treatment, and delivery of services for elderly persons with mood disorders. C1 Depress & Bipolar Support Alliance, Chicago, IL 60610 USA. NIMH, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. Cornell Univ, Weill Med Coll, Dept Psychiat, White Plains, NY USA. Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. Indiana Univ, Sch Med, Dept Med, Indianapolis, IN USA. Univ Rochester, Med Ctr, Dept Psychiat, Rochester, NY 14642 USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. Columbia Univ, Coll Phys & Surg, Dept Neurol, New York, NY USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. AARP Publ Policy Inst, Washington, DC USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Sci Therapeut Informat Inc, Springfield, NJ USA. Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. Consumer Advocate, Philadelphia, PA USA. Univ Michigan, Sch Med, Dept Family Med, Ann Arbor, MI USA. Merck Res Labs, W Point, PA USA. Univ Calif Los Angeles, Inst Neuropsychiat, Dept Psychiat, Los Angeles, CA 90024 USA. RP Lewis, L (reprint author), Depress & Bipolar Support Alliance, 730 N Franklin St,Suite 501, Chicago, IL 60610 USA. OI Weissman, Myrna/0000-0003-3490-3075 NR 120 TC 259 Z9 265 U1 9 U2 18 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 JUL PY 2003 VL 60 IS 7 BP 664 EP 672 DI 10.1001/archpsyc.60.7.664 PG 9 WC Psychiatry SC Psychiatry GA 698YE UT WOS:000184027200002 PM 12860770 ER PT J AU Saluja, G Kotch, J Lee, LC AF Saluja, G Kotch, J Lee, LC TI Effects of child abuse and neglect - Does social capital really matter? SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID SUPPORT; FAMILY AB Objective: To explore whether social capital and social support moderate the relationship between child maltreatment and emotional and behavioral outcomes such as depression-anxiety and aggression in 6-year-old children. Design: Data from Longitudinal Studies of Child Abuse and Neglect were used. Data were collected through interviews and questionnaires at the child's birth and at the age of 6 years. Setting: General community. Participants: Two hundred fifteen maternal care-givers of children at high risk for child abuse and neglect were included in this study. Main Outcome Measures: Depression-anxiety and aggression were measured through the Child Behavior Checklist. Results: Among 5 potential effect modifiers (3 social capital constructs and 2 measures of social support), only 1 (instrumental support) significantly modified the relationship between maltreatment and child aggression. Conclusions: Social capital did not modify the relationship between child maltreatment and either aggression or depression-anxiety. This might be related to the fact that many previous studies looked at social capital ecologically, whereas this study uses individuals as the unit of analysis. The results of this study might also indicate that previous studies of social capital and health outcomes might actually be using social capital as a proxy for social support. C1 NICHHD, NIH, Div Epidemiol Stat & Prevent Res, US Dept HHS, Bethesda, MD 20892 USA. Univ N Carolina, Sch Publ Hlth, Dept Maternal & Child Hlth, Chapel Hill, NC USA. RP Saluja, G (reprint author), NICHHD, NIH, Div Epidemiol Stat & Prevent Res, US Dept HHS, 6100 Execut Blvd,Room 7B03 MSC 7510, Bethesda, MD 20892 USA. FU NICHD NIH HHS [1 R01 HD39689-01] NR 18 TC 17 Z9 17 U1 1 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD JUL PY 2003 VL 157 IS 7 BP 681 EP 686 DI 10.1001/archpedi.157.7.681 PG 6 WC Pediatrics SC Pediatrics GA 699EZ UT WOS:000184044800013 PM 12860791 ER PT J AU Chen, Q Reis, SE Kammerer, CM McNamara, DM Holubkov, R Sharaf, BL Sopko, G Pauly, DF Merz, CNB Kamboh, MI AF Chen, Q Reis, SE Kammerer, CM McNamara, DM Holubkov, R Sharaf, BL Sopko, G Pauly, DF Merz, CNB Kamboh, MI CA WISE study grp TI APOE polymorphism and angiographic coronary artery disease severity in the Women's Ischemia Syndrome Evaluation (WISE) study SO ATHEROSCLEROSIS LA English DT Article DE apolipoproteins; coronary disease; risk factors ID APOLIPOPROTEIN-E POLYMORPHISM; LOW-DENSITY-LIPOPROTEIN; HEART-DISEASE; E ALLELES; ATHEROSCLEROSIS; PLASMA; RISK; METAANALYSIS; CHOLESTEROL; ASSOCIATION AB Genetic variation in the apolipoprotein E (APOE) gene is a significant determinant of variation in plasma cholesterol levels and it also affects the risk of coronary artery disease (CAD). We examined the association of the APOE polymorphism with CAD severity in women from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) study. Quantitative coronary angiography was used to classify subjects as having normal/minimal CAD (<20% stenosis), mild CAD (20-49% stenosis) and significant CAD (greater than or equal to50% stenosis). The women with greater than or equal to50% stenosis were further stratified according to the number of vessel disease they have (one, two, or three). In white subjects, the frequency of APOE*4 carriers (3/4 and 4/4 genotypes) was significantly higher in the combined mild/significant CAD group (greater than or equal to20% stenosis) compared with the normal/minimal CAD group (<20% stenosis) (31.3 vs. 19.2%; P = 0.025) with an adjusted OR of 2.40 (95% CI: 1.47-3.93; P = 0.0005). Furthermore, the APOE*4 allele was found to be significantly associated with the increased vessel disease number (chi(2) = 8.04; P = 0.0046). This association of the APOE*4 allele with CAD severity was present only in women with family history of CAD. APOE polymorphism also showed significant associations with increasing plasma total cholesterol (P = 0.0 1) and low-density lipoprotein (LDL)-cholesterol (P < 0.001) in whites. These data support the hypothesis that the APOE*4 allele is an independent risk factor not only for the presence of CAD and hyperlipidemia, but also for the angiographic severity of CAD in white women with a family history of disease. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Cardiovasc Inst, Dept Med, Pittsburgh, PA 15261 USA. Univ Utah, Dept Family & Prevent Med, Salt Lake City, UT 84108 USA. Rhode Isl Hosp, Div Cardiol, Providence, RI 02903 USA. NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. Univ Florida, Div Cardiol, Gainesville, FL 32611 USA. Cedars Sinai Med Ctr, Div Cardiol, Los Angeles, CA 90048 USA. RP Kamboh, MI (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, 130 De Soto St, Pittsburgh, PA 15261 USA. RI Reis, Steven/J-3957-2014; OI Kamboh, M. Ilyas/0000-0002-3453-1438 FU NHLBI NIH HHS [R01 HL64914-01, N01-HV-68164, HL54900, HL 70169, R01 HL64829-01, N01-HV-68162, R01 HL64924-01, N01-HV-68163] NR 35 TC 29 Z9 32 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD JUL PY 2003 VL 169 IS 1 BP 159 EP 167 DI 10.1016/S0021-9150(03)00160-6 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 706WJ UT WOS:000184477800019 PM 12860263 ER PT J AU Devinney, BJ Berman, CM Rasmussen, KLR AF Devinney, BJ Berman, CM Rasmussen, KLR TI Individual differences in response to sibling birth among free-ranging yearling rhesus monkeys (Macaca mulatta) on Cayo Santiago SO BEHAVIOUR LA English DT Article DE sibling birth; Macaca mulatta; rhesus; juveniles; mother-offspring relationships ID MOTHER-INFANT SEPARATION; JAPANESE MACAQUES; SOCIAL SEPARATION; PLAY; LACTATION; BEHAVIOR; PATTERNS; CHILD AB The birth of a younger sibling is a normal event in the life of a nonhuman primate, yet commonly it is thought to be a stressful transition for the older sibling. In our previous research, we found that yearling rhesus monkeys (Macaca mulatta) experienced increases in one mild form of distress but no significant increases in overt forms of distress, in spite of significant reductions in mother-yearling interaction. Nevertheless, some individual yearlings were distressed by this transition and here we examine variables that may structure individual differences in distress. We observed 31 yearling rhesus monkeys on Cayo Santiago, Puerto Rico, during the month before and month after their siblings' births using focal animal sampling methods. Attachment theory (Bowlby, 1969), parent-offspring conflict theory (Trivers, 1974), and dynamic assessment models (Bateson, 1994) all predict a relationship between reduction in maternal care and increase in offspring distress, yet no previous study of sibling birth in primates has examined this relationship. We found that the reduction in the proportion of time on the nipple from the month before sibling birth to the month after was related to the rate of geckering (a distress vocalization) after sibling birth, and that the increase in time out of sight of the mother was related to the proportion of time yearlings spent in a tense state after sibling birth. Maternal aggression after sibling birth also was related to the yearlings' rate of geckering. Yearling distress was related to qualities of the mother-yearling relationship, in that yearlings that had relatively greater responsibility for maintaining proximity with their mothers before sibling birth were relatively more tense afterwards. Yearlings displayed increases in play, grooming, and contact with group members other than the mother after sibling birth, suggesting a marked shift toward greater maturity in their social relationships. C1 NICHD, Comparat Ethol Lab, Poolesville, MD 20837 USA. SUNY Buffalo, Dept Anthropol, Buffalo, NY 14260 USA. Caribbean Primate Res Ctr, Punta Santiago, PR USA. RP Devinney, BJ (reprint author), NICHD, Comparat Ethol Lab, POB 529, Poolesville, MD 20837 USA. NR 36 TC 7 Z9 7 U1 4 U2 8 PU BRILL ACADEMIC PUBLISHERS PI LEIDEN PA PLANTIJNSTRAAT 2, P O BOX 9000, 2300 PA LEIDEN, NETHERLANDS SN 0005-7959 J9 BEHAVIOUR JI Behaviour PD JUL PY 2003 VL 140 BP 899 EP 924 DI 10.1163/156853903770238373 PN 7 PG 26 WC Behavioral Sciences; Zoology SC Behavioral Sciences; Zoology GA 743HW UT WOS:000186567200005 ER PT J AU Hua, LV Hidaka, K Pesesse, X Barnes, LD Shears, SB AF Hua, LV Hidaka, K Pesesse, X Barnes, LD Shears, SB TI Paralogous murine Nudt10 and Nudt11 genes have differential expression patterns but encode identical proteins that are physiologically competent diphosphoinositol polyphosphate phosphohydrolases SO BIOCHEMICAL JOURNAL LA English DT Article DE inositol pyrophosphates; type 3 diphosphoinositol polyphosphate phosphohydrolase (DIPP3) ID NUDIX HYDROLASES; INOSITOL HEXAKISPHOSPHATE; SCHIZOSACCHAROMYCES-POMBE; SACCHAROMYCES-CEREVISIAE; RIBOSE 1,5-BISPHOSPHATE; DUPLICATE GENES; INTEGRITY; ENZYMES; FAMILY; ASSAY AB We previously described paralogous human genes {NUDT10 and NUDT11 [where NUDT is (nucleoside diphosphate attached moiety 'X')-type motif, also known as the 'nudix'-type motif]} encoding type 3 diphosphoinositol polyphosphate, phosphohydrolases (DIPP3) [Hidaka, Caffrey, Hua, Zhang, Falck, Nickel, Carrel, Barnes and Shears (2002) J. Biol. Chem. 277, 32730-32738]. Normally, gene duplication is redundant, and lacks biological significance. Is this true for the DIPP3 genes? We address this question by characterizing highly-conserved murine Nudt10 and Nudt11 homologues of the human genes. Thus these genes must have been duplicated prior to the divergence of primates and sciurognath rodents, approx. 115 million years ago, greatly exceeding the 4 million year half-life for inactivation of redundant paralogues; our data therefore indicate that the DIPP3 duplication is unusual in being physiologically significant. One possible functional consequence is gene neofunctionalization, but we exclude that, since Nudt10 and Nudt11 encode identical proteins. Another possibility is gene subfunctionalization, which we studied by conducting the first quantitative expression analysis of these genes. We demonstrated high Nudt10 expression in liver, kidney and testis; Nudt11 expression is primarily restricted to the brain. This differential, but complementary, expression pattern indicates that subfunctionalization is the evolutionary consequence of DIPP3 gene duplication. Our kinetic data argue that diphosphoinositol polyphosphates are more physiologically relevant substrates for DIPP3 than are either diadenosine hexaphosphate or 5-phosphotibosyl 1-pyrophosphate. Thus the significance of the Nudt10/Nudt11 duplication is specific hydrolysis of diphosphoinositol polyphosphates in a tissue-dependent manner. C1 NIEHS, Lab Signal Transduct, Inositide Signaling Sect, NIH, Res Triangle Pk, NC 27709 USA. Univ Texas, Hlth Sci Ctr, Dept Biochem, San Antonio, TX 78229 USA. RP Shears, SB (reprint author), NIEHS, Lab Signal Transduct, Inositide Signaling Sect, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 28 TC 17 Z9 21 U1 0 U2 0 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD JUL 1 PY 2003 VL 373 BP 81 EP 89 DI 10.1042/BJ20030142 PN 1 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 699MG UT WOS:000184060200010 PM 12689335 ER PT J AU Baek, JY Jun, DY Taub, D Kim, YH AF Baek, JY Jun, DY Taub, D Kim, YH TI Characterization of human phosphoserine aminotransferase involved in the phosphorylated pathway Of L-serine biosynthesis SO BIOCHEMICAL JOURNAL LA English DT Article DE alternative splicing; cell-cycle progression; human phosphoserine aminotransferase gene; L-serine synthesis; phosphoserine aminotransferase alpha and beta; tissue specificity ID 3-PHOSPHOGLYCERATE DEHYDROGENASE-DEFICIENCY; BLOOD-BRAIN-BARRIER; MOLECULAR CHARACTERIZATION; NONPHOTOSYNTHETIC TISSUES; ESCHERICHIA-COLI; EXPRESSION; METABOLISM; SEQUENCE; PROTEIN; CLONING AB In the present study, we first report two forms of human phosphoserine aminotransferase (PSAT) cDNA (HsPSATalpha and HsPSATbeta). HsPSATalpha has a predicted open reading frame comprising 324 amino acids, encoding a 35.2 kDa protein (PSATalpha), whereas HsPSATbeta consists of an open reading frame comprising 370 amino acids that encodes a 40 kDa protein (PSATbeta). PSATalpha is identical with PSATbeta, except that it lacks 46 amino acids between Val(290) and Ser(337) of PSATbeta, which is encoded by the entire exon 8 (138 bp). Both PSATalpha and PSATbeta can functionally rescue the deletion mutation of the Saccharomyces cerevisiae counterpart. Reverse transcriptase-PCR analysis revealed that the expression of PSATbeta mRNA was more dominant when compared with PSATalpha mRNA in all human cell lines tested. PSATbeta was easily detected in proportion to the level of mRNA; however, PSATalpha was detected only in K562 and HepG2 cells as a very faint band. The relative enzyme activity of glutathione S-transferase (GST)-PSATbeta expressed in Escherichia coli appeared to be 6.8 times higher than that of GST-PSATalpha. PSAT mRNA was expressed at high levels (approx. 2.2 kb) in the brain, liver, kidney and pancreas, and very weakly expressed in the thymus, prostate, testis and colon. In U937 cells, the levels of PSAT mRNA and protein appeared to be up-regulated to support proliferation. Accumulation of PSAT mRNA reached a maximum in the S-phase of Jurkat T-cells. These results demonstrate that although two isoforms of human PSAT can be produced by alternative splicing, PSATbeta rather than PSATalpha is the physiologically functional enzyme required for the phosphorylated pathway, and indicate that the human PSAT gene is regulated depending on tissue specificity as well as cellular proliferation status with a maximum level expression in the S-phase. C1 Kyungpook Natl Univ, Coll Nat Sci, Dept Microbiol, Immunol Lab, Taegu 702701, South Korea. NIA, Immunol Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Kim, YH (reprint author), Kyungpook Natl Univ, Coll Nat Sci, Dept Microbiol, Immunol Lab, Taegu 702701, South Korea. NR 31 TC 31 Z9 32 U1 1 U2 9 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD JUL 1 PY 2003 VL 373 BP 191 EP 200 DI 10.1042/BJ20030144 PN 1 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 699MG UT WOS:000184060200020 PM 12633500 ER PT J AU Zhang, MC Liu, HP Guo, RB Ling, Y Wu, XJ Li, BH Roller, PP Wang, SM Yang, DJ AF Zhang, MC Liu, HP Guo, RB Ling, Y Wu, XJ Li, BH Roller, PP Wang, SM Yang, DJ TI Molecular mechanism of gossypol-induced cell growth inhibition and cell death of HT-29 human colon carcinoma cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE HT-29; cell cycle; apoptosis; cyclin D1; P21; BCI-X-L; caspases; DFF45; PARP; cytochrome c release ID PROSTATE-CANCER CELLS; PROTEIN-KINASE-C; MURINE ERYTHROLEUKEMIA-CELLS; APOPTOTIC DNA FRAGMENTATION; BEARING COPENHAGEN RATS; BREAST-CANCER; CYTOCHROME-C; RETINOBLASTOMA GENE; MAGNETIC-RESONANCE; ORAL GOSSYPOL AB Gossypol, a male contraceptive drug, has been demonstrated to have antiproliferative and antimetastatic effects on many kinds of cancer cells in vitro. HT-29 human carcinoma cell line is one of the most susceptible cell lines to gossypol-induced cell death. Here, it is shown that treatment of HT-29 cells with gossypol not only induces cell cycle arrest on the G0/G1 phase, but also induces apoptosis. With a serial of Western blot analysis, it is revealed that gossypol-induced cell cycle arrest is involved in P21 up-regulation and cyclin D1 down-regulation; gossypol-induced apoptosis triggers down-regulation of anti-apoptosis Bcl-2 members: Bcl-X-L, Bag-1 and Mcl-1, upregulation of pro-apoptosis Bcl-2 member Bak, activation of caspase-3, -6,-7, -8, and -9, up-regulation of Apaf-1, release of cytochrome c (cyto-c) from mitochondria, and activation of both DFF45 and PARP Taken together, gossypol-induced cell death initiates extensive alterations of cell cycle and apoptosis proteins. Gossypol-induced apoptosis of HT-29 cells is through first the mitochondrial pathway, then the death receptor pathway, and the mitochondria pathway is, at least in part, involved in cyto-c release. (C) 2003 Elsevier Science Inc. All rights reserved. C1 NCI, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. RP Zhang, MC (reprint author), Univ Michigan, Dept Internal Med, Div Hematol Oncol, 3111 CCGC,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. NR 77 TC 128 Z9 139 U1 0 U2 11 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 JUL 1 PY 2003 VL 66 IS 1 BP 93 EP 103 DI 10.1016/S0006-2952(03)00248-X PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 695FH UT WOS:000183820100010 PM 12818369 ER PT J AU Dowd, TL Rosen, JF Li, L Gundberg, CM AF Dowd, TL Rosen, JF Li, L Gundberg, CM TI The three-dimensional structure of bovine calcium ion-bound osteocalcin using HNMR spectroscopy SO BIOCHEMISTRY LA English DT Article ID GAMMA-CARBOXYGLUTAMIC ACID; 2-DIMENSIONAL NMR-SPECTROSCOPY; MEMBRANE-BINDING; FACTOR-IX; HYDROXYAPATITE FORMATION; MINERALIZED TISSUE; CONTAINING PROTEIN; DEFICIENT MICE; CHEMICAL-SHIFT; BONE PARTICLES AB Structural information on osteocalcin or other noncollagenous bone proteins is very limited. We have solved the three-dimensional structure of calcium bound osteocalcin using H-1 2D NMR techniques and proposed a mechanism for mineral binding. The protons in the 49 amino acid sequence were assigned using standard two-dimensional homonuclear NMR experiments. Distance constraints, dihedral angle constraints, hydrogen bonds, and H-1 and C-13 chemical shifts were all used to calculate a family of 13 structures. The tertiary structure of the protein consisted of an unstructured N terminus and a C-terminal loop (residues 16-49) formed by long-range hydrophobic interactions. Elements of secondary structure within residues 16-49 include type III turns (residues 20-25) and two (x-helical regions (residues 2735 and 41-44). The three Gla residues project from the same face of the helical turns and are surface exposed. The genetic algorithm-molecular dynamics simulation approach was used to place three calcium atoms on the NMR-derived structure. One calcium atom was coordinated by three side chain oxygen atoms, two from Asp30, and one from Gla24. The second calcium atom was coordinated to four oxygen atoms, two from the side chain in Gla 24, and two from the side chain of Gla 21. The third calcium atom was coordinated to two oxygen atoms of the side chain of Gla17. The best correlation of the distances between the uncoordinated Gla oxygen atoms is with the intercalcium distance of 9.43 Angstrom in hydroxyapatite. The structure may provide further insight into the function of osteocalcin. C1 Albert Einstein Coll Med, Montefiore Med Ctr, Dept Pediat, Bronx, NY 10467 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Yale Univ, Sch Med, Dept Orthoped, New Haven, CT USA. RP Dowd, TL (reprint author), Albert Einstein Coll Med, Montefiore Med Ctr, Dept Pediat, Moses Bldg,Rm 401,111 E 210th St, Bronx, NY 10467 USA. FU NIAMS NIH HHS [R01 AR038460, AR-38460]; NIEHS NIH HHS [ES-02030, R01 ES009032] NR 62 TC 40 Z9 41 U1 3 U2 24 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 1 PY 2003 VL 42 IS 25 BP 7769 EP 7779 DI 10.1021/bi034470s PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 695FV UT WOS:000183821200015 PM 12820886 ER PT J AU Ferrari, D Niks, D Yang, LH Miles, EW Dunn, MF AF Ferrari, D Niks, D Yang, LH Miles, EW Dunn, MF TI Allosteric communication in the tryptophan synthase bienzyme complex: Roles of the beta-subunit aspartate 305 arginine 141 salt bridge SO BIOCHEMISTRY LA English DT Article ID ULTRAVIOLET VISIBLE SPECTROSCOPY; INDUCED CONFORMATIONAL-CHANGES; MONOVALENT CATION ACTION; SERINE O-SULFATE; ESCHERICHIA-COLI; ALPHA-SUBUNIT; INTERSUBUNIT COMMUNICATION; SALMONELLA-TYPHIMURIUM; ALPHA(2)BETA(2) COMPLEX; 3-DIMENSIONAL STRUCTURE AB The allosteric interactions that regulate substrate channeling and catalysis in the tryptophan synthase bienzyme complex from Salmonella typhimurium are triggered by covalent reactions at the beta-site and binding of substrate/product to the alpha-site. The transmission of these allosteric signals between the alpha- and beta-catalytic sites is modulated by an ensemble of weak bonding interactions consisting of salt bridges, hydrogen bonds, and van der Waals contacts that switch the subunits between open and closed conformations. Previous work has identified a scaffolding of salt-bridges extending between the alpha- and beta-sites consisting of alphaAsp 56, betaLys 167, and betaAsp 305. This work investigates the involvement of yet another salt bridging interaction involving the betaAsp 305-betaArg 141 pair via comparison of the spectroscopic, catalytic, and allosteric properties of the betaD305A and betaR141A mutants with the behavior of the wild-type enzyme. These mutations were found to give bienzyme complexes with impaired allosteric communication. The betaD305A mutant also exhibits altered beta-site substrate reaction specificity, while the catalytic activity of the betaR141A mutant exhibits impaired beta-site catalytic activity. The >25-fold activation of the alpha-site by alpha-aminoacrylate Schiff base formation at the beta-site found in the Na+ form of the wildtype enzyme is abolished in the Na+ forms of both mutants. Replacing Na+ by NH4+ or Cs+ restores the betaD305A to a wild-type-like behavior, whereas only partial restoration is achieved with the betaR141A mutant. These studies establish that the betaD305-betaR141 salt bridge plays a crucial role both in the formation of the closed conformation of the beta-site and in the transmission of allosteric signals between the alpha- and beta-sites that switch the alpha-site on and off. C1 Univ Calif Riverside, Dept Biochem, Riverside, CA 92521 USA. NIDDK, NIH, Lab Biochem & Genet, Bethesda, MD 20892 USA. RP Dunn, MF (reprint author), Univ Calif Riverside, Dept Biochem, Riverside, CA 92521 USA. EM michael.dunn@ucr.edu NR 50 TC 27 Z9 27 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 1 PY 2003 VL 42 IS 25 BP 7807 EP 7818 DI 10.1021/bi034291a PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 695FV UT WOS:000183821200019 PM 12820890 ER PT J AU Geho, DH Smith, WI Liotta, LA Roberts, DD AF Geho, DH Smith, WI Liotta, LA Roberts, DD TI Fibronectin-based masking molecule blocks platelet adhesion SO BIOCONJUGATE CHEMISTRY LA English DT Article ID POLYETHYLENE-GLYCOL AB Vessel wall extracellular matrix, which underlies the endothelium, is a potent stimulator of platelet adhesion and activation. Exposure of this matrix can result from damage incurred by vascular interventions, such as saphenous vein bypass grafting and angioplasty. Fibrillar collagens are an important component of the thrombogenic extracellular matrix. Herein we describe a means of targeting poly(ethylene glycol) (PEG)-mediated blockade directly to platelet-binding ECM molecules, such as type I collagen, thereby selectively blocking platelet adhesion to vascular matrix. Purified fibronectin (FN), a matrix protein that interacts with fibrillar collagens and platelets, was selectively pegylated to generate a targeted molecular shielding reagent that masked ECM ligands from platelet recognition and adhesion. This approach protects the functions of other vascular proteins, including surface proteins on intact endothelium. To mask the platelet-binding site of FN, PEG-propyl moieties (5000 Da) were covalently appended to lysine residues on the surface of FN, generating FNPEG-5K. To preserve the collagen-binding function of FN, it was pegylated while bound to a gelatin agarose matrix. We demonstrate that FNPEG-5K blocks platelet adhesion to purified type I collagen. Moreover, the same preparation blocks platelet adhesion to vascular wall components, including collagens. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Suburban Hosp, Dept Pathol, Bethesda, MD 20814 USA. RP Geho, DH (reprint author), NCI, Pathol Lab, NIH, Bldg 10-2N212,10 Ctr Dr, Bethesda, MD 20892 USA. RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 NR 18 TC 6 Z9 6 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD JUL-AUG PY 2003 VL 14 IS 4 BP 703 EP 706 DI 10.1021/bc034037v PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 703LK UT WOS:000184280700001 PM 12862420 ER PT J AU Bura, E Pfeiffer, RM AF Bura, E Pfeiffer, RM TI Graphical methods for class prediction using dimension reduction techniques on DNA microarray data SO BIOINFORMATICS LA English DT Article ID SLICED INVERSE REGRESSION; GENE-EXPRESSION DATA; BINARY RESPONSE; CANCER; CLASSIFICATION AB Motivation: We introduce simple graphical classification and prediction tools for tumor status using gene-expression profiles. They are based on two dimension estimation techniques sliced average variance estimation (SAVE) and sliced inverse regression (SIR). Both SAVE and SIR are used to infer on the dimension of the classification problem and obtain linear combinations of genes that contain sufficient information to predict class membership, such as tumor type. Plots of the estimated directions as well as numerical thresholds estimated from the plots are used to predict tumor classes in cDNA microarrays and the performance of the class predictors is assessed by cross-validation. A microarray simulation study is carried out to compare the power and predictive accuracy of the two methods. Results: The methods are applied to cDNA microarray data on BRCA1 and BRCA2 mutation carriers as well as sporadic tumors from Hedenfalk et al. (2001). All samples are correctly classified. C1 George Washington Univ, Dept Stat, Washington, DC 20052 USA. NCI, DCEG, Bethesda, MD 20892 USA. RP Bura, E (reprint author), George Washington Univ, Dept Stat, 2201 G St NW, Washington, DC 20052 USA. RI Pfeiffer, Ruth /F-4748-2011 NR 24 TC 33 Z9 33 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JUL 1 PY 2003 VL 19 IS 10 BP 1252 EP 1258 DI 10.1093/bioinformatics/btg150 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 701BG UT WOS:000184145200011 PM 12835269 ER PT J AU Dror, O Benyamini, H Nussinov, R Wolfson, H AF Dror, O. Benyamini, H. Nussinov, R. Wolfson, H. TI MASS: multiple structural alignment by secondary structures SO BIOINFORMATICS LA English DT Article DE Structural Bioinformatics; Subset alignment; Non-sequential alignment; Non-topological motif; Supersecondary structural motif AB We present a novel method for multiple alignment of protein structures and detection of structural motifs. To date, only a few methods are available for addressing this task. Most of them are based on a series of pairwise comparisons. In contrast, MASS (Multiple Alignment by Secondary Structures) considers all the given structures at the same time. Exploiting the secondary structure representation aids in filtering out noisy results and in making the method highly efficient and robust. MASS disregards the sequence order of the secondary structure elements. Thus, it can find non-sequential and even non-topological structural motifs. An important novel feature of MASS is subset alignment detection: It does not require that all the input molecules be aligned. Rather, MASS is capable of detecting structural motifs shared only by a subset of the molecules. Given its high efficiency and capability of detecting subset alignments, MASS is suitable for a broad range of challenging applications: It can handle large-scale protein ensembles (on the order of tens) that may be heterogeneous, noisy, topologically unrelated and contain structures of low resolution. C1 [Dror, O.; Wolfson, H.] Tel Aviv Univ, Sch Comp Sci, IL-69978 Tel Aviv, Israel. [Benyamini, H.; Nussinov, R.] Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. [Nussinov, R.] NCI, Frederick Canc Res & Dev Ctr, Basic Res Program,SAIC Frederick Inc, Lab Expt & Computat Biol, Frederick, MD 21702 USA. RP Dror, O (reprint author), Tel Aviv Univ, Sch Comp Sci, IL-69978 Tel Aviv, Israel. EM oranit@post.tau.ac.il RI Wolfson, Haim/A-1837-2011 FU NCI NIH HHS [N01-CO-12400] NR 34 TC 40 Z9 42 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUL PY 2003 VL 19 SU 1 BP i95 EP i104 DI 10.1093/bioinformatics/btg1012 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA V09ZL UT WOS:000207434200014 PM 12855444 ER PT J AU Inbar, Y Benyamini, H Nussinov, R Wolfson, HJ AF Inbar, Yuval Benyamini, Hadar Nussinov, Ruth Wolfson, Haim J. TI Protein structure prediction via combinatorial assembly of sub-structural units SO BIOINFORMATICS LA English DT Article DE structure prediction; multiple docking; hierarchical model; combinatorial assembly AB Following the hierarchical nature of protein folding, we propose a three-stage scheme for the prediction of a protein structure from its sequence. First, the sequence is cut to fragments that are each assigned a structure. Second, the assigned structures are combinatorially assembled to form the overall 3D organization. Third, highly ranked predicted arrangements are completed and refined. This work focuses on the second stage of this scheme: the combinatorial assembly. We present CombDock, a combinatorial docking algorithm. CombDock gets an ordered set of protein sub-structures and predicts the inter-contacts that define their overall organization. We reduce the combinatorial assembly to a graph-theory problem, and give a heuristic polynomial solution to this computationally hard problem. We applied CombDock to various examples of structural units of two types: protein domains and building blocks, which are relatively stable sub-structures of domains. Moreover, we tested CombDock using increasingly distorted input, where the native structural units were replaced by similarly folded units extracted from homologous proteins and, in the more difficult cases, from globally unrelated proteins. The algorithm is robust, showing low sensitivity to input distortion. This suggests that CombDock is a useful tool in protein structure prediction that may be applied to large target proteins. C1 [Inbar, Yuval; Wolfson, Haim J.] Tel Aviv Univ, Sch Comp Sci, IL-69978 Tel Aviv, Israel. [Benyamini, Hadar; Nussinov, Ruth] Tel Aviv Univ, Sackler Fac Med, Inst Mol Med, IL-69978 Tel Aviv, Israel. [Nussinov, Ruth] NCI, Frederick Canc Res & Dev Ctr, Basic Res Program,SAIC Frederick Inc, Lab Expt & Computat Biol, Frederick, MD 21702 USA. RP Inbar, Y (reprint author), Tel Aviv Univ, Sch Comp Sci, IL-69978 Tel Aviv, Israel. EM inbaryuv@tau.ac.il RI Wolfson, Haim/A-1837-2011 FU NCI NIH HHS [N01-CO-12400] NR 33 TC 16 Z9 17 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JUL PY 2003 VL 19 SU 1 BP i158 EP i168 DI 10.1093/bioinformatics/btg1020 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA V09ZL UT WOS:000207434200022 PM 12855452 ER PT J AU Shaywitz, SE Shaywitz, BA Fulbright, RK Skudlarski, P Mencl, WE Constable, RT Pugh, KR Holahan, JM Marchione, KE Fletcher, JM Lyon, GR Gore, JC AF Shaywitz, SE Shaywitz, BA Fulbright, RK Skudlarski, P Mencl, WE Constable, RT Pugh, KR Holahan, JM Marchione, KE Fletcher, JM Lyon, GR Gore, JC TI Neural systems for compensation and persistence: Young adult outcome of childhood reading disability SO BIOLOGICAL PSYCHIATRY LA English DT Article DE dyslexia; reading disability; fMRI; outcome; compensation ID LOW ACHIEVEMENT DEFINITIONS; WORD FORM AREA; FUNCTIONAL CONNECTIVITY; DEVELOPMENTAL DYSLEXIA; CEREBRAL MECHANISMS; PREFRONTAL CORTEX; EPISODIC MEMORY; BRAIN; CHILDREN; ORGANIZATION AB Background: This study examined whether and how two groups of young adults who were poor readers as children (a relatively compensated group and a group with persistent reading difficulties) differed from non-impaired readers and if there were any factors distinguishing the compensated from persistently poor readers that might account for their different outcomes. Methods: Using functional magnetic resonance imaging, we studied three groups of young adults, ages 18.5-22.5 years, as they read pseudowords and real words: 1) persistently poor readers (PPR; n = 24); 2) accuracy improved (compensated) readers (AIR; n = 19); and 3) nonimpaired readers (NI, n = 27). Results: Compensated readers, who are accurate but not fluent, demonstrate a relative underactivation in posterior neural systems for reading located in left parietotemporal and occipitotemporal regions. Persistently poor readers, who are both not fluent and less accurate, activate posterior reading systems but engage them differently from nonimpaired readers, appearing to rely more on memory-based rather than analytic word identification strategies. Conclusions: These findings of divergent neural outcomes as young adults are both new and unexpected and suggest a neural basis for reading outcomes of compensation and persistence in adults with childhood dyslexia. Biol Psychiatry 2003;54:25-33 (C) 2003 Society of Biological Psychiatry. C1 Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. Yale Univ, Sch Med, Dept Diagnost Radiol, New Haven, CT 06510 USA. Haskins Labs Inc, New Haven, CT 06510 USA. Univ Texas, Hlth Sci Ctr, Dept Pediat, Houston, TX 77225 USA. NICHHD, Child Behav & Learning Branch, NIH, Bethesda, MD 20892 USA. Yale Univ, Dept Appl Phys, New Haven, CT 06520 USA. RP Shaywitz, SE (reprint author), Yale Univ, Sch Med, Dept Pediat, POB 3333, New Haven, CT 06510 USA. FU NICHD NIH HHS [P01 HD 21888, P50 HD25802] NR 61 TC 232 Z9 232 U1 6 U2 23 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 JUL 1 PY 2003 VL 54 IS 1 BP 25 EP 33 DI 10.1016/S0006-3223(02)01836-X PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 696BT UT WOS:000183866000004 PM 12842305 ER PT J AU Gallinat, J Bajbouj, M Sander, T Schlattmann, P Xu, K Ferro, EF Goldman, D Winterer, G AF Gallinat, J Bajbouj, M Sander, T Schlattmann, P Xu, K Ferro, EF Goldman, D Winterer, G TI Association of the G1947A COMT (Val(108/158)Met) gene polymorphism with prefrontal P300 during information processing SO BIOLOGICAL PSYCHIATRY LA English DT Article DE genotype; dopamine; P300; prefrontal noise; schizophrenia ID CATECHOL-O-METHYLTRANSFERASE; FUNCTIONAL POLYMORPHISM; LINKAGE DISEQUILIBRIUM; DOPAMINE TRANSPORTER; FRONTAL-CORTEX; SCHIZOPHRENIA; PERFORMANCE; POTENTIALS; DEXTROAMPHETAMINE; PHARMACOGENETICS AB Background: A common functional polymorphism, G1947A, of the catechol-O-methyltransferase (COMT) enzyme has gained interest in schizophrenia research because of its critical involvement in cortical dopamine catabolism and frontal lobe function. An assumed mechanism of dopamine is the reduction of noise in prefrontal neural networks during information processing. Therefore, the hypothesis was tested whether a variation of the COMT genotype is associated with prefrontal noise, which is in part reflected by the frontal P300 amplitude. It was predicted that homozygous Met allele carriers have a lower frontal P300 amplitude. Methods: The P300 component (auditory oddball) was recorded in 49 schizophrenic patients and 170 healthy control subjects. Three single nucleotide polymorphisms (SNPs) of the COMT gene (G1947A, C1883G, and G1243A) were investigated. Results: We observed a significant effect of G1947A COMT genotype on frontal P300 amplitude, with evidence for a genotype x diagnosis interaction. Lower frontal P300 amplitudes occurred in homozygous carriers of the Met allele, particularly in schizophrenic patients. Conclusions: The association of the frontal P300 amplitude with the G1947A COMT genotype further emphasizes the functional role of this SNP. As the finding was mainly observed in schizophrenic patients, this may indicate that additional factors are required to interact with COMT genotype to affect prefrontal function. The smaller frontal P300 amplitude in Met carriers suggests that the amount of noise in prefrontal neural networks during information processing might be in part under genetic control, which is mediated by dopamine. Biol Psychiatry 2003;54: 40-48 (C) 2003 Society of Biological Psychiatry. C1 Free Univ Berlin, Dept Psychiat, Lab Clin Psychophysiol, D-14050 Berlin, Germany. Max Delbruck Ctr, Gene Mapping Ctr, Berlin, Germany. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Gallinat, J (reprint author), Free Univ Berlin, Dept Psychiat, Lab Clin Psychophysiol, Eschenallee 3, D-14050 Berlin, Germany. RI Schlattmann, Peter/B-5289-2008; Bajbouj, Malek/B-3579-2012; Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 59 TC 132 Z9 139 U1 2 U2 5 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 JUL 1 PY 2003 VL 54 IS 1 BP 40 EP 48 DI 10.1016/S0006-3223(02)01973-X PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 696BT UT WOS:000183866000006 PM 12842307 ER PT J AU Smith, JC O'Connor, PJ AF Smith, JC O'Connor, PJ TI Physical activity does not disturb the measurement of startle and corrugator responses during affective picture viewing SO BIOLOGICAL PSYCHOLOGY LA English DT Review DE physical activity; startle response; international affective picture system; perceived exertion; muscle pain ID EMOTION; DEPRESSION; INTENSITY; EXERCISE; STIMULUS; REFLEX AB Healthy college females (n = 24) completed counterbalanced conditions of 20 min of very low and low intensity cycling exercise and seated rest. Startle and corrugator supercilii responses, and baseline orbicularis oculi and corrugator supercilii electromyographic (EMG) activity, were measured during each exercise condition while participants viewed pleasant, neutral and unpleasant pictures. The exercise conditions did not alter the magnitude of the startle or corrugator responses compared with the resting control condition. Baseline orbicularis EMG increased slightly and baseline corrugator EMG increased significantly, during the low intensity exercise condition. In conclusion, low intensity physical activity is not sufficient to after emotional responsiveness as assessed by the acoustic startle eyeblink response and corrugator supercilii EMG responses during the viewing of pleasant, neutral, and unpleasant pictures. Despite modestly increased baseline EMG levels, reliable startle and corrugator EMG responses can be obtained in healthy college females during picture viewing while performing low intensity cycling exercise. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Univ Georgia, Dept Exercise Sci, Athens, GA 30602 USA. RP Smith, JC (reprint author), Univ Florida, Ctr Study Emot & Attent, NIMH, Dept Clin & Hlth Psychol, POB 100165 HSC, Gainesville, FL 32610 USA. RI Smith, J. Carson/G-6404-2013 OI Smith, J. Carson/0000-0001-6142-0920 NR 36 TC 8 Z9 8 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 J9 BIOL PSYCHOL JI Biol. Psychol. PD JUL PY 2003 VL 63 IS 3 BP 293 EP 310 DI 10.1016/S0301-0511(03)00072-3 PG 18 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 709KN UT WOS:000184624500006 PM 12853173 ER PT J AU Zhou, J Wang, J Penny, D Monget, P Arraztoa, JA Fogelson, LJ Bondy, CA AF Zhou, J Wang, J Penny, D Monget, P Arraztoa, JA Fogelson, LJ Bondy, CA TI Insulin-like growth factor binding protein 4 expression parallels luteinizing hormone receptor expression and follicular luteinization in the primate ovary SO BIOLOGY OF REPRODUCTION LA English DT Article DE follicular development; granulosa cells; human chorionic gonadotropin; insulin-like growth factor receptor; ovulation ID FACTOR BINDING PROTEIN-4; FACTOR SYSTEM COMPONENTS; I GENE-EXPRESSION; IGF-I; GRANULOSA-CELLS; MESSENGER-RNA; FOLLICLES; FLUID; LOCALIZATION; SELECTION AB it has been suggested that locally produced insulin-like growth factor binding protein 4 (IGFBP4) inhibits ovarian follicular growth and ovulation by interfering with IGF action. According to this hypothesis, IGFBP4-expressing follicles should demonstrate atresia, whereas healthy dominant follicles should be devoid of IGFBP4. Alternatively, according to this view, there could be constitutive expression of the inhibitory IGFBP4 but selective expression of an IGFBP4 protease in dominant follicles, allowing the follicle to,, mature and ovulate because of degradation of the binding protein. To examine these views concerning the role of IGFBP4 in primate follicular selection, we analyzed cellular patterns of IGFs 1 and 2, IGFBP4, and the IGFBP4 protease (pregnancy-associated plasma protein A [PAPP-A]) mRNA expression in ovaries from late follicular phase rhesus monkeys using in situ hybridization. The IGF1 mRNA was not detected, but the IGF2 mRNA was abundant in theca interna and externa of all antral follicles and was present in the granulosa of large preovulatory and ovulatory follicles. The IGFBP4 mRNA was selectively expressed by LH receptor (LHR) mRNA-positive theca interna cells of healthy antral follicles (defined by aromatase and gonadotropin receptor expression) and by LHR-expressing granulosa cells found only in large preovulatory and ovulatory follicles (defined by size and aromatase expression). The PAPP-A mRNA was abundant in granulosa cells of most follicles without obvious relation to IGFBP4 expression. Ovarian IGFBP4 mRNA levels were markedly increased after treatment with the LH analog, hCG, whereas IGF2 and PAPP-A mRNAs were not significantly altered. In summary, IGFBP4 expression appears to be associated with follicular selection, not with atresia, in the monkey ovary. The IGFBP4 is consistently expressed in healthy theca interna and in luteinized granulosa cells, likely under LH regulation. The IGFBP4 protease, PAPP-A, is widely expressed without apparent selectivity for IGFBP4-expressing follicles or for dominant follicles. These observations suggest that IGFBP4 or an IGFBP4 proteolytic product may be involved with LH-induced steroidogenesis and/or luteinization rather than with inhibition of follicular growth. C1 NICHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. INRA, PRMD, CNRS, URA 1291, F-37380 Nouzilly, France. RP Zhou, J (reprint author), NICHD, Dev Endocrinol Branch, NIH, Bg 10,Rm 10N262, Bethesda, MD 20892 USA. NR 30 TC 18 Z9 18 U1 1 U2 5 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 JUL PY 2003 VL 69 IS 1 BP 22 EP 29 DI 10.1095/biolreprod.102.009191 PG 8 WC Reproductive Biology SC Reproductive Biology GA 695FP UT WOS:000183820700004 PM 12606427 ER PT J AU Cho, C Jung-Ha, H Willis, WD Goulding, EH Stein, P Xu, Z Schultz, RM Hecht, NB Eddy, EM AF Cho, C Jung-Ha, H Willis, WD Goulding, EH Stein, P Xu, Z Schultz, RM Hecht, NB Eddy, EM TI Protamine 2 deficiency leads to sperm DNA damage and embryo death in mice SO BIOLOGY OF REPRODUCTION LA English DT Article DE early development; gamete biology; gametogenesis; sperm; spermatogenesis ID CHROMATIN STRUCTURE; NUCLEAR PROTEINS; MALE-INFERTILITY; TRANSGENIC MICE; COMET ASSAY; SPERMATOZOA; EXPRESSION; DIFFERENTIATION; FERTILIZATION; FERTILITY AB Cytokinesis is incomplete in spermatogenic cells, and the descendants of each stem cell form a clonal syncytium. As a result, a heterozygous mutation in a gene expressed postmeiotically affects all of the haploid spermatids within a syncytium. Previously, we have found that disruption of one copy of the gene for either protamine I (PRM1) or protamine 2 (PRM2) in the mouse results in a reduction in the amount of the respective protein, abnormal processing of PRM2, and inability of male chimeras to transmit either the mutant or wild-type allele derived from the 129-genotype embryonic stem cells to the next generation. Although it is believed that protamines are essential for compaction of the sperm nucleus and to protect the DNA from damage, this has not been proven experimentally. To test the hypothesis that failure of chimeras to transmit the 129 genotype to offspring was due to alterations in the organization and integrity of sperm DNA, we used the single-cell DNA electrophoresis (comet) assay, ultrastructural analysis, and the intracytoplasmic sperm injection (ICSI) procedure. Comet assay demonstrated a direct correlation between the fraction of sperm with haploinsufficiency of PRM2 and the frequency of sperm with damaged DNA. Ultrastructural analysis revealed reduced compaction of the chromatin. ICSI with PRM2-deficient sperm resulted in activation of most metaphase II-arrested mouse eggs, but few were able to develop to the blastocyst stage. These findings suggest that development fails because of damage to paternal DNA and that PRM2 is crucial for maintaining the integrity of sperm chromatin. C1 NIEHS, Gamete Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. K JIST, Dept Life Sci, Kwangju 500712, South Korea. Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. Univ Penn, Ctr Res Reprod & Womens Hlth, Philadelphia, PA 19104 USA. Univ Penn, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. RP Eddy, EM (reprint author), NIEHS, Gamete Biol Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. FU NICHD NIH HHS [HD28832, HD22681, HD22732] NR 30 TC 187 Z9 199 U1 0 U2 8 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 JUL PY 2003 VL 69 IS 1 BP 211 EP 217 DI 10.1095/biolreprod.102.015115 PG 7 WC Reproductive Biology SC Reproductive Biology GA 695FP UT WOS:000183820700027 PM 12620939 ER PT J AU Laquerriere, P Grandjean-Laquerriere, A Jallot, E Balossier, G Frayssinet, P Guenounou, M AF Laquerriere, P Grandjean-Laquerriere, A Jallot, E Balossier, G Frayssinet, P Guenounou, M TI Importance of hydroxyapatite particles characteristics on cytokines production by human monocytes in vitro SO BIOMATERIALS LA English DT Article DE hydroxyapatite particles; cytokines; inflammation; physical characteristics ID MACROPHAGES IN-VITRO; MESSENGER-RNA; SURFACE-AREA; PHOSPHATE; BONE; SIZE; DEGRADATION; TOXICITY; CELLS AB Calcium phosphate bioceramics have been applied as bone substitutes for several decades. Aseptic loosening after total joint arthroplasty is a major problem in orthopaedic surgery. Hydroxyapatite particles from materials wear have been reported as the main cause of implant failure. For this reason, an investigation into possible wear particles from materials used in the implant may lead to longevity after arthroplasty. Monocytes are among the first cells to colonize the inflammatory site. In the present study, we have evaluated the inflammatory response after exposition to particles with different characteristics (size, sintering temperature and shape). Our data demonstrate that the most important characteristic was the shape and the size of the particles. The needle shaped particles induced the larger production of TNF-alpha, IL-6 and IL-10 by cells. To a less manner, the smallest particles induced an increase of the expression and production of the cytokines studied (TNF-alpha, IL-6 and IL-10). The sintering temperature appeared to be a less important characteristic even though it was involved in the dissolution/precipitation process. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 UFR Sci, Lab Microscopie Elect, F-51685 Reims 2, France. UFR Pharm, Lab Immunol & Biotechnol, F-51100 Reims, France. CNRS, Lab Phys Corpusculaire, IN2P3, F-63177 Clermont Ferrand, France. Le Gaillard, F-31470 St Lys, France. RP Laquerriere, P (reprint author), NIH, Div Bioengn & Phys Sci, ORS, Bldg 13,Room 3E73,13 South Dr, Bethesda, MD 20892 USA. RI Laquerriere, Patrice/P-1025-2016 OI Laquerriere, Patrice/0000-0001-7637-9094 NR 33 TC 95 Z9 100 U1 2 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD JUL PY 2003 VL 24 IS 16 BP 2739 EP 2747 DI 10.1016/S0142-9612(03)00089-9 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 679HB UT WOS:000182913700008 PM 12711520 ER PT J AU Hall, D AF Hall, D TI The effects of Tubulin denaturation on the characterization of its polymerization behavior SO BIOPHYSICAL CHEMISTRY LA English DT Article DE microtubules; tubulin denaturation; kinetics; thermodynamics; polymerization ID COLCHICINE-BINDING-ACTIVITY; MICROTUBULE PROTEIN; KINETIC-ANALYSIS; NEUTRAL PH; DYNAMIC INSTABILITY; SELF-ASSOCIATION; ASSEMBLY INVITRO; PURIFIED TUBULIN; IN-VITRO; STABILIZATION AB We report here upon a simulation study examining the effect of a dynamic mode of Tubulin denaturation upon the kinetic and thermodynamic characterization of the polymer formed for two idealized models of a Tubulin polymerization reaction: W an irreversibly polymerizing system; and (ii) a reversibly polymerizing system. The effects of each denaturation mode upon the two model systems behavior are highlighted by interpretation of the data in terms of the classical Oosawa reversible condensation polymerization model. We reveal here findings which suggest that the measurement strategy in concert with Tubulin's instability over the time course of the experiment may bias the results obtained so as to make an irreversible system's behavior conform to the equilibrium model or alternatively distort the results obtained from a truly reversible system to produce values of the critical concentration quite seriously in error. It was also found that Tubulin denaturation may seriously distort parameter estimates gained from a kinetic characterization of the system (e.g. nucleus size and growth rate constant). (C) 2003 Elsevier Science B.V. All rights reserved. C1 NIDDKD, Sect Phys Biochem, NIH, Bethesda, MD 20892 USA. RP Hall, D (reprint author), Univ Cambridge, Dept Chem, Biophys Sect, Lensfield Rd, Cambridge CB2 1EW, England. RI Hall, Damien/D-9927-2012 OI Hall, Damien/0000-0003-1538-7618 NR 68 TC 16 Z9 16 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 J9 BIOPHYS CHEM JI Biophys. Chem. PD JUL 1 PY 2003 VL 104 IS 3 BP 655 EP 682 DI 10.1016/S0301-4622(03)00040-1 PG 28 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA 713MT UT WOS:000184862600011 PM 12914911 ER PT J AU Hummer, G Szabo, A AF Hummer, G Szabo, A TI Kinetics from nonequilibrium single-molecule pulling experiments SO BIOPHYSICAL JOURNAL LA English DT Article ID DYNAMIC FORCE SPECTROSCOPY; ADHESION BONDS; TITIN; PROTEIN; SIMULATION; DETACHMENT; STRENGTH; POLYMER; SURFACE; DOMAIN AB Mechanical forces exerted by laser tweezers or atomic force microscopes can be used to drive rare transitions in single molecules, such as unfolding of a protein or dissociation of a ligand. The phenomenological description of pulling experiments based on Bell's expression for the force-induced rupture rate is found to be inadequate when tested against computer simulations of a simple microscopic model of the dynamics. We introduce a new approach of comparable complexity to extract more accurate kinetic information about the molecular events from pulling experiments. Our procedure is based on the analysis of a simple stochastic model of pulling with a harmonic spring and encompasses the phenomenological approach, reducing to it in the appropriate limit. Our approach is tested against computer simulations of a multimodule titin model with anharmonic linkers and then an illustrative application is made to the forced unfolding of 127 subunits of the protein titin. Our procedure to extract kinetic information from pulling experiments is simple to implement and should prove useful in the analysis of experiments on a variety of systems. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5,Rm 132, Bethesda, MD 20892 USA. RI Szabo, Attila/H-3867-2012; Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 34 TC 293 Z9 296 U1 6 U2 105 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUL PY 2003 VL 85 IS 1 BP 5 EP 15 PG 11 WC Biophysics SC Biophysics GA 695FN UT WOS:000183820600002 PM 12829459 ER PT J AU Brum, G Piriz, N DeArmas, R Rios, E Stern, M Pizarro, G AF Brum, G Piriz, N DeArmas, R Rios, E Stern, M Pizarro, G TI Differential effects of voltage-dependent inactivation and local anesthetics on kinetic phases of Ca2+ release in frog skeletal muscle SO BIOPHYSICAL JOURNAL LA English DT Article ID CALCIUM-RELEASE; SARCOPLASMIC-RETICULUM; TWITCH FIBERS; TETRACAINE; COMPONENTS; CHANNELS; DEPOLARIZATION; MECHANISMS; MOVEMENTS; PROCAINE AB In voltage-clamped frog skeletal muscle fibers, Ca2+ release rises rapidly to a peak, then decays to a nearly steady state. The voltage dependence of the ratio of amplitudes of these two phases (p/s) shows a maximum at low voltages and declines with further depolarization. The peak phase has been attributed to a component of Ca2+ release induced by Ca2+, which is proportionally greater at low voltages. We compared the effects of two interventions that inhibit Ca2+ release: inactivation of voltage sensors, and local anesthetics reputed to block Ca2+ release induced by Ca2+. Holding the cells partially depolarized strongly reduced the peak and steady levels of Ca2+ release elicited by a test pulse and suppressed the maximum of the p/s ratio at low voltages. The p/s ratio increased monotonically with test voltage, eventually reaching a value similar to the maximum found in noninactivated fibers. This implies that the marked peak of Ca2+ release is a property of a cooperating collection of voltage sensors rather than individual ones. Local anesthetics reduced the peak of release flux at every test voltage, and the steady phase to a lesser degree. At variance with sustained depolarization, they made p/s low at all voltages. These observations were well-reproduced by the "couplon" model of dual control, which assumes that depolarization and anesthetics respectively, and selectively, disable its Ca2+-dependent or its voltage-operated channels. This duality of effects and their simulation under such hypotheses are consistent with the operation of a dual, two-stage control of Ca2+ release in muscle, whereby Ca2+ released through multiple directly voltage-activated channels builds up at junctions to secondarily open Ca2+-operated channels. C1 Fac Med, Dept Biofis, Montevideo 11800, Uruguay. Univ Republ Montevideo, Fac Ciencias, Secc Biofis, Montevideo, Uruguay. Rush Univ, Dept Physiol & Mol Biophys, Chicago, IL USA. NIH, Bethesda, MD USA. RP Pizarro, G (reprint author), Fac Med, Dept Biofis, Gral Flores 2125, Montevideo 11800, Uruguay. NR 37 TC 10 Z9 11 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 JUL PY 2003 VL 85 IS 1 BP 245 EP 254 PG 10 WC Biophysics SC Biophysics GA 695FN UT WOS:000183820600023 PM 12829480 ER PT J AU Davis, JS Epstein, ND AF Davis, JS Epstein, ND TI Kinetic effects of fiber type on the two subcomponents of the Huxley-Simmons phase 2 in muscle SO BIOPHYSICAL JOURNAL LA English DT Article ID ENDOTHERMIC FORCE GENERATION; LIGHT-CHAIN PHOSPHORYLATION; LASER TEMPERATURE-JUMP; FROG SKELETAL-MUSCLE; CONTRACTING MUSCLE; TENSION TRANSIENTS; PHOSPHATE RELEASE; MYOSIN-FILAMENTS; RAPID REGENERATION; PRESSURE RELEASE AB The Huxley-Simmons phase 2 controls the kinetics of the first stages of tension recovery after a step-change in fiber length and is considered intimately associated with tension generation. It had been shown that phase 2 is comprised of two distinct unrelated phases. This is confirmed here by showing that the properties of phase 2(fast) are independent of fiber type, whereas those of phase 2(slow) are fiber type dependent. Phase 2fast has a rate of 1000-2000 s(-1) and is temperature insensitive (Q(10) similar to 1.16) in fast, medium, and slow speed fibers. Regardless of fiber type and temperature, the amplitude of phase 2(fast) is half (similar to0.46) that of phase 1 (fiber instantaneous stiffness). Consequently, fiber compliance (cross-bridge and thick/thin filament) appears to be the common source of both phase 1 elasticity and phase 2(fast) viscoelasticity. In fast fibers, stiffness increases in direct proportion to tension from an extrapolated positive origin at zero tension. The simplest explanation is that tension generation can be approximated by two-state transition from attached preforce generating (moderate stiffness) to attached force generating (high stiffness) states. Phase 2(slow) is quite different, progressively slowing in concert with fiber type. An interesting interpretation of the amplitude and rate data is that reverse coupling of phase 2(slow) back to Pi release and ATP hydrolysis appears absent in fast fibers, detectable in medium speed fibers, and marked in slow fibers contracting isometrically. Contracting slow and heart muscles stretched under load could employ this enhanced reversibility of the cross-bridge cycle as a mechanism to conserve energy. C1 NHLBI, Mol Physiol Sect, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Davis, JS (reprint author), NHLBI, Mol Physiol Sect, Mol Cardiol Lab, NIH, 10 Ctr Dr,MSC 1760, Bethesda, MD 20892 USA. NR 51 TC 14 Z9 14 U1 0 U2 1 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUL PY 2003 VL 85 IS 1 BP 390 EP 401 PG 12 WC Biophysics SC Biophysics GA 695FN UT WOS:000183820600036 PM 12829493 ER PT J AU Fekete, RA Miller, MJ Chattoraj, DK AF Fekete, RA Miller, MJ Chattoraj, DK TI Fluorescently labeled oligonucleotide extension: a rapid and quantitative protocol for primer extension SO BIOTECHNIQUES LA English DT Article ID P1 PLASMID REPLICATION; ESCHERICHIA-COLI; PROTEIN; TRANSCRIPTION; INITIATION; PROMOTERS; COMPLEX; ORIGIN; REPA AB Identification of nucleotides used for RNA chain initiation or for contacting DNA binding proteins is basic to our understanding of gene regulation. Normally, a radioactive primer is used to copy RNA or DNA. The polymerase extension stops at free ends of mRNA (as in promoter mapping) or at the position of template cleavage or modification (as in footprinting). The locations of these positions are then analyzed by polyacrylamide gel eleetrophoresis. These analyses have been improved using fluorescently labeled primers and commonly available DNA sequencing machines. The protocol, which we call,fluorescently labeled oligonucleotide extension (FLOE), eliminates the need for handling radioactivity and polyacrylamide. The DNA sequencer delivers data as a "trace" that is ready for quantification, which eliminates the need to trace gels separately. The data analysis is further improved by new software, Scanalyze, which we present here. We demonstrate that by using promoter mapping and footprinting, FLOE shortens experimental time, extends the stretch of analyzable sequence, and simplfies quantification compared to radioactive methods and is ay sensitive in terms of detecting templates. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Fekete, RA (reprint author), NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NR 24 TC 30 Z9 31 U1 0 U2 2 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD JUL PY 2003 VL 35 IS 1 BP 90 EP + PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 698WA UT WOS:000184021300011 PM 12866410 ER PT J AU Bream, JH Curiel, RE Yu, CR Egwuagu, CE Grusby, MJ Aune, TM Young, HA AF Bream, JH Curiel, RE Yu, CR Egwuagu, CE Grusby, MJ Aune, TM Young, HA TI IL-4 synergistically enhances both IL-2- and IL-12-induced IFN-gamma expression in murine NK cells SO BLOOD LA English DT Article ID NATURAL-KILLER-CELLS; ACTIVATED PROTEIN-KINASE; CD4(+) T-CELLS; INTERFERON-GAMMA; GENE-EXPRESSION; TH2 CELLS; PROMOTER ACTIVATION; STAT4 ACTIVATION; DENDRITIC CELLS; CUTTING EDGE AB Interleukin-4 (IL-4) is thought to influence T and natural killer (NK) cells by down-regulating T helper 1 (Th1)-type cytokines like interferon-gamma (IFN-gamma). While investigating IL-4 regulation of IFN-gamma expression, we found that IL-4 synergized with IL-2 or IL-12 to enhance IFN-gamma production and mRNA expression in spleen-derived, IL-2-cultured NK cells, as well as negatively sorted fresh DX5(+)/CD3(-) NK cells albeit at lower levels. The positive effect of IL-4 on IL-2-induced IFN-gamma production was dependent upon signal transducer and activator of transcription 6 (Stat6) because this response was virtually abrogated in Stat6(-/-) mice. Notably, though, IL-12 plus IL-4 synergy on IFN-gamma expression was intact in Stat6(-/-) mice. In exploring possible molecular mechanisms to account for the synergistic effects of IL-4 on murine NK cells, we found that IL-2 plus IL-4 stimulation resulted in a modest increase in tyrosine phosphorylation of Stat5, while IL-12 plus IL-4 treatment resulted in a more substantial increase in tyrosine-phosphorylated Stat4. Finally, to identify regions of the IFN-gamma promoter that may be involved, NK cells from human IFN-gamma promoter/luciferase transgenic mice were treated with cytokines. NK cells from proximal (-110 to +64) promoter region mice did not respond to cytokine stimulation; however, the intact -565 to +64 IFN-gamma promoter responded synergistically to IL-2 plus IL-4 and to IL-12 plus IL-4 in NK cells. These data demonstrate a role for IL-4 in enhancing IFN-gamma expression in murine NK cells that is partially dependent on Stat6 in IL-2 costimulation and completely independent of Stat6 in IL-12 costimulations. (C) 2003 by The American Society of Hematology. C1 NIAMSD, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. NCI, Expt Immunol Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. Div Eli Lilly, Greenfield, IN USA. NEI, Lab Immunol, Bethesda, MD USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN USA. RP Bream, JH (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, Bldg 10,Rm 9N262, Bethesda, MD 20892 USA. RI Young, Howard/A-6350-2008 OI Young, Howard/0000-0002-3118-5111 FU NCI NIH HHS [N01 CO 12400] NR 76 TC 27 Z9 29 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 JUL 1 PY 2003 VL 102 IS 1 BP 207 EP 214 DI 10.1182/blood-2002-08-2602 PG 8 WC Hematology SC Hematology GA 695FK UT WOS:000183820300038 PM 12637316 ER PT J AU Zhang, Z Zhang, ML Ravetch, JV Goldman, C Waldmann, TA AF Zhang, Z Zhang, ML Ravetch, JV Goldman, C Waldmann, TA TI Effective therapy for a murine model of adult T-cell leukemia with the humanized anti-CD2 monoclonal antibody, MEDI-507 SO BLOOD LA English DT Article ID FC-RECEPTORS; CD2; SURFACE; MAB; ACTIVATION; LYMPHOMA; BTI-322; COMPLEX AB Adult T-cell leukemia (ATL) develops in a small proportion of individuals infected with the retrovirus human T-cell leukemia virus (HTLV-1). We evaluated the efficacy of MEDI-507 (a humanized monoclonal antibody directed against CD2) alone and in combination with humanized anti-Tac (HAT) directed toward CD25, the interleukin-2 receptor alpha (IL-2Ralpha) using a human adult T-cell leukemia xenograft model. Weekly treatments (4) with HAT significantly prolonged the survival of the ATL-bearing mice when compared with phosphate-buffered saline (PBS)-treated controls (P < .0001). Mice treated with MEDI-507 (100 mug/wk for 4 weeks) survived longer than those treated with HAT (P < .0025). Furthermore, prolonged treatment (6 months) of ATL with MEDI-507 significantly improved the outcome when compared with a short course (4 weeks) of therapy (P < .0036). Such treatment with weekly MEDI-507 for 6 months led to a prolonged survival of the ATL-bearing mice that was comparable with the survival observed in the control group of mice that did not receive a tumor or therapeutic agent. We also found that the expression of Fcgamma receptors (FcRgamma) on polymorphonuclear leukocytes and monocytes was required for MEDI-507-mediated tumor killing in vivo. Thus, the tumor-killing mechanism with MEDI-507 in vivo required the expression of the receptor FcRgammaIII on polymorphonuclear leukocytes and monocytes, suggesting that it is mediated by a form of antibody-dependent cellular cytotoxicity. These results demonstrate that MEDI-507 has therapeutic efficacy on ATL in vivo and provides support for a clinical trial involving this monoclonal antibody in the treatment of patients with CD2-expressing leukemias and lymphomas. (C) 2003 by The American Society of Hematology. C1 NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Rockefeller Univ, Lab Mol Genet & Immunol, New York, NY USA. RP Waldmann, TA (reprint author), NCI, Metab Branch, Ctr Canc Res, Bldg 10,Rm 4N115,10 Ctr Dr, Bethesda, MD 20892 USA. NR 22 TC 48 Z9 49 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 JUL 1 PY 2003 VL 102 IS 1 BP 284 EP 288 DI 10.1182/blood-2002-11-3601 PG 5 WC Hematology SC Hematology GA 695FK UT WOS:000183820300048 PM 12649132 ER PT J AU Sayers, TJ Brooks, AD Koh, CY Ma, WH Seki, N Raziuddin, A Blazar, BR Zhang, X Elliott, PJ Murphy, WJ AF Sayers, TJ Brooks, AD Koh, CY Ma, WH Seki, N Raziuddin, A Blazar, BR Zhang, X Elliott, PJ Murphy, WJ TI The proteasorne inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP SO BLOOD LA English DT Article ID NF-KAPPA-B; OVERCOMES DRUG-RESISTANCE; HIGH-DOSE CHEMOTHERAPY; LIGAND TRAIL; MULTIPLE-MYELOMA; BREAST-CANCER; IN-VIVO; ACTIVATION; DEATH; TRANSPLANTATION AB Because of the pivotal role the proteasome plays in apoptosis, inhibitors of this enzyme, such as PS-341, provide a great opportunity for exploring synergy between proteasome inhibition and other apoptosis-inducing agents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in tumor cells. In overnight assays, combinations of PS-341 and TRAIL were much more effective than either agent alone in promoting apoptosis of a murine myeloid leukemia, C1498, and a murine renal cancer, Renca. For C1498 cells, apoptosis sensitization by PS-341 affected neither the activity of nuclear factor kappaB (NF-kappaB) nor the levels of most antiapoptotic proteins. However, reductions in the antiapoptotic protein c-FLIP in response to PS-341 were observed in both C1498 and Renca cells. Treatment of normal bone marrow mixed with C1498 tumor cells for 18 hours with a combination of PS-341 and TRAIL resulted in a specific depletion of the tumor cells. Upon transfer to irradiated syngeneic recipient mice, mixtures treated with the PS-341 plus TRAIL combination resulted in enhanced long-term tumor-free survival of mice. These data therefore support the targeting of apoptotic pathways in tumor cells, using combinations of agents such as PS-341 and TRAIL that interact synergistically to preferentially promote tumor cell apoptosis. (C) 2003 by The American Society of Hematology. C1 NCI, Canc Res Ctr, Basic Sci Program, SAIC Frederick,Lab Mol Immunoregulat, Frederick, MD 21701 USA. NCI, Canc Res Ctr, Expt Immunol Lab, Frederick, MD 21701 USA. Univ Minnesota, Ctr Canc, Minneapolis, MN USA. Univ Minnesota, Dept Pediat, Div BMT, Minneapolis, MN USA. Millennium Pharmaceut, Cambridge, MA USA. RP Sayers, TJ (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Bldg 560,Rm 31-30, Frederick, MD 21702 USA. RI Zhang, Xia/B-8152-2008; Koh, Crystal/D-9986-2013; Sayers, Thomas/G-4859-2015 OI Zhang, Xia/0000-0002-9040-1486; FU NCI NIH HHS [R01 CA 72699]; PHS HHS [N01 C0 12400] NR 48 TC 184 Z9 190 U1 0 U2 6 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 JUL 1 PY 2003 VL 102 IS 1 BP 303 EP 310 DI 10.1182/blood-2002-09-2975 PG 8 WC Hematology SC Hematology GA 695FK UT WOS:000183820300051 PM 12637321 ER PT J AU Cai, JL Limke, TL Ginis, I Rao, MS AF Cai, JL Limke, TL Ginis, I Rao, MS TI Identifying and tracking neural stem cells SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article; Proceedings Paper CT Workshop on Stem Cell Plasticity CY APR 08-11, 2003 CL PROVIDENCE, RHODE ISLAND ID HEMATOPOIETIC PROGENITOR CELLS; ALDEHYDE DEHYDROGENASE; TELOMERASE ACTIVITY; PARKINSONS-DISEASE; SELF-RENEWAL; IN-VIVO; TRANSPLANTATION; BLOOD; DIFFERENTIATION; RHODAMINE-123 AB Hematopoietic stem cells, unlike neural stem cells, can be readily identified and isolated from developing and adult cell populations using positive and negative selection criteria. Isolating stem cells and progenitor cells from neural tissue has been more difficult because of difficulties in separating cells in solid tissue, the limited numbers of stem cells that persist in the adult, and the paucity of rigorously characterized markers. Nevertheless, strategies that have worked successfully in hematopoietic stem cell isolation can be adapted to isolate multiple classes of stem and progenitor cells from neural tissue. Neural stem cells also share cellular and molecular properties with other stem cell populations that may serve as surrogate identifiers of multipotentiality. Such potential markers are described. Unlike hematopoietic stem cells, tracking neural cells after transplantation is both necessary and more difficult. It will therefore be necessary to develop invasive and non-invasive strategies to follow transplanted cells and develop useful quantifiable readouts. Some potential strategies are described and current results are discussed. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Univ Utah, Dept Neurobiol & Anat, Salt Lake City, UT 84132 USA. NIA, Gerontol Res Ctr, Neurosci Lab, Stem Cell Biol Unit, Baltimore, MD 21224 USA. RP Rao, MS (reprint author), Univ Utah, Dept Neurobiol & Anat, Salt Lake City, UT 84132 USA. NR 39 TC 21 Z9 26 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JUL-AUG PY 2003 VL 31 IS 1 BP 18 EP 27 DI 10.1016/S1079-9796(03)00130-X PG 10 WC Hematology SC Hematology GA 700FF UT WOS:000184101400004 PM 12850479 ER PT J AU Feng, YQ Besse, A Olivier, E Ermakova, OV Graf, T Aladjem, M Bouhassira, EE AF Feng, YQ Besse, A Olivier, E Ermakova, OV Graf, T Aladjem, M Bouhassira, EE TI Transcriptional oscillation, timing of replication and methylation: A unified theory of position effects. SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 13th Conference on Hemoglobin Switching CY SEP 26-30, 2002 CL OXFORD, ENGLAND C1 Albert Einstein Coll Med, Bronx, NY 10467 USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JUL-AUG PY 2003 VL 31 IS 1 BP 131 EP 132 PG 2 WC Hematology SC Hematology GA 700FF UT WOS:000184101400038 ER PT J AU Gui, CY Dean, A AF Gui, CY Dean, A TI Recruitment of chromatin modifying complexes to a globin promoter. SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 13th Conference on Hemoglobin Switching CY SEP 26-30, 2002 CL OXFORD, ENGLAND C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JUL-AUG PY 2003 VL 31 IS 1 BP 136 EP 136 PG 1 WC Hematology SC Hematology GA 700FF UT WOS:000184101400053 ER PT J AU Felsenfeld, G Burgess-Beusse, B Farrell, C Gaszner, M Litt, M Mutskov, V Recillas-Targa, F Simpson, M West, A AF Felsenfeld, G Burgess-Beusse, B Farrell, C Gaszner, M Litt, M Mutskov, V Recillas-Targa, F Simpson, M West, A TI Analysis of chromatin domain boundaries. SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 13th Conference on Hemoglobin Switching CY SEP 26-30, 2002 CL OXFORD, ENGLAND C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JUL-AUG PY 2003 VL 31 IS 1 BP 141 EP 141 PG 1 WC Hematology SC Hematology GA 700FF UT WOS:000184101400067 ER PT J AU Gallagher, PG Wong, C Nilson, DG Weisbein, JL Bodine, DM AF Gallagher, PG Wong, C Nilson, DG Weisbein, JL Bodine, DM TI TFIID binding and insulator defects in the ankyrin promoter leading to ankyrin deficiency. SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 13th Conference on Hemoglobin Switching CY SEP 26-30, 2002 CL OXFORD, ENGLAND C1 Yale Univ, New Haven, CT 06520 USA. NHGRI, New Haven, CT 06520 USA. NR 0 TC 0 Z9 0 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JUL-AUG PY 2003 VL 31 IS 1 BP 143 EP 144 PG 2 WC Hematology SC Hematology GA 700FF UT WOS:000184101400074 ER PT J AU Gallagher, PG Pilon, AM Nilson, DG Orkin, SH Bodine, DM AF Gallagher, PG Pilon, AM Nilson, DG Orkin, SH Bodine, DM TI Decreased mRNA expression and altered chromatin configuration of non-globin erythroid krupple-like factor (EKLF) target genes in EKLF-deficient mice. SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 13th Conference on Hemoglobin Switching CY SEP 26-30, 2002 CL OXFORD, ENGLAND C1 Yale Univ, Sch Med, Dept Pediat, New Haven, CT USA. Childrens Hosp, HHMI, Boston, MA 02115 USA. NHGRI, GMBB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JUL-AUG PY 2003 VL 31 IS 1 BP 143 EP 143 PG 1 WC Hematology SC Hematology GA 700FF UT WOS:000184101400073 ER PT J AU Dempsey, NJ Ojalvo, LS Little, JA AF Dempsey, NJ Ojalvo, LS Little, JA TI SCFAS can act through 'adult' transcription factors like EKLF to up-regulate embryonic/fetal globin gene expression. SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 13th Conference on Hemoglobin Switching CY SEP 26-30, 2002 CL OXFORD, ENGLAND C1 Univ Minnesota, Minneapolis, MN 55455 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JUL-AUG PY 2003 VL 31 IS 1 BP 153 EP 153 PG 1 WC Hematology SC Hematology GA 700FF UT WOS:000184101400105 ER PT J AU Wen, J Dickinson, LA Pack, SD Kohwi-Shigematsu, T Noguchi, CT AF Wen, J Dickinson, LA Pack, SD Kohwi-Shigematsu, T Noguchi, CT TI Tall exhibits transcriptional repression and modifies RARb gene expression by targeting satellite DNA. SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 13th Conference on Hemoglobin Switching CY SEP 26-30, 2002 CL OXFORD, ENGLAND C1 NIDDK, Biol Chem Lab, Bethesda, MD USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. LBNL, Dept Cell & Mol Biol, Berkeley, CA USA. RI Pack, Svetlana/C-2020-2014 NR 0 TC 0 Z9 0 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JUL-AUG PY 2003 VL 31 IS 1 BP 156 EP 157 PG 2 WC Hematology SC Hematology GA 700FF UT WOS:000184101400117 ER PT J AU Wen, J Noguchi, CT AF Wen, J Noguchi, CT TI SATB1 activates early globin genes by binding to matrix attachment regions (MARs) in the beta-globin gene cluster. SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 13th Conference on Hemoglobin Switching CY SEP 26-30, 2002 CL OXFORD, ENGLAND C1 NIDDK, Biol Chem Lab, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JUL-AUG PY 2003 VL 31 IS 1 BP 157 EP 157 PG 1 WC Hematology SC Hematology GA 700FF UT WOS:000184101400118 ER PT J AU Tang, DC Zhu, JQ Chin, K Rodgers, GP AF Tang, DC Zhu, JQ Chin, K Rodgers, GP TI Hydroxyurea induction of gamma-globin gene expression is mediated through a small GTPase, SAR-e. SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 13th Conference on Hemoglobin Switching CY SEP 26-30, 2002 CL OXFORD, ENGLAND C1 NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JUL-AUG PY 2003 VL 31 IS 1 BP 162 EP 162 PG 1 WC Hematology SC Hematology GA 700FF UT WOS:000184101400136 ER PT J AU Cokic, VP Smith, RD Beleslin-Cokic, BB Gladwin, MT Schechter, AN AF Cokic, VP Smith, RD Beleslin-Cokic, BB Gladwin, MT Schechter, AN TI Nitric oxide donors induce fetal hemoglobin in human erythroid cells by a mechanism involving cGMP. SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 13th Conference on Hemoglobin Switching CY SEP 26-30, 2002 CL OXFORD, ENGLAND C1 NIDDKD, Biol Chem Lab, Bethesda, MD 20892 USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JUL-AUG PY 2003 VL 31 IS 1 BP 164 EP 164 PG 1 WC Hematology SC Hematology GA 700FF UT WOS:000184101400142 ER PT J AU Tanimoto, K Fukamizu, A Felsenfeld, G Engel, JD AF Tanimoto, K Fukamizu, A Felsenfeld, G Engel, JD TI Human b-globin HS5 carries an insulator activity in vivo. SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 13th Conference on Hemoglobin Switching CY SEP 26-30, 2002 CL OXFORD, ENGLAND C1 Univ Tsukuba, Tsukuba, Ibaraki 305, Japan. NIH, Bethesda, MD 20892 USA. Univ Michigan, Ann Arbor, MI 48109 USA. RI Fukamizu, Akiyoshi/J-5350-2012; Tanimoto, Keiji/B-2600-2014 OI Fukamizu, Akiyoshi/0000-0002-8786-6020; NR 0 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JUL-AUG PY 2003 VL 31 IS 1 BP 166 EP 166 PG 1 WC Hematology SC Hematology GA 700FF UT WOS:000184101400150 ER PT J AU Trainor, C AF Trainor, C TI The actions and interactions of GATA zinc fingers. SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 13th Conference on Hemoglobin Switching CY SEP 26-30, 2002 CL OXFORD, ENGLAND C1 NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JUL-AUG PY 2003 VL 31 IS 1 BP 166 EP 167 PG 2 WC Hematology SC Hematology GA 700FF UT WOS:000184101400153 ER PT J AU Dimitrov, M Nakic, M Elpern-Waxman, J Granetz, J O'Grady, J Phipps, M Milne, E Logan, GD Hasher, L Grafman, J AF Dimitrov, M Nakic, M Elpern-Waxman, J Granetz, J O'Grady, J Phipps, M Milne, E Logan, GD Hasher, L Grafman, J TI Inhibitory attentional control in patients with frontal lobe damage SO BRAIN AND COGNITION LA English DT Article DE prefrontal cortex; inhibition; negative priming; stop-sipal; attention ID ANTERIOR CINGULATE CORTEX; DEFICIT HYPERACTIVITY DISORDER; PREFRONTAL CORTEX; RESPONSE SELECTION; FUNCTIONAL-ANATOMY; BASAL GANGLIA; DEFICIT/HYPERACTIVITY DISORDER; FRONTOTEMPORAL DEMENTIA; SUSTAINED ATTENTION; MOTOR CONTROL AB The performance of a group of frontal lobe lesion and a group of frontal lobe dementia patients was compared with the performance of their respective matched normal control groups on two tests of inhibitory attentional control-the stop-signal reaction time task and a negative priming task. Both patient groups responded significantly slower than their respective normal control groups, but they showed only marginally significant selective impairments on the measures of inhibition. The data suggest that the specific inhibitory processes evaluated by these two tests are, in general, spared in patients with focal frontal lobe lesions or frontal lobe degeneration. Published by Elsevier Science (USA). C1 NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Nashville, TN USA. Univ Toronto, Dept Psychol, Toronto, ON M5S 1A1, Canada. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bldg 10,Room 5C205,10 Ctr Dr,MSC 1440, Bethesda, MD 20892 USA. OI Phipps, Michael/0000-0001-8398-5404; Grafman, Jordan H./0000-0001-8645-4457 FU NIA NIH HHS [R37 AG004306-17] NR 78 TC 30 Z9 32 U1 4 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 J9 BRAIN COGNITION JI Brain Cogn. PD JUL PY 2003 VL 52 IS 2 BP 258 EP 270 DI 10.1016/S0278-2626(03)00080-0 PG 13 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 696TF UT WOS:000183902800015 PM 12821109 ER PT J AU Bartelink, H Benz, C Cleveland, D Dorn, R Gralow, J Gradishar, WJ Grant, K Heimann, R Hellman, S Hudis, C Kerbel, R Lippman, M Lung, J Posner, MC Steeg, P Vestal, R Weichselbaum, RR Zetter, B AF Bartelink, H Benz, C Cleveland, D Dorn, R Gralow, J Gradishar, WJ Grant, K Heimann, R Hellman, S Hudis, C Kerbel, R Lippman, M Lung, J Posner, MC Steeg, P Vestal, R Weichselbaum, RR Zetter, B TI Expedition Inspiration Fund for Breast Cancer Research Meeting 2003 SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article C1 Univ Chicago, Chicago, IL 60637 USA. Netherlands Canc Inst, Amsterdam, Netherlands. Buck Inst Age Res, Novato, CA USA. Ludwig Inst Canc Res, New York, NY USA. Mt States Tumor Inst, Boise, ID USA. Univ Washington, Seattle, WA 98195 USA. Northwestern Univ, Sch Med, Evanston, IL USA. Calif Pacific Med Ctr, San Francisco, CA USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Sunnybrook & Womens Coll Hlth Sci Ctr, N York, ON, Canada. Univ Michigan Hlth Syst, Ann Arbor, MI USA. NCI, Bethesda, MD 20892 USA. Clin Pharmacol Consulting, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Hellman, S (reprint author), Univ Chicago, 5758 S Maryland Ave,MC 9006, Chicago, IL 60637 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2003 VL 80 IS 2 BP 139 EP 144 DI 10.1023/A:1024529119454 PG 6 WC Oncology SC Oncology GA 695XW UT WOS:000183856500001 PM 12908816 ER PT J AU Hyman, T Huizing, M Blumberg, PM Falik-Zaccai, TC Anikster, Y Gahl, WA AF Hyman, T Huizing, M Blumberg, PM Falik-Zaccai, TC Anikster, Y Gahl, WA TI Use of a cDNA microarray to determine molecular mechanisms involved in grey platelet syndrome SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE microarrays; RNA expression; fibronectin; grey platelet syndrome; granules ID GENE-EXPRESSION; DNA MICROARRAYS; CLASSIFICATION; IDENTIFICATION; FIBROBLASTS; DISORDERS; CANCER; TARGET AB The grey platelet syndrome (GPS) is a bleeding disorder of unknown aetiology with phenotypic and genetic heterogeneity. Affected patients exhibit macrothrombocytopenia, decreased alpha-granule content and, sometimes, myelofibrosis. We used microarray technology to investigate changes in gene expression that might reveal mechanisms involved in GPS. The expression of 4900 unique genes and expressed sequence tags was evaluated in fibroblasts from a GPS patient; normal fibroblasts provided the reference standard. Genes that were differentially regulated in the GPS cells were categorized into gene clusters based upon similarity/differences of expression differences. The results showed that genes with functional similarities clustered together. This analysis revealed significant upregulation of selected biological processes involving the production of cytoskeleton proteins, including fibronectin 1, thrombospondins 1 and 2, and collagen VI alpha. These genes appear to play a role in the pathogenesis of GPS. Indeed, Northern blot analyses confirmed that fibronectin, thrombospondin and matrix metalloprotease-2 were overexpressed in GPS fibroblasts compared with normal fibroblasts. Moreover, immunohistochemistry studies revealed robust fibronectin staining in GPS fibroblasts compared with normal ones. Our findings support the feasibility of using cDNA microarray techniques to detect distinctive and informative differences in gene expression patterns relevant to GPS, and suggest that the molecular basis for myelofibrosis in GPS involves upregulation of cytoskeleton proteins. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. Techn Israel Inst Technol, Div Med Genet, Hosp Western Galillee Naharia, Rappaport Fac Med, Haifa, Israel. RP Huizing, M (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr,MSC 1851,Bldg 10,Room 10C-103, Bethesda, MD 20892 USA. NR 25 TC 12 Z9 13 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 JUL PY 2003 VL 122 IS 1 BP 142 EP 149 DI 10.1046/j.1365-2141.2003.04410.x PG 8 WC Hematology SC Hematology GA 692ZH UT WOS:000183689800017 PM 12823356 ER PT J AU Sherman, ME Devesa, SS AF Sherman, ME Devesa, SS TI Analysis of racial differences in incidence, survival, and mortality for malignant tumors of the uterine corpus SO CANCER LA English DT Article DE uterus; malignant; neoplasm; incidence; survival; mortality; SEER ID ENDOMETRIAL CANCER; UNITED-STATES; RISK-FACTORS; NATURAL MENOPAUSE; SEROUS CARCINOMA; WHITE PATIENTS; HORMONE LEVELS; BLACK-WOMEN; TRENDS; DIAGNOSIS AB BACKGROUND. In the United States, incidence rates for malignant tumors of the uterine corpus are lower among blacks than among whites, whereas mortality rates are higher among blacks. Reasons for the higher level of mortality among blacks have been debated. METHODS. Using data from the Surveillance, Epidemiology, and End Results program, the authors compared incidence rates by histopathologic type for malignant tumors of the uterine corpus (including uterus, not otherwise specified) during the period 1992-1998 among white Hispanic, black, and white non-Hispanic patients. The authors also compared cumulative relative survival rates for blacks and whites by histopathologic type and by other factors, and they calculated estimated type-specific mortality rates. RESULTS. Overall incidence (per 100,000 woman-years) of corpus malignancy was significantly lower among white Hispanics (14.04; 95% confidence interval [CI], 13.39-14.72) and blacks (15.31; 95% CI, 14.61-16.04) compared with white nonHispanics (23.43; 95% CI, 23.06-23.81). Compared with white non-Hispanics, blacks had significantly higher incidence rates of serous/clear cell carcinoma (rate ratio, 1.85; 95% CI, 1.61-2.12), carcinosarcoma (rate ratio, 2.33; 95% CI, 1.99-2.72), and sarcoma (rate ratio, 1.56; 95% CI, 1.31-1.86). Survival was worse for blacks than for whites in every histopathologic category and in 'usual' types of endometrial adenocarcinoma, stratified by stage, grade, and age. Rare aggressive tumor types accounted for 53% of mortality among blacks, compared with 36% among whites. CONCLUSIONS. Less favorable outcomes for usual types of endometrial adenocarcinoma and for rare aggressive tumors contribute equally to the relatively high mortality due to corpus cancer among black women. Cancer 2003;98:176-86. Published 2003 by the American Cancer Sociery. C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Sherman, ME (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, 6120 Execut Blvd,Room 7080, Bethesda, MD 20892 USA. NR 45 TC 99 Z9 99 U1 2 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUL 1 PY 2003 VL 98 IS 1 BP 176 EP 186 DI 10.1002/cncr.11484 PG 11 WC Oncology SC Oncology GA 692QE UT WOS:000183671100023 PM 12833470 ER PT J AU Senderowicz, AM AF Senderowicz, AM TI Novel small molecule cyclin-dependent kinases modulators in human clinical trials SO CANCER BIOLOGY & THERAPY LA English DT Review DE cell cycle; molecular targets; cyclin-dependent kinases; flavopiridol; UCN-01; CYC202; BMS 687032; drug development ID CANCER-CELL-LINES; BREAST-CARCINOMA CELLS; CONTINUOUS-INFUSION FLAVOPIRIDOL; HUMAN EPIDERMOID CARCINOMA; SKIN TUMOR-DEVELOPMENT; ACTIVITY IN-VIVO; PROTEIN-KINASE; LUNG-CANCER; SELECTIVE INHIBITOR; PHASE-I AB Aberrations in cell cycle control occurs in the majority of human malignancies due to inactivation of tumor suppressor gene Rb by the phosphorylation induced by "hyperactive" cyclin-dependent kinases. Thus, it is quite reasonable to design cdk modulators for the prevention and treatment of human neoplasms. In order to target the cdk complexes, 2 main strategies were considered: to target the ATP binding site of calks (direct cdk modulators) and to target upstream pathways required for cdk activation (indirect cdk modulators). Examples for the first group include flavopiridol, roscovitine, BMS-387032. Examples for the second group include perifosine, lovastatin, UCN-01. The first example of a direct small molecule cdk modulator tested in the clinic, flavopiridol, is a pan-cdk inhibitor that not only promotes cell cycle arrest but also halts transcriptional elongation, promotes apoptosis, induces differentiation and has antiangiogenic properties. Clinical trials with this agent were performed with at least 3 different schedules of administration: 1 hour infusion, 24 hour infusion and 72 hour infusion. Main toxicities for infusions greater than or equal to24 hours are secretory diarrhea and pro-inflammatory syndrome. In addition, patients receiving shorter infusions have nausea/vomiting and neutropenia. Some clinical responses were observed in several patients with refractory malignancies. Based on these encouraging results, a Phase 3 trial comparing standard combination chemotherapy versus combination chemotherapy plus flavopiridol is currently under investigation. The second example of direct small molecule cdk modulator tested in clinical trials is UCN-01 (7-hydroxi-staurosporine). UCN-01 has interesting preclinical features: inhibits ca2(+)-dependent PKCs, promotes apoptosis, arrest cell cycle progression at G(1)/S and abrogates checkpoints upon DNA damage. The first Phase I trial of UCN-01 demonstrated a very prolonged half-life. Based on this novel feature, UCN-01 is administered as a 72 hour continuous infusion every 4 weeks (second and subsequent cycles UCN-01 is administered as a 36-hour infusion). Other shorter schedules (i.e., 3 hours) are being tested. Dose-limiting toxicities include nausea/vomiting, hypoxemia and insulin-resistant hyperglycemia. Combination trials with cisplatin and other DNA-damaging agents are being tested. Recently, Phase I trials with two novel small molecule cdk modulators, BMS 387032 and R-Roscovitine (CYC202), have commenced with good tolerability. Phase 2 trials and Phase I trials in combination with standard chemotherapy is being planned with these agents. In summary, novel small molecule cdk modulators are being tested in the clinic with interesting results. Although these small molecules are directed towards a very prevalent cause of carcinogenesis, we need to test them in advanced clinical trials to determine the future of this class of agents for the prevention and therapy of human malignancies. C1 NICDR, Mol Therapeut Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Senderowicz, AM (reprint author), NICDR, Mol Therapeut Unit, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Bldg 30,Room 212, Bethesda, MD 20892 USA. NR 204 TC 74 Z9 76 U1 0 U2 4 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD JUL-AUG PY 2003 VL 2 IS 4 SU 1 BP S84 EP S95 PG 12 WC Oncology SC Oncology GA 754RQ UT WOS:000187345600012 PM 14508085 ER PT J AU Von Eschenbach, AC AF Von Eschenbach, AC TI Special review issue - Models of anti-cancer therapy - Introductory comments SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Von Eschenbach, AC (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD JUL-AUG PY 2003 VL 2 IS 4 SU 1 BP S1 EP S1 PG 1 WC Oncology SC Oncology GA 754RQ UT WOS:000187345600001 PM 14508074 ER PT J AU Guo, XD Harold, N Saif, MW Schuler, B Szabo, E Hamilton, JM Monahan, BP Quinn, MG Cliatt, J Nguyen, D Grollman, F Thomas, RR McQuigan, EA Wilson, R Takimoto, CH Grem, JL AF Guo, XD Harold, N Saif, MW Schuler, B Szabo, E Hamilton, JM Monahan, BP Quinn, MG Cliatt, J Nguyen, D Grollman, F Thomas, RR McQuigan, EA Wilson, R Takimoto, CH Grem, JL TI Pharmacokinetic and pharmacodynamic effects of oral eniluracil, fluorouracil and leucovorin given on a weekly schedule SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE fluorouracil; thymidylate synthase; dihydropyrimidine dehydrogenase; eniluracil; pharmacokinetics ID MULTICENTER PHASE-II; METASTATIC COLORECTAL-CANCER; ADVANCED BREAST-CANCER; DIHYDROPYRIMIDINE DEHYDROGENASE; THYMIDYLATE SYNTHASE; PLUS FLUOROURACIL; 28-DAY REGIMEN; SOLID TUMORS; 5-FLUOROURACIL; INACTIVATOR AB Purpose. To determine the toxicities and pharmacokinetic effects of eniluracil (EU) given on two weekly dosing schedules with 5-fluorouracil (5-FU) and leucovorin (LV). Methods. A group of 26 patients received a single 24-h i.v. infusion of 5-FU 2300 mg/m(2) to provide a pharmacokinetic reference. After 2 weeks, patients received oral EU 20 mg plus LV 30 mg on days 1-3 with a single dose of 5-FU 15-29 mg/m(2) on day 2, or LV 30 mg on days 1-2 with a single dose of EU at least 1 h prior to 5-FU 29 mg/m(2) on day 2 weekly for 3 of 4 weeks. Results. Diarrhea was the most common dose-limiting toxicity. The recommended dose of 5-FU is 29 mg/m(2) per day. EU on either schedule decreased 5-FU plasma clearance by 48 to 52-fold, prolonged the half-life to >5 h, and increased the percentage of 5-FU excreted in the urine from 2% to 64-66%. With EU, plasma fluoro-beta-alanine was not detected while urinary excretion was reduced to <1% of that seen with i.v. 5-FU alone. Marked increases in both plasma and urinary uracil were seen. Thymidylate synthase ternary complex formation was demonstrated in bone marrow mononuclear cells isolated 24 h after the first oral 5-FU dose; the average was 66.5% bound. Conclusions. Either a single 20-mg dose of EU given prior to or for 3 days around the oral 5-FU dose led to comparable effects on 5-FU pharmacokinetic parameters, and inhibition of dihydropyrimidine dehydrogenase and thymidylate synthase. C1 Natl Naval Med Res Inst, Natl Canc Inst Navy Med Oncol, Ctr Canc Res, Canc Therapeut Branch, Bethesda, MD 20889 USA. Natl Naval Med Res Inst, Dept Med, Hematol Oncol Sect, Bethesda, MD 20889 USA. Natl Naval Med Res Inst, Dept Radiol, Bethesda, MD 20889 USA. RP Grem, JL (reprint author), Natl Naval Med Res Inst, Natl Canc Inst Navy Med Oncol, Ctr Canc Res, Canc Therapeut Branch, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM gremj@mail.nih.gov NR 27 TC 12 Z9 12 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JUL PY 2003 VL 52 IS 1 BP 79 EP 85 DI 10.1007/s00280-003-0613-0 PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 698TE UT WOS:000184014200011 PM 12707718 ER PT J AU Senderowicz, AM AF Senderowicz, AM TI Novel direct and indirect cyclin-dependent kinase modulators for the prevention and treatment of human neoplasms SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article; Proceedings Paper CT 18th International Cancer Treatment Symposium CY NOV 08-09, 2002 CL NAGOYA, JAPAN SP Bristol Myers Squibb Nagoya DE cell cycle; flavopiridol; cyclin-dependent kinases; clinical trials; apoptosis ID BREAST-CARCINOMA CELLS; SMALL-MOLECULE INHIBITORS; FLAVOPIRIDOL INDUCES APOPTOSIS; HUMAN EPIDERMOID CARCINOMA; CDK-ACTIVATING KINASE; RNA-POLYMERASE-II; ACTIVITY IN-VIVO; PROTEIN-KINASE; CANCER-CELLS; SELECTIVE INHIBITOR AB Abnormalities in the cell cycle are responsible for the majority of human neoplasias. Most abnormalities occur due to hyperphosphorylation of the tumor suppressor gene Rb by the key regulators of the cell cycle, the cyclin-dependent kinases (CDKs). Thus, a pharmacological CDK inhibitor may be useful in the prevention and/or treatment of human neoplasms. Flavopiridol is a flavonoid with interesting preclinical properties: (1) potent CDK inhibitory activity; (2) it depletes cyclin D1 and vascular endothelial growth factor mRNA by transcriptional and posttranscriptional mechanisms, respectively; (3) it inhibits positive elongation factor B, leading to transcription "halt"; and (4) it induces apoptosis in several preclinical models. The first phase I trial of a CDK inhibitor, flavopiridol, has been completed. Dose-limiting toxicities included secretory diarrhea and proinflammatory syndrome. Antitumor activity was observed in some patients with non-Hodgkin's lymphoma and renal, colon, and prostate cancers. Concentrations between 300 and 500 nM necessary to inhibit CDK-were achieved safely. Phase II trials with infusional flavopiridol and phase I infusional trials in combination with standard chemotherapy are being completed with encouraging results. A novel phase I trial of I-h flavopiridol administration was recently completed. The maximum tolerated doses using flavopiridol daily for 5, 3, and 1 consecutive days are 37.5, 50, and 62.5 mg/m(2) per day. Dose-limiting toxicities include vomiting, neutropenia, proinflammatory syndrome, and diarrhea. Plasma flavopiridol concentrations achieved were in the range 1.5-3.5 muM. Phase II/III trials using this 1-h schedule in several tumor types including non-small-cell lung cancer, chronic lymphocytic leukemia, mantle cell lymphoma, and head and neck cancer are being conducted worldwide. UCN-01, the second CDK modulator that has entered clinical trials, has unique preclinical properties: (1) it inhibits protein kinase C (PKC) activity; (2) it promotes cell-cycle arrest by accumulation in p21/p27; (3) it induces apoptosis in several preclinical models; and (4) it abrogates the G(2) checkpoint by inhibition of chk1. The last of these represents a novel strategy to combine UCN-01 with DNA-damaging agents. In the initial UCN-01 clinical trial (continuous infusion for 72 h), a prolonged half-life of about 600 h (100 times longer than in preclinical models) was observed. The maximum tolerated dose was 42.5 mg/m(2) per day for 3 days. Dose-limiting toxicities were nausea/vomiting, hypoxemia, and symptomatic hyperglycemia. One patient with melanoma achieved a partial response (8 months). Another patient with refractory anaplastic large-cell lymphoma had no evidence of disease at >4 years. Bone marrow and tumor samples obtained from some patients revealed loss in adducin phosphorylation, a substrate of PKC. Phase I trials with shorter infusions are being completed. In summary, the first two CDK modulators have shown encouraging results in early clinical trials. A question that remains unanswered is "Which is the best schedule for combination with standard antitumor agents?" Moreover, it is still unclear which pharmacodynamic endpoint reflects loss of CDK activity in tissue samples from patients in these trials. Despite these caveats, we feel that CDKs are sensible targets for cancer therapy and that there are several small-molecule CDK modulators in clinical trials with encouraging results. C1 Natl Inst Dent & Craniofacial Res, Mol Therapeut Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Senderowicz, AM (reprint author), Natl Inst Dent & Craniofacial Res, Mol Therapeut Unit, Oral & Pharyngeal Canc Branch, NIH, Bldg 30,Room 211, Bethesda, MD 20892 USA. NR 169 TC 39 Z9 42 U1 1 U2 7 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JUL PY 2003 VL 52 SU 1 BP S61 EP S73 DI 10.1007/s00280-003-0624-x PG 13 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 720JN UT WOS:000185257800010 PM 12819936 ER PT J AU Kelloff, GJ O'Shaughnessy, JA Gordon, GB Hawk, ET Sigman, CC AF Kelloff, GJ O'Shaughnessy, JA Gordon, GB Hawk, ET Sigman, CC TI Counterpoint: Because some surrogate end point biomarkers measure the neoplastic process they will have high utility in the development of cancer chemopreventive agents against sporadic cancers SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material ID SURGICAL ADJUVANT BREAST; CHRONIC MYELOID-LEUKEMIA; GENETIC PROGRESSION; PREVENTION; CHEMOTHERAPY; PATTERNS; HEAD C1 NCI, Div Canc Treatment & Diag, Biomed Imaging Program, Bethesda, MD 20892 USA. US Oncol, Baylor Sammons Canc Ctr, Dallas, TX 75246 USA. Abbott Labs, Abbott Pk, IL 60064 USA. NCI, Div Canc Prevent, Gastrointestinal & Other Canc Grp, Bethesda, MD 20892 USA. CCS Associates, Mountain View, CA 94043 USA. RP Kelloff, GJ (reprint author), NCI, Div Canc Treatment & Diag, Biomed Imaging Program, EPN Room 6058,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kelloffg@mail.nih.gov NR 34 TC 10 Z9 10 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2003 VL 12 IS 7 BP 593 EP 596 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 703YW UT WOS:000184311700002 PM 12869396 ER PT J AU Boyapati, SM Bostick, RM McGlynn, KA Fina, MF Roufail, WM Geisinger, KR Wargovich, M Coker, A Hebert, JR AF Boyapati, SM Bostick, RM McGlynn, KA Fina, MF Roufail, WM Geisinger, KR Wargovich, M Coker, A Hebert, JR TI Calcium, vitamin D, and risk for colorectal adenoma: Dependency on vitamin D receptor BsmI polymorphism and nonsteroidal anti-inflammatory drug use? SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID COLON-CANCER; DAIRY-PRODUCTS; UNITED-STATES; DIETARY CALCIUM; CELL-PROLIFERATION; GENE POLYMORPHISM; PHYSICAL-ACTIVITY; SUPPLEMENT USE; RECTAL-CANCER; OLDER WOMEN AB Previous epidemiological studies have been inconclusive in demonstrating an inverse association among calcium, vitamin D, and risk for colorectal adenoma. The purpose of this analysis was to evaluate the associations among calcium and vitamin D and risk for incident, sporadic colorectal adenoma according to the vitamin D receptor BsmI polymorphism and nonsteroidal anti-inflammatory drug (NSAID) use. We analyzed data from a colonoscopy-based case-control study (n = 177 cases, 228 controls) conducted in North Carolina between 1995 and 1997. Adjusted odds ratios (ORs) comparing participants in the highest to those in the lowest tertiles of total calcium and vitamin D intakes were 0.64 [95% confidence interval (CI), 0.35-1.15], P-trend = 0.14 and 0.69 (95% CI, 0.41-1.18), and P-trend = 0.19, respectively. Adjusted ORs for those in the upper tertile of total calcium intake relative to those in the lower were 0.25 (95% CI, 0.08-0.80) among those who had a Bb genotype, 0.57 (95% CI, 0.18-1.82) among those who had a bb genotype, and 0.36 (95% CI, 0.15-0.85) among those who did not take NSAIDs. The ORs for the highest tertile of calcium intake was 0.05 (95% CI, 0.01-0.41), P-trend < 0.01 among those who were Bb and did not take NSAIDs, and 0.16 (95% CI, 0.02-1.36), P-trend = 0.47 among those who were bb and did not take NSAIDs. These data support the hypotheses that higher calcium intakes may decrease risk for colorectal neoplasms, and that such a relationship is more readily detectable among those who do not take NSAIDs, and may be strongest among those who have at least one vitamin D receptor BsmI b allele. C1 Vanderbilt Univ, Ctr Hlth Serv Res, Nashville, TN USA. Univ S Carolina, Sch Med, Dept Family & Prevent Med, Columbia, SC USA. Univ S Carolina, Sch Med, Dept Pathol, Columbia, SC 29208 USA. Univ S Carolina, Norman J Arnold Sch Publ Hlth, Columbia, SC 29208 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Forsyth Med Specialists PA, Winston Salem, NC USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Univ Texas, Sch Publ Hlth, Houston, TX USA. RP Bostick, RM (reprint author), Div Populat Studies, 15 Med Pk,Suite 301, Columbia, SC 29203 USA. FU NCI NIH HHS [R01 CA66539] NR 62 TC 34 Z9 35 U1 0 U2 1 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 JUL PY 2003 VL 12 IS 7 BP 631 EP 637 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 703YW UT WOS:000184311700007 PM 12869402 ER PT J AU Lee, MM Gomez, SL Chang, JS Wey, M Wang, RT Hsing, AW AF Lee, MM Gomez, SL Chang, JS Wey, M Wang, RT Hsing, AW TI Soy and isoflavone consumption in relation to prostate cancer risk in China SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID PHYTOESTROGEN INTAKE; UNITED-STATES; DIET; GENISTEIN; GROWTH; MICE; DATABASE; ADENOCARCINOMA; APOPTOSIS; PATTERNS AB This case-control study in China evaluated the effect of soy food consumption and isoflavones (genistein and daidzein) on the risk of prostate cancer. One hundred and thirty-three cases and 265 age- and residential community-matched controls between the ages of 50 and 89 years were interviewed in person between 1989 and 1992. Usual consumption of soy foods and isoflavones was assessed using a food frequency questionnaire developed in China and a nutrient database developed and validated in Asian-American populations. The age- and total calorie-adjusted odds ratio (OR) of prostate cancer risk comparing the highest tertile of tofu intake to the lowest tertile was 0.58 [95% confidence interval (CI), 0.35-0.96]. There were also statistically significant associations comparing the highest quartile of intake of soy foods (OR, 0.51; 95% CI, 0.28-0.95) and genistein (OR, 0.53; 95% CI, 0.29-0.97) with the lowest quartiles. There was also an indication of a reduced risk associated with intake of daidzein (OR, 0.56; 95% CI, 0.31-1.04 for the highest versus lowest quartile). Our results indicate a reduced risk of prostate cancer associated with consumption of soy foods and isoflavones. These findings should be confirmed in longitudinal follow-up studies in populations with varying risk of prostate cancer. C1 Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. No Calif Canc Ctr, Union City, CA 94587 USA. Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. Beijing Med Univ, Dept Epidemiol, Beijing 10083, Peoples R China. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Lee, MM (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, MU 420 W,Box 0560, San Francisco, CA 94143 USA. RI Chang, Jeffrey Shu-Ming /B-1092-2010 NR 24 TC 131 Z9 137 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2003 VL 12 IS 7 BP 665 EP 668 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 703YW UT WOS:000184311700014 PM 12869409 ER PT J AU Gottesman, MM AF Gottesman, MM TI Cancer gene therapy: an awkward adolescence SO CANCER GENE THERAPY LA English DT Article DE vectors; apoptosis; tumor suppressors; angiogenesis; immunotherapy ID WILD-TYPE P53; PHASE-I TRIAL; REPLICATION-COMPETENT; ADENOVIRUS VECTOR; INTRATUMORAL INJECTION; MULTIDRUG-RESISTANCE; PROSTATE-CANCER; LUNG-CANCER; CELL-LINE; TUMOR AB At the Eleventh International Conference on Gene Therapy of Cancer (December 12-14, 2002, San Diego, CA) progress on using gene transfer technology to treat cancer was presented. Although there is as yet no cancer gene therapy being marketed, considerable progress has been made in defining likely strategies and likely targets for gene therapy of cancer. These strategies, including viral and non-viral delivery systems, and potential targets in cancer cells linked to our developing knowledge of cancer cell biology, are reviewed in this paper. Use of gene therapy to sensitize tumors to radiation and chemotherapy is one promising area of investigation. Some of the ancillary benefits of research on cancer gene therapy, including the development of public-private partnerships, recruitment of laboratory scientists into clinical research, and credentialing of potential cancer cell targets for therapies other than gene therapy, are noted. C1 NCI, Cell Biol Lab, Ctr Canc Res, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH,Dept Hlth & Human Serv, Bldg 37,Room 1A09, Bethesda, MD 20892 USA. NR 50 TC 58 Z9 62 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD JUL PY 2003 VL 10 IS 7 BP 501 EP 508 DI 10.1038/sj.cgt.7700602 PG 8 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 699QG UT WOS:000184067000001 PM 12833130 ER PT J AU Vijayachandra, K Lee, J Glick, AB AF Vijayachandra, K Lee, J Glick, AB TI Smad3 regulates senescence and malignant conversion in a mouse multistage skin carcinogenesis model SO CANCER RESEARCH LA English DT Article ID TGF-BETA RECEPTOR; CELL-CYCLE ARREST; TUMOR-SUPPRESSOR; TARGETED DISRUPTION; RAS ONCOGENE; C-MYC; GENE; KERATINOCYTES; P15(INK4B); PROTEIN AB Transforming growth factor beta (TGF-beta) is a growth-inhibitory cytokine for epithelial cells. In the mouse multistage skin carcinogenesis model, defects in TGF-beta1 signaling reduce senescence in vitro and accelerate malignant progression in vivo. However, the precise postreceptor signaling pathways and specific roles played by Smad proteins in this process have not been defined. Here we show that senescence of v-ras(Ha) -transduced Smad3 null keratinocytes is delayed, whereas overexpression of Smad3, but not Smad2 or Smad4, induced senescence. The TGF-beta1 target genes c-myc and p15(ink4b) were deregulated in the absence of Smad3. When transplanted to a graft site on nude mice, the v-raS(Ha)-transduced Smad3 null keratinocytes underwent rapid conversion from benign papilloma to malignant carcinoma, whereas wild-type keratinocytes predominantly formed papillomas. These results link Smad3-mediated regulation of growth control genes to senescence in vitro and tumor suppression in vivo. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. RP Glick, AB (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bldg 37, Bethesda, MD 20892 USA. NR 30 TC 61 Z9 64 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 JUL 1 PY 2003 VL 63 IS 13 BP 3447 EP 3452 PG 6 WC Oncology SC Oncology GA 697KL UT WOS:000183941800001 PM 12839923 ER PT J AU Salnikow, K Davidson, T Zhang, QW Chen, LC Su, WC Costa, M AF Salnikow, K Davidson, T Zhang, QW Chen, LC Su, WC Costa, M TI The involvement of hypoxia-inducible transcription factor-1-dependent pathway in nickel carcinogenesis SO CANCER RESEARCH LA English DT Article ID ZINC-FINGER PROTEIN; GENE-EXPRESSION; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; MAMMALIAN-CELLS; CANCER CELLS; CYCLE ARREST; IN-VIVO; P53; ACTIVATION; INDUCTION AB Nickel is a potent environmental pollutant in industrial countries. Because nickel compounds are carcinogenic, exposure to nickel represents a serious hazard to human health. The understanding of how nickel exerts its toxic and carcinogenic effects at a molecular level may be important in risk assessment, as well as in the treatment and prevention of occupational diseases. Previously, using human and rodent cells in vitro, we showed that hypoxia-inducible signaling pathway was activated by carcinogenic nickel compounds. Acute exposure to nickel resulted in the accumulation of hypoxia-inducible transcription factor (HIF)-1, which strongly activated hypoxia-inducible genes, including the recently discovered tumor marker NDRG1 (Cap43). To further identify HIF-1-dependent nickel-inducible genes and to understand the role of the HIF-dependent signaling pathway in nickel-induced transformation, we used the Affymetrix GeneChip to compare the gene expression profiles in wild-type cells or in cells from HIF-1alpha knockout mouse embryos exposed to nickel chloride. As expected, when we examined 12,000 genes for expression changes, we found that genes coding for glycolytic enzymes and glucose transporters, known to be regulated by HIF-1 transcription factor, were induced by nickel only in HIF-1alpha-proficient cells. In addition, we found a number of other hypoxia-inducible genes up-regulated by nickel in a HIF-dependent manner including BCL-2-binding protein Nip3, EGLN1, hypoxia-inducible gene (HIG1), and prolyl 4-hydroxylase. Additionally, we found a number of genes induced by nickel in a HIF-independent manner, suggesting that Ni activated other signaling pathways besides HIF-1. Finally, we found that in HIF-1alpha knockout cells, nickel strongly induced the expression of the whole group of genes that were not expressed in the presence of HIF-1. Because the majority of modulated genes were induced or suppressed by nickel in a HIF-1-dependent manner, we elucidated the role of HIF-1 transcription factor in cell transformation. In HIF-1alpha-proficient cells, nickel exposure increased soft agar growth, whereas it decreased soft agar growth in HIF-1alpha-deficient cells. We hypothesize that the induction of HIF-1 transcription factor by nickel may be important during the nickel-induced carcinogenic process. C1 NIEHS Ctr, Dept Environm Med, Nelson Inst Environm Med, New York, NY 10016 USA. NYU, Sch Med, Inst Canc, New York, NY 10016 USA. RP Salnikow, K (reprint author), NIEHS Ctr, Dept Environm Med, Nelson Inst Environm Med, 550 1st Ave, New York, NY 10016 USA. RI costa, max/H-1754-2012; Cjem, Lung-Chi/H-5030-2012 FU NCI NIH HHS [CA16087]; NIEHS NIH HHS [ES10344, ES00260, ES05512, T32 ES07324] NR 55 TC 66 Z9 73 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 JUL 1 PY 2003 VL 63 IS 13 BP 3524 EP 3530 PG 7 WC Oncology SC Oncology GA 697KL UT WOS:000183941800015 PM 12839937 ER PT J AU Wax, A Yang, CH Muller, MG Nines, R Boone, CW Steele, VE Stoner, GD Dasari, RR Feld, MS AF Wax, A Yang, CH Muller, MG Nines, R Boone, CW Steele, VE Stoner, GD Dasari, RR Feld, MS TI In situ detection of neoplastic transformation and chemopreventive effects in rat esophagus epithelium using angle-resolved low-coherence interferometry SO CANCER RESEARCH LA English DT Article ID TOMOGRAPHY; LIGHT AB We present a quantitative study of the nuclear morphometry of epithelial cells in an animal model of esophageal carcinogenesis. Changes in the size and texture of cell nuclei as a result of neoplastic transformation and chemopreventive action are observed in situ using a new optical technique, angle-resolved low-coherence interferometry (a/LCI). The capabilities of a/LCI are demonstrated via quantitative in situ measurements of the nuclear morphometry of basal epithelial cells, similar to50-100 mum beneath the tissue surface without the need for exogenous contrast agents or tissue fixation. The measurements quantify changes in nuclear size, characterized by average diameter, and nuclear texture, characterized by fractal dimension of the subcellular structures. Using this technique, we observed changes in the morphometry of rat esophageal epithelial cells in response to treatment with the carcinogen N-nitrosomethylbenzylamine. In addition, morphometric changes were observed in the esophagi of rats treated with N-nitrosomethylbenzylamine and two chemopreventive agents, difluoromethylornithine and perillyl alcohol. These agents induced either apoptosis in the basal epithelium (difluoromethylornithine) or both apoptosis and vacuolation of basal epithelial cells (perillyl alcohol). Vacuolation was associated with cellular toxicity. The light-scattering measurements were compared with histological images of the same tissues. The potential of a/LCI as a noninvasive means to investigate the development of epithelial neoplasia and for tracking the efficacy of chemopreventive agents appears high. This technique also may provide a new screening tool for intraepithelial neoplasia. C1 Duke Univ, Dept Biomed Engn, Durham, NC 27708 USA. MIT, George R Harrison Spect Lab, Cambridge, MA 02139 USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Wax, A (reprint author), Duke Univ, Dept Biomed Engn, Box 90281, Durham, NC 27708 USA. RI Wax, Adam/A-4760-2008; OI Wax, Adam/0000-0002-1827-5112 FU NCI NIH HHS [CN15011-72]; NCRR NIH HHS [P41-RR02594, F32 RR05075] NR 11 TC 89 Z9 90 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2003 VL 63 IS 13 BP 3556 EP 3559 PG 4 WC Oncology SC Oncology GA 697KL UT WOS:000183941800019 PM 12839941 ER PT J AU Chikamatsu, K Albers, A Stanson, J Kwok, WW Appella, E Whiteside, TL DeLeo, AB AF Chikamatsu, K Albers, A Stanson, J Kwok, WW Appella, E Whiteside, TL DeLeo, AB TI p53(110-124)-specific human CD4(+) T-helper cells enhance in vitro generation and antitumor function of tumor-reactive CD8(+) T cells SO CANCER RESEARCH LA English DT Article ID WILD-TYPE; P53 PROTEIN; ANTIGEN PRESENTATION; COLORECTAL-CANCER; DENDRITIC CELLS; BREAST-CANCER; LYMPHOCYTES; CARCINOMAS; ANTIBODIES; PEPTIDE AB Current evidence suggests that the optimal vaccines for cancer should incorporate tumor-specific cytotoxic as well as helper epitopes. Wild-type sequence (wt) p53 peptides are attractive candidates for broadly applicable cancer vaccines, which could combine multiple tumor epitopes defined by CD8(+) CTLs, as well as CD4(+) T-helper cells. To test this possibility, we generated anti-p53 CD4(+) T cells from peripheral blood obtained from an HLA-DRB1*0401(+) donor by in vitro stimulation with dendritic cells and recombinant human p53 protein. We identified the wt p53(110-124) peptide as a naturally presented epitope. In a series of ex vivo experiments, performed in an autologous human system, we then demonstrated the ability of anti-wt p53(110-124) CD4+ T cells to enhance the generation and antitumor functions of CD8(+) effector cells. The results demonstrate the crucial role of T helper-defined epitopes in shaping the immune response to multiepitope cancer vaccines targeting p53. This model of tumor-specific CD8(+) and CD4(+) T-cell interactions suggests that future vaccination strategies targeting tumor cells should incorporate helper and cytotoxic T cell-defined epitopes. C1 Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, 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. Virginia Mason Res Inst, Seattle, WA 98101 USA. Univ Washington, Sch Med, Seattle, WA 98101 USA. NCI, Bethesda, MD 20892 USA. RP DeLeo, AB (reprint author), Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Div Basic Res, Res Pavil,5117 Ctr Ave, Pittsburgh, PA 15213 USA. FU NIDCR NIH HHS [P0-1 DE-12321] NR 29 TC 45 Z9 45 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 JUL 1 PY 2003 VL 63 IS 13 BP 3675 EP 3681 PG 7 WC Oncology SC Oncology GA 697KL UT WOS:000183941800036 PM 12839958 ER PT J AU Horikawa, I Barrett, JC AF Horikawa, I Barrett, JC TI Transcriptional regulation of the telomerase hTERT gene as a target for cellular and viral oncogenic mechanisms SO CARCINOGENESIS LA English DT Editorial Material ID HUMAN-PAPILLOMAVIRUS TYPE-16; MAMMARY EPITHELIAL-CELLS; CATALYTIC SUBUNIT HTERT; BREAST-CANCER CELLS; HISTONE DEACETYLASE INHIBITOR; KINASE SIGNALING PATHWAY; HUMAN PROSTATE-CANCER; HUMAN SOMATIC-CELLS; HUMAN TUMOR-CELLS; REVERSE-TRANSCRIPTASE AB Malignant transformation from mortal, normal cells to immortal, cancer cells is generally associated with activation of telomerase and subsequent telomere maintenance. A major mechanism to regulate telomerase activity in human cells is transcriptional control of the telomerase catalytic subunit gene, human telomerase reverse transcriptase (hTERT). Several transcription factors, including oncogene products (e.g. c-Myc) and tumor suppressor gene products (e.g. WT1 and p53), are able to control hTERT transcription when over-expressed, although it remains to be determined whether a cancer-associated alteration of these factors is primarily responsible for the hTERT activation during carcinogenic processes. Microcell-mediated chromosome transfer experiments have provided evidence for endogenous factors that function to repress the telomerase activity in normal cells and are inactivated in cancer cells. At least one of those endogenous telomerase repressors, which is encoded by a putative tumor suppressor gene on chromosome 3p, acts through transcriptional repression of the hTERT gene. The hTERT gene is also a target site for viruses frequently associated with human cancers, such as human papillomavirus (HPV) and hepatitis B virus (HBV). HPV E6 protein contributes to keratinocyte immortalization and carcinogenesis through trans-activation of the hTERT gene transcription. In at least some hepatocellular carcinomas, the hTERT gene is a non-random integration site of HBV genome, which activates in cis the hTERT transcription. Thus, a variety of cellular and viral oncogenic mechanisms converge on transcriptional control of the hTERT gene. Regulation of chromatin structure through the modification of nucleosomal histones may mediate the action of these cellular and viral mechanisms. Further elucidation of the hTERT transcriptional regulation, including identification and characterization of the endogenous repressor proteins, should lead to better understanding of the complex regulation of human telomerase in normal and cancer cells and may open up new strategies for anticancer therapy. C1 NCI, Lab Biosyst & Canc, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Horikawa, I (reprint author), NCI, Lab Biosyst & Canc, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 37,Room 5046,MSC-4264, Bethesda, MD 20892 USA. NR 120 TC 142 Z9 158 U1 4 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2003 VL 24 IS 7 BP 1167 EP 1176 DI 10.1093/carcin/bgg085 PG 10 WC Oncology SC Oncology GA 705MY UT WOS:000184399900002 PM 12807729 ER PT J AU Mammen, JS Pittman, GS Li, Y Abou-Zahr, F Bejjani, BA Bell, DA Strickland, PT Sutter, TR AF Mammen, JS Pittman, GS Li, Y Abou-Zahr, F Bejjani, BA Bell, DA Strickland, PT Sutter, TR TI Single amino acid mutations, but not common polymorphisms, decrease the activity of CYP1B1 against (-)benzo[a]pyrene-7R-trans-7,8-dihydrodiol SO CARCINOGENESIS LA English DT Article ID PRIMARY CONGENITAL GLAUCOMA; CYTOCHROME P4501B1 VARIANTS; GENETIC-POLYMORPHISM; BREAST-CANCER; BENZOPYRENE; METABOLISM; ASSOCIATION; 1B1; IDENTIFICATION; CARCINOGENESIS AB Genetic differences that underlie inter-individual variation in the metabolism of common carcinogens are important potential sources of cancer susceptibility. Cytochrome P450 1B1 (CYP1B1), a central enzyme in the activation of the ubiquitous environmental carcinogen benzo[a]pyrene (B[a]P), has several genetic variants. This study investigated six rare mutations and four common polymorphisms for their effects on B[a]P metabolism. Five missense mutations associated with congenital glaucoma (Gly61Glu, Gly365Trp, Asp374Asn, Pro437Leu and Arg469Tryp) dramatically decreased the capacity of CYP1B1 to convert (-)benzo[a]pyrene-7R-trans-7,8-dihyrodiol (B[a]P-7,8-diol) to (+/-)benzo[a]pyrene-r-7,t-8-dihydrodiol-9,10-epoxides. These five mutations resulted in enzymes with 3-12% of normal activity when assayed in vitro using an Saccharomyces cerevisiae microsomal expression system. A 10 bp deletion mutation produced no detectable protein or activity. In contrast, proteins containing all possible combinations of four common single nucleotide polymorphisms (Arg48Gly, Ala199Ser, Val432Leu, Asn453Ser) had modest effects on B[a]P-7,8-diol metabolism. Michaelis-Menten analysis suggested that two alleles, Arg48, Ala119, Val432, Ser453 (RAVS) and Arg48, Ala119, Leu432, Ser453 (RALS), have K-M values 2-fold lower than Arg48, Ala119, Val432, Ser453 (RAVN): 1.4 +/- 0.3 and 1.3 +/- 0.4 muM, respectively, compared with 2.8 +/- 0.8 muM (P < 0.05). However, these differences could not be confirmed with direct measurements of rate at low substrate concentration. There were no significant differences for either of two other kinetic parameters, k(cat) or k(cat)/K-M. Allele frequency analysis in three populations reveals the Ser453 variant is rare among those of Asian (< 1 %) and African ancestry (< 4 %), and more common in individuals of European ancestry (16%). Haplotypes containing the Ser453 variant were uncommon; only RALS was detectable in our small populations. The RALS allele occurred between 0.5% in Asians and 15 % in Europeans. Our study demonstrates that rare, disease-associated mutations in CYP1B1 significantly decrease the enzyme's metabolism of B[a]P-7,8-diol; however, our results do not identify any major differences in this metabolism due to four common single amino acid polymorphisms. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. NIEHS, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. Baylor Coll Med Sch, Kleberg Cytogenet Lab, Houston, TX 77030 USA. Univ Memphis, W Harry Feinstone Ctr Genom Res, Memphis, TN 38152 USA. RP Strickland, PT (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, 615 N Wolfe St, Baltimore, MD 21205 USA. FU NIEHS NIH HHS [ES03819, ES08148] NR 41 TC 27 Z9 28 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2003 VL 24 IS 7 BP 1247 EP 1255 DI 10.1093/carcin/bgg088 PG 9 WC Oncology SC Oncology GA 705MY UT WOS:000184399900012 PM 12807732 ER PT J AU Patti, JW Neeman, Z Wood, BJ AF Patti, JW Neeman, Z Wood, BJ TI Radiofrequency ablation treatment in proximity to the gallbladder without subsequent acute cholecystitis SO CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article DE cholecystitis; radiofrequency ablation; RFA; gallbladder; liver ID HEPATIC NEOPLASMS; TUMOR ABLATION; METASTASES; CARCINOMA; SAFETY; LIVER AB Initial reports have suggested that proximity of liver tumors to the gallbladder may increase the risk for cholecystitis after radiofrequency ablation. A colon adenocarcinoma metastasis to the liver in contact with the gallbladder was successfully treated with radiofrequency ablation without subsequent cholecystitis. C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Neeman, Z (reprint author), NIH, Ctr Clin, Bldg 10,Room 1C387, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 12 TC 3 Z9 4 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0174-1551 J9 CARDIOVASC INTER RAD JI Cardiovasc. Interv. Radiol. PD JUL-AUG PY 2003 VL 26 IS 4 BP 413 EP 415 DI 10.1007/s00270-003-0015-z PG 3 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 720TP UT WOS:000185276300017 PM 14667129 ER PT J AU Minners, J McLeod, CJ Sack, MN AF Minners, J McLeod, CJ Sack, MN TI Mitochondrial plasticity in classical ischemic preconditioning - moving beyond the mitochondrial K-ATP channel SO CARDIOVASCULAR RESEARCH LA English DT Review DE preconditioning; mitochondria; K-ATP channel; energy metabolism; infarction ID SENSITIVE POTASSIUM CHANNELS; PERMEABILITY TRANSITION PORE; RAT VENTRICULAR MYOCYTES; PROTEIN-KINASE-C; CARDIAC MITOCHONDRIA; POSSIBLE MECHANISM; ENERGY-METABOLISM; CA2+ OVERLOAD; MATRIX CA2+; CARDIOPROTECTION AB Ischemic preconditioning is a powerful biologic phenomenon that activates innate cell survival programs to protect the heart from ischemic injury. The preponderance of research into classical ischemic preconditioning has focused on signaling pathways orchestrating cardioprotection. Conceptually classified into triggers, mediators and end effectors of preconditioning multiple distinct signaling pathways appear to 'converge' on the mitochondria possibly via activation of the mitochondrial ATP-sensitive potassium (mK(ATP)) channel. The mechanisms by which mK(ATP) channel activation induces preconditioning are incompletely elucidated but include perturbations of mitochondrial architecture and function. Since evidence invoking the mK(ATP) channel has almost exclusively been based on studies using diazoxide and 5-hydroxydecanote the finding that these two compounds have mitochondrial effects independent of the mK(ATP) channel has initiated a controversy regarding the exclusivity of this particular channel in preconditioning. A concerted effort to characterize the mitochondrial phenotype is important to advance our understanding of the mechanistic events that underlie the robust cardioprotective phenotype unmasked by preconditioning. The purpose of this review is to collate the information available on mitochondrial biology associated with classical preconditioning, to delineate the distinct temporal presentation of these mitochondrial perturbations, to reassess the role of the mitochondrial K-ATP channel and to propose a working model integrating the mitochondrial adaptations into the biology driving this cyto-protective phenotype. (C) 2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved. C1 Univ Cape Town, Sch Med, Hatter Inst Cardiol Res, ZA-7925 Cape Town, South Africa. Univ Cape Town, Sch Med, MRC, Interuniv Cape Heart Grp, ZA-7925 Cape Town, South Africa. RP Sack, MN (reprint author), NHLBI, Cardiovasc Branch, NIH, 10-7B15, Bethesda, MD 20892 USA. NR 43 TC 26 Z9 29 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD JUL 1 PY 2003 VL 59 IS 1 BP 1 EP 6 DI 10.1016/S0008-6363(03)00337-7 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 702JT UT WOS:000184221300002 PM 12829170 ER PT J AU Gomez-Angelats, M Cidlowski, JA AF Gomez-Angelats, M Cidlowski, JA TI Molecular evidence for the nuclear localization of FADD SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE FADD/Mort-1; FAS; nuclear localization signal; nuclear export signal ID DOMINANT INTERFERING MUTANT; RECEPTOR-INDUCED APOPTOSIS; SIGNALING COMPLEX; PROTEIN-KINASE; DEATH DOMAIN; INHIBITS PROLIFERATION; T-CELLS; FAS; FADD/MORT1; ACTIVATION AB The Fas-associated death domain (FADD) adaptor protein FADD/Mort-1 is recruited by several members of the tumor necrosis factor receptor (TNFR) superfamily during cell death activated via death receptors. Since most studies have focused on the interaction of FADD with plasma membrane proteins, FADD's subcellular location is thought to be confined to the cytoplasm. In this report, we show for the first time that FADD is present in both the cytoplasm and the nucleus of cells, and that its nuclear localization relies on strong nuclear localization and nuclear export signals (NLS and NES, respectively) that reside in the death-effector domain (DED) of the protein. Specifically, we found that a conserved basic KRK35 sequence of the human protein is necessary for FADD's nuclear localization, since disruption of this motif leads to the confinement of FADD in the cytoplasm. Furthermore, we show that the leucine-rich motif LTELKFLCL28 in the DED is necessary for FADD's nuclear export. Functionally, mutation of the NES of FADD and its seclusion in the nucleus reduces the cell death-inducing efficacy of FADD reconstituted in FADD-deficient T cells. C1 NIEHS, Lab Signal Transduct, Mol Endocrinol Grp, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, Mol Endocrinol Grp, NIH, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 32 TC 61 Z9 63 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD JUL PY 2003 VL 10 IS 7 BP 791 EP 797 DI 10.1038/sj.cdd.4401237 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 691NN UT WOS:000183612500005 PM 12815462 ER PT J AU Arnoult, D Karbowski, M Youle, RJ AF Arnoult, D Karbowski, M Youle, RJ TI Caspase inhibition prevents the mitochondrial release of apoptosis-inducing factor SO CELL DEATH AND DIFFERENTIATION LA English DT Letter ID CELL-DEATH; PATHWAYS; AIF; BAX C1 NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Arnoult, D (reprint author), NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NR 11 TC 27 Z9 28 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD JUL PY 2003 VL 10 IS 7 BP 845 EP 849 DI 10.1038/sj.cdd.4401240 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 691NN UT WOS:000183612500010 PM 12815467 ER PT J AU Mohiddin, SA Lu, SJ Cardoso, JP Carroll, S Jha, S Horowits, R Fananapazir, L AF Mohiddin, SA Lu, SJ Cardoso, JP Carroll, S Jha, S Horowits, R Fananapazir, L TI Genomic organization, alternative splicing, and expression of human and mouse N-RAP, a nebulin-related LIM protein of striated muscle SO CELL MOTILITY AND THE CYTOSKELETON LA English DT Article ID CULTURED CHICK CARDIOMYOCYTES; CARDIAC MYOFIBRILLOGENESIS; DILATED CARDIOMYOPATHY; INTERCALATED DISKS; LOCALIZATION; MYOFIBRILS; TROPOMYOSIN; ANTIBODIES; SEQUENCE; TITIN AB Linkage analysis identifies 10q24-26 as a disease locus for dilated cardiomyopathy (DCM), a region including the N-RAP gene. N-RAP is a nebulin-like LIM protein that may mediate force transmission and myofibril assembly in cardiomyocytes. We describe the sequence, genomic structure, and expression of human N-RAP, as well as an initial screen to determine whether N-RAP mutations cause cardiomyopathy. Human expressed sequence tag databases were searched with the published 3,528-bp mouse N-RAP open reading frame (ORF). Putative cDNA sequences were interrogated by direct sequencing from cardiac and skeletal muscle RNA. We identified two human N-RAP isoforms with ORFs of 5,085 bp (isoform C) and 5,190 bp (isoform S), encoding products of 193-197 kDa. Genomic database searches localize N-RAP to human chromosome 10q25.3 and match isoforms C and S to 41 and 42 exons. Only isoform C is detected in human cardiac RNA; in skeletal muscle, approximately 10% is isoform C and approximately 90% is isoform S. We investigated apparent differences between human N-RAP cDNA and mouse sequences. Two mouse N-RAP isoforms with ORFs of 5,079 and 5,184 bp were identified with similar to85% similarity to human isoforms; published mouse sequences include cloning artifacts truncating the ORF. Murine and human isoforms have similar gene structure, tissue specificity, and size. N-RAP is especially conserved within its nebulin-like and LIM domains. We expressed both N-RAP isoforms and the previously described truncated N-RAP in embryonic chick cardiomyocytes. All constructs targeted to myofibril precursors and the cell periphery, and inhibited myofibril assembly. Several human N-RAP polymorphisms were detected, but none were unique to cardiomyopathy patients. N-RAP is highly conserved and exclusively expressed in cardiac and skeletal muscle. Genetic abnormalities remain excellent candidate causes for cardiac and skeletal myopathies. (dagger)Published 2003 Wiley-Liss, Inc. C1 NHLBI, NIH, Bethesda, MD 20892 USA. NIAMSD, NIH, Bethesda, MD 20892 USA. Boston Childrens Hosp, Boston, MA USA. RP Mohiddin, SA (reprint author), NHLBI, NIH, Bldg 10,Room 7B15, Bethesda, MD 20892 USA. NR 23 TC 20 Z9 24 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 0886-1544 J9 CELL MOTIL CYTOSKEL JI Cell Motil. Cytoskeleton PD JUL PY 2003 VL 55 IS 3 BP 200 EP 212 DI 10.1002/cm.10123 PG 13 WC Cell Biology SC Cell Biology GA 696TL UT WOS:000183903300005 PM 12789664 ER PT J AU Lujan, HD Touz, MC AF Lujan, HD Touz, MC TI Protein trafficking in Giardia lamblia SO CELLULAR MICROBIOLOGY LA English DT Review ID CYST WALL PROTEIN; REGULATED SECRETORY PATHWAY; PARASITE TOXOPLASMA-GONDII; VARIANT SURFACE PROTEIN; PRIMITIVE EUKARYOTE; ENDOPLASMIC-RETICULUM; MOLECULAR CHAPERONES; ENDOMEMBRANE SYSTEM; TRANSPORT VESICLES; SNARE COMPLEXES AB Giardia , a protozoan parasite of humans and other vertebrates, is a common cause of intestinal disease worldwide. Besides its medical importance, Giardia is considered an excellent system to study the evolution of fundamental cellular processes because it belongs to the earliest branches of the eukaryotic lineage of descent. Giardia trophozoites lack organelles typical of higher eukaryotes such mitochondria, peroxisomes and compartments involved in intracellular protein trafficking and secretion, such as the Golgi apparatus and secretory granules. Nevertheless, the minimal machinery for protein transport and sorting is present in this parasite. When Giardia undergoes encystation, the biogenesis of secretory organelles necessary to transport cyst wall constituents to the cell surface takes place. Recent studies in both vegetative and encysting trophozoites have provided interesting information regarding the secretory pathway of this important human pathogen. C1 Univ Nacl Cordoba, Catedra Bioquim & Biol Mol, Fac Ciencias Med, RA-5000 Cordoba, Argentina. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Lujan, HD (reprint author), Univ Nacl Cordoba, Catedra Bioquim & Biol Mol, Fac Ciencias Med, Pabellon Argentina 2do Piso,Ciudad Univ, RA-5000 Cordoba, Argentina. NR 54 TC 30 Z9 34 U1 2 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1462-5814 J9 CELL MICROBIOL JI Cell Microbiol. PD JUL PY 2003 VL 5 IS 7 BP 427 EP 434 DI 10.1046/j.1462-5822.2003.00284.x PG 8 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 691GB UT WOS:000183596700001 PM 12814433 ER PT J AU Neckers, L AF Neckers, L TI Screening for inducers of kinase degradation SO CHEMISTRY & BIOLOGY LA English DT Editorial Material ID GROWTH-FACTOR RECEPTOR; HUMAN BREAST-CANCER; TYROSINE KINASES; ERBB2; PHOSPHORYLATION; GELDANAMYCIN; HETERODIMERS; EXPRESSION AB Targeted small molecule-induced protein degradation is a promising approach to inhibit signaling within kinase cascades. In this issue, researchers describe a simple assay for the rapid, high-throughput identification of novel agents that promote degradation of the kinases Her2 and EGFR. C1 NCI, Canc Res Ctr, Urol Oncol Branch, Rockville, MD 20850 USA. RP Neckers, L (reprint author), NCI, Canc Res Ctr, Urol Oncol Branch, 9610 Med Ctr Dr, Rockville, MD 20850 USA. NR 18 TC 1 Z9 1 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD JUL PY 2003 VL 10 IS 7 BP 587 EP 589 DI 10.1016/S1074-5521(03)00151-0 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 705CF UT WOS:000184378100004 PM 12890531 ER PT J AU Allhusen, V Belsky, J Booth, CL Bradley, R Brownell, CA Burchinal, M Campbell, SB Clarke-Stewart, KA Cox, M Friedman, SL Hirsh-Pasek, K Huston, A Jaeger, E Johnson, DJ Kelly, JF Knoke, B McCartney, K O'Brien, M Owen, MT Payne, C Phillips, D Pianta, R Randolph, SM Redden, D Robeson, W Spieker, S Vandell, DL Weinraub, M AF Allhusen, V Belsky, J Booth, CL Bradley, R Brownell, CA Burchinal, M Campbell, SB Clarke-Stewart, KA Cox, M Friedman, SL Hirsh-Pasek, K Huston, A Jaeger, E Johnson, DJ Kelly, JF Knoke, B McCartney, K O'Brien, M Owen, MT Payne, C Phillips, D Pianta, R Randolph, SM Redden, D Robeson, W Spieker, S Vandell, DL Weinraub, M CA Natl Inst Child Hlth Human Dev TI Does amount of time spent in child care predict socioemotional adjustment during the transition to kindergarten? SO CHILD DEVELOPMENT LA English DT Review ID NATIONAL LONGITUDINAL SURVEY; INFANT DAY-CARE; MATERNAL EMPLOYMENT; BEHAVIORAL OUTCOMES; NONMATERNAL CARE; LANGUAGE-DEVELOPMENT; HOME CARE; QUALITY; MOTHER; ATTACHMENT AB To examine relations between time in nonmaternal care through the first 4.5 years of life and children's socioemotional adjustment, data on social competence and problem behavior were examined when children participating in the National Institute of Child Health and Human Development (NICHD) Study of Early Child Care were 4.5 years of age and when in kindergarten. The more time children spent in any of a variety of nonmaternal care arrangements across the first 4.5 years of life, the more externalizing problems and conflict with adults they manifested at 54 months of age and in kindergarten, as reported by mothers, caregivers, and teachers. These effects remained, for the most part, even when quality, type, and instability of child care were controlled, and when maternal sensitivity and other family background factors were taken into account. The magnitude of quantity of care effects were modest and smaller than those of maternal sensitivity and indicators of family socioeconomic status, though typically greater than those of other features of child care, maternal depression, and infant temperament. There was no apparent threshold for quantity effects. More time in care not only predicted problem behavior measured on a continuous scale in a dose-response pattern but also predicted at-risk (though not clinical) levels of problem behavior, as well as assertiveness, disobedience, and aggression. C1 NICHD, Early Child Care Res Network, OEP, Off Director, Rockville, MD 20852 USA. RP Allhusen, V (reprint author), NICHD, Early Child Care Res Network, OEP, Off Director, 6100 Execut Blvd,Room 4A01, Rockville, MD 20852 USA. NR 102 TC 208 Z9 208 U1 11 U2 48 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-3920 EI 1467-8624 J9 CHILD DEV JI Child Dev. PD JUL-AUG PY 2003 VL 74 IS 4 BP 976 EP 1005 PG 30 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 706EB UT WOS:000184438900002 ER PT J AU Brotman, LM Gouley, KK Klein, RG Castellanos, FX Pine, DS AF Brotman, LM Gouley, KK Klein, RG Castellanos, FX Pine, DS TI Children, stress, and context: Integrating basic, clinical, and experimental prevention research SO CHILD DEVELOPMENT LA English DT Article ID MATERNAL-CARE; NEUROENDOCRINE ACTIVITY; SOCIAL COMPETENCE; CORTISOL; RESPONSES; BEHAVIOR; PRESCHOOLERS; TEMPERAMENT; REACTIVITY; INFANCY AB Findings from the Watamura, Donzella, Alwin, and Gunnar (this issue) study support the growing recognition of the importance of context on physiology and affective and behavioral regulation early in human development. This discussion focuses on the role of context and development on hypothalamic-pituitary-adrenal (HPA) axis regulation in young children. Discussed in this article are the Watamura et al. findings with regard to relevant animal studies, extension of these observations to samples of children at elevated risk for psychopathology, and experimental prevention studies with young children. It is contended that environmental factors operating at key points in development may shape affective and behavioral regulation as well as HPA axis function in children, much as environmental factors have been shown to shape HPA axis regulation in animals. C1 NYU, Dept Psychiat, Inst Children Risk, Ctr Child Study, New York, NY 10016 USA. NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. RP Brotman, LM (reprint author), NYU, Dept Psychiat, Inst Children Risk, Ctr Child Study, 577 1st Ave, New York, NY 10016 USA. NR 21 TC 15 Z9 15 U1 1 U2 4 PU BLACKWELL PUBLISHERS PI MALDEN PA 350 MAIN STREET, STE 6, MALDEN, MA 02148 USA SN 0009-3920 J9 CHILD DEV JI Child Dev. PD JUL-AUG PY 2003 VL 74 IS 4 BP 1053 EP 1057 DI 10.1111/1467-8624.00589 PG 5 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 706EB UT WOS:000184438900009 PM 12938701 ER PT J AU Chen, Q Reis, SE Kammerer, C Craig, WY LaPierre, SE Zimmer, EL McNamara, DM Pauly, DF Sharaf, B Holubkov, R Merz, NB Sopko, G Bontempo, F Kamboh, MI AF Chen, Q Reis, SE Kammerer, C Craig, WY LaPierre, SE Zimmer, EL McNamara, DM Pauly, DF Sharaf, B Holubkov, R Merz, NB Sopko, G Bontempo, F Kamboh, MI TI Genetic variation in lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) gene and the risk of coronary artery disease SO CIRCULATION LA English DT Article DE risk factors; coronary disease; genetics ID OX-LDL RECEPTOR-1; ENDOTHELIAL-CELLS; MESSENGER-RNA; BINDING; EXPRESSION; RESIDUES; DOMAIN AB Background-We examined the association of 3 polymorphisms in the lectin-like oxidized LDL receptor-1 (LOX1 or OLR1) gene with coronary artery disease in the Women's Ischemia Syndrome Evaluation (WISE) study population. Methods and Results-The WISE sample comprised 589 white and 122 black women who underwent angiography for suspected ischemia. The sample was divided into 3 groups: <20% stenosis (38.7%), 20% to 49% stenosis (24.9%), and &GE;50% stenosis (35.3%). The three LOX1 polymorphisms (intron 4/G-->A, intron 5/T-->G, and 3' UTR/T-->C) were in linkage disequilibrium and thus behaved as a single polymorphism. The frequency of the 3' UTR/T allele was significantly higher in whites than blacks (49% versus 19%; P<0.0001). Among white women, the frequency of the 3'UTR/T allele carriers (TC+TT genotypes) increased gradually from 67.9% to 75.0% and 79.2% in the <20%, 20% to 49%, and greater than or equal to50% stenosis groups, respectively (chi(2) trend=6.23; P=0.013). Logistic regression analyses indicated that APOE (odds ratio, 1.90; P=0.007) and LOX1 (odds ratio, 1.67; P=0.025) genotypes were independently associated with the risk of disease and that there was no interaction between the two genes. The 3'UTR/T allele carriers also had significantly higher IgG anti-oxLDL levels than individuals carrying the CC genotype (0.94+/-0.20 versus 0.86+/-0.16; P=0.032). Furthermore, our electrophoretic mobility shift assay data show that the 3'UTR polymorphic sequence affects the binding of a putative transcription factor in an allele-specific manner. Conclusions-Our data suggest that common genetic variation in the LOX1 gene may be associated with the risk of coronary artery disease in white women. C1 Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. Univ Pittsburgh, Cardiovasc Inst, Pittsburgh, PA USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. Fdn Blood Res, Scarborough, ME USA. Univ Florida, Div Cardiol, Gainesville, FL USA. Brown Univ, Div Cardiol, Providence, RI 02912 USA. Univ Utah, Dept Family & Prevent Med, Salt Lake City, UT USA. Cedars Sinai Med Ctr, Div Cardiol, Los Angeles, CA 90048 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Kamboh, MI (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, 130 DeSoto St, Pittsburgh, PA 15261 USA. RI Reis, Steven/J-3957-2014; OI Kamboh, M. Ilyas/0000-0002-3453-1438 FU NHLBI NIH HHS [N01-HV-68164, HL54900, HL70169, N01-HV-68161, N01-HV-68162, N01-HV-68163, R01-HL64829-01, R01-HL64914-01, R01-HL64924-01] NR 20 TC 62 Z9 65 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 JUL 1 PY 2003 VL 107 IS 25 BP 3146 EP 3151 DI 10.1161/01.CIR.0000074207.85796.36 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 696KY UT WOS:000183887100007 PM 12810610 ER PT J AU McDermott, MM Greenland, P Green, D Guralnik, JM Criqui, MH Liu, K Chan, CL Pearce, WH Taylor, L Ridker, PM Schneider, JR Martin, G Rifai, N Quann, M Fornage, M AF McDermott, MM Greenland, P Green, D Guralnik, JM Criqui, MH Liu, K Chan, CL Pearce, WH Taylor, L Ridker, PM Schneider, JR Martin, G Rifai, N Quann, M Fornage, M TI D-dimer, inflammatory markers, and lower extremity functioning in patients with and without peripheral arterial disease SO CIRCULATION LA English DT Article DE coagulation; fibrinolysis; epidemiology; peripheral vascular disease; claudication ID C-REACTIVE PROTEIN; PHYSICAL PERFORMANCE BATTERY; ATHEROSCLEROTIC PLAQUES; SUBSEQUENT DISABILITY; WOMENS HEALTH; ASSOCIATION; FIBRIN; EXPRESSION; SERUM; INDEX AB Background-We determined whether higher levels of D-dimer, C-reactive protein (CRP), fibrinogen, and serum amyloid A are associated independently with functional impairment in patients with and without peripheral arterial disease (PAD). Methods and Results-Participants were 370 men and women with PAD (ankle brachial index <0.90) and 231 without PAD. Functional outcomes were 6-minute walk distance and 4-meter walking velocity. A summary performance score combined performance in walking speed, standing balance, and time for 5 repeated chair rises into an ordinal score ranging from 0 to 12 (12=best). Adjusting for age, sex, ankle brachial index, comorbidities, and other potential mediators and confounders, D-dimer levels were associated independently and inversely with performance on all 3 functional measures in the entire cohort and among patients with and without PAD, respectively. Adjusting for known and potential confounders, CRP levels were associated independently with 6-minute walk distance and the summary performance score among participants with PAD. No significant associations were observed between CRP and the functional measures among participants without PAD. Fibrinogen and SAA levels were not associated independently with the functional measures. Conclusions-Higher D-dimer levels are associated with poorer functioning among individuals with and without PAD. Higher CRP levels were associated with poorer 6-minute walk performance and a lower summary performance score among participants with PAD but not among those without PAD. Additional study is needed to determine whether D-dimer and CRP are involved in the pathophysiology of functional impairment or whether they are simply sensitive markers of the extent of systemic atherosclerosis. C1 Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Surg, Chicago, IL 60611 USA. NIA, Bethesda, MD 20892 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Harvard Univ, Sch Med, Boston, MA USA. Northwestern Univ, Evanston Hosp, Dept Surg, Evanston, IL 60201 USA. Univ Texas, Houston, TX USA. RP McDermott, MM (reprint author), 675 N St Clair,Suite 18-200, Chicago, IL 60611 USA. FU NCRR NIH HHS [RR-00048]; NHLBI NIH HHS [R01-HL58099, R01-HL64739] NR 25 TC 69 Z9 71 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 JUL 1 PY 2003 VL 107 IS 25 BP 3191 EP 3198 DI 10.1161/01.CIR.0000074227.53616.CC PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 696KY UT WOS:000183887100014 PM 12810614 ER PT J AU Yu, C Engle, RE Bryan, JP Emerson, SU Purcell, RH AF Yu, C Engle, RE Bryan, JP Emerson, SU Purcell, RH TI Detection of immunoglobulin M antibodies to hepatitis E virus by class capture enzyme immunoassay SO CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY LA English DT Article ID NON-B-HEPATITIS; TRANSMITTED NON-A; VIRAL-HEPATITIS; IGM ANTIBODIES; UNITED-STATES; ORF3 PROTEIN; INSECT CELLS; E INFECTION; EPIDEMIC; TRANSMISSION AB The measurement of antibodies to hepatitis E virus (anti-HEV) has been essential for understanding the epidemiology of hepatitis E. Studies to determine the prevalence of HEV infections require a reliable serologic assay that is sensitive and specific. It is also important to distinguish the acute from the convalescent phase of an infection; this usually requires the detection of the immunoglobulin M (IgM) class of antibody. Few enzyme immunoassays (EIAs) that measure IgM anti-HEV have been described, and most have utilized the sandwich method. The present study describes an EIA that detects IgM anti-HEV by antibody class capture methodology. The assay was validated by using serum and/or plasma panels from experimentally infected nonhuman primates. It was used to demonstrate an anamnestic response and the reappearance of IgM anti-HEV in a chimpanzee experimentally challenged with HEV at two different times 45 months apart. The class capture method was more sensitive than the sandwich EIA when used to test clinical samples from two hepatitis E epidemics in Pakistan; it also had the advantage of distinguishing IgM anti-HEV in the presence of high titers of IgG anti-HEV. C1 NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Rockville, MD 20852 USA. Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. RP Yu, C (reprint author), NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Twinbrook 1,Room 1502,5640 Fishers Lane, Rockville, MD 20852 USA. NR 43 TC 31 Z9 33 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1071-412X J9 CLIN DIAGN LAB IMMUN JI Clin. Diagn. Lab. Immunol. PD JUL PY 2003 VL 10 IS 4 BP 579 EP 586 DI 10.1128/CDLI.10.4.579-586.2003 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 703MU UT WOS:000184284100014 PM 12853389 ER PT J AU Rangel, LBA Agarwal, R D'Souza, T Pizer, ES Alo, PL Lancaster, WD Gregoire, L Schwartz, DR Cho, KR Morin, PJ AF Rangel, LBA Agarwal, R D'Souza, T Pizer, ES Alo, PL Lancaster, WD Gregoire, L Schwartz, DR Cho, KR Morin, PJ TI Tight junction proteins claudin-3 and claudin-4 are frequently overexpressed in ovarian cancer but not in ovarian cystadenomas SO CLINICAL CANCER RESEARCH LA English DT Article ID CLOSTRIDIUM-PERFRINGENS ENTEROTOXIN; GENE-EXPRESSION; EPITHELIAL-CELLS; DOWN-REGULATION; SERIAL ANALYSIS; BREAST-CANCER; OCCLUDIN; STRANDS; TUMORS; ARRAY AB Purpose: Claudin proteins represent a large family of integral membrane proteins crucial for tight junction (TJ) formation and function. Claudius have been shown to be up-regulated in various cancers and have been suggested as possible biomarkers and targets for cancer therapy. Because claudin-3 and claudin-4 have been proposed to be expressed in epithelial ovarian cancer, we have performed a detailed analysis of CLDN3 and CLDN4 expression in a panel of ovarian tumors of various subtypes and cell lines. We also investigated whether high expression of claudin-3 and claudin-4 was associated with TJ function in ovarian cancer cells. Experimental Design: RNA was obtained from a panel of 39 microdissected epithelial ovarian tumors of various histological subtypes for real-time reverse transcription-PCR analysis. In addition, a total of 70 cases of ovarian carcinomas, ovarian cysts, and normal ovarian epithelium from a tissue array were analyzed by immunohistochemistry. Finally, a panel of cell lines was used for Western analysis of claudin expression and TJ permeability studies. Results: Although expressed at low levels in some normal human tissues, including the ovary, CLDN3 and CLDN4 are highly up-regulated in epithelial ovarian cancers of all subtypes. Immunohistochemical analyses using our ovarian tissue array confirmed the high level of expression of claudin-3 and claudin-4 in the majority of ovarian carcinomas, including many tumors exhibiting cytoplasmic staining. Ovarian cystadenoma did not frequently overexpress these proteins, suggesting that the expression of these proteins is associated with malignancy. In ovarian cancer cell lines, claudin-3 and claudin-4 expression was not associated with functional TJs as measured by transepithelial electrical resistance. Conclusions: These results show that CLDN3 and CLDN4 are frequently up-regulated in ovarian tumors and cell lines and may represent novel markers for this disease. Overexpression of these genes in ovarian cancer also suggests interesting scenarios for the involvement of TJ in tumorigenesis. A better knowledge of the mechanisms underlying ovarian tumorigenesis will likely result in the development of novel approaches for the diagnosis and therapy of this deadly disease. C1 NIA, Cellular & Mol Biol Lab, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. Univ Fed Rio de Janeiro, Dept Basic & Clin Pharmacol, Rio De Janeiro, Brazil. Univ Rome, Dipartimento Med Sperimentale & Patol, Rome, Italy. Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21287 USA. RP Morin, PJ (reprint author), NIA, Cellular & Mol Biol Lab, Ctr Gerontol Res, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 37 TC 218 Z9 227 U1 0 U2 12 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL PY 2003 VL 9 IS 7 BP 2567 EP 2575 PG 9 WC Oncology SC Oncology GA 700JK UT WOS:000184108700025 PM 12855632 ER PT J AU Dahlstrom, KR Adler-Storthz, K Etzel, CJ Liu, ZS Dillon, L El-Naggar, AK Spitz, MR Schiller, JT Wei, QY Sturgis, EM AF Dahlstrom, KR Adler-Storthz, K Etzel, CJ Liu, ZS Dillon, L El-Naggar, AK Spitz, MR Schiller, JT Wei, QY Sturgis, EM TI Human papillomavirus type 16 infection and squamous cell carcinoma of the head and neck in never-smokers: A matched pair analysis SO CLINICAL CANCER RESEARCH LA English DT Article ID CERVICAL INTRAEPITHELIAL NEOPLASIA; VIRUS-LIKE PARTICLES; EPIDEMIOLOGIC EVIDENCE; ORAL-CANCER; RISK; WOMEN; DNA; SEROREACTIVITY; ASSOCIATIONS; ANTIBODIES AB Purpose: Infection with human papillomavirus (HPV) type 16 has been suggested to be a risk factor for squamous cell carcinoma of the head and neck (SCCHN) and to be more commonly associated with SCCHN occurring in the oropharynx and in never-smokers. We hypothesized that HPV-16 exposure, as evidenced by seropositivity, is a risk factor for SCCHN and may be of particular importance in never-smokers. Experimental Design: To test this hypothesis, we conducted a hospital-based case-control study of 120 patients with SCCHN (60 never-smokers and 60 matched smokers) and 120 cancer-free matched controls. We compared the presence of HPV-16 antibodies in ever-smoker and never-smoker patients matched on age (+/-5 years), sex, and tumor site. Each patient was also matched with a corresponding ever-smoker or never-smoker cancer-free control on age (+/-5 years) and sex. Serum was collected from study subjects and assayed for IgG reactivity to HPV-16 L1 virus-like particles by using an ELISA. Results: Forty-nine of the 120 case subjects (40.8%) but only 11 (9.2%) of the control subjects tested positive for HPV-16 antibodies (adjusted odds ratio, 6.69; 95% confidence interval, 3.01-14.90). Among cases, HPV-16 seropositivity was more common in those with oropharyngeal cancer (41 of 70, 58.6%) and poorly differentiated tumors (25 of 43, 58.1%). HPV-16 seropositivity was associated with a significantly increased risk of oropharyngeal cancer (adjusted odds ratio, 59.53; 95% confidence interval, 5.71-620.20). Whereas HPV-16 seropositivity was more common in never-smokers with SCCHN than in ever-smokers (43.3% versus 38.3%, respectively), this difference was not statistically significant. Conclusions: HPV-16 infection is associated with a significant increased risk for oropharyngeal cancer but not oral cavity cancer. Furthermore, HPV-16 infection does not appear to be more common in never-smokers than ever-smokers with SCCHN. C1 Univ Texas, MD Anderson Canc Ctr, Dept Head & Neck Surg, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. Univ Texas, Hlth Sci Ctr, Houston Dent Branch, Houston, TX 77225 USA. NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Sturgis, EM (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Head & Neck Surg, Unit 441,1515 Holcombe Blvd, Houston, TX 77030 USA. NR 39 TC 99 Z9 100 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL PY 2003 VL 9 IS 7 BP 2620 EP 2626 PG 7 WC Oncology SC Oncology GA 700JK UT WOS:000184108700032 PM 12855639 ER PT J AU Gustafson, RA Levine, B Stout, PR Klette, KL George, MP Moolchan, ET Huestis, MA AF Gustafson, RA Levine, B Stout, PR Klette, KL George, MP Moolchan, ET Huestis, MA TI Urinary cannabinoid detection times after controlled oral administration of Delta(9)-tetrahydrocannabinol to humans SO CLINICAL CHEMISTRY LA English DT Article ID EXCRETION HALF-LIFE; GC-MS ANALYSIS; HEMP SEED OIL; MARIJUANA USERS; FOOD-PRODUCTS; INGESTION; CONSUMPTION; TETRAHYDROCANNABINOL; METABOLISM; ACID AB Background: Urinary cannabinoid excretion and immunoassay performance were evaluated by semiquantitative immunoassay and gas chromatography-mass spectrometry (GC/MS) analysis of metabolite concentrations in 4381 urine specimens collected before, during, and after controlled oral administration of tetrahydrocannabinol (THC). Methods: Seven individuals received 0, 0.39, 0.47, 7.5, and 14.8 mg THC/day in this double-blind, placebo-controlled, randomized, clinical study conducted on a closed research ward. THC doses (hemp oils with various THC concentrations and the therapeutic drug Marinol(R)) were administered three times daily for 5 days. All urine voids were collected over the 10-week study and later tested by Emit II(R), DRI(R), and CEDIA(R) immunoassays and by GC/MS. Detection rates, detection times, and sensitivities, specificities, and efficiencies of the immunoassays were determined. Results: At the federally mandated immunoassay cutoff (50 mug/L), mean detection rates were <0.2% during ingestion of the two low doses typical of current hemp oil THC concentrations. The two high doses produced mean detection rates of 23-46% with intermittent positive tests up to 118 h. Maximum metabolite concentrations were 5.4-38.2 mug/L for the low doses and 19.0-436 mug/L for the high doses. Emit II, DRI, and CEDIA immunoassays had similar performance efficiencies of 92.8%, 95.2%, and 93.9%, respectively, but differed in sensitivity and specificity. Conclusions: The use of cannabinoid-containing foodstuffs and cannabinoid-based therapeutics, and continued abuse of oral cannabis require scientific data for accurate interpretation of cannabinoid tests and for making reliable administrative drug-testing policy. At the federally mandated cannabinoid cutoffs, it is possible but unlikely for a urine specimen to test positive after ingestion of manufacturer-recommended doses of low-THC hemp oils. Urine tests have a high likelihood of being positive after Marinol therapy. The Emit II and DRI assays had adequate sensitivity and specificity, but the CEDIA assay failed to detect many true-positive specimens. (C) 2003 American Association for Clinical Chemistry. C1 NIDA, Chem & Drug Metab Intramural Res Program, NIH, Baltimore, MD 21224 USA. Off Chief Med Examiner, Baltimore, MD 21201 USA. Aegis Sci Corp, Nashville, TN USA. Navy Drug Screening Lab, Jacksonville, FL 32212 USA. Quest Diagnost Inc, Schaumburg, IL 60173 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 34 TC 15 Z9 18 U1 4 U2 16 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUL PY 2003 VL 49 IS 7 BP 1114 EP 1124 DI 10.1373/49.7.1114 PG 11 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 694TD UT WOS:000183789600013 PM 12816908 ER PT J AU Petricoin, EF Liotta, LA AF Petricoin, EF Liotta, LA TI Mass spectrometry-based diagnostics: The upcoming revolution in disease detection has already arrived - Response SO CLINICAL CHEMISTRY LA English DT Letter C1 US FDA, Bethesda, MD 20892 USA. NIH, Pathol Lab, Bethesda, MD 20892 USA. RP Petricoin, EF (reprint author), US FDA, Bldg 29A,Room 2D12,8800 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUL PY 2003 VL 49 IS 7 BP 1228 EP 1229 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 694TD UT WOS:000183789600043 ER PT J AU Slavotinek, AM Lacbawan, F AF Slavotinek, AM Lacbawan, F TI Large interstitial deletion of chromosome 13q and severe short stature: clinical report and review of the literature SO CLINICAL DYSMORPHOLOGY LA English DT Letter DE interstitial deletion of chromosome 13; severe short stature ID DEFINITION; REGION AB We report a 16 year old African American female with an interstitial deletion of chromosome 13 comprising approximately 40% of the long arm of this chromosome [karyotype 46,XX, del(13)(q14.12q31.2)]. We believe that this case is interesting because of the large size of the chromosome deletion, the severe growth retardation seen in the proband and her prolonged survival. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Med Genet, Washington, DC 20010 USA. RP Slavotinek, AM (reprint author), Univ Calif San Francisco, Dept Pediat, Div Genet, Room U585P,531 Parnassus St, San Francisco, CA 94143 USA. NR 6 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0962-8827 J9 CLIN DYSMORPHOL JI Clin. Dysmorphol. PD JUL PY 2003 VL 12 IS 3 BP 195 EP 196 DI 10.1097/00019605-200307000-00010 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 705VQ UT WOS:000184417000010 PM 14564160 ER PT J AU Edwards, R Augustson, E Fillingim, R AF Edwards, R Augustson, E Fillingim, R TI Differential relationships between anxiety and treatment-associated pain reduction among male and female chronic pain patients SO CLINICAL JOURNAL OF PAIN LA English DT Article DE chronic pain; anxiety; PASS; sex; gender ID LOW-BACK-PAIN; IRRITABLE-BOWEL-SYNDROME; GENDER DIFFERENCES; SEX-DIFFERENCES; PSYCHOLOGICAL-FACTORS; COPING STRATEGIES; TEMPOROMANDIBULAR DISORDERS; BEHAVIORAL TREATMENT; POSTOPERATIVE PAIN; CONTROLLED TRIAL AB Objectives: Clinical, epidemiological, and laboratory-based studies have all suggested that female sex and elevated anxiety are associated with greater experience of pain. However, several recent reports have also indicated that sex may moderate the relationship between anxiety and responses to noxious stimuli, with anxiety more strongly related to pain among males. The present study examined whether anxiety differentially impacts outcomes for pain treatment among males and females. Methods: Seventy-four chronic pain patients (34 males, 40 females) completed the Pain Anxiety Symptoms Scale and several other psychologic measures before undergoing a variety of treatment procedures including epidural steroids, trigger point injections, and participation in brief, cognitive-behaviorally oriented psychoeducational groups. Patients provided pre- and post-treatment ratings of pain for all interventions. Results: Consistent with findings from previous investigations, the present study noted stronger relationships between baseline anxiety and pre-treatment pain severity among males relative to females. In addition, while lower levels of baseline anxiety were related to greater treatment-associated pain reduction among females, the reverse pattern emerged for males. These relationships persisted even after controlling for other psychologic factors such as depression, coping style, and hypervigilance. Discussion: These findings suggest differential relationships between anxiety and pain relief as a function of sex. While we are unable to identify a mechanism for this effect, higher anxiety may have predicted more pain relief among males and less pain relief among females due to sex differences in coping strategies or placebo effects. C1 Rush Univ, Rush Presbyterian St Lukes Med Ctr, Dept Psychol, Chicago, IL 60612 USA. Natl Canc Inst, Div Canc Prevent, Bethesda, MD USA. Univ Florida, Dept Psychol, Gainesville, FL 32611 USA. RP Edwards, R (reprint author), Rush Univ, Rush Presbyterian St Lukes Med Ctr, Dept Psychol, 1653 West Congress Parkway, Chicago, IL 60612 USA. NR 68 TC 21 Z9 22 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0749-8047 J9 CLIN J PAIN JI Clin. J. Pain PD JUL-AUG PY 2003 VL 19 IS 4 BP 208 EP 216 DI 10.1097/00002508-200307000-00003 PG 9 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 698JH UT WOS:000183995000002 PM 12840614 ER PT J AU Henderson, DK AF Henderson, DK TI Managing occupational risks for hepatitis C transmission in the health care setting SO CLINICAL MICROBIOLOGY REVIEWS LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; POLYMERASE-CHAIN-REACTION; HYPERVARIABLE REGION 1; NON-B-HEPATITIS; INTRAVENOUS IMMUNE GLOBULIN; TO-PATIENT TRANSMISSION; CHRONIC LIVER-DISEASE; ANTI-D IMMUNOGLOBULIN; CLASS-II GENOTYPE; PARENTERALLY TRANSMITTED HEPATITIS AB Hepatitis C virus (HCV) infection is a significant contemporary health problem in the United States and elsewhere. Because it is primarily transmitted via blood, hepatitis C infection presents risks for both nosocomial transmission to patients and occupational spread to health care workers. Recent insights into the pathogenesis, immunopathogenesis, natural history, and treatment of infection caused by this unique flavivirus provide a rationale for the use of new strategies for managing occupational hepatitis C infections when they occur. This article reviews this developing information. Recently published data demonstrate success rates in the treatment of "acute hepatitis C syndrome" that approach 100%, and although these studies are not directly applicable to all occupational infections, they may provide important clues to optimal management strategies. In addition, the article delineates approaches to the prevention of occupational exposures and also addresses the difficult issue of managing HCV-infected health care providers. The article summarizes currently available data about the nosocomial epidemiology of HCV infection and the magnitude of risk and discusses several alternatives for managing exposure and infection. No evidence supports the use of immediate postexposure prophylaxis with immunoglobulin, immunomodulators, or antiviral agents. Based on the very limited data available, the watchful waiting and preemptive therapy strategies described in detail in this article represent reasonable interim approaches to the complex problem of managing occupational HCV infections, at least until more definitive data are obtained. C1 NIH, Warren G Magnuson Clin Ctr, US Dept HHS, Bethesda, MD 20892 USA. RP Henderson, DK (reprint author), Bldg 10,Room 2C 146,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 376 TC 61 Z9 65 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0893-8512 J9 CLIN MICROBIOL REV JI Clin. Microbiol. Rev. PD JUL PY 2003 VL 16 IS 3 BP 546 EP + DI 10.1128/CMR.16.3.546-568.2003 PG 24 WC Microbiology SC Microbiology GA 702UX UT WOS:000184243900011 PM 12857782 ER PT J AU Belmaker, B Fitzgerald, P George, MS Lisanby, SH Pascual-Leone, A Schlaepfer, TE Wassermann, E AF Belmaker, B Fitzgerald, P George, MS Lisanby, SH Pascual-Leone, A Schlaepfer, TE Wassermann, E TI Managing the risks of repetitive transcranial stimulation SO CNS SPECTRUMS LA English DT Editorial Material C1 Ben Gurion Univ Negev, Dept Psychiat, IL-84105 Beer Sheva, Israel. Stanley Int Res Ctr, Beer Sheva, Israel. Alfred Hosp, Prahran, Vic 3181, Australia. Med Univ S Carolina, Dept Psychiat, Charleston, SC USA. Med Univ S Carolina, Dept Radiol, Charleston, SC USA. Med Univ S Carolina, Dept Neurol, Charleston, SC USA. Med Univ S Carolina, Brain Stimulat Lab, Charleston, SC USA. Med Univ S Carolina, Ctr Adv Imaging Res, Charleston, SC USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10027 USA. New York State Psychiat Inst & Hosp, Dept Biol Psychiat, Magnet Brain Stimulat Lab, New York, NY USA. Harvard Univ, Sch Med, Dept Neurol, Cambridge, MA 02138 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Univ Bonn, Dept Psychiat & Psychotherapy, Bonn, Germany. Johns Hopkins Univ, Dept Psychiat, Baltimore, MD USA. Natl Inst Neurol Disorders & Stroke, Brain Stimulat Unit, Bethesda, MD USA. RP Belmaker, B (reprint author), Ben Gurion Univ Negev, Dept Psychiat, IL-84105 Beer Sheva, Israel. RI Pascual-Leone, Alvaro/G-6566-2011; Fitzgerald, Paul/A-1225-2008 OI Fitzgerald, Paul/0000-0003-4217-8096 NR 1 TC 35 Z9 36 U1 0 U2 1 PU M B L COMMUNICATIONS, INC PI NEW YORK PA 333 HUDSON ST, 7TH FLOOR, NEW YORK, NY 10013 USA SN 1092-8529 J9 CNS SPECTR JI CNS Spectr. PD JUL PY 2003 VL 8 IS 7 BP 489 EP 489 PG 1 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 710MM UT WOS:000184684000012 PM 12894029 ER PT J AU Grillon, C Hill, J AF Grillon, C Hill, J TI Emotional arousal does not affect delay eyeblink conditioning SO COGNITIVE BRAIN RESEARCH LA English DT Article DE eyeblink conditioning; emotion; arousal; cerebellum; amygdala ID MEMORY; RESPONSES; ANXIETY; PERSONALITY; AWARENESS; STARTLE; RABBITS; HUMANS AB Arousal can modulate information processing, including associative learning. However, there are conflicting results as to whether arousal affects eyeblink conditioning in humans. One potential problem with previous studies is that they have not taken into account factors that are known to affect conditioning. One such factor is the strength of the unconditioned response (UR). Despite evidence that greater UR leads to greater conditioned responses (CR), prior studies have not examined the role of the UR in CR performance. Prior studies have also usually classified subjects into low and high arousal groups based on a priori categorization without reliance on objective measures of arousal. The present study was designed to examine the impact of arousal on delay eyeblink conditioning. Changes in arousal levels were obtained by having participants view pictures selected for their a priori emotional and arousal values as being pleasant/arousing, unpleasant/arousing, or neutral/not arousing. Each subject viewed pictures of only one category. The spontaneous fluctuation of the skin conductance was taken as an index of physiological arousal. Subjects were divided into low and high arousal groups according to a median-split. Results showed that the rate of CR was positively related to the amplitude of the UR, but was not affected by emotional pictures or by physiological arousal. It is argued that changes in CR during arousal could be due to differences in unconditioned eyeblink strength rather than to changes in associative processes. (C) 2003 Elsevier B.V. All rights reserved. C1 NIMH, Mood & Anxiety Disorder Program, DHHS, NIH, Bethesda, MD 20892 USA. Yale Univ, New Haven, CT USA. RP Grillon, C (reprint author), NIMH, Mood & Anxiety Disorder Program, DHHS, NIH, 15K N Dr,Bldg 15K,MSC 2670, Bethesda, MD 20892 USA. NR 37 TC 6 Z9 6 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0926-6410 J9 COGNITIVE BRAIN RES JI Cognit. Brain Res. PD JUL PY 2003 VL 17 IS 2 BP 400 EP 405 DI 10.1016/S0926-6410(03)00141-1 PG 6 WC Computer Science, Artificial Intelligence; Neurosciences; Neuroimaging SC Computer Science; Neurosciences & Neurology GA 735MY UT WOS:000186120200020 ER PT J AU Keck, PE McElroy, SL Havens, JR Altshuler, LL Nolen, WA Frye, MA Suppes, T Denicoff, KD Kupka, R Leverich, GS Rush, AJ Post, RM AF Keck, PE McElroy, SL Havens, JR Altshuler, LL Nolen, WA Frye, MA Suppes, T Denicoff, KD Kupka, R Leverich, GS Rush, AJ Post, RM TI Psychosis in bipolar disorder: Phenomenology and impact on morbidity and course of illness SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID FOLLOW-UP; MOOD-CONGRUENT; SYMPTOMS; UNIPOLAR; MANIA; SCHIZOPHRENIA; FAMILY; PREDICTION; DIAGNOSIS; FEATURES AB Although psychosis is common in bipolar disorder, few studies have examined the prognostic significance of psychotic features. In addition, some studies suggest that the presence of mood-incongruent psychosis, in particular, is associated with poorer outcome compared with mood-congruent psychosis. We assesses the phenomenology and prevalence of mood-congruent and mood-incongruent psychotic symptoms in 352 patients with bipolar I disorder participating in the Stanley Foundation Bipolar Treatment Network. We compared the demographic and clinical features, and measures of psychosocial and vocational functioning in patients with and without a history of psychosis. The phenomenology of psychosis in this cohort of patients with bipolar disorder was similar to that reported in earlier studies and supported the lack of diagnostic specificity of any one type of psychotic symptom. There were no significant differences between patients with and without a history of psychosis on any demographic, psychosocial, vocational, or course of illness variables. Only family history of bipolar disorder was significantly more common in patients with nonpsychotic bipolar disorder compared to patients with a history of psychosis. Among bipolar patients with a history of psychosis, only the proportion of women and lifetime prevalence rates of anxiety disorders occurred significantly more in patients with mood-incongruent delusions. In this large cohort of outpatients with bipolar I disorder, neither a history of psychosis nor of mood-incongruent psychosis had prognostic significance at entry into the Network. The lack of observable prognostic impact may have been, in part, due to the relatively high morbidity and poor functional outcome of a substantial portion of the total cohort. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Cincinnati, Coll Med, Dept Psychiat, Biol Psychiat Program, Cincinnati, OH 45267 USA. Univ Calif Los Angeles, Inst Neuropsychiat, Los Angeles, CA 90024 USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. SW Med Ctr, Dallas, TX USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Univ Utrecht, Ctr Med, Altrecht Inst Mental Hlth Care, Utrecht, Netherlands. RP Keck, PE (reprint author), Univ Cincinnati, Coll Med, Dept Psychiat, Biol Psychiat Program, 231 Albert Sabin Way,ML 559, Cincinnati, OH 45267 USA. RI Nolen, Willem/E-9006-2014; OI Rush, Augustus/0000-0003-2004-2382 FU NIMH NIH HHS [R01 MH079261] NR 34 TC 81 Z9 85 U1 0 U2 5 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0010-440X J9 COMPR PSYCHIAT JI Compr. Psychiat. PD JUL-AUG PY 2003 VL 44 IS 4 BP 263 EP 269 DI 10.1016/S0010-440X(03)00089-0 PG 7 WC Psychiatry SC Psychiatry GA 703YV UT WOS:000184311600001 PM 12923703 ER PT J AU Thornton, VB Davis, JA St Clair, MB Cole, MN AF Thornton, VB Davis, JA St Clair, MB Cole, MN TI Inoculation of Staphylococcus xylosus in SJL/J mice to determine pathogenicity SO CONTEMPORARY TOPICS IN LABORATORY ANIMAL SCIENCE LA English DT Article ID COAGULASE-NEGATIVE STAPHYLOCOCCI; IDENTIFICATION; DERMATITIS; STRAINS AB An experimental study was performed to investigate whether intradermal tail inoculations of Staphylococcus xylosus would result in pathologic lesions in the SJL/J strain of mice (Mus musculus). This organism historically has been classified as a nonpathogenic, commensal bacterium associated with skin and mucous membranes and rarely implicated in infections. In this study, SJL/J mice inoculated with S. xylosus developed cutaneous tail lesions post-inoculation, and the organism was recovered from those lesions. Inoculation was accomplished by surgically inserting silk suture impregnated with the concentrated suspension of bacteria. In addition, a superficial abrasion was created adjacent to the suture, and a bacterial suspension was applied. Approximately 80% of the mice in the inoculated groups developed dermatologic lesions, compared with 0% in the control group. Mice with lesions were treated with Sulfamethoxazole-Trimethoprim in the drinking water continuously for 28 days. For the mice assigned to the treatment group, this treatment resulted in resolution of the cutaneous tail lesions. C1 Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NINDS, DHHS, NIH, Bethesda, MD 20892 USA. NIDDK, DHHS, NIH, Bethesda, MD 20892 USA. RP Thornton, VB (reprint author), Uniformed Serv Univ Hlth Sci, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. NR 19 TC 8 Z9 8 U1 0 U2 2 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1060-0558 J9 CONTEMP TOP LAB ANIM JI Contemp. Top. Lab. Anim. Sci. PD JUL PY 2003 VL 42 IS 4 BP 49 EP 52 PG 4 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 710LB UT WOS:000184680700011 PM 12906403 ER PT J AU O'Grady, NP AF O'Grady, NP TI On the road to avoiding adverse events: Educational programs pave the way SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE educational program; intravascular catheter; bloodstream infection ID CRITICALLY ILL PATIENTS; CATHETER-RELATED INFECTIONS; BLOOD-STREAM INFECTION; ATTRIBUTABLE MORTALITY; PRACTICE GUIDELINES; PHYSICIANS; COSTS; UNIT C1 NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP O'Grady, NP (reprint author), NIH, Dept Crit Care Med, Bldg 10, Bethesda, MD 20892 USA. NR 14 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JUL PY 2003 VL 31 IS 7 BP 2077 EP 2078 DI 10.1097/01.CCM.0000069514.49863.BB PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 702HT UT WOS:000184219000031 PM 12847410 ER PT J AU Cookson, MR AF Cookson, MR TI Neurodegeneration: How does Parkin prevent Parkinson's disease? SO CURRENT BIOLOGY LA English DT Editorial Material ID MUTANT ALPHA-SYNUCLEIN; FIBRILLIZATION; NEUROTOXICITY; DROSOPHILA; SUBSTRATE; PROTECTS; NEURONS; BRAIN AB Mutations in parkin cause Parkinson's disease due to the loss of the ubiquitin-protein ligase activity of Parkin protein. Recent data suggest we may be beginning to understand the nature of the proteins that are targeted by Parkin and how these cause neuronal damage. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), NIA, Neurogenet Lab, NIH, Bldg 10,Room 6C103,MSC1589,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Cookson@mail.nih.gov NR 17 TC 11 Z9 11 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUL 1 PY 2003 VL 13 IS 13 BP R522 EP R524 DI 10.1016/S0960-9822(03)00446-9 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 698JP UT WOS:000183995700013 PM 12842030 ER PT J AU Snyder, JT Alexander-Miller, MA Berzofsky, JA Belyakov, IM AF Snyder, JT Alexander-Miller, MA Berzofsky, JA Belyakov, IM TI Molecular mechanisms and biological significance of CTL avidity SO CURRENT HIV RESEARCH LA English DT Article DE HIV; AIDS; cytotoxic T lymphocytes (CTL); CTL avidity; dendritic cells; MHC class I; viral infection; cancer ID CYTOTOXIC T-LYMPHOCYTES; HUMAN-IMMUNODEFICIENCY-VIRUS; TUMOR-NECROSIS-FACTOR; FUNCTIONAL AVIDITY; PROTECTIVE IMMUNITY; VIRAL-INFECTION; CELL RESPONSES; IN-VITRO; HIGH-FREQUENCY; AIDS VACCINE AB CD8 CTLs are a major effector for protection against cancer as well as many infectious diseases, including HIV/AIDS [2, 8, 11, 31, 35]. CD8 CTL recognize antigenic peptides in the context of class I MHC. CTL functional avidity has been shown to be an important determinant of in vivo efficacy. CTL that can recognize peptide/MHC only at high antigen density are termed low avidity CTL, while those that can recognize their cognate antigen at low densities are termed high avidity CTL [4, 14, 15]. Recent studies have demonstrated that high avidity CTLs are essential for the effective clearance of viral infections [4, 22] and for the elimination of tumor cells [39, 60, 62]. At this time, approaches that can target high avidity cells for expansion in vivo are not well defined; however, new insights are beginning to emerge. A recent study has shown that prime-boost immunization may be an effective method to generate high avidity CTLs that recognize HIV antigens [26]. In addition, we recently found that high levels of costimulation (signal 2) can skew the CTL response toward higher avidity cells [41]. Thus, vectors expressing a triad of costimulatory molecules (TRICOM) or dendritic cells expressing higher levels of costimulatory molecules, can be used to induce high avidity CTL. Finally a critical role for CD4(+) T cell help in the generation of high avidity cells has recently been identified (Palmer, manuscript submitted). While high avidity CTLs are superior for viral and tumor clearance, they also have a greater sensitivity to antigen induced cell death. In some types of chronic infections, such as HIV and HCV, as well as in cancer, the host may lose, by clonal exhaustion or other apoptotic mechanisms, the effector cells that are most critical to viral or tumor clearance [21, 38]. In this review, we examine the current knowledge concerning CTL avidity. We discuss the factors that may distinguish high avidity CTLs from low avidity CTLs and describe some of the mechanisms these cells use to clear viral infections. In addition, we study possible immunization strategies that may be used to elicit higher avidity CTLs and describe what is known about the factors that render these cells more susceptible to apoptosis than low avidity CTLs. Finally, we will incorporate these various elements into a general discussion of possible approaches for induction and maintenance of an effective immune response that can result in clearance of tumors or chronic viral infections and the relevance to vaccine development. C1 NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Dept Microbiol & Immunol, Med Ctr Blvd, Winston Salem, NC 27157 USA. RP Belyakov, IM (reprint author), NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bldg 10-Rm 6B-12,MSC-1578, Bethesda, MD 20892 USA. EM belyakov@mail.nih.gov RI Yang, Chen/G-1379-2010 NR 62 TC 55 Z9 57 U1 0 U2 5 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1570-162X J9 CURR HIV RES JI Curr. HIV Res. PD JUL PY 2003 VL 1 IS 3 BP 287 EP 294 DI 10.2174/1570162033485230 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 761VE UT WOS:000187935500003 PM 15046253 ER PT J AU O'Shea, JJ Holland, S Candotti, F AF O'Shea, JJ Holland, S Candotti, F TI Primary immunodeficiencies and the rheumatologist SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Editorial Material ID AUTOIMMUNITY C1 NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD USA. RP O'Shea, JJ (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bldg 10,Room 9N252,10 Ctr Dr MSC-1820, Bethesda, MD USA. NR 8 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8711 J9 CURR OPIN RHEUMATOL JI CURR. OPIN. RHEUMATOL. PD JUL PY 2003 VL 15 IS 4 BP 413 EP 416 DI 10.1097/00002281-200307000-00007 PG 4 WC Rheumatology SC Rheumatology GA 695QB UT WOS:000183840800007 PM 12819468 ER PT J AU Sneller, MC Dale, JK Straus, SE AF Sneller, MC Dale, JK Straus, SE TI Autoimmune lymphoproliferative syndrome SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Review ID PYRIMETHAMINE-SULFADOXINE FANSIDAR; LYMPHOCYTE APOPTOSIS; DEFECTIVE LYMPHOCYTE; MUTATIONS; FAS; DISEASE; FEATURES AB Autoimmune lymphoproliferative syndrome arises early in childhood in people who inherit mutations in genes that mediate lymphocyte apoptosis, or programed cell death. In the immune system, antigen-induced lymphocyte apoptosis maintains immune homeostasis by limiting lymphocyte accumulation and minimizing reactions against self-antigens. In autoimmune lymphoproliferative syndrome, defective lymphocyte apoptosis manifests as chronic, nonmalignant adenopathy and splenomegaly; the expansion of an unusual population of CD4(-)CD8(-) T cells; and the development of autoimmune disease. Most cases of autoimmune lymphoproliferative syndrome involve heterozygous mutations in the lymphocyte surface protein Fas (CD95, Apo1) that impair a major apoptotic pathway. Prospective evaluations of patients and their families have revealed an ever-expanding spectrum of autoimmune lymphoproliferative syndrome and its major complications. (C) 2003 Lippincott Williams Wilkins. C1 NIAID, Clin Invest Lab, Bethesda, MD 20892 USA. Immunoregulat Lab, Immunol Dis Sect, Bethesda, MD 20892 USA. NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Sneller, MC (reprint author), NIAID, Immunol Dis Sect, Immunoregulat Lab, NIH, Bldg 10,Room 11B-13, Bethesda, MD 20892 USA. NR 20 TC 58 Z9 62 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8711 J9 CURR OPIN RHEUMATOL JI CURR. OPIN. RHEUMATOL. PD JUL PY 2003 VL 15 IS 4 BP 417 EP 421 DI 10.1097/00002281-200307000-00008 PG 5 WC Rheumatology SC Rheumatology GA 695QB UT WOS:000183840800008 PM 12819469 ER PT J AU Schurman, SH Candotti, F AF Schurman, SH Candotti, F TI Autoimmunity in Wiskott-Aldrich syndrome SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Review DE Wiskott-Aldrich syndrome; immunodeficiency; autoimmunity; interleukin-2; apoptosis ID BONE-MARROW TRANSPLANTATION; IMMUNOLOGICAL SELF-TOLERANCE; X-LINKED THROMBOCYTOPENIA; HENOCH-SCHONLEIN PURPURA; HEMATOPOIETIC STEM-CELLS; NONOBESE DIABETIC MICE; NATURAL-KILLER-CELLS; T-CELLS; SYNDROME PROTEIN; LYMPHOPROLIFERATIVE SYNDROME AB As many as 40% of patients with Wiskott-Aldrich syndrome may eventually suffer from an autoimmune disorder, with an increased chance of developing a malignancy. Vasculitides and autoimmune hemolytic anemia are the two most common autoimmune manifestations and often cause considerable morbidity and mortality, because they may require treatment with bone marrow transplantation. Insights into the mechanisms of autoimmunity have provided clues to the pathogenesis of these disorders in Wiskott-Aldrich syndrome. Chronic inflammation, interleukin-2 deficiency, and increased apoptosis may all play a possible role in the loss of peripheral tolerance to self-antigens in this disease. This article reviews the manifestations and consequences of autoimmunity in Wiskott-Aldrich syndrome, its possible mechanisms, and available treatments. C1 Natl Human Genome Res Inst, Disorders Immun Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Candotti, F (reprint author), Natl Human Genome Res Inst, Disorders Immun Sect, Genet & Mol Biol Branch, NIH, 49 Convent Dr,Bldg 49,Rm 3A20, Bethesda, MD 20892 USA. OI Schurman, Shepherd/0000-0002-9133-7906 NR 92 TC 61 Z9 63 U1 3 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8711 J9 CURR OPIN RHEUMATOL JI CURR. OPIN. RHEUMATOL. PD JUL PY 2003 VL 15 IS 4 BP 446 EP 453 DI 10.1097/00002281-200307000-00012 PG 8 WC Rheumatology SC Rheumatology GA 695QB UT WOS:000183840800012 PM 12819473 ER PT J AU Telford, WG Hawley, TS Hawley, RG AF Telford, WG Hawley, TS Hawley, RG TI Analysis of violet-excited fluorochromes by flow cytometry using a violet laser diode SO CYTOMETRY PART A LA English DT Article DE violet laser diode; Cascade Blue; Pacific Blue; cyan fluorescent protein; 2-(5 '-chloro-2 '-phosphoryloxyphenyl)-6-chloro-4-(3H)-quinazoline ID HEMATOPOIETIC STEM-CELLS; ALKALINE-PHOSPHATASE; FLUORESCENT PROTEINS; RETROVIRAL VECTORS; GREEN; YELLOW; CYAN AB Background: Low power violet laser diodes (VLDs) have been evaluated as potential replacements for water-cooled argon-ion and krypton-ion ultraviolet and violet lasers for DNA content analysis using the Hoechst dyes and 4,6diamidino-2-phenylindole (Shapiro HMN, Perlmutter NG: Cytometry 44:133-136, 2001). In this study, we used a VLD to excite a variety of violet-excited fluorescent molecules important in biomedical analysis, including the fluorochromes Cascade Blue and Pacific Blue, the expressible fluorescent protein cyan fluorescent protein (CFP), and the fluorogenic alkaline phosphatase (AP) substrate 2-(5'-chloro-2'-phosphoryloxyphenyl)-6-chloro-4-(3H)-quinazoline (ELF-97; for endogenous AP detection and cell surface labeling with AP-conjugated antibodies). Methods: Comparisons were made between VLD excitation and a krypton-ion laser emitting at 407 nm (both at higher power levels and with the beam attenuated at levels approximating the VLD) on the same FACSVantage SE stream-in-air flow cytometer. We evaluated a Power Technology 408-nm VLD (30 mW) equipped with circularization optics (18 mW maximum output, set to 15 mW) and a Coherent I-302C krypton-ion laser emitting at power levels ranging from 15 to 75 mW. Results: Cascade Blue, Pacific Blue, and CFP showed comparable signal-to-noise ratios and levels of sensitivity with VLD excitation versus the krypton-ion laser at high and VLD-matched power outputs. Multicolor fluorescent protein analysis with 488-nm excitation of green fluorescent protein and DsRed and VLD excitation of CFP was therefore feasible and was demonstrated. Similar levels of excitation efficiency between krypton-ion and VLD sources also were observed for ELF-97 detection. Conclusions: These evaluations confirmed that VLDs may be cost- and maintenance-effective replacements for water-cooled gas lasers for applications requiring violet excitation in addition to DNA binding dyes. Published 2003 Wiley-Liss, Inc. C1 NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Amer Red Cross, Holland Lab, Rockville, MD USA. RP Telford, WG (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bldg 10,Room 12C121,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 21 TC 19 Z9 19 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0196-4763 J9 CYTOM PART A JI Cytom. Part A PD JUL PY 2003 VL 54A IS 1 BP 48 EP 55 DI 10.1002/cyto.a.10046 PG 8 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 698QB UT WOS:000184009300006 PM 12820120 ER PT J AU Stump, RJW Ang, S Chen, YJ von Bahr, T Lovicu, FJ Pinson, K de Iongh, RU Yamaguchi, TP Sassoon, DA McAvoy, JW AF Stump, RJW Ang, S Chen, YJ von Bahr, T Lovicu, FJ Pinson, K de Iongh, RU Yamaguchi, TP Sassoon, DA McAvoy, JW TI A role for Wnt/beta-catenin signaling in lens epithelial differentiation SO DEVELOPMENTAL BIOLOGY LA English DT Article DE lens development; Wnt signaling; beta-catenin; LRP6; lens epithelium ID BETA-CATENIN; REPRODUCTIVE-TRACT; WNT CORECEPTOR; CELL-DIVISION; GROWTH-FACTOR; TGF-BETA; RECEPTOR; PATHWAY; EXPRESSION; EMBRYO AB The differentiation of epithelial cells and fiber cells from the anterior and posterior compartments of the lens vesicle, respectively, give the mammalian lens its distinctive polarity. While much progress has been made in understanding the molecular basis of fiber differentiation, little is known about factors that govern the differentiation of the epithelium. Members of the Wnt growth factor family appear to be key regulators of epithelial differentiation in various organ systems. Writs are ligands for Frizzled receptors and can activate several signaling pathways, of which the best understood is the Wnt/beta-catenin pathway. The presence of LDL-related protein coreceptors (LRPs) 5 or 6 has been shown to be a requirement for Wnt signaling through the beta-catenin pathway. To access the role of this signaling pathway in the lens, we analyzed mice with a null mutation of lrp6. These mice had small eyes and aberrant lenses, characterized by an incompletely formed anterior epithelium resulting in extrusion of the lens fibers into the overlying corneal stroma. We also showed that multiple Wnts, including 5a, 5b, 7a, 7b, 8a, 8b, and Frizzled receptors 1, 2, 3, 4, and 6, were detected in the lens. Expression of these molecules was generally present throughout the lens epithelium and extended into the transitional zone, where early fiber elongation occurs. In addition to both LRP5 and LRP6, we also showed the expression of other molecules involved in Wnt signaling and its regulation, including Dishevelleds, Dickkopfs, and secreted Frizzled-related proteins. Taken together, these results indicate a role for Wnt signaling in regulating the differentiation and behavior of lens cells. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Univ Sydney, Sydney Hosp, Save Sight Inst, Sydney, NSW 2006, Australia. Univ Sydney, Hosp Eye, Save Sight Inst, Sydney, NSW 2006, Australia. Univ Sydney, Dept Anat & Histol, Sydney, NSW 2006, Australia. Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. Univ Melbourne, Dept Anat & Cell Biol, Parkville, Vic 3010, Australia. NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. Brookdale Ctr Dev & Mol Biol, New York, NY 10029 USA. RP McAvoy, JW (reprint author), Univ Sydney, Sydney Hosp, Save Sight Inst, GPO Box 4337, Sydney, NSW 2006, Australia. RI McAvoy, John/B-6229-2012; OI de Iongh, Robbert/0000-0001-7013-1610 FU NEI NIH HHS [R01 EYO3177] NR 55 TC 78 Z9 79 U1 0 U2 5 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 JUL 1 PY 2003 VL 259 IS 1 BP 48 EP 61 DI 10.1016/S0012-1606(03)00179-9 PG 14 WC Developmental Biology SC Developmental Biology GA 694UB UT WOS:000183791900005 PM 12812787 ER PT J AU Frejtag, W Burnette, J Kang, BL Smith, RM Vogel, SS AF Frejtag, W Burnette, J Kang, BL Smith, RM Vogel, SS TI An increase in surface area is not required for cell division in early sea urchin development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE FM 1-43; exocytosis; compensatory endocytosis; multiphoton microscopy; cell division; sea urchin ID MEMBRANE CAPACITANCE; EGGS; EXOCYTOSIS; FERTILIZATION; FUSION; MICROVILLI; ENDOCYTOSIS; CYTOKINESIS; RETRIEVAL; EMBRYO AB Cell division requires an increase in surface area to volume ratio. During early development, surface area can increase, volume can decrease, or surface topography can be optimized to allow for division. While exocytosis is thought to be essential for division [Mol. Biol. Cell 10 (1999), 2735; Proc. Natl. Acad. Sci. USA 99 (2002), 3633], exocytosis doesn't always yield an increase in surface area [Proc. Natl. Acad. Sci. USA 79 (1982), 6712]. We used multiphoton laser scanning microscopy, fluorescence spectroscopy, and electron microscopy to monitor membrane trafficking, surface area, volume, and surface topography during early sea urchin development. Despite extensive membrane trafficking monitored by FM 1-43 fluorescence, we find that the net surface area of the embryo does not change prior to the eight-cell stage. During this period, embryo volume decreases by 15%, and microvilli disappear from interior facing membrane segments. Thus, the first three cell divisions utilize residual membrane liberated by decreasing cytoplasmic volume, and reducing microvilli density on interior facing membranes. Only after the eight-cell stage was a net increase in FM 1-43 fluorescence from the embryo surface detected. Our data suggest that compensatory endocytosis is downregulated after this developmental stage to yield an increase in surface area for cell division. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Med Coll Georgia, Dept Med, Inst Mol Med & Genet, Augusta, GA 30912 USA. RP Vogel, SS (reprint author), NIAAA, Lab Mol Physiol, Sect Confocal Microscopy, NIH, Flow Bldg,Room 19,12501 Washington Ave, Rockville, MD 20852 USA. RI Vogel, Steven/A-3585-2012; OI Vogel, Steven/0000-0002-3005-2667 FU NINDS NIH HHS [NS41055] NR 26 TC 3 Z9 3 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 JUL 1 PY 2003 VL 259 IS 1 BP 62 EP 70 DI 10.1016/S0012-1606(03)00184-2 PG 9 WC Developmental Biology SC Developmental Biology GA 694UB UT WOS:000183791900006 PM 12812788 ER PT J AU Golden, A Cohen-Fix, O AF Golden, A Cohen-Fix, O TI Getting (chromosomes) loaded - A new role for timeless SO DEVELOPMENTAL CELL LA English DT Editorial Material ID SISTER-CHROMATID COHESION; CAENORHABDITIS-ELEGANS; PROTEINS; SIMILARITY; RHYTHM; CLOCK; GENE AB A recent study in C. elegans reveals an unanticipated link between sister chromatid cohesion and the TIM-1 protein, a homolog of the Drosophila circadian rhythm protein TIMELESS. The phenotypes of tim-1 mutants suggest that cohesin subunits load onto chromosomes in a stepwise manner. Whether TIM-1 is also involved in circadian rhythms is discussed. C1 NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NIDDK, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Golden, A (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NR 13 TC 1 Z9 6 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 JUL PY 2003 VL 5 IS 1 BP 7 EP 9 DI 10.1016/S1534-5807(03)00209-0 PG 3 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 700MB UT WOS:000184114800005 PM 12852847 ER PT J AU Rankin, TL Coleman, JS Epifano, O Hoodbhoy, T Turner, SG Castle, PE Lee, E Gore-Langton, R Dean, J AF Rankin, TL Coleman, JS Epifano, O Hoodbhoy, T Turner, SG Castle, PE Lee, E Gore-Langton, R Dean, J TI Fertility and taxon-specific sperm binding persist after replacement of mouse sperm receptors with human homologs SO DEVELOPMENTAL CELL LA English DT Article ID ZONA-PELLUCIDA GLYCOPROTEIN; O-LINKED OLIGOSACCHARIDES; ACROSOME REACTION; MONOCLONAL-ANTIBODIES; TRANSGENIC MICE; EGG INTERACTION; KNOCKOUT MICE; IN-VITRO; ZP3; FERTILIZATION AB The zona pellucida surrounding ovulated mouse eggs contains three glycoproteins, two of which (ZP2 and ZP3) are reported sperm receptors. After fertilization, the zona pellucida is modified ad minimus by cleavage of ZP2, and sperm no longer bind. Crosstaxa sperm binding is limited among mammals, and human sperm do not bind to mouse eggs. Using transgenesis to replace mouse ZP2 and/or ZP3 with human homologs, mouse lines with human-mouse chimeric zonae pellucidae have been established. Unexpectedly, mouse, but not human, sperm bind to huZP2 and huZP2/huZP3 rescue eggs, eggs fertilized in vitro with mouse sperm progress to two-cell embryos, and rescue mice are fertile. Also unanticipated, human ZP2 remains uncleaved after fertilization, and mouse sperm continue to bind early rescue embryos. These observations are consistent with a model in which the supramolecular structure of the zona pellucida necessary for sperm binding is modulated by the cleavage status of ZP2. C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NICHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Bethesda, MD 20892 USA. Suburban Hosp, Dept Reprod Med, Bethesda, MD 20892 USA. RP Dean, J (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NR 55 TC 116 Z9 121 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD JUL PY 2003 VL 5 IS 1 BP 33 EP 43 DI 10.1016/S1534-5807(03)00195-3 PG 11 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 700MB UT WOS:000184114800008 PM 12852850 ER PT J AU Arnaoutov, A Dasso, M AF Arnaoutov, A Dasso, M TI The ran GTPase regulates kinetochore function SO DEVELOPMENTAL CELL LA English DT Article ID XENOPUS EGG EXTRACTS; SPINDLE ASSEMBLY CHECKPOINT; ANAPHASE-PROMOTING COMPLEX; IMPORTIN-BETA; IN-VITRO; CENP-E; PROTEIN; ACTIVATION; TRANSPORT; BINDING AB The Ran GTPase is required for nuclear assembly, nuclear transport, spindle assembly, and mitotic regulation. While the first three processes are relatively well understood, details of Ran's role in mitotic progression remain obscure. We have found that elevated levels of Ran's exchange factor (RCC1) abrogate the spindle assembly checkpoint in Xenopus egg extracts, restore APC/C activity, and disrupt the kinetochore localization of checkpoint regulators, including Mad2, CENP-E, Bub1, and Bub3. Depletion of Ran's GTPase activating protein (RanGAP1) and its accessory factor (RanBP1) similarly abrogates checkpoint arrest. By contrast, the addition of RanGAP1 and RanBP1 to extracts with exogenous RCC1 restores the spindle checkpoint. Together, these observations suggest that the spindle checkpoint is directly responsive to Ran-GTP levels. Finally, we observe a clear wave of RCC1 association to mitotic chromosomes at the metaphase-anaphase transition in normal cycling extracts, suggesting that this mechanism has an important role in unperturbed cell cycles. C1 NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Dasso, M (reprint author), NICHD, Lab Gene Regulat & Dev, NIH, Bldg 18,Room 106, Bethesda, MD 20892 USA. OI Dasso, Mary/0000-0002-5410-1371 NR 35 TC 97 Z9 101 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD JUL PY 2003 VL 5 IS 1 BP 99 EP 111 DI 10.1016/S1534-5807(03)00194-1 PG 13 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 700MB UT WOS:000184114800013 PM 12852855 ER PT J AU Kim, H Haluzik, M Asghar, Z Yau, D Joseph, JW Fernandez, AM Reitman, ML Yakar, S Stannard, B Heron-Milhavet, L Wheeler, MB LeRoith, D AF Kim, H Haluzik, M Asghar, Z Yau, D Joseph, JW Fernandez, AM Reitman, ML Yakar, S Stannard, B Heron-Milhavet, L Wheeler, MB LeRoith, D TI Peroxisome proliferator-activated receptor-alpha agonist treatment in a transgenic model of type 2 diabetes reverses the lipotoxic state and improves glucose homeostasis SO DIABETES LA English DT Article ID FREE FATTY-ACIDS; PROTEIN-KINASE-C; INDUCED INSULIN-RESISTANCE; SKELETAL-MUSCLE; UNCOUPLING PROTEIN-3; PPAR-ALPHA; LIPID-METABOLISM; GENE-EXPRESSION; ADIPOSE-TISSUE; BETA-CELLS AB Abnormalities in insulin action are the characteristics of type 2 diabetes. Dominant-negative muscle-specific IGF-I receptor (MKR) mice exhibit elevated lipid levels at an early age and eventually develop type 2 diabetes. To evaluate the role of elevated lipids in the progression of the diabetic state, MKR mice were treated with WY14,643, a peroxisome proliferator-activated receptor (PPAR)-alpha agonist. WY14,643 treatment markedly reduced serum fatty acid and triglyceride levels within a few days, as well as muscle triglyceride levels, and subsequently normalized glucose and insulin levels in MKR mice. Hyperinsulinemic-euglycemic clamp analysis showed that WY14,643 treatment enhanced muscle and adipose tissue glucose uptake by improving whole-body insulin sensitivity. Insulin suppression of endogenous glucose production by the liver of MKR mice was also improved. The expression of genes involved in fatty acid oxidation was increased in liver and skeletal muscle, whereas gene expression levels of hepatic gluconeogenic enzymes were decreased in WY14,643-treated MKR mice. WY14,643 treatment also improved the pattern of glucose-stimulated insulin secretion from the perfused pancreata of MKR mice and reduced the P-cell mass. Taken together, these findings suggest that the reduction in circulating or intracellular lipids by activation of PPAR-alpha improved insulin sensitivity and the diabetic condition of MKR mice. C1 NIDDK, Diabet Branch, Mol & Cellular Physiol Sect, NIH, Bethesda, MD 20892 USA. Univ Toronto, Dept Physiol, Toronto, ON, Canada. RP LeRoith, D (reprint author), NIDDK, Diabet Branch, Mol & Cellular Physiol Sect, NIH, 9000 Rockville Pike,Bldg 10,RM 8D12, Bethesda, MD 20892 USA. RI Reitman, Marc/B-4448-2013; OI Reitman, Marc/0000-0002-0426-9475; Wheeler, Michael/0000-0002-7480-7267 NR 50 TC 111 Z9 120 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUL PY 2003 VL 52 IS 7 BP 1770 EP 1778 DI 10.2337/diabetes.52.7.1770 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 695PF UT WOS:000183838900026 PM 12829645 ER PT J AU Muller, YL Bogardus, C Beamer, BA Shuldiner, AR Baier, LJ AF Muller, YL Bogardus, C Beamer, BA Shuldiner, AR Baier, LJ TI A functional variant in the peroxisome proliferator-activated receptor gamma 2 promoter is associated with predictors of obesity and type 2 diabetes in Pima Indians SO DIABETES LA English DT Article ID HEPATIC INSULIN SENSITIVITY; IMPAIRED GLUCOSE-TOLERANCE; GAMMA PPAR-GAMMA; PRO12ALA POLYMORPHISM; ADIPOCYTE DIFFERENTIATION; GENE-EXPRESSION; RESISTANCE; PPAR-GAMMA-2; METABOLISM; ALPHA AB Peroxisome proliferator-activated receptor gamma (PPARgamma)-2 is a member of the nuclear hormone receptor superfamily that is expressed predominantly in adipocytes and is thought to have a role in energy homeostasis, adipogenesis, and insulin sensitivity. A functional single nucleotide polymorphism (SNP) that predicts a proline to alanine substitution (Pro12Ala) within the coding region of this gene has previously been associated with obesity and type 2 diabetes in several populations. In this study, we identified several novel SNPs in the promoter region of PPARgamma2 and genotyped them, along with the previously identified Pro12A1a SNP. In 241 nondiabetic Pima subjects, the Pro12A1a was associated with whole-body insulin action (P = 0.05), hepatic insulin action (P = 0.03), and fasting plasma insulin concentrations (P = 0.01). One of the promoter SNPs positioned within a putative E2 box was in high linkage disequilibrium (\D'\ = 0.98) with the Pro12Ala. This promoter SNP was similarly associated with whole-body insulin action (P = 0.04) and hepatic insulin action (P = 0.05), but not fasting plasma insulin concentrations. Functional studies in transfected 3T3-L1 cells demonstrated that this single base substitution in the putative E2 box significantly altered transcriptional activity from a luciferase reporter construct. These data indicate that this promoter SNP, via its effect on PPARgamma2 expression, may also have functional consequences on PPARgamma2-activated pathways, and perhaps both the promoter SNIP and the Pro12Ala contribute to PPARgamma2-related phenotypes. C1 NIDDK, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. Johns Hopkins Univ, Dept Med, Baltimore, MD USA. Univ Maryland, Dept Med, Baltimore, MD 21201 USA. RP Baier, LJ (reprint author), NIDDK, Clin Diabet & Nutr Sect, NIH, 4212 N 16Th St, Phoenix, AZ 85016 USA. NR 35 TC 63 Z9 67 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUL PY 2003 VL 52 IS 7 BP 1864 EP 1871 DI 10.2337/diabetes.52.7.1864 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 695PF UT WOS:000183838900039 PM 12829658 ER PT J AU de Rekeneire, N Rooks, RN Simonsick, EM Shorr, RI Kuller, LH Schwartz, AV Harris, TB AF de Rekeneire, N Rooks, RN Simonsick, EM Shorr, RI Kuller, LH Schwartz, AV Harris, TB TI Racial differences in glycemic control in a well-functioning older diabetic population - Findings from the Health, Aging and Body Composition study SO DIABETES CARE LA English DT Article ID ETHNIC-DIFFERENCES; MEXICAN-AMERICANS; AFRICAN-AMERICANS; CONTROLLED-TRIAL; CARE; EDUCATION; ADULTS; ASSOCIATION; PREVALENCE; DISEASE AB OBJECTIVE - To evaluate racial differences and factors associated with worse glycemic control in well-functioning older individuals with type 2 diabetes. Our hypothesis was that glycemic control would be worse among black than white diabetic individuals but that this association would be explained by differences in severity of diabetes, health status, health care indicators, and social, psychological, or behavorial factors. We further hypothesized that the association of race with poorer glycemic control would be limited to those with lower education or lower income. RESEARCH DESIGN AND METHODS - Cross-sectional analysis of 468 diabetic participants among a cohort of 3,075 nondisabled blacks and whites aged 70-79 years living in the community enrolled in the Health, Aging and Body Composition Study. Glycemic control was measured by the level of HbA(1c). RESULTS - A total of 58.5% of the diabetic individuals were black. Although control was poor in all diabetic participants (HbA(1c) greater than or equal to7% in 73.7%), blacks had worse glycemic control than whites (age- and sex-adjusted mean HbA(1c) 8.4% in blacks and 7.4% in whites; P < 0.01). Race differences in glycemic control remained significant, even after adjusting for current insulin therapy, cardiovascular disease, higher total cholesterol, and not receiving a flu shot in the previous year, all of which were associated with higher HbA(1c) concentrations. Controlling for these factors reduced the association by 27%. Race remained an important factor in glycemic control, even when results Were stratified by education or income. CONCLUSIONS - HbA(1c) concentrations were higher in older black diabetic individuals. Differences in glycemic control by race were associated with disease severity, health status, and poorer quality of care, but these factors did not fully explain the higher HbA(1c) levels in older black diabetic individuals. C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Univ Michigan, Inst Social Res Social Environm & Hlth, Ann Arbor, MI 48109 USA. NIA, Ctr Gerontol Res, Baltimore, MD 21224 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN USA. Univ Pittsburgh, Div Geriatr Med, Pittsburgh, PA USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP de Rekeneire, N (reprint author), NIA, Lab Epidemiol Demog & Biometry, Gateway Bldg,Suite 3C-309,7201 Wisconsin Ave, Bethesda, MD 20892 USA. FU NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] NR 26 TC 60 Z9 60 U1 2 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2003 VL 26 IS 7 BP 1986 EP 1992 DI 10.2337/diacare.26.7.1986 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 729RK UT WOS:000185787600006 PM 12832300 ER PT J AU Saremi, A Tulloch-Reid, M Knowler, WC AF Saremi, A Tulloch-Reid, M Knowler, WC TI Coffee consumption and the incidence of type 2 diabetes SO DIABETES CARE LA English DT Letter ID GLUCOSE-TOLERANCE; INSULIN; INGESTION; CAFFEINE; MELLITUS; RISK C1 NIDDK, Diabet & Arthrit Epidemiol Sect, Phoenix, AZ USA. RP Saremi, A (reprint author), 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. RI Tulloch-Reid, Marshall/E-4383-2012 NR 8 TC 43 Z9 45 U1 3 U2 6 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2003 VL 26 IS 7 BP 2211 EP 2212 DI 10.2337/diacare.26.7.2211 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 729RK UT WOS:000185787600047 PM 12832341 ER PT J AU Ashktorab, H Ahmed, A Littleton, G Wang, XW Allen, CR Tackey, R Walters, C Smoot, DT AF Ashktorab, H Ahmed, A Littleton, G Wang, XW Allen, CR Tackey, R Walters, C Smoot, DT TI P53 and p14 increase sensitivity of gastric cells to H. pylori-induced apoptosis SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE AGS cells; mouse embryonic fibroblasts; p14(ARF); p19(ARF); Kato III; p21; gastric carcinogenesis; gastric ID HELICOBACTER-PYLORI; EPITHELIAL-CELLS; VACUOLATING CYTOTOXIN; HYPERPLASTIC POLYPS; TUMOR-SUPPRESSOR; STABILIZES P53; MALT LYMPHOMA; GROWTH-FACTOR; MDM2; INFECTION AB H. pylori infection of the gastric mucosa is associated with increased epithelial cell apoptosis. In vitro, interferon-gamma and TNF-alpha have been shown to increase the sensitivity of cells to apoptosis induced by H. pylori. The p53 tumor suppressor gene is frequently mutated in many cancers, including gastric cancer. Since p53 protein can induce apoptosis, we sought to determine whether or not p53 increases the ability of gastric epithelial cells to undergo apoptosis in response to H. pylori-induced cell injury. Human gastric epithelial cell lines, AGS ( p53 wild-type) cells and AGS cells infected with HPV E6 gene (AGS-E6) to inactivate p53 were exposed to H. pylori. The p53, p21, and p14(ARF) proteins were measured in gastric epithelial cells by immunoelectrophoresis. Gastric epithelial cell apoptosis was measured by DNA end-labeling assay ( TUNEL) and subG(0) cell fractions using flow cytometry, and by agarose gel electrophoresis of DNA. Exposure to H. pylori increased the levels of p53, p21, and p14(ARF) proteins two fold in AGS cells. Gastric AGS cells with fragmented DNA increased from 1.1% to 68% in after exposure to H. pylori for 24 hr. However, AGS-E6 cells were relatively resistant to apoptosis induced by H. pylori (only 15% of cells underwent apoptosis). In additional experiments, mouse embryonic fibroblasts (MEFs) were used to further investigate the role of ARF in stabilizing p53 after exposure to H. pylori. Wild-type and p19(ARF-/-) MEFs were exposed to H. pylori and evaluated for activation of p53, p19(ARF), and apoptosis. As with AGS cells, H. pylori stimulated a 2-fold increase in p53 and p19(ARF) in wild-type MEFs; however, there was no increase in p53 in ARF-null MEFs. H. pylori easily stimulated apoptosis in wild-type MEFs, although, the absence of p19(ARF) significantly reduced the ability of H. pylori to induce apoptosis in these cells. Activation of ARF by H. pylori is important in stabilizing p53 resulting in increased apoptosis. Thus, inactivation of either ARF or p53 in gastric cells may reduce their ability to undergo apoptosis in response to injury induced by H. pylori. C1 Howard Univ, Coll Med, Ctr Canc, Washington, DC 20060 USA. Howard Univ, Coll Med, Dept Med, Div Gastroenterol, Washington, DC 20060 USA. Howard Univ, Coll Med, Dept Physiol, Washington, DC 20060 USA. Howard Univ, Coll Med, Dept Microbiol, Washington, DC 20060 USA. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Ashktorab, H (reprint author), Howard Univ, Coll Med, Ctr Canc, 2041 Georgia Ave, Washington, DC 20060 USA. RI Wang, Xin/B-6162-2009 FU NIDDK NIH HHS [DK53713, DK6444, R01 DK053713] NR 41 TC 8 Z9 8 U1 0 U2 1 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD JUL PY 2003 VL 48 IS 7 BP 1284 EP 1291 DI 10.1023/A:1024198807619 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 689DK UT WOS:000183476200012 PM 12870784 ER PT J AU Balliet, AG Hollander, MC Fornace, AJ Hoffman, B Liebermann, DA AF Balliet, AG Hollander, MC Fornace, AJ Hoffman, B Liebermann, DA TI Comparative analysis of the genetic structure and chromosomal mapping of the murine Gadd45g/CR6 gene SO DNA AND CELL BIOLOGY LA English DT Article ID P53-REGULATED PROTEIN GADD45; QUANTITATIVE TRAIT LOCI; NEGATIVE GROWTH-CONTROL; CELL-CYCLE CHECKPOINT; NF-KAPPA-B; DNA-DAMAGE; MYD GENES; MYELOID DIFFERENTIATION; GENOTOXIC STRESS; TERMINAL KINASE AB Gadd45g/CR6, Gadd45b/MyD118, and Gadd45a/Gadd45 are members of a gene family that displays distinct patterns of gene expression in response to stimuli that induce differentiation, growth arrest, and/or apoptosis. All three of these highly conserved proteins interact with a number of critical cell cycle and cell survival regulatory proteins such as PCNA, p21(WAF1/CIP1), CDK1 (cdc2-p34), and MTK1/MEKK4, and have been reported to influence the activity of the p38 and JNK kinases. Species-blot analysis showed that Gadd45g is an evolutionarily conserved gene and sequence analysis showed that Gadd45g has a gene structure conserved with that of other members of its gene family. A comparison of the putative transcription factor binding sites found in the sequences of the gene family members suggests, that like Gadd45b, NF-kappaB and STATs may be responsible for the differences in regulation of expression observed between Gadd45g and Gadd45a. Analysis of the Gadd45b/MyD118 promoter shows that there are three different enhanceosome-like regions that may allow cell-type specific responses to TGF-beta1 by the Gadd45b/MyD118 promoter. Fluorescent in situ hybridization (FISH) confirmed the localization of the Gadd45g gene to mouse chromosome band 13A5-B, which has been reported to contain a quantitative trait locus that regulates body weight in mice. This suggests that alleles; of the Gadd45g gene may function in the regulation of body weight, in addition to its currently recognized roles in differentiation and stress responses. C1 Temple Univ, Sch Med, Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19140 USA. Temple Univ, Sch Med, Dept Biochem, Philadelphia, PA 19140 USA. NCI, Gene Response Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Liebermann, DA (reprint author), Temple Univ, Sch Med, Fels Inst Canc Res & Mol Biol, 3307 N Broad St, Philadelphia, PA 19140 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X FU PHS HHS [89718-302] NR 56 TC 7 Z9 7 U1 0 U2 5 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1044-5498 J9 DNA CELL BIOL JI DNA Cell Biol. PD JUL PY 2003 VL 22 IS 7 BP 457 EP 468 DI 10.1089/104454903322247334 PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity GA 709FP UT WOS:000184615400003 PM 12932304 ER PT J AU Kitanaka, N Kitanaka, J Walther, D Wang, XB Uhl, GR AF Kitanaka, N Kitanaka, J Walther, D Wang, XB Uhl, GR TI Comparative inter-strain sequence analysis of the putative regulatory region of murine psychostimulant-regulated gene GNB1 (G protein beta 1 subunit gene) SO DNA SEQUENCE LA English DT Article DE GNB1 gene; inter-strain polymorphism; 5 ' flanking region; promoter sequence; methamphetamine; psychostimulant-regulated gene ID SIGNAL-TRANSDUCTION; FRONTAL-CORTEX; EXPRESSION; COCAINE; RAT; SENSITIZATION; ASSOCIATION; ADDICTION; RECEPTOR; VARIANT AB We isolated a cDNA clone from a murine genomic library of C57BL/6 strain, carrying 13.8 kb of nucleotides including exon 1 of heterotrimeric GTP-binding protein beta1 subunit gene (genetic symbol, GNB1 ) and 10.6 kb of the 5' flanking region. Sequence comparison with GNB1 gene locus from 129Sv strain revealed a 0.2% divergence in a 13.2 kb common region between these two strains. The divergence consisted of eight single nucleotide polymorphisms, three insertions and one deletion, with 129Sv used as the reference. The exon 1 and the putative regulation elements, such as cyclic AMP response element, AP1, AP2, Sp1 and nuclear factor-kappaB recognition sites, were perfectly conserved. The expression of GNB1 mRNA was significantly increased in mouse striatum 2 h after single methamphetamine administration with an approximately 150% expression level compared with the basal level. In contrast, no change in the expression level was observed in the cerebral cortex. After the chronic methamphetamine treatment regimen, the expression level of GNB1 mRNA did not change in any brain regions examined. These results suggest (1) that the 5' flanking nucleotide sequence of GNB1 gene was strictly conserved for its possible contribution to the same change in the expression level between the mouse strains in response to psychostimulants and (2) that the initial process of development of behavioral sensitization appeared to occur parallel to the significant increase in the expression level of GNB1 gene in the mouse striatum. C1 NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH,US Dept HHS, Baltimore, MD 21224 USA. RP Kitanaka, J (reprint author), Hyogo Med Univ, Dept Pharmacol, 1-1 Mukogawa Cho, Nishinomiya, Hyogo 6638501, Japan. NR 22 TC 8 Z9 8 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-5179 J9 DNA SEQUENCE JI DNA Seq. PD JUL PY 2003 VL 14 IS 4 BP 257 EP 263 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 706CC UT WOS:000184433200003 PM 14631649 ER PT J AU Chen, LJ Lebetkin, EH Burka, LT AF Chen, LJ Lebetkin, EH Burka, LT TI Comparative disposition of (R)-(+)-pulegone in B6C3F1 mice and F344 rats SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID PULEGONE; HEPATOTOXICITY; TOXICITY; GLUTATHIONE; METABOLISM; MOUSE AB Pulegone is a monoterpene ketone that is usually associated with the herb pennyroyal but is also found in the essential oils from many other mint species. It is the major constituent of pennyroyal oil. Pennyroyal is used as a flavoring and fragrance and as an herbal medicine to induce menstruation and abortion. A disposition study of C-14-pulegone in B6C3F1 mice and F344 rats has been conducted at doses from 0.8 to 80 mg/kg. Mice excrete 85 to 100% of the dose in 24 h. Rats excrete only 59 to 81% of the administered radioactivity in the same time, primarily in urine and feces, with a trace in respired air. Consequently, tissue concentrations are lower in mice than in rats. Male rats tend to have higher tissue concentrations, especially in kidney, than female rats have, but this sex difference is not seen in mice. The residual radioactivity at 24 h demonstrates potential for accumulation of pulegone-derived material in several tissues following multiple doses. The metabolic profile is complex in both species, with at least three pathways involving hydroxylation, reduction, or conjugation with glutathione as first steps. Mercapturic acid pathway metabolites were detected in bile in mice and both bile and urine in rats. C1 NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Burka, LT (reprint author), NIEHS, Lab Pharmacol & Chem, POB 12233, Res Triangle Pk, NC 27709 USA. NR 17 TC 7 Z9 7 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD JUL PY 2003 VL 31 IS 7 BP 892 EP 899 DI 10.1124/dmd.31.7.892 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 691NU UT WOS:000183613000010 PM 12814966 ER PT J AU Hu, M Krausz, K Chen, J Ge, X Li, JQ Gelboin, HL Gonzalez, FJ AF Hu, M Krausz, K Chen, J Ge, X Li, JQ Gelboin, HL Gonzalez, FJ TI Identification of CYP1A2 as the main isoform for the phase I hydroxylated metabolism of genistein and a prodrug converting enzyme of methylated isoflavones SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID INHIBITORY MONOCLONAL-ANTIBODIES; HUMAN CYTOCHROME-P450 ENZYMES; OXIDATIVE-METABOLISM; SOYBEAN ISOFLAVONES; SOY ISOFLAVONES; DAIDZEIN; PHYTOESTROGENS; HUMANS; VITRO; PHARMACOKINETICS AB This study determined the cytochrome P450 (P450) isoforms responsible for metabolism of isoflavones using human liver microsomes (HLM) and expressed P450s. The primary metabolite of genistein is 3'-OH-genistein, as identified with an authentic chemically synthesized standard. CYP1A2 was predominantly responsible for 3'-OH-genistein formation since its formation was inhibited (>50%, p < 0.05) by a monoclonal antibody specific for CYP1A2, was correlated with CYP1A2 activities of HLM, and was catalyzed by expressed CYP1A2. In addition to CYP1A2, CYP2E1 also catalyzed, although to a lesser extent, its formation. The contribution of these P450s to the formation of 3'-OH-genistein was also confirmed with a panel of expressed enzymes. Methylated isoflavones biochanin A, prunetin, and formononetin (10-100 μM) were rapidly converted by HLM and expressed CYP1A2 to more active genistein and daidzein. The conversion of biochanin A to genistein appears to be mainly mediated by CYP1A2 because of the strong correlation between the conversion rates and CYP1A2 activities in HLM. Thus, CYP1A2 is an effective prodrug-converting enzyme for less active methylated isoflavones. CYP1A2-catalyzed conversion of biochanin A to genistein (K-m, 7.80 μM; V-max, 903 pmol/min/mg of protein; V-max/K-m, 116 μl/min/mg of protein) was much faster than 3'-hydroxylation of genistein (K-m, 12.7 μM and V-max, 109 pmol/min/mg of protein; V-max/K-m, 8.6 μl/min/mg of protein). The interaction studies showed that genistein inhibited formation of acetaminophen from phenacetin with an IC50 value of 16 μM. Additional studies showed that phenacetin and genistein were mutually inhibitory. In conclusion, CYP1A2 and CYP2E1 metabolized genistein and CYP1A2 acted as prodrug-converting enzymes for other less active methylated isoflavones. C1 Washington State Univ, Coll Pharm, Dept Pharmaceut Sci, Pullman, WA 99164 USA. NCI, Mol Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Shanghai Inst Pharmaceut Ind, Dept Med Chem, Shanghai, Peoples R China. RP Hu, M (reprint author), Washington State Univ, Coll Pharm, Dept Pharmaceut Sci, Pullman, WA 99164 USA. FU NCI NIH HHS [CA87779] NR 28 TC 76 Z9 79 U1 2 U2 7 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD JUL PY 2003 VL 31 IS 7 BP 924 EP 931 DI 10.1124/dmd.31.7.924 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 691NU UT WOS:000183613000014 PM 12814970 ER PT J AU Kong, DC Coleman, TR DePamphilis, ML AF Kong, DC Coleman, TR DePamphilis, ML TI Xenopus origin recognition complex (ORC) initiates DNA replication preferentially at sequences targeted by Schizosaccharomyces pombe ORC SO EMBO JOURNAL LA English DT Article DE AT-rich sequences; ATPase; DNA replication origin; Orc4; ORC-DNA binding ID EPSTEIN-BARR-VIRUS/; FISSION YEAST; LICENSING SYSTEM; ADENINE/THYMINE STRETCHES; TRANSCRIPTION FACTORS; BINDING; PROTEIN; SITES; IDENTIFICATION; CHROMATIN AB Budding yeast (Saccharomyces cerevisiae) origin recognition complex (ORC) requires ATP to bind specific DNA sequences, whereas fission yeast (Schizosaccharomyces pombe) ORC binds to specific, asymmetric A:T-rich sites within replication origins, independently of ATP, and frog (Xenopus laevis) ORC seems to bind DNA non-specifically. Here we show that despite these differences, ORCs are functionally conserved. Firstly, SpOrc1, SpOrc4 and SpOrc5, like those from other eukaryotes, bound ATP and exhibited ATPase activity, suggesting that ATP is required for pre-replication complex (pre-RC) assembly rather than origin specificity. Secondly, SpOrc4, which is solely responsible for binding SpORC to DNA, inhibited up to 70% of XlORC-dependent DNA replication in Xenopus egg extract by preventing XlORC from binding to chromatin and assembling pre-RCs. Chromatin-bound SpOrc4 was located at AT-rich sequences. XlORC in egg extract bound preferentially to asymmetric A:T-sequences in either bare DNA or in sperm chromatin, and it recruited XlCdc6 and XlMcm proteins to these sequences. These results reveal that XlORC initiates DNA replication preferentially at the same or similar sites to those targeted in S.pombe. C1 NICHHD, NIH, Bethesda, MD 20892 USA. Kenneth S Warren Inst, Ossining, NY 10562 USA. RP DePamphilis, ML (reprint author), NICHHD, NIH, Bldg 6-416,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 56 TC 34 Z9 34 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JUL 1 PY 2003 VL 22 IS 13 BP 3441 EP 3450 DI 10.1093/emboj/cdg319 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 697QD UT WOS:000183954000024 PM 12840006 ER PT J AU Redon, C Pilch, DR Rogakou, EP Orr, AH Lowndes, NF Bonner, WM AF Redon, C Pilch, DR Rogakou, EP Orr, AH Lowndes, NF Bonner, WM TI Yeast histone 2A serine 129 is essential for the efficient repair of checkpoint-blind DNA damage SO EMBO REPORTS LA English DT Article ID DOUBLE-STRAND BREAKS; CELL-CYCLE; TOPOISOMERASE-I; REPLICATION; H2AX; PATHWAY; RAD53; ATM AB Cells maintain genomic stability by the coordination of DNA-damage repair and cell-cycle checkpoint control. In replicating cells, DNA damage usually activates intra-S-phase checkpoint controls, which are characterized by delayed S-phase progression and increased Rad53 phosphorylation. We show that in budding yeast, the intra-S-phase checkpoint controls, although functional, are not activated by the topoisomerase I inhibitor camptothecin (CPT). In a CPT-hypersensitive mutant strain that lacks the histone 2A (H2A) phosphatidylinositol-3-OH kinase (PI(3) K) motif at Ser 129 (h2a-s129a), the hypersensitivity was found to result from a failure to process full-length chromosomal DNA molecules during ongoing replication. H2A Ser 129 is not epistatic to the RAD24 and RAD9 checkpoint genes, suggesting a non-checkpoint role for the H2A PI(3) K site. These results suggest that H2A Ser 129 is an essential component for the efficient repair of DNA double-stranded breaks (DSBs) during replication in yeast, particularly of those DSBs that do not induce the intra-S-phase checkpoint. C1 NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Natl Univ Ireland Univ Coll Galway, Dept Biochem, Galway, Ireland. RP Redon, C (reprint author), BSRC Alexander Fleming, 14-16 Fleming St, Vari 16672, Attika, Greece. OI Lowndes, Noel/0000-0002-3216-4427 NR 18 TC 120 Z9 123 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD JUL PY 2003 VL 4 IS 7 BP 678 EP 684 DI 10.1038/sj.embor.embor871 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 699QR UT WOS:000184067900008 PM 12792653 ER PT J AU Geracioti, TD Kling, MA Post, RM Gold, PW AF Geracioti, TD Kling, MA Post, RM Gold, PW TI Antithyroid antibody-linked symptoms in borderline personality disorder SO ENDOCRINE LA English DT Article DE borderline personality disorder; carbamazepine; antithyroid antibodies; cortisol; Hashimoto thyroiditis ID CORTICOTROPIN-RELEASING HORMONE; AUTOIMMUNE-THYROIDITIS; ENCEPHALOPATHY; DEPRESSION; CARBAMAZEPINE; DISEASE AB Circulating thyroid autoantibodies are more prevalent in patients with mood disorders than in the general population, but longitudinal clinical data that establish a relationship between thyroid antibody status and the course of any psychiatric syndrome have been lacking. In addition, scant attention has been paid to thyroid hormones and autoimmunity in borderline personality disorder (BPD). We report a case of a patient with classic BPD whose fluctuating mood and, especially, psychotic symptoms-rated using a double-blind method-were directly linked to antithyroglobulin antibody titers serially determined over an inpatient period of 275 d. Significantly lower psychosis and depression ratings were seen during a 4-wk period of relatively low antithyroid antibody titers, during blinded treatment with carbamazepine, than were observed during two high autoantibody epochs. The significant positive correlations between nurse- and patient-rated depression and thyroid autoantibodies over the entire period of inpatient study were similar to those also observed between urinary free cortisol levels and depression; the positive correlation between antithyroglubulin antibody titers and psychotic symptoms was stronger (r = +0.544; p < 0.002). Although this patient had biochemical indices of primary hypothyroidism, she showed only marginal improvement to triiodothyronine (T 3) and no apparent clinical response to sustained levorotatory thyroxine (T 4) administration; neither were antithyroid antibody titers significantly associated with changes in T 31 free T V or thyroid-stimulating hormone concentrations. She clinically deteriorated during a 50-d fluoxetine trial. The present data demonstrate a clinically significant, longitudinal correlation between fluctuating antithyroid antibody titers and symptoms of borderline psychopathology in our patient. it will be of interest to determine the prevalence, pathophysiologic mechanisms, and treatment implications of this putative autoimmune-BPD link. C1 Vet Adm Med Ctr, Psychiat Serv, Cincinnati, OH 45220 USA. NIMH, Clin Neuroendocrinol, Bethesda, MD USA. NIMH, Biol Psychiat Branches, Bethesda, MD USA. Univ Cincinnati, Cincinnati, OH USA. RP Geracioti, TD (reprint author), Vet Adm Med Ctr, Psychiat Serv, Box 116A,3200 Vine St, Cincinnati, OH 45220 USA. RI Kling, Mitchel/F-4152-2010 OI Kling, Mitchel/0000-0002-2232-1409 NR 23 TC 6 Z9 6 U1 0 U2 7 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0969-711X J9 ENDOCRINE JI Endocrine PD JUL PY 2003 VL 21 IS 2 BP 153 EP 158 DI 10.1385/ENDO:21:2:153 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 707QN UT WOS:000184521500008 PM 12897379 ER PT J AU Sugimura, Y Murase, T Ishizaki, S Tachikawa, K Arima, H Miura, Y Usdin, TB Oiso, Y AF Sugimura, Y Murase, T Ishizaki, S Tachikawa, K Arima, H Miura, Y Usdin, TB Oiso, Y TI Centrally administered tuberoinfundibular peptide of 39 residues inhibits arginine vasopressin release in conscious rats SO ENDOCRINOLOGY LA English DT Article ID MESSENGER-RIBONUCLEIC-ACID; HORMONE-RELATED PEPTIDE; PARATHYROID-HORMONE; PTH2 RECEPTOR; SUPRAOPTIC NUCLEUS; IN-VITRO; EXPRESSION; OXYTOCIN; TIP39; NEUROPEPTIDE AB Tuberoinfundibular peptide of 39 residues (TIP39) is a recently discovered neuropeptide identified on the basis of its ability to activate the PTH2 receptor, and it is thought to be the brain PTH2 receptor's endogenous ligand. The PTH2 receptor is highly expressed in the hypothalamus, suggesting a role in the modulation of neuroendocrinological functions. PTHrP, which also belongs to the PTH-related peptides family, stimulates arginine vasopressin (AVP) release. In the present study, therefore, we investigated the effect of centrally administered TIP39 on AVP release in conscious rats. Intracerebroventricular administration of TIP39 (10-500 pmol/rat) significantly suppressed the plasma AVP concentration in dehydrated rats, and the maximum effect was obtained 5 min after administration ( dehydration with 100 pmol/rat TIP39, 4.32 +/- 1.17 pg/ml; vs. control, 8.21 +/- 0.70 pg/ml). The plasma AVP increase in response to either hyperosmolality [ip injection of hypertonic saline (HS), 600 mosmol/kg] or hypovolemia [ ip injection of polyethylene glycol ( PEG)] was also significantly attenuated by an intracerebroventricular injection of TIP39 ( HS with 100 pmol/rat TIP39, 2.65 +/- 0.52 pg/ml; vs. HS alone, 4.69 +/- 0.80 pg/ml; PEG with 100 pmol/rat TIP39, 4.10 +/- 0.79 pg/ml; vs. PEG alone, 6.19 +/- 0.34 pg/ml). Treatment with naloxone [1.5 mg/rat, sc injection], a nonselective opioid receptor antagonist, significantly reversed the inhibitory effects of TIP39 on AVP release. These results suggest that central TIP39 plays an inhibitory role in the osmoregulation and baroregulation of AVP release and that intrinsic opioid systems are involved in its mechanism. C1 Nagoya Univ, Environm Med Res Inst, Dept Teratol & Genet, Chikusa Ku, Nagoya, Aichi 4648601, Japan. Nagoya Univ, Grad Sch Med, Dept Internal Med, Aichi 4668550, Japan. NIMH, Genet Lab, NIH, Bethesda, MD 20892 USA. RP Murase, T (reprint author), Nagoya Univ, Environm Med Res Inst, Dept Teratol & Genet, Chikusa Ku, Furo Cho, Nagoya, Aichi 4648601, Japan. RI Arima, Hiroshi/I-7383-2014 OI Arima, Hiroshi/0000-0003-3746-1997 NR 35 TC 23 Z9 23 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 JUL PY 2003 VL 144 IS 7 BP 2791 EP 2796 DI 10.1210/en.2002-0017 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 690KL UT WOS:000183547800007 PM 12810532 ER PT J AU Andric, SA Gonzalez-Iglesias, AE Van Goor, F Tomic, M Stojilkovic, SS AF Andric, SA Gonzalez-Iglesias, AE Van Goor, F Tomic, M Stojilkovic, SS TI Nitric oxide inhibits prolactin secretion in pituitary cells downstream of voltage-gated calcium influx SO ENDOCRINOLOGY LA English DT Article ID RAT ANTERIOR-PITUITARY; LONG-TERM POTENTIATION; GUANYLYL CYCLASE ACTIVITY; VASCULAR SMOOTH-MUSCLE; HORMONE-SECRETION; INTERFERON-GAMMA; GROWTH-HORMONE; SYNTHASE; CHANNELS; EXPRESSION AB The coupling between nitric oxide (NO)-cGMP signaling pathway and prolactin (PRL) release in pituitary lactotrophs has been established previously. However, the messenger that mediates the action of this signaling pathway on hormone secretion and the secretory mechanism affected, calcium dependent or independent, have not been identified. In cultured pituitary cells, basal PRL release was controlled by spontaneous voltage-gated calcium influx and was further enhanced by depolarization of cells and stimulation with TRH. Inhibition of constitutively expressed neuronal NO synthase decreased NO and cGMP levels and increased basal PRL release. The addition of a slowly releasable NO donor increased cGMP levels and inhibited basal PRL release in a time-dependent Expression of inducible NO synthase also increased NO and cGMP levels and inhibited basal, depolarization-induced, and TRH-induced PRL release, whereas inhibition of this enzyme decreased NO and cGMP production and recovered PRL release. None of these treatments affected spontaneous and stimulated voltage-gated calcium influx. At basal NO levels, the addition of permeable cGMP analogs did not inhibit PRL secretion. At elevated NO levels, inhibition of cGMP production and facilitation of its degradation did not reverse inhibited PRL secretion. These experiments indicate that NO inhibits calcium-dependent PRL secretion in a cGMP-independent manner and downstream of voltage-gated calcium influx. 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 50 TC 14 Z9 14 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 JUL PY 2003 VL 144 IS 7 BP 2912 EP 2921 DI 10.1210/en.2002-0147 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 690KL UT WOS:000183547800023 PM 12810546 ER PT J AU Robertson, FG Harris, J Naylor, MJ Oakes, SR Kindblom, J Dillner, K Wennbo, H Tornell, J Kelly, PA Green, J Ormandy, CJ AF Robertson, FG Harris, J Naylor, MJ Oakes, SR Kindblom, J Dillner, K Wennbo, H Tornell, J Kelly, PA Green, J Ormandy, CJ TI Prostate development and carcinogenesis in prolactin receptor knockout mice SO ENDOCRINOLOGY LA English DT Article ID TRANSGENIC MICE; LATERAL PROSTATE; ORGAN-CULTURE; RAT PROSTATE; CRISP-1 GENE; EXPRESSION; ANDROGEN; HORMONE; CANCER; MOUSE AB Hyperprolactinemia results in prostatic hypertrophy and hyperplasia, but it is not known whether prolactin plays an essential role in these processes in the prostate. To address this question, we investigated prostate development, gene expression, and simian virus 40 ( SV40) T-induced prostate carcinogenesis in prolactin receptor knockout mice. These animals showed a small increase in dorsolateral and ventral prostate weight but no change in the weight of the anterior prostate. The dorsal but not ventral or lateral lobes showed a 12% loss of epithelial cells; all other morphological parameters were normal. The area of SV40T-induced prostate intraepithelial neoplasia was reduced by 28% in the ventral lobe but not the dorsal lobe, and no tumors were seen in 20 prolactin receptor knockout animals, compared with 1 of 11 detected in wild-type and 4 of 21 found in heterozygous animals. Oligonucleotide microarrays were used to identify essential transcriptional roles of prolactin and revealed a small set of genes with decreased expression involved in sperm/oocyte interaction and copulatory plug formation. Infertility or reduced fertility was apparent in these animals. These findings establish essential though subtle roles for prolactin in the regulation of prostate morphology, gene expression, SV40T-induced neoplasia, and reproductive function. C1 St Vincents Hosp, Garvan Inst Med Res, Canc Res Program, Darlinghurst, NSW 2010, Australia. Univ Gothenburg, Dept Physiol, Res Ctr Endocrinol & Metab, S-40530 Gothenburg, Sweden. Fac Med Necker Enfants Malad, Inst Natl Sante, F-75730 Paris, France. Fac Med Necker Enfants Malad, UMR 584, F-75730 Paris, France. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Ormandy, CJ (reprint author), St Vincents Hosp, Garvan Inst Med Res, Canc Res Program, 384 Victoria St, Darlinghurst, NSW 2010, Australia. RI Kelly, Paul/A-7951-2008; Ormandy, Chris/G-4165-2014; OI Oakes, Samantha/0000-0003-1838-2310 NR 44 TC 38 Z9 38 U1 0 U2 3 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 JUL PY 2003 VL 144 IS 7 BP 3196 EP 3205 DI 10.1210/en.2003-0068 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 690KL UT WOS:000183547800053 PM 12810576 ER PT J AU Wallace, LA Mitchell, H O'Connor, GT Neas, L Lippmann, M Kattan, M Koenig, J Stout, JW Vaughn, BJ Wallace, D Walter, M Adams, K Liu, LJS AF Wallace, LA Mitchell, H O'Connor, GT Neas, L Lippmann, M Kattan, M Koenig, J Stout, JW Vaughn, BJ Wallace, D Walter, M Adams, K Liu, LJS TI Particle concentrations in inner-city homes of children with asthma: The effect of smoking, cooking, and outdoor pollution SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE continuous monitors; environmental tobacco smoke; gravimetric measurements; indoor air; MIE pDR; optical scattering; PM10; PM2.5 ID PARTICULATE AIR-POLLUTION; PERSONAL EXPOSURE; FINE PARTICLES; HOSPITAL ADMISSIONS; AIRBORNE PARTICLES; INDOOR; SEATTLE; BALTIMORE; MATTER; EPIDEMIOLOGY AB inner-city children have high rates of asthma. Exposures to particles, including allergens, may cause or exacerbate asthma symptoms. As part of an epidemiologic study of inner-city children with asthma, continuous (10-min average) measurements of particle concentrations were made for 2-week periods in 294 homes drawn from seven cities. Measurements were made using an optical scattering device that is most sensitive to fine particles. The concentrations recorded by these devices were corrected to agree with colocated outdoor gravimetric PM2.5 monitors. Indoor concentrations in the homes averaged 27.7 (standard deviation = 35.9) mug/m(3), compared with concurrent outdoor concentrations of 13.6 (7.5) mug/m(3). A multivariate model indicated that outdoor particles penetrated indoors with an efficiency of 0.48 and were therefore responsible for only 25% of the mean indoor concentration. The major indoor source was smoking, which elevated indoor concentrations by 37 mug/m(3) in the 10 1 homes with smokers. Other significant sources included frying, smoky cooking events, use of incense, and apartment housing, although the increases due to these events ranged only from 3 to 6 mug/m(3). The 10-min averaging time allowed calculation of an average diurnal variation, showing large increases in the evening due to smoking and smaller increases at meal times due to cooking. Most of the observed variance in indoor concentrations was day to day, with roughly similar contributions to the variance from visit to visit and home to home within a city and only a small contribution made by variance among cities. The small variation among cities and the similarity across cities of the observed indoor air particle distributions suggest that sources of indoor concentrations do not vary considerably from one city to the next, and thus that simple models can predict indoor air concentrations in cities having only outdoor measurements. C1 US EPA, Reston, VA 20191 USA. Rho Inc, Chapel Hill, NC USA. Boston Univ, Boston, MA 02215 USA. US EPA, Res Triangle Pk, NC 27711 USA. NYU, Sch Med, Tuxedo Pk, NY 10987 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Univ Washington, Seattle, WA 98195 USA. NIAID, Bethesda, MD 20892 USA. RP Wallace, LA (reprint author), US EPA, 11568 Woodhollow Ct, Reston, VA 20191 USA. RI Neas, Lucas/J-9378-2012; Wallace, Lance/K-7264-2013; OI O'Connor, George/0000-0002-6476-3926; Wallace, Lance/0000-0002-6635-2303 FU NIAID NIH HHS [AI-39761, AI-39769, AI-39776, AI-39785, AI-39789, AI-39900, AI-39901, AI-39902] NR 46 TC 119 Z9 122 U1 5 U2 33 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2003 VL 111 IS 9 BP 1265 EP 1272 DI 10.1289/ehp.6135 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 715VH UT WOS:000184992700041 PM 12842784 ER PT J AU Vollmayer, P Clair, T Goding, JW Sano, K Servos, J Zimmermann, H AF Vollmayer, P Clair, T Goding, JW Sano, K Servos, J Zimmermann, H TI Hydrolysis of diadenosine polyphosphates by nucleotide pyrophosphatases/phosphodiesterases SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Article DE diadenosine polyphosphate; diguanosine polyphosphate; ectonucleotidase; nucleotide pyrophosphatase; nucleotide phosphodiesterase ID ALKALINE PHOSPHODIESTERASE-I; MOTILITY-STIMULATING PROTEIN; AORTIC ENDOTHELIAL-CELLS; TORPEDO ELECTRIC ORGAN; 5'-NUCLEOTIDE PHOSPHODIESTERASE; EXTRACELLULAR METABOLISM; LYSOPHOSPHOLIPASE-D; MOLECULAR-CLONING; CHROMAFFIN CELLS; PLASMA-MEMBRANES AB Diadenosine polyphosphates (Ap(n)As) act as extracellular signaling molecules in a broad variety of tissues. They were shown to be hydrolyzed by surface-located enzymes in an asymmetric manner, generating AMP and Ap(n-1) from Ap(n)A. The molecular identity of the enzymes responsible remains unclear. We analyzed the potential of NPP1, NPP2, and NPP3, the three members of the ecto-nucleotide pyrophosphatase/phosphodiesterase family, to hydrolyze the diadenosine polyphosphates diadenosine 5',5'''-P-1,P-3-triphosphate (Ap(3)A), diadenosine 5',5'''-P-1,P-4-tetraphosphate (Ap(4)A), and diadenosine 5',5'''-P-1,P-5-pentaphosphate, (Ap(5)A), and the diguanosine polyphosphate, diguanosine 5',5'''-P-1,P-4-tetraphosphate (Gp(4)G). Each of the three enzymes hydrolyzed Ap(3)A, Ap(4)A, and Ap(5)A at comparable rates. Gp(4)G was hydrolyzed by NPP1 and NPP2 at rates similar to Ap(4)A, but only at half this rate by NPP3. Hydrolysis was asymmetric, involving the alpha,beta-pyrophosphate bond. Ap(n)A hydrolysis had a very alkaline pH optimum and was inhibited by EDTA. Michaelis constant (K-m) values for Ap(3)A were 5.1 mum, 8.0 mum, and 49.5 mum for NPP1, NPP2, and NPP3, respectively. Our results suggest that NPP1, NPP2, and NPP3 are major enzyme candidates for the hydrolysis of extracellular diadenosine polyphosphates in vertebrate tissues. C1 Univ Frankfurt, AK Neurochem, Biozentrum, D-60439 Frankfurt, Germany. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Monash Univ, Dept Pathol & Immunol, Alfred Hosp, Prahran, Vic, Australia. Kobe Univ, Sch Med, Dept Pediat, Kobe, Hyogo 650, Japan. RP Zimmermann, H (reprint author), Univ Frankfurt, AK Neurochem, Biozentrum, Marie Curie Str 9, D-60439 Frankfurt, Germany. NR 60 TC 59 Z9 59 U1 0 U2 6 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD JUL PY 2003 VL 270 IS 14 BP 2971 EP 2978 DI 10.1046/j.1432-1033.2003.03674.x PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 697TT UT WOS:000183959900007 PM 12846830 ER PT J AU Maccalli, C Pende, D Castelli, C Mingari, MC Robbins, PF Parmiani, G AF Maccalli, C Pende, D Castelli, C Mingari, MC Robbins, PF Parmiani, G TI NKG2D engagement of colorectal cancer-specific T cells strengthens TCR-mediated antigen stimulation and elicits TCR independent anti-tumor activity SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE colorectal cancer; tumor immunity; T lymphocytes; NG2D receptors; costimulation ID I-RELATED CHAIN; NK CELLS; RECOGNITION; EXPRESSION; RECEPTOR; MICA; CYTOTOXICITY; ACTIVATION; MOLECULES; LIGANDS AB The NKG2D receptor is expressed by human NK, gammadelta T and alpha/beta T lymphocytes and its engagement results in the stimulation of effector cells. We evaluated the role of NKG2D receptor in anti-colorectal cancer (CRC) immune response. The cell surface expression of stress-inducible NKG2D ligands MICA/B (MHC class I-related chain molecules A/B) and ULBP (UL16 binding protein) by a panel of CRC lines was evaluated by flow cytometry. MICA and ULBP2/3 were widely expressed by the analyzed lines, with a minority of them being also ULBP-1(+), whereas MICB was undetectable. CD8(+) and CD4(+) HLA-restricted anti-tumor T cell clones of a CRC patient were used to evaluate whether NKG2D engagement could mediate tumor recognition. Three out of four CD8(+) T cell clones recognized the autologous tumor with a marginal NKG2D engagement, a finding that was correlated with the weak expression of NKG2D ligands by the autologous tumor. On the contrary, NKG2D triggering of these CD8(+) T cell clones induced recognition of allogeneic CRC lines showing high expression of MICA and ULBP. A costimulatory role of NKG2D was observed with one CD4(+)/NKG2D(+)T cell clone when stimulated by tumors sharing the HILA class II alleles and expressing NKG2D ligands. Taken together these data indicate that the engagement of NKG2D, depending on the expression of its ligands by target cells, can influence the pattern of antitumor reactivity by T lymphocytes. C1 Ist Nazl Tumori, Unit Immunotherapy Human Tumors, I-20133 Milan, Italy. Ist Nazl Ric Canc, I-16132 Genoa, Italy. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Parmiani, G (reprint author), Ist Nazl Tumori, Unit Immunotherapy Human Tumors, Via Venezian 1, I-20133 Milan, Italy. RI Pende, Daniela/J-7429-2016; castelli, chiara/K-6899-2012 OI Pende, Daniela/0000-0003-1565-451X; castelli, chiara/0000-0001-6891-8350 NR 26 TC 43 Z9 47 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2003 VL 33 IS 7 BP 2033 EP 2043 DI 10.1002/eji.200323909 PG 11 WC Immunology SC Immunology GA 701ZM UT WOS:000184199100030 PM 12884870 ER PT J AU Karcz-Kubicha, M Quarta, D Hope, BT Antoniou, K Muller, CE Morales, M Schindler, CW Goldberg, SR Ferre, S AF Karcz-Kubicha, M Quarta, D Hope, BT Antoniou, K Muller, CE Morales, M Schindler, CW Goldberg, SR Ferre, S TI Enabling role of adenosine A(1) receptors in adenosine A(2A) receptor-mediated striatal expression of c-fos SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE adenosine; c-fos; dopamine; rat; striatum ID RAT NUCLEUS-ACCUMBENS; DOPAMINE-D-2 RECEPTORS; MICE LACKING; NERVOUS-SYSTEM; DARPP-32 PHOSPHORYLATION; STRIATOPALLIDAL NEURONS; EXTRACELLULAR DOPAMINE; PRESYNAPTIC INHIBITION; SYNAPTIC TRANSMISSION; PROJECTION NEURONS AB When striatal neurons are strongly activated they produce adenosine, which activates nearby adenosine A(1) receptors (A1Rs) and adenosine A(2A) receptors (A2ARs). Although the effects of A1R or A2AR activation on neural activity in the striatum have been examined separately, the effects of coactivating both receptors has not been investigated. Using c-Fos immunohistochemistry as an indicator of neural activity, we examined the effects of coactivation of A1Rs and A2ARs on neural activity and their mechanism of interaction in the caudate-putamen, nucleus accumbens (NAc) and prefrontal cortex in rats. Administration of a motor-depressant dose of the A2AR agonist CGS 21680 (0.5 mg/kg i.p.) did not significantly induce c-fos expression in any of these brain regions. Administration of a motor-depressant dose of the A1R agonist CPA (0.3 mg/kg, i.p.) produced a small but significant induction of c-fos expression only in the shell of the NAc. Coadministration of CGS 21680 and CPA produced a synergistic induction of c-fos expression in the caudate-putamen, cingulate cortex, and especially the NAc. In the shell of the NAc administration of CPA significantly decreased extracellular dopamine levels measured by in vivo microdialysis and blocked CGS 21680-induced increases in dopamine levels. Because it has been previously shown that activation of dopamine D-2 receptors (D2Rs) by endogenous dopamine blocks A2AR-mediated c-fos expression, it is hypothesized that the enabling role of A1Rs in A2AR-mediated striatal c-fos expression is related to the A1R-mediated inhibition of dopamine release. C1 NIDA, Preclin Pharmacol Sect, Dept Hlth & Human Serv, NIH,IRP, Baltimore, MD 21224 USA. NIDA, Behav Neurosci Sect, Dept Hlth & Human Serv, NIH,IRP, Baltimore, MD 21224 USA. NIDA, Cellular Neurobiol Sect, Dept Hlth & Human Serv, NIH,IRP, Baltimore, MD 21224 USA. Univ Bonn, Inst Pharmaceut, D-53115 Bonn, Germany. RP Ferre, S (reprint author), NIDA, Behav Neurosci Branch, Dept Hlth & Human Serv, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sferre@intra.nida.nih.gov RI Hope, Bruce/A-9223-2010; Ferre, Sergi/K-6115-2014; Muller, Christa/C-7748-2014 OI Hope, Bruce/0000-0001-5804-7061; Ferre, Sergi/0000-0002-1747-1779; Muller, Christa/0000-0002-0013-6624 NR 56 TC 29 Z9 29 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JUL PY 2003 VL 18 IS 2 BP 296 EP 302 DI 10.1046/j.1460-9568.2003.02747.x PG 7 WC Neurosciences SC Neurosciences & Neurology GA 704AW UT WOS:000184316400008 PM 12887411 ER PT J AU Lipska, BK Lerman, DN Khaing, ZZ Weickert, CS Weinberger, DR AF Lipska, BK Lerman, DN Khaing, ZZ Weickert, CS Weinberger, DR TI Gene expression in dopamine and GABA systems in an animal model of schizophrenia: effects of antipsychotic drugs SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE clozapine; dopamine receptors; GAD-67; haloperidol; neurotensin; prodynorphin; proenkephalin ID DECARBOXYLASE MESSENGER-RNA; GLUTAMIC-ACID DECARBOXYLASE; PHASEOLUS-VULGARIS-LEUKOAGGLUTININ; EXCITOTOXIC HIPPOCAMPAL DAMAGE; NEONATAL BILATERAL LESION; NUCLEUS-ACCUMBENS; PREFRONTAL CORTEX; CHRONIC HALOPERIDOL; VENTRAL HIPPOCAMPUS; BASAL GANGLIA AB We used in situ hybridization histochemistry to assess expression of dopamine receptors (D1R, D2R and D3R), neurotensin, proenkephalin and glutamate decarboxylase-67 (GAD67) in the prefrontal cortex, striatum, and/or nucleus accumbens in adult rats with neonatal ventral hippocampal (VH) lesions and in control animals after acute and chronic treatment with antipsychotic drugs clozapine and haloperidol. We also acquired these measures in a separate cohort of treatment-naive sham and neonatally VH-lesioned rats used as an animal model of schizophrenia. Our results indicate that the neonatal VH lesion did not alter expression of D1R, D3R, neurotensin or proenkephalin expression in any brain region examined. However, D2R mRNA expression was down-regulated in the striatum, GAD67 mRNA was down-regulated in the prefrontal cortex and prodynorphin mRNA was up-regulated in the striatum of the VH-lesioned rats as compared with sham controls. Antipsychotic drugs did not alter expression of D1R, D2R or D3R receptor mRNAs but elevated neurotensin and proenkephalin expression in both groups of rats; patterns of changes were dependent on the duration of treatment and brain area examined. GAD67 mRNA was up-regulated by chronic antispychotics in the nucleus accumbens and the striatum and by chronic haloperidol in the prefrontal cortex in both sham and lesioned rats. These results indicate that the developmental VH lesion changed the striatal expression of D2R and prodynorphin and robustly compromised prefrontal GAD67 expression but did not modify drug-induced expression of any genes examined in this study. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Lipska, BK (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bldg 10,Rm 4N306, Bethesda, MD 20892 USA. RI Shannon Weickert, Cynthia/G-3171-2011; Lipska, Barbara/E-4569-2017 NR 72 TC 74 Z9 79 U1 1 U2 4 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 JUL PY 2003 VL 18 IS 2 BP 391 EP 402 DI 10.1046/j.1460-9568.2003.02738.x PG 12 WC Neurosciences SC Neurosciences & Neurology GA 704AW UT WOS:000184316400018 PM 12887421 ER PT J AU Biermann, CH Kessing, BD Palumbi, SR AF Biermann, CH Kessing, BD Palumbi, SR TI Phylogeny and development of marine model species: strongylocentrotid sea urchins SO EVOLUTION & DEVELOPMENT LA English DT Article ID AMINO-ACID-SEQUENCES; PALLIDUS GO SARS; MITOCHONDRIAL-DNA; HEMICENTROTUS-PULCHERRIMUS; GENUS STRONGYLOCENTROTUS; MOLECULAR PHYLOGENETICS; NUCLEOTIDE-SEQUENCE; MAXIMUM-LIKELIHOOD; S-PALLIDUS; EGG SIZE AB The phylogenetic relationships of ten strongy-locentrotid sea urchin species were determined using mitochondrial DNA sequences. This phylogeny provides a backdrop for the evolutionary history of one of the most studied groups of sea urchins. Our phylogeny indicates that a major revision of this group is in order. All else remaining unchanged, it supports the inclusion of three additional species into the genus Strongylocentrotus (Hemicentrotus pulcherrimus , Allocentrotus fragilis , and Pseudocentrotus depressus). All were once thought to be closely related to this genus, but subsequent revisions separated them into other taxonomic groupings. Most strongylocentrotid species are the result of a recent burst of speciation in the North Pacific that resulted in an ecological diversification. There has been a steady reduction in the complexity of larval skeletons during the expansion of this group. Gamete attributes like egg size, on the other hand, are not correlated with phylogenetic position. In addition, our results indicate that the rate of replacement substitutions is highly variable among phylogenetic lineages. The branches leading to S. purpuratus and S. franciscanus were three to six times longer than those leading to closely related species. C1 Harvard Univ, Radcliffe Inst Adv Study, Cambridge, MA 02138 USA. NCI, Frederick, MD 21702 USA. Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. RP Biermann, CH (reprint author), Harvard Univ, Radcliffe Inst Adv Study, Cambridge, MA 02138 USA. NR 93 TC 52 Z9 55 U1 0 U2 6 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1520-541X J9 EVOL DEV JI Evol. Dev. PD JUL-AUG PY 2003 VL 5 IS 4 BP 360 EP 371 DI 10.1046/j.1525-142X.2003.03043.x PG 12 WC Evolutionary Biology; Developmental Biology; Genetics & Heredity SC Evolutionary Biology; Developmental Biology; Genetics & Heredity GA 694VY UT WOS:000183796900004 PM 12823452 ER PT J AU Picut, CA Aoyama, H Holder, JW Gold, LS Maronpot, RR Dixon, D AF Picut, CA Aoyama, H Holder, JW Gold, LS Maronpot, RR Dixon, D TI Bromoethane, chloroethane and ethylene oxide induced uterine neoplasms in B6C3F1 mice from 2-year NTP inhalation bioassays: pathology and incidence data revisited SO EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY LA English DT Article DE ethylene oxide; bromoethane; chloroethane; ethyl chloride; ethyl bromide; epigenetic; glutathione conjugation; Estrogen Receptor (ER); uterine cancer; animal cancer test; mouse uterus ID SPECIES-DIFFERENCES; BIOTRANSFORMATION; CARCINOGENS; METABOLISM; CHLORIDE AB Chloroethane, bromoethane and ethylene oxide represent a unique set of chemicals that induce endometrial neoplasms in the uterus of B6C3F1 mice following an inhalation route of exposure. The results of the NTP's chronic bioassays with these three compounds resulted in an unusually high incidence of uterine epithelial neoplasms in B6C3F1 mice (chloroethane 86%, bromoethane 56%) and a lower incidence for ethylene oxide (10%). The uterine neoplasms were classified as adenomas, adenocarcinomas, and squamous cell carcinomas for bromoethane, and as adenocarcinomas for both chloroethane and ethylene oxide. The adenocarcinomas and squamous cell carcinomas were invasive into the myometrium and the serosa, and metastasized to a wide variety of organs. Metastatic sites included most commonly the lung, lymph nodes, and ovary at unusually high rates of metastases (79% for chloroethane and 38% for bromoethane). Because of the dramatically high rates of uterine neoplasms (induced by chemicals given by the inhalation route) and metastases, a re-evaluation of the pathology and incidence data was undertaken. The earlier results were confirmed. The mechanism of uterine carcinogenesis by chloroethane, bromoethane and ethylene oxide is unclear. C1 NIEHS, Lab Expt Pathol, NIH, DHHS, Res Triangle Pk, NC 27709 USA. Biotech Inc, Hillsborough, NC USA. Inst Environm Toxicol, Lab Reprod Toxicol, Ibaraki, Japan. Natl Ctr Environm Assessment, Off Res & Dev, US EPA, Washington, DC USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. Lawrence Berkeley Lab, Berkeley, CA 94720 USA. RP Dixon, D (reprint author), NIEHS, Lab Expt Pathol, NIH, DHHS, POB 12233,MDC2-09, Res Triangle Pk, NC 27709 USA. FU NIDCR NIH HHS [DE-AC-03-76FO0098]; NIEHS NIH HHS [ESO1896] NR 20 TC 10 Z9 12 U1 0 U2 0 PU URBAN & FISCHER VERLAG PI JENA PA BRANCH OFFICE JENA, P O BOX 100537, D-07705 JENA, GERMANY SN 0940-2993 J9 EXP TOXICOL PATHOL JI Exp. Toxicol. Pathol. PD JUL PY 2003 VL 55 IS 1 BP 1 EP 9 DI 10.1078/0940-2993-00303 PG 9 WC Pathology; Toxicology SC Pathology; Toxicology GA 712PG UT WOS:000184805600001 PM 12940622 ER PT J AU Chen, J Young, N AF Chen, J Young, N TI Bystander marrow destruction in a mouse model of human bone marrow failure SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology CY JUL 05-08, 2003 CL PARIS, FRANCE SP Int Soc Exptl Hematol C1 NHLBI, 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 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2003 VL 31 IS 7 SU 1 MA 34 BP 70 EP 71 PG 2 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 701HR UT WOS:000184162600030 ER PT J AU Krosl, G Lacombe, J Herblot, S Martin, R Aplan, P Begley, C Sauvageau, G Hoang, T AF Krosl, G Lacombe, J Herblot, S Martin, R Aplan, P Begley, C Sauvageau, G Hoang, T TI Combinatorial interaction between SCL and c-KIT in hematopoietic cell survival SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology CY JUL 05-08, 2003 CL PARIS, FRANCE SP Int Soc Exptl Hematol C1 Univ Montreal, Montreal, PQ, Canada. Natl Canc Inst, Dept Genet, Gaithersburg, MD USA. Univ Western Australia, Perth, WA, Australia. RI Aplan, Peter/K-9064-2016 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 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2003 VL 31 IS 7 SU 1 MA 57 BP 78 EP 78 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 701HR UT WOS:000184162600053 ER PT J AU Welniak, L Sun, K Sayers, T Murphy, W AF Welniak, L Sun, K Sayers, T Murphy, W TI Proteasome inhibitor PS-341 improves outcome in acute lethal murine GVHD SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology CY JUL 05-08, 2003 CL PARIS, FRANCE SP Int Soc Exptl Hematol C1 NCI, Frederick Canc Res & Dev Ctr, Frederick, MD USA. Univ Nevada, Reno, NV 89557 USA. RI Sayers, Thomas/G-4859-2015 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 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2003 VL 31 IS 7 SU 1 MA 75 BP 84 EP 84 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 701HR UT WOS:000184162600071 ER PT J AU Orlic, D AF Orlic, D TI Treatment of cardiac infarctions with direct stem cell infusion and mobilization SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology CY JUL 05-08, 2003 CL PARIS, FRANCE SP Int Soc Exptl Hematol C1 NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2003 VL 31 IS 7 SU 1 MA 226 BP 135 EP 135 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 701HR UT WOS:000184162600216 ER PT J AU Gurevich, R Aplan, P Humphries, R AF Gurevich, R Aplan, P Humphries, R TI Topoisomerase catalytic activity is dispensable for the myeloproliferative effects of the AML associated NUP98-topoisomerase I (NUP98-TOPI) fusion SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology CY JUL 05-08, 2003 CL PARIS, FRANCE SP Int Soc Exptl Hematol C1 BC Canc Agcy, Vancouver, BC, Canada. Natl Canc Inst, Gaithersburg, MD USA. RI Aplan, Peter/K-9064-2016 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 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2003 VL 31 IS 7 SU 1 MA 236 BP 139 EP 139 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 701HR UT WOS:000184162600226 ER PT J AU Zoueva, O Rodgers, G AF Zoueva, O Rodgers, G TI Inhibition of beta protein 1 (BP1) expression results in enhanced beta-globin promoter activity and beta-globin mRNA levels in K562 cells SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology CY JUL 05-08, 2003 CL PARIS, FRANCE SP Int Soc Exptl Hematol C1 NIDDK, Mol & Clin Hematol Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2003 VL 31 IS 7 SU 1 MA 312 BP 165 EP 165 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 701HR UT WOS:000184162600302 ER PT J AU Cokic, V Beleslin-Cokic, B Gladwin, M Noguchi, C Schechter, A AF Cokic, V Beleslin-Cokic, B Gladwin, M Noguchi, C Schechter, A TI Hydroxyurea-induced nitric oxide production: Effects on human erythroid and endothelial cells SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology CY JUL 05-08, 2003 CL PARIS, FRANCE SP Int Soc Exptl Hematol C1 NIDDK, LCB, NIH, Bethesda, MD USA. CCMD, CC, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2003 VL 31 IS 7 SU 1 MA 319 BP 167 EP 168 PG 2 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 701HR UT WOS:000184162600309 ER PT J AU Sanchez-Izquierdo, D Buchonnet, G Siebert, R Gascoyne, R Climent, J Marin, M Rosenwald, A Blesa, D Pinkel, D Garcia-Conde, J Dyer, M Martinez-Climent, JA AF Sanchez-Izquierdo, D Buchonnet, G Siebert, R Gascoyne, R Climent, J Marin, M Rosenwald, A Blesa, D Pinkel, D Garcia-Conde, J Dyer, M Martinez-Climent, JA TI MALT1 is deregulated by both chromosomal translocation and amplification in B-cell non-Hodgkin lymphoma SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology CY JUL 05-08, 2003 CL PARIS, FRANCE SP Int Soc Exptl Hematol C1 Univ Valencia, Dept Hematol Oncol, Valencia, Spain. Univ Leicester, Spain Dept Haematol, Leicester, Leics, England. Univ Hosp Kiel, Inst Human Genet, Kiel, Germany. British Columbia Canc Agcy, Dept Pathol, Vancouver, BC, Canada. Natl Canc Inst, Bethesda, MD USA. Univ Calif San Francisco, San Francisco, CA 94143 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 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2003 VL 31 IS 7 SU 1 MA 371 BP 185 EP 185 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 701HR UT WOS:000184162600361 ER PT J AU Calmels, B Kulka, M Metzger, M Keyvanfar, K Sellers, S Metcalfe, D Dunbar, C AF Calmels, B Kulka, M Metzger, M Keyvanfar, K Sellers, S Metcalfe, D Dunbar, C TI Genetic tracking of basophil and mast cell lineage relationships in vivo SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology CY JUL 05-08, 2003 CL PARIS, FRANCE SP Int Soc Exptl Hematol C1 NHLBI, Hematol Branch, Bethesda, MD USA. NIAID, Lab Allerg Dis, Bethesda, MD USA. RI calmels, boris/R-2538-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2003 VL 31 IS 7 SU 1 MA 385 BP 190 EP 190 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 701HR UT WOS:000184162600375 ER PT J AU Nicot, C Dundr, M Johnson, J Fullen, J Fukumoto, R Misteli, T Franchini, G AF Nicot, C Dundr, M Johnson, J Fullen, J Fukumoto, R Misteli, T Franchini, G TI A novel post-transcriptional mechanism for viral latency SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology CY JUL 05-08, 2003 CL PARIS, FRANCE SP Int Soc Exptl Hematol C1 NCI, 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 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2003 VL 31 IS 7 SU 1 MA 517 BP 232 EP 232 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 701HR UT WOS:000184162600506 ER PT J AU Hill, GD Mangum, JB Moss, OR Everitt, JI AF Hill, GD Mangum, JB Moss, OR Everitt, JI TI Soluble ICAM-1, MCP-1, and MIP-2 protein secretion by rat pleural mesothelial cells following exposure to amosite asbestos SO EXPERIMENTAL LUNG RESEARCH LA English DT Article DE adhesion molecules; amosite asbestos; chemokines; grunerite; ICAM-1; inflammation; MCP-1; MIP-2; pleural mesothelial cells ID INTERCELLULAR-ADHESION MOLECULE-1; IN-VITRO; ENDOTHELIAL-CELLS; EXPRESSION; INFLAMMATION; PARTICLES; MIGRATION; CYTOKINES; GROWTH; INJURY AB Pleural inflammation is a sequela of exposure to toxic mineral fibers such as amosite asbestos. This inflammatory response involves the influx of leukocytes from the vasculature into the pleural space. Adhesion molecules such as intercellular adhesion molecule-1 (ICAM)-1 and chemokines such as monocyte chemoattractant protein-1 (MCP)-1 and macrophage inhibitory protein-2 (MIP)-2 are known to be important in pulmonary inflammation following inhalation of particulate matter. However, little is known about their role in pleural inflammation secondary to amosite asbestos exposure. Because the pleural mesothelial cell is believed to be a key target cell of asbestos exposure, the purpose of this study was to determine if ICAM-1, MCP-1, and MIP-2 proteins were secreted by these mesothelial cells following in vitro and in vivo exposure to amosite asbestos. Increased levels of ICAM-1 and MCP-1 protein were measured following 24 or 48 hours exposure of cultured rat pleural mesothelial cells to amosite fibers (1.5 to 5.0 mug/cm(2)). Increased levels of ICAM-1, MCP-1, and MIP-2 protein were found in pleural lavage fluid from Fischer-344 rats exposed to amosite asbestos for 4 and 12 weeks and after a 12-week recovery period (following the 12-week exposure period). These findings suggest that the secretion of ICAM-1, MCP-1, and MIP-2 by rat pleural mesothelial cells may contribute to amosite-induced pleural inflammation. C1 CIIT Ctr Hlth Res, Dept Resp Toxicol, Res Triangle Pk, NC USA. RP Hill, GD (reprint author), NIEHS, 111 TW Alexander Dr,MD B3-06, Res Triangle Pk, NC 27709 USA. EM hill9@niehs.nih.gov FU NIEHS NIH HHS [ES05811-03] NR 30 TC 13 Z9 15 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0190-2148 J9 EXP LUNG RES JI Exp. Lung Res. PD JUL-AUG PY 2003 VL 29 IS 5 BP 277 EP 290 DI 10.1080/01902140390196654 PG 14 WC Respiratory System SC Respiratory System GA 676NK UT WOS:000182758300001 PM 12746042 ER PT J AU Kawano, H Horie, M Honma, S Kawamura, K Takeuchi, K Kimura, S AF Kawano, H Horie, M Honma, S Kawamura, K Takeuchi, K Kimura, S TI Aberrant trajectory of ascending dopaminergic pathway in mice lacking Nkx2.1 SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Nkx2.1; mouse; mesencephalon; dopamine; development; axon; pathway ID SEMAPHORIN-III; THALAMOCORTICAL PATHWAY; CORTICAL PROJECTIONS; MAMMALIAN FOREBRAIN; BASAL TELENCEPHALON; MOUSE; EXPRESSION; PROTEIN; GUIDANCE; NEURONS AB In the embryonic brain, the transcription factor Nkx2.1 is localized in the medial ganglionic eminence and the ventromedial part of the hypothalamus. In the present study, we examined the development of mesencephalic dopamine (DA) neuron system in mice lacking Nkx2.1. In normal mice, tyrosine hydroxylase-immunoreactive axons from mesencephalic DA cells extended bilaterally in the lateral hypothalamus at embryonic day 12.5 (E12.5) and project to the ipsilateral striatum by E14.5. In the mutant brain, mesencephalic DA cell groups appeared to develop normally, but the majority of their ascending axons were observed to cross the ventral midline of the caudal hypothalamus and project to the contralateral striatum. DiI, a fluorescent dye, placed in the ventrolateral mesencephalon of E14.5 mutant mice, further revealed that majority of DiI-labeled axons projected to the contralateral striatum, while a minor ipsilateral projection was also observed. In the ventromedial hypothalamus of mutants, the neuroepithelium of third ventricle was missing, and immunoreactivity of semaphorin 3A, a soluble type of axon repellent, which was normally localized in the neuroepithelium, was remarkably reduced. Together with the recent evidence that the expression of slit2, another axon-repellent diffusible factor, is also eliminated in the hypothalamic neuroepithelium of Nkx2.1-deficient mice, the abnormal crossing of ascending DA axons observed may be attributed to the elimination of these chemorepulsive signals in the medial part of the mutant hypothalamus. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Tokyo Metropolitan Inst Neurosci, Dept Dev Morphol, Fuchu, Tokyo 1838526, Japan. Yokohama City Univ, Grad Sch Integrated Sci, Kanazawa Ku, Yokohama, Kanagawa 2360027, Japan. Nagoya Univ, Dept Sci Biol, Nagoya, Aichi 4648602, Japan. NCI, Mol Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Kawano, H (reprint author), Tokyo Metropolitan Inst Neurosci, Dept Dev Morphol, 2-6 Musashidai, Fuchu, Tokyo 1838526, Japan. NR 35 TC 38 Z9 42 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUL PY 2003 VL 182 IS 1 BP 103 EP 112 DI 10.1016/S0014-4886(03)00030-X PG 10 WC Neurosciences SC Neurosciences & Neurology GA 695NQ UT WOS:000183837400009 PM 12821380 ER PT J AU Caplen, NJ AF Caplen, NJ TI RNAi as a gene therapy approach SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE gene silencing; gene therapy; post-transcriptional gene silencing; PTGS; RNAi; RNA interference; siRNA; small interfering RNA ID SMALL INTERFERING RNA; DOUBLE-STRANDED-RNA; FUNCTIONAL GENOMIC ANALYSIS; CULTURED-MAMMALIAN-CELLS; RECOMBINANT HUMAN DICER; GERM-LINE DEVELOPMENT; SMALL TEMPORAL RNAS; HUMAN CANCER-CELLS; VECTOR-BASED RNAI; C-ELEGANS AB RNA duplexes of 21 - 23 nucleoticles (nts), with similar to2 nt 3' overhangs (called small interfering RNAs or siRNAs), have recently been shown to mediate sequence-specific inhibition of gene expression in mammalian cells via a post-transcriptional gene silencing (PTGS) mechanism termed RNA interference (RNAi). RNAi has been rapidly adopted as a functional genomics tool in a wide range of species, has been adapted to allow for the transient or stable knockdown of gene expression generation in cell lines and animals, and has been developed for high-throughput analysis of gene function in Caenorhabditis elegans. With an increasing list of genes successfully knocked-down by RNAi in mammalian cells and improvements in the delivery of siRNAs to cells, including in vivo delivery to mice, attention is now turning to assessing the potential RNAi has as a gene therapy approach. RNAi is likely to have the greatest impact as a therapeutic tool in two key clinical areas, cancer and infectious disease, but it also has the potential as a therapy for other disorders including some dominant genetic diseases. This review will describe the status of the science behind this novel mechanism and will illustrate the therapeutic potential of RNAi-based technologies, using examples from these critical clinical research areas. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Caplen, NJ (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr,10C103, Bethesda, MD 20892 USA. RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 NR 168 TC 52 Z9 68 U1 5 U2 14 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD JUL PY 2003 VL 3 IS 4 BP 575 EP 586 DI 10.1517/14712598.3.4.575 PG 12 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 701BX UT WOS:000184147600005 PM 12831363 ER PT J AU Bagnato, F Pozzilli, C AF Bagnato, F Pozzilli, C TI Pharmacological methods to overcome IFN-beta antibody formation in the treatment of multiple sclerosis SO EXPERT OPINION ON INVESTIGATIONAL DRUGS LA English DT Review DE combination therapy; immunosuppressive drugs; IFN-beta; magnetic resonance activity; multiple sclerosis; neutralising antibodies; steroids ID RANDOMIZED CONTROLLED TRIAL; SECONDARY PROGRESSIVE MS; RECOMBINANT HUMAN INTERFERON-BETA-1A; INTRAVENOUS IMMUNOGLOBULIN-G; LONG-TERM TREATMENT; NEUTRALIZING ANTIBODIES; COMPARATIVE PHARMACOKINETICS; PULSE CYCLOPHOSPHAMIDE; IV METHYLPREDNISOLONE; IFN-BETA-1B TREATMENT AB Diminished efficacy in terms of clinical relapses and lesion load on magnetic resonance images for patients developing neutralising antibodies (NAbs) to recombinant IFN-beta may be found in multiple sclerosis. NAbs become detectable over the first few years of therapy, disappearing during the treatment course in some patients and persisting longer in some others. Therefore, the administration of concomitant therapies to recombinant IFN-beta to prevent the formation of NAbs could be indicated mainly in the latter group of patients at the early stage of the treatment. Among those therapies, steroids meet the best criteria in terms of either safety or impact on the development of NAbs, at the present time. C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Univ Roma La Sapienza, Dept Neurol Sci, Rome, Italy. RP Bagnato, F (reprint author), NINDS, Neuroimmunol Branch, NIH, Bldg 10,Room 5B16,10 Ctr Dr,MSC 1400, Bethesda, MD 20892 USA. NR 101 TC 2 Z9 2 U1 1 U2 1 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1354-3784 J9 EXPERT OPIN INV DRUG JI Expert Opin. Investig. Drugs PD JUL PY 2003 VL 12 IS 7 BP 1153 EP 1163 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 704HL UT WOS:000184333900007 PM 12831350 ER PT J AU Conrods, TP Zhou, M Petricoin, EF Liotta, L Veenstra, TD AF Conrods, TP Zhou, M Petricoin, EF Liotta, L Veenstra, TD TI Cancer diagnosis using proteomic patterns SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Review DE bioinformatics; biomarkers; cancer; early diagnosis; mass spectrometry; proteomic patterns ID OVARIAN-CANCER; PROSTATE-CANCER; MASS-SPECTROMETRY; SERUM; BIOMARKERS; MEN AB The advent of proteomics has brought with it the hope of discovering novel biomarkers that can be used to diagnose diseases, predict susceptibility and monitor progression. Much of this effort has focused upon the mass spectral identification of the thousands of proteins that populate complex biosystems such as serum and tissues. A revolutionary approach in proteomic pattern analysis has emerged as an effective method for the early diagnosis of diseases such as ovarian cancer. Proteomic pattern analysis relies on the pattern of proteins observed and does not rely on the identification of a traceable biomarker. Hundreds of clinical samples per day can be analyzed utilizing this technology, which has the potential to be a novel, highly sensitive diagnostic tool for the early detection of cancer. C1 SAIC Frederick Inc, Biomed Proteom Program, NCI, Mass Spectrometry Ctr, Frederick, MD 21702 USA. NCI, Clin Proteom Program, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. NCI, Clin Proteom Program, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. SAIC Frederick Inc, Biomed Proteom Program, NCI, Analyt Chem Lab, Frederick, MD 21702 USA. RP Veenstra, TD (reprint author), SAIC Frederick Inc, Biomed Proteom Program, NCI, Mass Spectrometry Ctr, POB B, Frederick, MD 21702 USA. EM conrads@ncifcrf.gov; mzhou@ncifcrf.gov; petricoin@cber.FDA.gov; liottal@nih.gov; veenstra@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 35 TC 97 Z9 107 U1 0 U2 9 PU FUTURE DRUGS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEYY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7159 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD JUL PY 2003 VL 3 IS 4 BP 411 EP 420 DI 10.1586/14737159.3.4.411 PG 10 WC Pathology SC Pathology GA 767KC UT WOS:000188437900002 PM 12877381 ER PT J AU Eisenhofer, G Tian, H Holmes, C Matsunaga, J Roffler-Tarlov, S Hearing, VJ AF Eisenhofer, G Tian, H Holmes, C Matsunaga, J Roffler-Tarlov, S Hearing, VJ TI Tyrosinase: a developmentally specific major determinant of peripheral dopamine SO FASEB JOURNAL LA English DT Article DE L-dopa; tyrosine hydroxylase; sympathetic nervous system; melanocyte; melanin ID TARGETED DISRUPTION; MONOAMINE-OXIDASE; SUBSTANTIA-NIGRA; CATECHOLAMINES; HYDROXYLASE; BRAIN; GENE; POPULATIONS; EXPRESSION; METABOLISM AB L-3,4-dihydroxyphenylalanine, the immediate precursor of dopamine, can be formed by two enzymes: tyrosine hydroxylase (TH) in catecholamine-producing neurons and chromaffin cells and tyrosinase in melanocytes. In this study we examined whether tyrosinase contributes to production of dopamine. Deficiency of TH caused marked reductions in norepinephrine in albino and pigmented 15-day-old mice. In contrast, peripheral levels of dopamine were reduced only in albino TH-deficient mice and were higher in pigmented than in albino mice, regardless of the presence or absence of TH. We next examined age-related changes in dopamine and cutaneous expression of tyrosinase and melanin in albino and pigmented TH wild-type mice. We found that the differences in peripheral dopamine between pigmented and albino mice disappeared with advancing age following changes in expression and function of tyrosinase. In young animals, tyrosinase was present in epidermis but did not produce detectable melanin. With advancing age, tyrosinase was localized only around hair follicles, melanin synthesis became more pronounced, and dopamine synthesis decreased. The data reveal a previously unrecognized TH-independent major pathway of peripheral dopamine synthesis in young, but not adult, mice. The transient nature of this source of dopamine reflects a developmental switch in tyrosinase-dependent production of dopamine to production of melanin. C1 NINDS, Sect Clin Neurocardiol, NIH, Bethesda, MD 20892 USA. NINDS, Sect Neural Dev, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Tufts Univ, Sch Med, Dept Neurosci, Boston, MA 02111 USA. Tufts Univ, Sch Med, Dept Anat, Boston, MA 02111 USA. Tufts Univ, Sch Med, Dept Cell Biol, Boston, MA 02111 USA. RP Eisenhofer, G (reprint author), NINDS, Sect Clin Neurocardiol, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC 1620, Bethesda, MD 20892 USA. EM ge@box-g.nih.gov FU NINDS NIH HHS [NS35639] NR 38 TC 36 Z9 36 U1 4 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUL PY 2003 VL 17 IS 10 BP 1248 EP 1255 DI 10.1096/fj.02-0736com PG 8 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 706TR UT WOS:000184471600036 PM 12832289 ER PT J AU Shankar, K Vaidya, VS Corton, JC Bucci, TJ Liu, J Waalkes, MP Mehendale, HM AF Shankar, K Vaidya, VS Corton, JC Bucci, TJ Liu, J Waalkes, MP Mehendale, HM TI Activation of PPAR-alpha in streptozotocin-induced diabetes is essential for resistance against acetaminophen toxicity SO FASEB JOURNAL LA English DT Article DE cell proliferation; microarray; real-time PCR; tissue repair ID PEROXISOME PROLIFERATOR CIPROFIBRATE; HEAT-SHOCK-PROTEIN; CARBON-TETRACHLORIDE HEPATOTOXICITY; ANTIMITOTIC AGENT COLCHICINE; AMELIORATES LIVER-INJURY; RECEPTOR-ALPHA; THIOACETAMIDE HEPATOTOXICITY; N-ACETYLCYSTEINE; COVALENT BINDING; MAP KINASE AB Diabetic (DB) mice exhibit significant resistance to hepatotoxicants. The role of peroxisome proliferator receptor (PPAR)-alpha activation in diabetes, in protection against lethal acetaminophen (APAP) challenge, was investigated. Upon treatment with APAP (600 mg/kg, i.p., a LD100 dose in wild-type [WT] non-DB mice), WT-DB mice showed only 30% mortality and 40% less liver injury as measured by alanine aminotransferase and histopathology. In contrast, diabetes in PPAR knockout (PPAR-alpha(-/-)) mice failed to protect against APAP toxicity, suggesting the importance of PPAR-alpha in diabetes-induced protection. S-phase DNA synthesis and PCNA immunohistochemical staining after injury showed early and robust tissue repair in WT-DB mice, but not in the PPAR-alpha(-/-) DB mice. Microarray analyses were performed on livers from non-DB and DB (WT and PPAR-alpha(-/-)) mice at 0 and 12 h after APAP. Microarray data were confirmed via real-time polymerase chain reaction analysis of several genes, including stress response, immediate early genes, DNA damage, heat shock proteins, and cell cycle regulators, followed by Western analyses of selected proteins. Gel shift assays revealed higher activation of nuclear factor-kappaB in WT-DB mice after APAP treatment. These findings suggest PPAR-alpha activation as a hepatoprotective adaptive response mediating protection against APAP in diabetes. C1 Univ Louisiana Monroe, Dept Toxicol, Sch Pharm, Coll Hlth Sci, Monroe, LA 71209 USA. Toxicogenomics, Chapel Hill, NC USA. Natl Ctr Toxicol Res, Pathol Associates Int, Jefferson, AR 72079 USA. NIEHS, Inorgan Carcinogenesis Sect, NCI, Res Triangle Pk, NC 27709 USA. RP Mehendale, HM (reprint author), Univ Louisiana Monroe, Dept Toxicol, Sch Pharm, Coll Hlth Sci, 700 Univ Ave,Sugar Hall 306, Monroe, LA 71209 USA. EM mehendale@ulm.edu NR 61 TC 38 Z9 38 U1 1 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUL PY 2003 VL 17 IS 10 BP 1748 EP + DI 10.1096/fj.02-1186fje PG 33 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 706TR UT WOS:000184471600016 PM 12958197 ER PT J AU Qian, SY Guo, Q Mason, RP AF Qian, SY Guo, Q Mason, RP TI Identification of spin trapped carbon-centered radicals in soybean lipoxygenase-dependent peroxidations of omega-3 polyunsaturated fatty acids by LC/ESR, LC/MS, and tandem MS SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE lipid-derived radicals; on-line LC/ESR; on-line LUMS; tandem mass spectrometry; lipoxygenase dependent peroxidation; free radicals ID MURINE LEUKEMIA-CELLS; FAST-ATOM-BOMBARDMENT; LIVED FREE RADICALS; IN-VIVO EVIDENCE; LIPID-PEROXIDATION; MASS-SPECTROMETRY; PHOTOFRIN PHOTOSENSITIZATION; LIQUID-CHROMATOGRAPHY; RESONANCE; DISEASE AB With the combined techniques of on-line liquid chromatography/electron spin resonance (LC/ESR) and on-line liquid chromatography/mass spectrometry (LC/MS), we have previously characterized all classes of lipid-derived carbon-centered radicals (L-.(d)) formed from omega-6 polyunsaturated fatty acids (PUFAs: linoleic acid and arachidonic acid). In the present study, the carbon-centered radicals formed from two omega-3 PUFAs (linolenic acid and docosahexaenoic acid) resulting from their reactions with soybean lipoxygenase in the presence of alpha-[4-pyridyl 1-oxide]-N-tert-butylnitrone (POBN) were investigated using the combination of LC/ESR and LC/MS techniques. A total of 16 POBN trapped carbon-centered radicals formed from the peroxidation of linolenic acid and 11 formed from the peroxidation of docosahexaenoic acid were detected by LC/ESR, identified by LC/MS, and structurally confirmed by tandem mass analysis (MS/MS). The on-line ESR chromatograms and MS chromatograms obtained from two w-3 PUFAs closely resembled each other not only because the four major beta-scission products, including an ethyl radical and three isomeric pentenyl radicals, were formed from each PUFA, but also because isomeric POBN adducts of lipid dihydroxyallylic radicals from both PUFAs had almost identical chromatographic retention times. @2003 Elsevier Inc. (C) 2003 Elsevier Inc. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Qian, SY (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 1223, Res Triangle Pk, NC 27709 USA. NR 31 TC 32 Z9 33 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL 1 PY 2003 VL 35 IS 1 BP 33 EP 44 DI 10.1016/S0891-5849(03)00217-X PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 693ME UT WOS:000183720700005 PM 12826254 ER PT J AU Dikalov, S Tordo, P Motten, A Mason, RP AF Dikalov, S Tordo, P Motten, A Mason, RP TI Characterization of the high resolution ESR spectra of the methoxyl radical adducts of 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide (DEPMPO) SO FREE RADICAL RESEARCH LA English DT Article DE spin trap; DEPMPO; alkoxyl radical; radical adduct; oxygen-17; superhyperfine structure ID SPIN TRAPS; DMPO; HYDROXYL; ALKOXYL; REASSIGNMENT; SPECTROSCOPY; ION AB Spin-trapping investigators are largely limited by the instability of the radical adducts. Spin trap 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N -oxide (DEPMPO) forms very stable alkoxyl radical adducts. However, the presence of two chiral centers in the DEPMPO alkoxyl radical adduct results in two diastereomers with distinctive ESR spectra, which complicates the interpretation of the ESR spectra. We have analyzed the high resolution ESR spectra of the DEPMPO/(OCH3)-O-. radical adduct. DEPMPO/(OCH3)-O-. has been synthesized by the nucleophilic addition of alcohols to DEPMPO. The electron spin resonance (ESR) spectrum of DEPMPO/(OCH3)-O-. in oxygen-free methanol solution reveals superhyperfine structure with hyperfine coupling constants as small as 0.3 G. In order to simplify the analysis of the electron spin resonance (ESR) spectrum, we synthesized the DEPMPO/(OCD3)-O-. radical adduct. Computer simulation of the DEPMPO/(OCD3)-O-. ESR spectrum revealed two diastereomers. Hyperfine coupling constants of gamma-protons and O-17 from the -OCH3 group were also determined. ESR spectra of DEPMPO/(OCH3)-O-. in phosphate buffer have also been characterized. The presence of specific hyperfine couplings from the -OCH3 group can be used for the unambiguous identification of the DEPMPO/(OCH3)-O-. radical adducts. We suggest that the analysis of high resolution ESR spectra can be used for the unambiguous characterization of DEPMPO radical adducts. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Univ Marseilles, Lab Struct & React Paramagnet Species, F-13397 Marseille, France. RP Dikalov, S (reprint author), Emory Univ, Sch Med, Free Rad Med Core, Div Cardiol, 1639 Pierce Dr, Atlanta, GA 30322 USA. NR 19 TC 14 Z9 14 U1 0 U2 10 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1071-5762 J9 FREE RADICAL RES JI Free Radic. Res. PD JUL PY 2003 VL 37 IS 7 BP 705 EP 712 DI 10.1080/1071576031000097508 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 678UC UT WOS:000182884000002 PM 12911266 ER PT J AU Sun, ZL Klein, AS Radaeva, S Hong, F El-Assal, O Pan, HN Jaruga, B Batkai, S Hoshino, S Tian, ZG Kunos, G Diehl, AM Gao, B AF Sun, ZL Klein, AS Radaeva, S Hong, F El-Assal, O Pan, HN Jaruga, B Batkai, S Hoshino, S Tian, ZG Kunos, G Diehl, AM Gao, B TI In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats SO GASTROENTEROLOGY LA English DT Article ID SINUSOIDAL ENDOTHELIAL-CELLS; ISCHEMIA-REPERFUSION INJURY; RECOMBINANT HUMAN INTERLEUKIN-6; INDUCED APOPTOSIS; HEPATIC STEATOSIS; KUPFFER-CELLS; GROWTH-FACTOR; ISCHEMIA/REPERFUSION INJURY; STORAGE/REPERFUSION INJURY; CHELATABLE IRON AB Background & Aims: Orthotopic liver transplantation is currently the only curative therapy for chronic end-stage liver disease and acute liver failure. However, a scarcity of cadaveric donors has led to a critical shortage of organs available for transplant. This is further complicated by the prevalence of steatosis in about 13%-50% of donor livers, which is associated with a high risk of dysfunction and primary nonfunction. Methods: Steatotic Zucker rat livers and livers from alcohol-fed rats were transplanted into lean control rats. Liver injury, activation of survival signals, and hepatic microcirculation were compared in nontreated and interleukin-6 (IL-6)-treated steatotic isografts. Results: IL-6 pretreatment of steatotic Zucker rat liver isografts dramatically reduces mortality and liver injury following transplantation. Reperfusion after transplantation induces significant sinusoidal endothelial cell necrapoptosis in steatotic Zucker rat liver isografts, which is prevented by in vitro IL-6 pretreatment. IL-6 treatment activates cell survival signal transducer and activator of transcription factor 3 (STAT3) in hepatocytes and sinusoidal endothelial cells. Laser Doppler imaging and microsphere analyses demonstrate that IL-6 treatment markedly improves hepatic microcirculation, which is impaired in steatotic Zucker rat liver transplants. Finally, in vitro IL-6 treatment of donor livers also markedly reduces mortality associated with fatty liver transplants from alcohol-fed rats. Conclusions: IL-6 induces hepatoprotection of steatotic liver isografts via preventing sinusoidal endothelial cell necrapoptosis and consequent amelioration of hepatic microcirculation, and protecting against hepatocyte death. IL-6 pretreatment of steatotic livers may render such allografts useable for clinical transplantation. C1 NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. NIAAA, Sect Neuroendocrinol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA. Univ Sci & Technol China, Sch Life Sci, Inst Immunol, Hefei, Peoples R China. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Gao, B (reprint author), NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Pk Bldg Room 120,12420 Parklawn Dr,MSC 8115, Bethesda, MD 20892 USA. RI Batkai, Sandor/G-3889-2010; Batkai, Sandor/H-7983-2014; Tian, Zhigang/J-3512-2013 NR 72 TC 90 Z9 95 U1 0 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2003 VL 125 IS 1 BP 202 EP 215 DI 10.1016/S0016-5085(03)00696-6 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 699GH UT WOS:000184048000024 PM 12851884 ER PT J AU Kawakami, K Kawakami, M Husain, SR Puri, RK AF Kawakami, K Kawakami, M Husain, SR Puri, RK TI Potent antitumor activity of IL-13 cytotoxin in human pancreatic tumors engineered to express IL-13 receptor alpha 2 chain in vivo SO GENE THERAPY LA English DT Article DE tumor antigen; gene transfer; nitric oxide; innate immunity; orthotopic model ID INTERLEUKIN (IL)-13 BINDING; HIGH-AFFINITY INTERLEUKIN-4; CELL CARCINOMA-CELLS; PSEUDOMONAS EXOTOXIN; SIGNAL-TRANSDUCTION; CHIMERIC PROTEIN; CANCER-CELLS; HUMAN BREAST; MONOCLONAL-ANTIBODY; TARGETED CYTOTOXIN AB Interleukin-13 receptor (IL-13R) alpha2 chain plays a key role in ligand binding and internalization. We have recently demonstrated that this cytokine receptor chain has unique characteristics in tumor biology: it inhibits tumorigenicity of breast and pancreatic cancer in animal models. In this study, we have exploited IL-13Ralpha2 chain and established a novel approach for pancreatic cancer therapy. For this, a plasmid encoding the IL-13Ralpha2 chain gene was mixed with liposomes and injected into subcutaneously or orthotopically xenografted human pancreatic tumors in immunodeficient mice, followed by systemic or local therapy by a recombinant IL-13 cytotoxin. Only tumors forced to express IL-13Ralpha2 chain acquired extreme susceptibility to the antitumor effect of IL-13 cytotoxin. There was a dominant infiltration of cells including macrophages and natural killer cells in the regressing tumors. Since macrophages were found to produce nitric oxide, IL-13Ralpha2-targeted cancer therapy involved not only a direct tumor cell killing by IL-13 cytotoxin but also activation of innate immune response at the tumor site. Therefore, this approach may be a new powerful tool for pancreatic cancer or other localized cancer therapy. C1 US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Lab Mol Tumor Biol, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Lab Mol Tumor Biol, NIH Bldg,29B,Room 2NN10,29 Lincoln Dr,MSC 4555, Bethesda, MD 20892 USA. NR 50 TC 16 Z9 16 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD JUL PY 2003 VL 10 IS 13 BP 1116 EP 1128 DI 10.1038/sj.gt.3301956 PG 13 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 689ZZ UT WOS:000183524000006 PM 12808442 ER PT J AU Yang, YK Yeh, TL Chen, CC Lee, CK Lee, IH Lee, LC Jeffries, KJ AF Yang, YK Yeh, TL Chen, CC Lee, CK Lee, IH Lee, LC Jeffries, KJ TI Psychiatric morbidity and posttraumatic symptoms among earthquake victims in primary care clinics SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE psychiatric morbidity; posttraumatic stress disorder; earthquakes; medical setting ID HANSHIN-AWAJI EARTHQUAKE; STRESS-DISORDER; QUESTIONNAIRE CHQ; TRAUMATIC EVENTS; GENERAL HEALTH; AREA SURVEY; COMMUNITY; TAIWAN; PERSONALITY; PREVALENCE AB Three months after the devastating Chi-Chi earthquake (magnitude of 7.3 on the Richter scale) struck the central area of Taiwan, 663 victims were screened for psychiatric morbidity at a local general hospital in a community mental health program. The rate of psychiatric morbidity as defined by the 12-item Chinese Health Questionnaire as greater than 4, was 24.5%. Posttraumatic symptoms were still prevalent. The rate of posttraumatic stress disorder was 11.3%, and the rate of partial PTSD was 32.0%. Variables associated with the presence of psychiatric morbidity and posttraumatic symptoms included female gender, old age, financial loss, obsessive trait, and nervous trait. A disproportionate use of mental health services (18%) was found, suggesting an urgent need to deliver mental health care to disaster victims at local medical settings. In addition, health care professionals who work with the earthquake victims need to be promptly and efficiently trained in mental health crisis intervention. (C) 2003 Elsevier Science Inc. All rights reserved. C1 Natl Cheng Kung Univ & Univ Hosp, Coll Med & Hosp, Dept Psychiat, Tainan, Taiwan. Puli Christian Hosp, Dept Family Med, Nantou, Taiwan. Univ N Carolina, Sch Publ Hlth, Dept Maternal & Child Hlth, Chapel Hill, NC USA. Natl Inst Hlth, Bethesda, MD USA. Pharmacia Taiwan Inc, Taipei, Taiwan. RP Yeh, TL (reprint author), Natl Cheng Kung Univ & Univ Hosp, Coll Med & Hosp, Dept Psychiat, Tainan, Taiwan. NR 41 TC 69 Z9 73 U1 3 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD JUL-AUG PY 2003 VL 25 IS 4 BP 253 EP 261 DI 10.1016/S0163-8343(03)00022-7 PG 9 WC Psychiatry SC Psychiatry GA 702AH UT WOS:000184201800006 PM 12850657 ER PT J AU Pavlovich, CP Padilla-Nash, H Wangsa, D Nickerson, ML Matrosova, V Linehan, WM Ried, T Phillips, JL AF Pavlovich, CP Padilla-Nash, H Wangsa, D Nickerson, ML Matrosova, V Linehan, WM Ried, T Phillips, JL TI Patterns of aneuploidy in cell carcinoma revealed stage IV clear cell renal by comparative genomic hybridization and spectral karyotyping SO GENES CHROMOSOMES & CANCER LA English DT Article ID TUMOR-SUPPRESSOR GENE; MOLECULAR CYTOGENETIC CHARACTERIZATION; HIPPEL-LINDAU-DISEASE; MET PROTOONCOGENE; MUTATIONS; LINES; HEREDITARY; DELETIONS; PHENOTYPE; GERMLINE AB We report the use of spectral karyotyping (SKY) and comparative genomic hybridization (CGH) to describe the numerous genomic imbalances characteristic of stage IV clear cell renal cell carcinoma (CCRCC). SKY and CGH were performed on 10 cell lines established from nephrectomy specimens, and CGH on uncultured material from five of the primary renal tumors. The mutational status of VHL (3p25) and MET (7q31), genes implicated in renal carcinogenesis, were determined for each case. Each case showed marked aneuploidy, with an average number of copy alterations of 14.6 (+/-2.7) in the primary tumors and 19.3 (+/-4.6) in the cell lines. Both whole-chromosome and chromosome-segment imbalances were noted by CGH: consistent losses or gains included +5q23-->ter (100%), -3p14-->ter (80%), and +7 (70%). All VHL mutations and 83% of the genomic imbalances found in the primary tumors were also found in the cell lines derived from them. SKY showed many complex structural rearrangements that were undetected by conventional banding analysis in these solid tumors. All cases with VHL inactivation had 3p loss and 5q gain related primarily to unbalanced translocations between 3p and 5q. In contrast, gains of chromosome 7 resulted primarily from whole-chromosome gains and were not associated with mutations of MET. SKY and CGH demonstrated that genomic imbalances in advanced RCC were the result of either segregation errors [i.e., whole chromosomal gains and losses (7.8/case)] or chromosomal rearrangements (10.7/case), of which the majority were unbalanced translocations. (C) 2003 Wiley-Liss, Inc. C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. NCI, Immunobiol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Phillips, JL (reprint author), NCI, Urol Oncol Branch, NIH, 9000 Rockville Pike,Bldg 10,2B-47, Bethesda, MD 20892 USA. NR 32 TC 17 Z9 18 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 JUL PY 2003 VL 37 IS 3 BP 252 EP 260 DI 10.1002/gcc.10209 PG 9 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 687VH UT WOS:000183397300003 PM 12759923 ER PT J AU Knutsen, T Pack, S Petropavlovskaja, M Padilla-Nash, H Knight, C Mickley, LA Ried, T Elwood, PC Roberts, SJ AF Knutsen, T Pack, S Petropavlovskaja, M Padilla-Nash, H Knight, C Mickley, LA Ried, T Elwood, PC Roberts, SJ TI Cytogenetic, spectral karyotyping, fluorescence in situ hybridization, and comparative genomic hybridization characterization of two new secondary leukemia cell lines with 5q deletions, and MYC and MLL amplification SO GENES CHROMOSOMES & CANCER LA English DT Article ID ACUTE MYELOID-LEUKEMIA; THERAPY-RELATED LEUKEMIA; ACUTE NONLYMPHOCYTIC LEUKEMIA; MYELODYSPLASTIC SYNDROME; CHROMOSOME BAND-11Q23; ALKYLATING-AGENTS; 24-COLOR FISH; REARRANGEMENTS; COMMON; GENE AB Cytogenetic studies of patients with therapy-induced acute myeloid leukemia (t-AML) have demonstrated whole chromosome loss or cl-arm deletion of chromosomes 5 and/or 7 in a majority of cases. We have established two cell lines, SAML-1 and SAML-2, from two patients who developed t-AML after radiation and chemotherapy for Hodgkin disease. In both cases, the leukemia cells contained 5q deletions. SAML-1 has 58 chromosomes and numerous abnormalities, including der(1)(1qter-->1p22::5q31-->5qter), der(5)(5pter-->5q22::1p22-->1pter), +8, der(13)i(13)(q10)del(13)(q11q14.1), and t(10;11). Fluorescence in situ hybridization (FISH) with unique sequence probes for the 5q31 region showed loss of IL4, IL5, IRF1, and IL3, and translocation of IL9, DS5S89, EGR1, and CSFIR to 1p. SAML-2 has 45 chromosomes, del(5)(q11.2q31) with a t(12;13)ins(12;5), leading to the proximity of IRF1and RB1, and complex translocations of chromosomes 8 and 11, resulting in amplification of MYC and MLL. Comparative genomic hybridization and spectral karyotyping were consistent with the G-banding karyotype and FISH analyses. Because a potential tumor suppressor(s) in the 5q31 region has yet to be identified, these cell lines should prove useful in the study of the mechanisms leading to the development of t-AML. (C) 2003 Wiley-Liss, Inc. C1 NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NCI, Canc Therapeut Branch, NIH, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Knutsen, T (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, 50 South Dr,Room 1408, Bethesda, MD 20892 USA. RI Pack, Svetlana/C-2020-2014 NR 33 TC 9 Z9 9 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD JUL PY 2003 VL 37 IS 3 BP 270 EP 281 DI 10.1002/gcc.10200 PG 12 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 687VH UT WOS:000183397300005 PM 12759925 ER PT J AU Deveney, R Chervinsky, DS Jani-Sait, SN Grossi, M Aplan, PD AF Deveney, R Chervinsky, DS Jani-Sait, SN Grossi, M Aplan, PD TI Insertion of MLL sequences into chromosome band 5q31 results in an MLL-AF5Q31 fusion and is a rare but recurrent abnormality associated with infant leukemia SO GENES CHROMOSOMES & CANCER LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; DNA-TOPOISOMERASE-II; DROSOPHILA-TRITHORAX; ALL-1 GENE; TRANSLOCATIONS; REARRANGEMENTS; TRANSCRIPTS; BREAKPOINT; CLEAVAGE AB MLL gene rearrangements leading to production of MILL fusion proteins are commonly detected in infant leukemia patients; the most common MLL fusion associated with infant leukemia is the MLL-AF4 fusion. A single case of chromosomal rearrangement leading to production of an MILL fusion with AF5Q31, a gene structurally similar to AF4, has been detected recently in the malignant cells of an infant leukemia patient. We have identified a second case of MLL-AF5Q31 fusion, arising from an insertion of MLL sequences into chromosome 5, also in an infant leukemia patient. Because MLL and AF5Q31 are transcribed in opposite orientations, a simple balanced chromosomal translocation cannot produce a fusion protein, and complex chromosomal rearrangements such as insertions and inversions are required to produce an MLL-AF5Q31 fusion protein. This report demonstrates that chromosomal insertion of MLL sequences is a rare but recurrent abnormality associated with infant leukemia. (C) 2003 Wiley-Liss, Inc. C1 NCI, Genet Branch, Ctr Canc Res, Ctr Adv Technol, Gaithersburg, MD 20892 USA. Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA. Roswell Pk Canc Inst, Dept Expt Pathol, Buffalo, NY 14263 USA. Roswell Pk Canc Inst, Dept Pediat, Buffalo, NY 14263 USA. Childrens Hosp, Div Hematol Oncol, Buffalo, NY 14222 USA. RP Aplan, PD (reprint author), NCI, Genet Branch, Ctr Canc Res, Ctr Adv Technol, Room 109D,8717 Grovemont Circle, Gaithersburg, MD 20892 USA. RI Aplan, Peter/K-9064-2016 NR 27 TC 15 Z9 15 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD JUL PY 2003 VL 37 IS 3 BP 326 EP 331 DI 10.1002/gcc.10224 PG 6 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 687VH UT WOS:000183397300012 PM 12759932 ER PT J AU Georgel, PT Fletcher, TM Hager, GL Hansen, JC AF Georgel, PT Fletcher, TM Hager, GL Hansen, JC TI Formation of higher-order secondary and tertiary chromatin structures by genomic mouse mammary tumor virus promoters SO GENES & DEVELOPMENT LA English DT Article DE chromatin; nucleosome; higher-order structure; transcription; promoter ID AGAROSE-GEL ELECTROPHORESIS; HISTONE TAIL DOMAINS; LONG TERMINAL REPEAT; RNA-POLYMERASE-III; GLUCOCORTICOID-RECEPTOR; IN-VIVO; NUCLEOSOMAL ARRAYS; MMTV PROMOTER; TRANSCRIPTIONAL REGULATION; REMODELING ENZYMES AB Agarose multigel electrophoresis has been used to characterize the structural features of isolated genomic mouse mammary tumor virus (MMTV) promoters. The mouse 3134 cells used for these studies contain similar to200 stably integrated tandem repeats of a 2.4-kb MMTV promoter fragment. Inactive, basally active, and hormonally activated genomic promoters were liberated by restriction digestion of isolated nuclei, recovered in low-salt nuclear extracts, and electrophoresed in multigels consisting of nine individual agarose running gels. Specific bands were detected and characterized by Southern and Western blotting. We find that transcriptionally inactive promoters contain TBP and high levels of histone H1, and are present to varying extents in both untreated and dexamethasone (DEX)-treated 3134 cells. In contrast, the basally active promoter, present in untreated cells, is bound to RNA Pol II, TBP, and Oct1, contains acetylated H3 tail domains, and is depleted of histone H1. The DEX-activated promoter possessed similar composition as the basal promoter, but also contains stably bound Brg1. Strikingly, all forms of the MMTV promoter condense into higher-order secondary and/or tertiary chromatin structures in vitro in the presence of Mg2+. Thus, genomic MMTV promoter chromatin retains the ability to form classical higher-order structures under physiological salt conditions, even after dissociation of H1 and binding of several transcription factors and multiprotein complexes. These results suggest that transcriptionally active eukaryotic promoters may function in a locally folded chromatin environment in vivo. C1 Univ Texas, Hlth Sci Ctr, Dept Biochem, San Antonio, TX 78229 USA. NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Hansen, JC (reprint author), Univ Texas, Hlth Sci Ctr, Dept Biochem, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. NR 72 TC 25 Z9 25 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUL 1 PY 2003 VL 17 IS 13 BP 1617 EP 1629 DI 10.1101/gad.1097603 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 698KL UT WOS:000183998600007 PM 12842912 ER PT J AU Pandya, A Arnos, KS Xia, XJ Welch, KO Blanton, SH Friedman, TB Sanchez, GG Liu, XZ Morell, R Nance, WE AF Pandya, A Arnos, KS Xia, XJ Welch, KO Blanton, SH Friedman, TB Sanchez, GG Liu, XZ Morell, R Nance, WE TI Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probands SO GENETICS IN MEDICINE LA English DT Article DE GJB2 (connexin 26); GJB6 (connexin 30); genetic hearing loss; national DNA repository; prevalence ID NONSYNDROMIC HEARING-LOSS; SENSORINEURAL DEAFNESS; RECESSIVE DEAFNESS; UNITED-STATES; GENE GJB2; FAMILIES; DFNB1 AB Purpose: Profound hearing loss occurs with a frequency of 1 in 1000 live births, half of which is genetic in etiology. The past decade has witnessed rapid advances in determining the pathogenesis of both syndromic and nonsyndromic deafness. The most significant clinical finding to date has been the discovery that mutations of GJB2 at the DFNB1 locus are the major cause of profound prelingual deafness in many countries. More recently, GJB2 mutations have been shown to cause deafness when present with a deletion of the GJB6 gene. We report on the prevalence of GJB2 and GJB6 mutations in a large North American Repository of DNA from deaf probands and document the profound effects of familial ethnicity and parental mating types on the frequency of these mutations in the population. Methods: Deaf probands were ascertained through the Annual Survey of Deaf and Hard of Hearing Children and Youth, conducted at the Research Institute of Gallaudet University. Educational, etiologic, and audiologic information was collected after obtaining informed consent. DNA studies were performed for the GJB2 and GJB6 loci by sequencing and PCR methods. Results: GJB2 mutations accounted for 22.2% of deafness in the overall sample but differed significantly among Asians, African-Americans and Hispanics and for probands from deaf by deaf and deaf by hearing matings, as well as probands from simplex and multiplex sibships of hearing parents. In our sample, the overall incidence of GJB2/GJB6 deafness was 2.57%. Conclusion: GJB2 mutations account for a large proportion of deafness in the US, with certain mutations having a high ethnic predilection. Heterozygotes at the GJB2 locus should be screened for the GJB6 deletion as a cause of deafness. Molecular testing for GJB2 and GJB6 should be offered to all patients with nonsyndromic hearing loss. C1 Virginia Commonwealth Univ, Med Coll Virginia, Dept Human Genet, Richmond, VA 23298 USA. Gallaudet Univ, Dept Biol, Washington, DC 20002 USA. Univ Virginia, Genet Sect, Dept Human Genet, Charlottesville, VA 22903 USA. NIH, Genet Mol Lab, Natl Inst Deafness & Other Commun Disorders, Bethesda, MD 20892 USA. Inst Commun Humana, Lomas De Plateros, Mexico. Univ Miami, Dept Otolaryngol, Miami, FL 33152 USA. RP Pandya, A (reprint author), Virginia Commonwealth Univ, Med Coll Virginia, Dept Human Genet, POB 980033, Richmond, VA 23298 USA. FU NICHD NIH HHS [K08-HD01172-01A1]; NIDCD NIH HHS [1 R01 DC02430, 1R01 DC04293]; NIMHD NIH HHS [263-MD-814375] NR 36 TC 90 Z9 98 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD JUL-AUG PY 2003 VL 5 IS 4 BP 295 EP 303 DI 10.1097/01.GIM.0000078026.01140.68 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 709QU UT WOS:000184636500005 PM 12865758 ER PT J AU Gollust, SE Wilfond, BS Hull, SC AF Gollust, SE Wilfond, BS Hull, SC TI Direct-to-consumer sales of genetic services on the Internet SO GENETICS IN MEDICINE LA English DT Article DE genetic testing; Internet; direct-to-consumer services; education ID MEDICAL GENETICS; HEALTH INFORMATION; PERSPECTIVE; KNOWLEDGE; DISCRIMINATION; ATTITUDES; RESOURCES; QUALITY; TESTS AB Purpose: The increasing use of the Internet to obtain genetics information and to order medical services without a prescription, combined with a rise in direct-to-consumer marketing for genetic testing, suggests the potential for the Internet to be used to sell genetic services. Methods: A systematic World Wide Web search was conducted in May 2002 to assess the availability of genetic services sold directly to consumers on the Internet. Results: Out of 105 sites that offered genetic services directly, most offered non-health-related services, including parentage confirmation testing (83%), identity testing (56%), and DNA banking (24%); however, health-related genetic tests were offered through 14 sites (13%). The health-related genetic tests available ranged from standard tests, such as hemochromatosis and cystic fibrosis, to more unconventional tests related to nutrition, behavior, and aging. Of these 14 sites, 5 described risks associated with the genetic services and 6 described the availability of counseling. Conclusions: The availability of direct sales of health-related genetic tests creates the potential for inadequate pretest decision making, misunderstanding test results, and access to tests of questionable clinical value. C1 NIH, Med Genet Branch, NHGRI, Bethesda, MD 20892 USA. NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Wilfond, BS (reprint author), NIH, Med Genet Branch, NHGRI, Bldg 10,Rm 1C118,9000 Rockville Pike,MSC 1156, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 HG999999] NR 37 TC 88 Z9 89 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD JUL-AUG PY 2003 VL 5 IS 4 BP 332 EP 337 DI 10.1097/01.GIM.0000076972.83711.48 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 709QU UT WOS:000184636500010 PM 12865763 ER PT J AU Alford, RL Friedman, TB Keats, BJB Kimberling, WJ Proud, VK Smith, RJH Arnos, KS Korf, BR Rehm, HL Toriello, HV AF Alford, RL Friedman, TB Keats, BJB Kimberling, WJ Proud, VK Smith, RJH Arnos, KS Korf, BR Rehm, HL Toriello, HV TI Early childhood hearing loss: Clinical and molecular genetics. An educational slide set of the American College of Medical Genetics SO GENETICS IN MEDICINE LA English DT Editorial Material DE education; hearing loss; deafness; slides AB An educational slide set entitled "Early Childhood Hearing Loss: Clinical and Molecular Genetics" is offered by the American College of Medical Genetics (ACMG). The slide set is produced in Microsoft PowerPoint 2002. It is extensively illustrated and supported with teaching tools, explanations of each slide and figure, links to Internet resources, and a bibliography. The slide set is expected to be used as a resource for self-directed learning and in support of medical genetics teaching activities. The slide set is available through the ACMG (http://www.acmg.net) for $20, plus applicable tax and shipping. It is the first in a series of educational slide sets to be developed by the ACMG. C1 Baylor Coll Med, Bobby R Alford Dept Otorhinolaryngol & Commun Sci, Houston, TX 77030 USA. NIH, Genet Mol Lab, Natl Inst Deafness & Other Commun Disorders, Rockville, MD USA. Louisiana State Univ, Hlth Sci Ctr, Dept Genet, New Orleans, LA 70112 USA. Boystown Natl Res Hosp, Omaha, NE USA. Childrens Hosp Kings Daughters, Norfolk, VA USA. Univ Iowa Hosp & Clin, Dept Otolaryngol Head & Neck Surg, Mol Otolaryngol Res Labs, Iowa City, IA 52242 USA. Gallaudet Univ, Dept Biol, Washington, DC 20002 USA. Univ Alabama, Sch Med, Dept Genet, Birmingham, AL USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. DeVos Childrens Hosp, Grand Rapids, MI USA. RP Alford, RL (reprint author), Baylor Coll Med, Bobby R Alford Dept Otorhinolaryngol & Commun Sci, 1 Baylor Plaza,NA102, Houston, TX 77030 USA. NR 3 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD JUL-AUG PY 2003 VL 5 IS 4 BP 338 EP 341 DI 10.1097/01.GIM.0000077415.19887.08 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 709QU UT WOS:000184636500011 PM 12865764 ER PT J AU Karaman, MW Houck, ML Chemnick, LG Nagpal, S Chawannakul, D Sudano, D Pike, BL Ho, VV Ryder, OA Hacia, JG AF Karaman, MW Houck, ML Chemnick, LG Nagpal, S Chawannakul, D Sudano, D Pike, BL Ho, VV Ryder, OA Hacia, JG TI Comparative analysis of gene-expression patterns in human and African great ape cultured fibroblasts SO GENOME RESEARCH LA English DT Article ID DENSITY OLIGONUCLEOTIDE ARRAYS; REFSUM-DISEASE; SEGMENTAL DUPLICATIONS; GLYPICAN-3 EXPRESSION; PERICENTRIC-INVERSION; HUMAN-EVOLUTION; HUMAN BRAIN; CHIMPANZEE; ACID; DIVERGENCE AB Although much is known about genetic variation in human and African great ape (chimpanzee, bonobo, and gorilla) genomes, substantially less is known about variation in gene-expression profiles within and among these species. This information is necessary for defining transcriptional regulatory networks that contribute to complex phenotypes unique to humans or the African great apes. We took a systematic approach to this problem by investigating gene-expression profiles in well-defined cell populations from humans, bonobos, and gorillas. By comparing these profiles from 18 human and 21 African great ape primary fibroblast cell lines, we found that gene-expression patterns could predict the species, but not the age, of the fibroblast donor. Several differentially expressed genes among human and African great ape fibroblasts involved the extracellular matrix, metabolic pathways, signal transduction, stress responses, as well as inherited overgrowth and neurological disorders. These gene-expression patterns could represent molecular adaptations that influenced the development of species-specific traits in humans and the African great apes. C1 Univ So Calif, Inst Med Genet, Los Angeles, CA 90089 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Zool Soc San Diego, Ctr Reprod Endangered Species, San Diego, CA 92112 USA. RP Hacia, JG (reprint author), Univ So Calif, Inst Med Genet, Los Angeles, CA 90089 USA. NR 59 TC 79 Z9 82 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD JUL PY 2003 VL 13 IS 7 BP 1619 EP 1630 DI 10.1101/gr.1289803 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 697YC UT WOS:000183970000008 PM 12840040 ER PT J AU Collins, JR Stephens, RM Gold, B Long, B Dean, M Burt, SK AF Collins, JR Stephens, RM Gold, B Long, B Dean, M Burt, SK TI An exhaustive DNA micro-satellite map of the human genome using high performance computing SO GENOMICS LA English DT Article ID ALIGNMENT SCORE; TANDEM REPEATS; SEQUENCES; ALGORITHMS AB The current pace of the generation of sequence data requires the development of software tools that can rapidly provide full annotation of the data. We have developed a new method for rapid sequence comparison using the exact match algorithm without repeat masking. As a demonstration, we have identified all perfect simple tandem repeats (STR) within the draft sequence of the human genome. The STR elements (chromosome, position, length and repeat subunit) have been placed into a relational database. Repeat flanking sequence is also publicly accessible at http://grid.abcc.ncifcrf.gov. To illustrate the utility of this complete set of STR elements, we documented the increased density of potentially polymorphic markers throughout the genome. The new STR markers may be useful in disease association studies because so many STR elements manifest multiallelic polymorphism. Also, because triplet repeat expansions are important for human disease etiology, we identified trinucleotide repeats that exist within exons of known genes. This resulted in a list that includes all 14 genes known to undergo polynucleotide expansion, and 48 additional candidates. Several of these are non-polyglutamine triplet repeats. Other examinations of the STR database demonstrated repeats spanning splice junctions and identified SNPs within repeat elements. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. NCI, Adv Biomed Comp Ctr, Frederick, MD 21701 USA. Cray Inc, Mendota Hts, MN USA. RP Dean, M (reprint author), NCI, Lab Genom Divers, Bldg 560,Rm 21-18, Frederick, MD 21702 USA. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU PHS HHS [N01-C0-12400] NR 24 TC 36 Z9 37 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD JUL PY 2003 VL 82 IS 1 BP 10 EP 19 DI 10.1016/S0888-7543(03)00076-4 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 693YV UT WOS:000183746700002 PM 12809672 ER PT J AU Suh, KS Tatunchak, TT Crutchley, JM Edwards, LE Marin, KG Yuspa, SH AF Suh, KS Tatunchak, TT Crutchley, JM Edwards, LE Marin, KG Yuspa, SH TI Genomic structure and promoter analysis of PKC-delta SO GENOMICS LA English DT Article DE PKC-delta; apoptosis; genomic; promoter; NF kappa B ID PROTEIN-KINASE-C; TUMOR-NECROSIS-FACTOR; KAPPA-B ACTIVATION; CAENORHABDITIS-ELEGANS; SIGNAL-TRANSDUCTION; FACTOR-ALPHA; CELL-GROWTH; EXPRESSION; GENE; APOPTOSIS AB Protein kinase C-delta (PKC-delta) is a ubiquitously expressed kinase involved in a variety of cellular signaling pathways including cell growth, differentiation, apoptosis, tumor promotion, and carcinogenesis. While signaling pathways downstream of PKC-delta are well studied, the regulation of the gene has not been extensively analyzed. A mouse genomic DNA fragment containing the PKC-delta gene was sequenced by the primer-walking method, and the subsequent DNA sequence data were used as a query to clone Caenorhabditis elegans and human genomic homologs from the publicly available genomic databases. The genomic structures of C. elegans, mouse, rat, and human PKC-delta were analyzed, and the result revealed that PKC-delta genes comprise 12, 18, 19, and 18 exons for C. elegans, mouse, rat, and human, respectively. The translation start methionine resides in the second exon in mouse and human and in the third exon in rat. The first intron between the first exon and the exon with the translation start methionine in mammalian genes represents a very large gap, as long as 17 kb in human, indicating a complexity involved in gene splicing. Overall exon-intron genomic structure is highly conserved among mammals, while significantly diverged in C. elegans. Putative transcription factor binding sites on the 1.7-kb promoter region of the mouse gene suggest that PKC-delta might be involved in spermatogenesis, embryogenesis, development, brain generation, immune response, oxidative environment, and oncogenesis. Studies on the promoter and subsequent biological testing on mouse keratinocytes indicate that tumor necrosis factor (TNF)-alpha increases the expression of PKC-delta, and this correlates with the time of NFkappaB nuclear translocation and activation. This TNF-alpha-mediated upregulation of PKC-delta is repressed in keratinocytes that are preinfected with IkappaB superrepressor adenovirus, suggesting that NFkappaB is involved directly in PKC-delta expression. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NCI, Ctr Canc Res, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. RP Yuspa, SH (reprint author), NCI, Ctr Canc Res, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. EM yuspas@dc37a.nci.nih.gov NR 44 TC 29 Z9 29 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 JUL PY 2003 VL 82 IS 1 BP 57 EP 67 DI 10.1016/S0888-7543(03)00072-7 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 693YV UT WOS:000183746700006 PM 12809676 ER PT J AU Young, WW Holcomb, DR Ten Hagen, KG Tabak, LA AF Young, WW Holcomb, DR Ten Hagen, KG Tabak, LA TI Expression of UDP-GaINAc : polypeptide N-acetylgalactosaminyltransferase isoforms in murine tissues determined by real-time PCR: a new view of a large family SO GLYCOBIOLOGY LA English DT Article DE glycosyltransferases; mucins; O-linked glycosylation; real-time PCR ID ALPHA-D-GALACTOSAMINE; GALNAC-TRANSFERASES; MOLECULAR-CLONING; MEMBER; N-ACETYLGALACTOSAMINYLTRANSFERASE-T3; DROSOPHILA; GLYCANS; GENE AB The members of the UDP-GalNAc:polypeptide N-acetyl-galactosaminyltransferase (ppGaNTase) family transfer GalNAc to serine and threonine sites and initiate mucin-type O-glycosylation. There are at least 13 functionally characterized family members in mammals. Explanations for the large size of this enzyme family have included functional redundancy, differences among isoforms in substrate specificity, and specific expression of individual isoforms in particular tissues or during certain developmental stages. To date no quantitative comparison of the levels of all ppGaNTase isoforms in any tissue of any species has been reported. We performed real-time polymerase chain reaction using the Taqman method to determine the expression of ppGaNTase isoforms in mouse tissues. Several tissues exhibited a common pattern in which isoforms T1 and T2 were the most strongly expressed, although the level of expression varied widely among tissues. In striking contrast to this general pattern, testis, sublingual gland, and colon exhibited distinctive profiles of isoform expression. Isoform T13 was expressed most strongly in brain, and one putative isoform was expressed only in testis. In mammary tissue the expression of several isoforms changed markedly during pregnancy and lactation. In summary these real-time PCR data indicate the contribution of each isoform to the overall ppGaNTase expression within each tissue and highlight the particular isoforms and tissues that will be the targets of future studies on the functions of the ppGaNTase family. C1 Univ Louisville, Sch Dent, Dept Mol Cellular & Craniofacial Biol, Louisville, KY 40292 USA. Univ Louisville, Sch Med, Dept Biochem & Mol Biol, Louisville, KY 40292 USA. Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. NIDDKD, Biol Chem Sect, NIH, Bethesda, MD 20892 USA. RP Young, WW (reprint author), Univ Louisville, Sch Dent, Dept Mol Cellular & Craniofacial Biol, Louisville, KY 40292 USA. NR 31 TC 47 Z9 52 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD JUL PY 2003 VL 13 IS 7 BP 549 EP 557 DI 10.1093/glycob/cwg062 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 693NX UT WOS:000183724600006 PM 12651884 ER PT J AU Annunziata, CM Kohn, EC AF Annunziata, CM Kohn, EC TI Is there a genomic basis for primary chemoresistance in ovarian cancer? SO GYNECOLOGIC ONCOLOGY LA English DT Editorial Material ID HYBRIDIZATION; MICROARRAYS C1 NCI, Med Ovarian Canc Clin, GU GYN Clin Res Sect, Med Oncol Clin Res Unit,Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Mol Signaling Sect, Pathol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. RP Kohn, EC (reprint author), NCI, Med Ovarian Canc Clin, GU GYN Clin Res Sect, Med Oncol Clin Res Unit,Ctr Canc Res, Bethesda, MD 20892 USA. RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 NR 12 TC 2 Z9 2 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 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUL PY 2003 VL 90 IS 1 BP 1 EP 2 DI 10.1016/S0090-8258(03)00315-9 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 695MA UT WOS:000183833600001 PM 12821333 ER PT J AU Agrawal, M Edgerly, M Fojo, T Kotz, H AF Agrawal, M Edgerly, M Fojo, T Kotz, H TI Treatment of recurrent cervical adenocarcinoma with BMS-247550, an epothilone B analog SO GYNECOLOGIC ONCOLOGY LA English DT Article ID GYNECOLOGIC-ONCOLOGY-GROUP; SQUAMOUS-CELL-CARCINOMA; PHASE-II TRIAL; UTERINE CERVIX; COMBINATION CHEMOTHERAPY; PROGNOSTIC FACTORS; CISPLATIN; PACLITAXEL; SURVIVAL; CANCER AB Objective. The incidence of recurrent cervical adenocarcinoma is rising relative to the squamous subtype. There are limited therapeutic options for women with advanced cervical adenocarcinoma. Only a few chemotherapy agents have demonstrated activity in this disease. This report describes results with BMS-247550, an epothilone B analog that stabilizes microtubules, with activity in previously treated adenocarcinoma of the cervix. Method. We present two women with recurrent cervical adenocarcinoma with metastases to the lung. Both women were treated previously with paclitaxel and were enrolled in a phase I study with BMS-247550. Results. Both women had partial responses to BMS-247550 with a decrease in tumor size and CA-125 levels. Conclusions. The demonstration of a response to BMS-247550, especially after additional chemotherapy had been administered, is encouraging, albeit preliminary. The ultimate role of BMS-247550 and multiagent chemotherapy in the treatment of adenocarcinoma of the cervix should be further investigated. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NCI, Canc Res Ctr, Bethesda, MD 20892 USA. RP Fojo, T (reprint author), NCI, Canc Res Ctr, Bldg 10-12C103,Room 12N226, Bethesda, MD 20892 USA. NR 23 TC 14 Z9 15 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 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUL PY 2003 VL 90 IS 1 BP 96 EP 99 DI 10.1016/S0090-8258(03)00146-X PG 4 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 695MA UT WOS:000183833600016 PM 12821348 ER PT J AU Li, SF Chiang, TC Richard-Davis, G Barrett, JC Mclachlan, JA AF Li, SF Chiang, TC Richard-Davis, G Barrett, JC Mclachlan, JA TI DNA hypomethylation and imbalanced expression of DNA methyltransferases (DNMT1, 3A, and 3B) in human uterine leiomyoma SO GYNECOLOGIC ONCOLOGY LA English DT Article DE uterine leiomyoma; methylation; DNA methyltransferase; real time PCR ID MENSTRUAL-CYCLE; IN-VITRO; METHYLATION; CANCER; TUMORS; GENE; MYOMETRIUM; HYPERMETHYLATION; OVEREXPRESSION; TRANSCRIPTION AB Objective. Despite the high prevalence of uterine leiomyoma in women, little is known about the pathophysiology of this tumor. This study intends to define the epigenetic modulation of this tumor. Methods. Twenty-three pairs of leiomyomas and their adjacent myometria were collected. Status of DNA global methylation was determined by using DNA methyl acceptance assay and immunohistochemistry staining with 5-methylcytidine antibody. MRNA level of DNA methyltransferases (DNMT1, 3A, and 313) was assessed by quantitative real time PCR. Results. DNA global hypomethylation was detected in the leiomyoma tissues as compared with the adjacent myometria. DNMT1 expression was increased in 47.5% and was equal in 47.5% in leiomyomas compared to the adjacent myometria. On the other hand, over 74% of cases showed decreased expression of DNMT3A and 313 in leiomyomas compared to the adjacent myometria. Conclusion. Global hypomethylation and imbalanced expression of DNMTs in uterine leiomyoma suggested a potential mechanism of epigenetic modulation in the development of this tumor. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Tulane Xavier Univ, Ctr Bioenvironm Res, New Orleans, LA 70112 USA. Tulane Xavier Univ, Dept Pharmacol, New Orleans, LA 70112 USA. NCI, Lab Biosyst & Canc, NIH, Bethesda, MD 20892 USA. RP Li, SF (reprint author), NIEHS, LBC, C2-10,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 44 TC 32 Z9 36 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUL PY 2003 VL 90 IS 1 BP 123 EP 130 DI 10.1016/S0090-8258(03)00194-X PG 8 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 695MA UT WOS:000183833600020 PM 12821352 ER PT J AU Amundson, SA Fornace, AJ AF Amundson, SA Fornace, AJ TI Monitoring human radiation exposure by gene expression profiling: Possibilities and pitfalls SO HEALTH PHYSICS LA English DT Article; Proceedings Paper CT 38th Annual Meeting of the National-Council-on-Radiation-Protection-and-Measurements CY APR 10-11, 2002 CL ARLINGTON, VA SP Natl Council Radiat Protect Measurements DE NCRP; dose, low; health effects; genetic effects, radiation ID ANTICANCER AGENTS; HUMAN FIBROBLASTS; GENOTOXIC STRESS; CDNA MICROARRAY; CELL-LINES; P53; APOPTOSIS; INDUCTION; CANCER; TUMOR AB Advances in high throughput analysis of mRNA expression have made it possible to establish gene expression profiles for different cells, tissues, diseases and exposure states. For instance, recent studies have demonstrated the utility of such an approach to classify sub-types of cancers with more detail than was previously possible. In addition, gene expression studies of ionizing radiation exposure both in vitro and in vivo are affording insight into the molecular mechanisms of mammalian radiation response. We have demonstrated that radiation expression profiles are a good predictor of p53 function in cell lines, and such profiles also indicate a major role for p53-regulated genes in the in vivo radiation response. Gene expression can be a sensitive indicator of radiation response as we have shown linear dose-responses for induction of several genes down to doses as low as 2 cGy. As profiles are established from radiation studies, it is hoped that they may be useful for identifying individuals with specific exposures or predisposition to negative outcome of exposure. Although this technology holds great promise, some obstacles remain to be overcome before it can be successfully applied to population studies. C1 NCI, Gene Response Sect, NIH, Bethesda, MD 20892 USA. RP Amundson, SA (reprint author), NCI, Gene Response Sect, NIH, 37 Convent Dr,Bldg 37,Rm 6144, Bethesda, MD 20892 USA. EM amundson@mail.nih.gov RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 36 TC 34 Z9 37 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUL PY 2003 VL 85 IS 1 BP 36 EP 42 DI 10.1097/00004032-200307000-00009 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 691JT UT WOS:000183603400009 PM 12852469 ER PT J AU Preston, DL Pierce, DA Shimizu, Y Ron, E Mabuchi, K AF Preston, DL Pierce, DA Shimizu, Y Ron, E Mabuchi, K TI Dose response and temporal patterns of radiation-associated solid cancer risks SO HEALTH PHYSICS LA English DT Article; Proceedings Paper CT 38th Annual Meeting of the National-Council-on-Radiation-Protection-and-Measurements CY APR 10-11, 2002 CL ARLINGTON, VA SP Natl Council Radiat Protect Measurements DE NCRP; cancer; health effects; dose ID ATOMIC-BOMB SURVIVORS; CONSUMPTION; MORTALITY AB Findings of the Life Span Study (LSS) cohort of atomic-bomb survivors are a primary source for quantitative risk estimates that underlie radiation protection. Because of the size and length of follow-up, the LSS provides considerable information on both the nature of the dose response and on how radiation-associated excess risks vary with age, age at exposure, sex, and other factors. Our current analyses extend the mortality follow-up by 7 y (through 1997) and add 8 y (through 1995) to the incidence follow-up. During the follow-up periods there have been a total of about 9,300 solid cancer deaths and almost 12,200 incident cases. As outlined in this presentation, while discussing issues related to the shape of the dose response and low dose risks in some detail, the new reports consider temporal patterns in greater detail than has been done previously. As we have reported, the LSS solid cancer dose response is well described by simple linear dose response over the 0 to 2 Sv range (with some leveling off at higher estimated doses). This remains the case with the extended follow-up. Although LSS is often referred to as a high dose study, about 75% of the 50,000 cohort members with doses in excess of 5 mSv have dose estimates in a range of direct interest for radiation protection (0-200 mSv). Analyses of data limited to this low dose range provide direct evidence of a significant solid cancer dose response with a risk per unit dose that is consistent with that seen for the full dose range. Previous LSS reports have focused on descriptions of the solid cancer excess risks in which the excess relative risk varies with age at exposure and sex. In addition to the age at exposure effects, our current analyses suggest excess relative risks also vary with age (at death or diagnosis). Excess relative risks are higher for those exposed earlier in life, with attained age-specific risks changing by about 20% per decade, but tend to decrease with increasing attained age, roughly in proportion to (1/attained-age)(1.5), for any age at exposure. Despite the decreasing relative risk, excess rates have increased rapidly throughout the study period with some indication, especially for the incidence data, that attained-age-specific rates are higher for those exposed at younger ages. Simple comparisons of site-specific excess risks are used to illustrate how the interpretation of age-at-exposure effects on excess relative risks or excess rates is complicated by changes in baseline rates with birth cohort or time period. C1 Radiat Effects Res Fdn, Dept Stat, Minami Ku, Hiroshima 7320815, Japan. Radiat Effects Res Fdn, Dept Epidemiol, Rockville, MD 20852 USA. NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Preston, DL (reprint author), Radiat Effects Res Fdn, Dept Stat, Minami Ku, 5-2 Hijiyama Koen, Hiroshima 7320815, Japan. EM preston@rerf.or.jp NR 11 TC 38 Z9 41 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUL PY 2003 VL 85 IS 1 BP 43 EP 46 DI 10.1097/00004032-200307000-00010 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 691JT UT WOS:000183603400010 PM 12852470 ER PT J AU Ron, E AF Ron, E TI Cancer risks from medical radiation SO HEALTH PHYSICS LA English DT Article; Proceedings Paper CT 38th Annual Meeting of the National-Council-on-Radiation-Protection-and-Measurements CY APR 10-11, 2002 CL ARLINGTON, VA SP Natl Council Radiat Protect Measurements DE NCRP; cancer; medical radiation; health effects ID ATOMIC-BOMB SURVIVORS; DIAGNOSTIC X-RAYS; CANADIAN FLUOROSCOPY COHORT; RATE IONIZING-RADIATION; INDUCED THYROID-CANCER; BREAST-CANCER; HODGKINS-DISEASE; CHILDHOOD-CANCER; RADIOACTIVE THOROTRAST; INTRAUTERINE EXPOSURE AB About 15% of the ionizing radiation exposure to the general public comes from artificial sources, and almost all of this exposure is due to medical radiation, largely from diagnostic procedures. Of the approximately 3 mSv annual global per caput effective dose estimated for the year 2000, 2.4 mSv is from natural background and 0.4 mSv from diagnostic medical exams. Diagnostic and therapeutic radiation was used in patients as early as 1896. Since then, continual improvements in diagnostic imaging and radiotherapy as well as the aging of our population have led to greater use of medical radiation. Temporal trends indicate that worldwide population exposure from medical radiation is increasing. In the United States, there has been a steady rise in the use of diagnostic radiologic procedures, especially x rays. Radiotherapy also has increased so that today about 40% of cancer patients receive some treatment with radiation. Epidentiologic data on medically irradiated populations are an important complement to the atomic-bomb survivors' studies. Significant improvement in cancer treatment over the last few decades has resulted in longer survival and a growing number of radiation-related second cancers. Following high-dose radiotherapy for malignant diseases, elevated risks of a variety of radiation-related second cancers have been observed. Risks have been particularly high following treatment for childhood cancer. Radiation treatment for benign disease was relatively common from the 1940's to the 1960's. While these treatments generally were effective, some resulted in enhanced cancer risks. As more was learned about radiation-associated cancer risks and new treatments became available, the use of radiotherapy for benign disease has declined. At moderate doses, such as those used to treat benign diseases, radiation-related cancers occur in or near the radiation field. Cancers of the thyroid, salivary gland, central nervous system, skin, and breast as well as leukemia have been associated with radiotherapy for tinea capitis, enlarged tonsils or thymus gland, other benign conditions of the head and neck, or benign breast diseases. Because doses from diagnostic examinations typically are low, they are difficult to study using epidentiologic methods, unless multiple examinations are performed. An excess risk of breast cancer has been reported among women with tuberculosis who had multiple chest fluoroscopies as well as among scoliosis patients who had frequent diagnostic x rays during late childhood and adolescence. Dental and medical diagnostic x rays performed many years ago, when doses were presumed to be high, also have been linked to increased cancer risks. The carcinogenic effects of diagnostic and therapeutic radionuclides are less well characterized. High risks of liver cancer and leukemia have been demonstrated following thorotrast injections, and patients treated with radium appear to have an elevated risk of bone sarcomas and possibly cancers of the breast, liver, kidney, thyroid, and bladder. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP NCI, Div Canc Epidemiol & Genet, EPS 7048,6120 Execut Blvd, Bethesda, MD 20892 USA. EM eron@mail.nih.gov NR 95 TC 190 Z9 197 U1 3 U2 23 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUL PY 2003 VL 85 IS 1 BP 47 EP 59 DI 10.1097/00004032-200307000-00011 PG 13 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 691JT UT WOS:000183603400011 PM 12852471 ER PT J AU Fan, XF Lang, DM Xu, YJ Lyra, AC Yusim, K Everhart, JE Korber, BTM Perelson, AS Di Bisceglie, AM AF Fan, XF Lang, DM Xu, YJ Lyra, AC Yusim, K Everhart, JE Korber, BTM Perelson, AS Di Bisceglie, AM TI Liver transplantation with hepatitis C virus-infected graft: Interaction between donor and recipient viral strains SO HEPATOLOGY LA English DT Article ID HYPERVARIABLE REGION-1; GENOTYPES; RECOMBINATION; HCV; SUPERINFECTION; EVOLUTION; GENOME; HEMOPHILIACS; REINFECTION; EXCLUSION AB Superinfection of different viral strains within a single host provides an opportunity for studying host-virus and virus-virus interactions, including viral interference and genetic recombination, which cannot be studied in infections with single viral strains. Hepatitis C virus (HCV) is a positive single-strand RNA virus that establishes persistent infection in as many as 85% of infected individuals. However, there are few reports regarding coinfection or superinfection of HCV. Because of the lack of tissue culture systems and small animal models supporting efficient HCV replication, we explored these issues in the setting of liver transplantation where both recipient and donor were infected with different HCV strains and therefore represent a distinct model for HCV superinfection. Serial serum samples collected at multiple time points were obtained from 6 HCV-positive liver donor/recipient pairs from the National Institute of Diabetes and Digestive and Kidney Diseases liver transplantation database. At each time point, HCV genotype was determined by both restriction fragment length polymorphism analysis and phylogenetic analysis. Furthermore, we selectively sequenced 3 full-length HCV isolates at the earliest time points after liver transplantation, including both 5' and 3' ends. Detailed genetic analyses showed that only one strain of HCV could be identified at each time point in all 6 cases. Recipient HCV strains took over in 3 cases, whereas donor HCV strains dominated after liver transplantation in the remaining 3 cases. In conclusion, in all 6 cases studied, there was no genetic recombination detected among HCV quasispecies or between donor and recipient HCV strains. C1 St Louis Univ, Sch Med, Dept Internal Med, Div Gastroenterol & Hepatol, St Louis, MO 63110 USA. NIDDK, Div Digest Dis & Nutr, Bethesda, MD USA. Los Alamos Natl Lab, Theoret Biol & Biophys Grp, Los Alamos, NM USA. RP Di Bisceglie, AM (reprint author), St Louis Univ, Sch Med, Dept Internal Med, Div Gastroenterol & Hepatol, 3635 Vista Ave, St Louis, MO 63110 USA. OI Korber, Bette/0000-0002-2026-5757 FU NCRR NIH HHS [RR06555]; NIDDK NIH HHS [R01 DK56435-01] NR 49 TC 22 Z9 22 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 JUL PY 2003 VL 38 IS 1 BP 25 EP 33 DI 10.1053/jhep.2003.50264 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 695MD UT WOS:000183833900005 PM 12829983 ER PT J AU Hoofnagle, JH Ghany, MG Kleiner, DE Doo, E Heller, T Promrat, K Ong, J Khokhar, F Soza, A Herion, D Park, Y Everhart, JE Liang, TJ AF Hoofnagle, JH Ghany, MG Kleiner, DE Doo, E Heller, T Promrat, K Ong, J Khokhar, F Soza, A Herion, D Park, Y Everhart, JE Liang, TJ TI Maintenance therapy with ribavirin in patients with chronic hepatitis C who fail to respond to combination therapy with interferon alfa and ribavirin SO HEPATOLOGY LA English DT Article ID PLUS RIBAVIRIN; HISTOLOGIC IMPROVEMENT; SUSTAINED RESPONSE; PROLONGED THERAPY; INITIAL TREATMENT; RANDOMIZED TRIAL; FOLLOW-UP; VIRUS; INFECTION; PLACEBO AB To assess the efficacy and safety of maintenance therapy with ribavirin alone in chronic hepatitis C, 108 patients were treated with the combination of interferon alfa and ribavirin for 24 weeks; those who failed to have a virologic response were offered enrollment in a randomized, double-blind, controlled trial of ribavirin (1,000-1,200 mg daily) versus placebo for the subsequent 48 weeks. Patients were monitored at regular intervals with symptom questionnaires, serum aminotransferase levels, hepatitis C virus (HCV) RNA levels, and complete blood counts and underwent liver biopsy at the completion of therapy. Among 108 patients, 50 were still HCV RNA positive after 24 weeks of treatment, of whom 34 agreed to be randomized to continue either ribavirin monotherapy or placebo. Among 17 patients who received placebo, there was no overall improvement in symptoms, serum alanine aminotransferase (ALT) levels, HCV RNA levels, or hepatic histology. Among the 17 patients who received ribavirin, serum ALT levels and necroinflammatory features of liver histology were improved, whereas symptoms, HCV RNA levels, and hepatic fibrosis scores were not changed significantly from baseline. Responses to ribavirin seemed to be categorical, such that 8 patients (47%) had definite improvement in liver histology. Patients with improved histology had improvements in serum ALT levels both on combination therapy and after switching to ribavirin monotherapy. In conclusion, continuation of ribavirin monotherapy may maintain serum biochemical improvements that occur during interferon-ribavirin combination therapy in some patients and that these improvements are often associated with decreases in necroinflammatory changes in the liver. Whether these improvements will ultimately result in prevention of progression of hepatitis C requires further study. C1 NIDDK, Liver Dis Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. NIDDK, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Hoofnagle, JH (reprint author), NIDDK, Liver Dis Sect, Digest Dis Branch, NIH, Bldg 31,Room 9A27,31 Ctr Dr, Bethesda, MD 20892 USA. RI Soza, Alejandro/C-2907-2009; OI Kleiner, David/0000-0003-3442-4453 NR 30 TC 69 Z9 75 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUL PY 2003 VL 38 IS 1 BP 66 EP 74 DI 10.1053/jhep.2003.50258 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 695MD UT WOS:000183833900010 PM 12829988 ER PT J AU Han, C Demetris, AJ Michalopoulos, GK Zhan, QM Shelhamer, JH Wu, T AF Han, C Demetris, AJ Michalopoulos, GK Zhan, QM Shelhamer, JH Wu, T TI PPAR gamma ligands inhibit cholangiocarcinoma cell growth through p53-dependent GADD45 and p21(WAF1/Cip1) pathway SO HEPATOLOGY LA English DT Article ID ACTIVATED-RECEPTOR-GAMMA; DEPENDENT KINASE INHIBITORS; CYCLE CHECKPOINTS; P53; ARREST; CARCINOMA; CANCER; ADIPOGENESIS; EXPRESSION; TRANSITION AB Ligands of peroxisome proliferator-activated receptor-gamma (PPARgamma) induce differentiation and growth inhibition in several human cancers. However, the role of PPARgamma ligands in the growth control of human cholangiocarcinoma. cells remains unknown. This study was designed to investigate the biological functions and molecular mechanisms of PPARgamma ligands in the growth regulation of human cholangiocarcinoma. cells. Western blot analysis showed that PPARgamma is expressed in all of the three human cholangiocarcinoma cell lines used in this study (SG231, CC-LP-1, and HuCCT1). Transient transfection assays using a peroxisome proliferator response element (PPRE) reporter construct showed that the PPARgamma expressed in human cholangiocarcinoma cells is functional as a transcription activator. Exposure of SG231, CC-LP-1, and HuCCT1 cells to PPARgamma ligands 15-deoxy-Delta12, 14-prostaglandin J(2) (15d-PGJ(2)) and troglitazone for 24 to 96 hours resulted in a dose-dependent inhibition of cell growth. Flow cytometry analysis showed that 15d-PGJ(2) and troglitazone-induced cell cycle arrest at the G2/M checkpoint. Consistent with these findings, both 15d-PGJ(2) and troglitazone significantly inhibited the G2/M cyclin-dependent kinase (CDK) Cdc2 activity. Furthermore, cells treated with 15d-PGJ(2) and troglitazone showed elevated expression of p53 and two p53-controlled downstream genes, GADD45 and P21(WAF1/Cip1). Dominant negative inhibition of p53 in SG231 cells significantly blocked the 15d-PGJ(2) and troglitazone-induced growth inhibition, G2/M arrest, and GADD45/p21 induction. 15d-PG(J2) and troglitazone failed to directly inhibit Cdc2 activity in a cell-free system in spite of direct association between GADD45 and PPARgamma proteins. In conclusion, these results show a novel p53-dependent mechanism in the PPARgamma ligand-mediated inhibition of cholangiocarcinoma. growth and suggest a potential therapeutic role of PPARgamma ligands in the treatment of human cholangiocarcinoma. C1 NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Pittsburgh Canc Inst, Dept Radiat Oncol, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. RP Wu, T (reprint author), Univ Pittsburgh, Presbyterian Univ Hosp, Sch Med, Dept Pathol, C902,200 Lothrop St, Pittsburgh, PA 15213 USA. FU NIDDK NIH HHS [DK 49615] NR 50 TC 49 Z9 55 U1 1 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUL PY 2003 VL 38 IS 1 BP 167 EP 177 DI 10.1053/jhep.2003.50296 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 695MD UT WOS:000183833900021 PM 12829999 ER PT J AU Soza, A Hoofnagle, JH AF Soza, A Hoofnagle, JH TI Mortality rate during interferon alfa-ribavirin combination therapy of chronic hepatitis C SO HEPATOLOGY LA English DT Letter C1 NIDDKD, Liver Dis Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Soza, A (reprint author), NIDDKD, Liver Dis Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RI Soza, Alejandro/C-2907-2009 NR 5 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUL PY 2003 VL 38 IS 1 BP 267 EP 267 DI 10.1053/jhep.2003.50213 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 695MD UT WOS:000183833900032 PM 12830010 ER PT J AU Vinores, SA Xiao, WH Zimmerman, R Whitcup, SM Wawrousek, EF AF Vinores, SA Xiao, WH Zimmerman, R Whitcup, SM Wawrousek, EF TI Upregulation of vascular endothelial growth factor (VEGF) in the retinas of transgenic mice overexpressing interleukin-1 beta (IL-1 beta) in the lens and mice undergoing retinal degeneration SO HISTOLOGY AND HISTOPATHOLOGY LA English DT Article DE interleukin-1 beta; vascular endothelial growth factor; blood-retinal barrier; retinal degeneration; angiogenesis ID EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; TUMOR-NECROSIS-FACTOR; PERMEABILITY FACTOR; EPITHELIAL-CELLS; FACTOR-BETA; INTRAOCULAR INFLAMMATION; BARRIER BREAKDOWN; GENE-EXPRESSION; RABBIT RETINA; TGF-BETA AB IL-1beta is a pro-inflammatory agent associated with angiogenesis and increased vascular permeability. To determine whether IL-1beta elicits these responses through an upregulation of VEGF, transgenic mice that overexpress IL-1beta in the lens were evaluated at various time points for the localization of VEGF, the location and extent of blood-retinal barrier (BRB) breakdown, and the origin and extent of neovascularization (NV). In homozygous and heterozygous transgenic mice, but not controls, intense VEGF immunoreactivity was scattered throughout the retina at postnatal days 5-7 (P5-7), just after the onset of inflammatory cell infiltration. VEGF staining in the retina remained widespread, but weak from P9-15. Beginning at P15, the intensity of VEGF immunoreactivity achieved a second peak, which it maintained through adulthood. This peak coincided with significant retinal destruction due to massive inflammation. The onset of BRB breakdown coincided with the upregulation of VEGF (P5-7) and widespread BRB breakdown was demonstrated from about P9. From P9-12, aggregates of cells positive for Griffonia simplicifolia isolectin-B4, a marker for vascular endothelial cells, formed on the retinal surface. These cells migrated into the retina at P12-15 with the more superficial cells forming a network of vessels and the deeper cells remaining in small clusters, thus demonstrating that NV occurs much later than BRB breakdown. Non-transgenic FVB/N mice, which undergo retinal degeneration beginning at about P9, also demonstrate the latter peak of VEGF upregulation and the accompanying BRB breakdown, but not the early upregulation. VEGF immunostaining of transgenic and non-transgenic mouse retinas was eliminated by preincubation of the VEGF antibodies with VEGF peptide. The data suggest that the early peak of VEGF upregulation (P5-7) and its accompanying BRB breakdown is due to IL-1beta expression and is likely to be dependent on inflammatory cell infiltration. The latter peak appears to be related to retinal destruction. C1 Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. NEI, NIH, Bethesda, MD 20892 USA. RP Vinores, SA (reprint author), Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, 825 Maumenee Bldg, Baltimore, MD 21287 USA. EM svinores@jhmi.edu RI Wawrousek, Eric/A-4547-2008 FU NEI NIH HHS [EY10017, EY05951] NR 68 TC 13 Z9 17 U1 1 U2 2 PU F HERNANDEZ PI MURCIA PA PLAZA FUENSANTA 2-7 C, 30008 MURCIA, SPAIN SN 0213-3911 J9 HISTOL HISTOPATHOL JI Histol. Histopath. PD JUL PY 2003 VL 18 IS 3 BP 797 EP 810 PG 14 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 695AK UT WOS:000183808800015 PM 12792892 ER PT J AU Chew, EY AF Chew, EY TI Epidemiology of diabetic retinopathy SO HOSPITAL MEDICINE LA English DT Article ID BLOOD-GLUCOSE CONTROL; MICROVASCULAR COMPLICATIONS; PROLIFERATIVE RETINOPATHY; INTENSIVE THERAPY; HARD EXUDATE; RISK-FACTORS; PROGRESSION; MELLITUS; ONSET; PREVALENCE AB Diabetic retinopathy is associated with a number of systemic risk factors, namely hyperglycaemia, elevated blood pressure and dyslipidaemia. Patients with diabetes should be vigorously treated for these modifiable risk factors to prevent the development and progression of diabetic retinopathy. C1 NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. RP Chew, EY (reprint author), NEI, Div Epidemiol & Clin Res, NIH, MSC 2510, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 EY999999] NR 34 TC 5 Z9 7 U1 1 U2 1 PU MARK ALLEN PUBLISHING LTD PI LONDON PA CROXTED MEWS, 286A-288 CROXTED ROAD, LONDON SE24 9BY, ENGLAND SN 1462-3935 J9 HOSP MED JI Hosp. Med PD JUL PY 2003 VL 64 IS 7 BP 396 EP 399 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 702ML UT WOS:000184227600004 PM 12886848 ER PT J AU Dols, A Smith, JW Meijer, SL Fox, BA Hu, HM Walker, E Rosenheim, S Moudgil, T Doran, T Wood, W Seligman, M Alvord, WG Schoof, D Urba, WJ AF Dols, A Smith, JW Meijer, SL Fox, BA Hu, HM Walker, E Rosenheim, S Moudgil, T Doran, T Wood, W Seligman, M Alvord, WG Schoof, D Urba, WJ TI Vaccination of women with metastatic breast cancer, using a costimulatory gene (CD80)-modified, HLA-A2-matched, allogeneic, breast cancer cell line: Clinical and immunological results SO HUMAN GENE THERAPY LA English DT Article ID PHASE-I TRIAL; MELANOMA-CELLS; T-CELLS; INTERLEUKIN-2; IMMUNOTHERAPY; IMMUNIZATION; LYMPHOCYTES; CARCINOMA; INDUCTION; RESPONSES AB MDA-MB-231, an HLA-A2(+), HER2/neu(+) allogeneic breast cancer cell line genetically modified to express the costimulatory molecule CD80 (B7-1), was used to vaccinate 30 women with previously treated stage IV breast cancer. Expression of CD80 conferred the ability to deliver a costimulatory signal and thereby improved the antigen presentation capability of the tumor cells to patient T cells in vitro. Patients were vaccinated with 10(7) or 10(8) irradiated gene-modified tumor cells with granulocyte-macrophage colony-stimulating factor (GMCSF) or BCG, three times at 2-week intervals and then monthly until progressive disease developed. GM-CSF-related flulike symptoms and minor injection site reactions were observed frequently. Prolonged disease stabilization was observed in four patients but no objective tumor regressions were seen. Immune responses were measured in matched peripheral blood samples collected before and after treatment from 9 of 15 patients treated at the 10(8) tumor cell dose. Four patients exhibited MHC class I-restricted cytokine production in response to the parental breast cancer cell line. One patient maintained an increased number of circulating tumor-specific, interferon gamma-secreting CD8(+) T cells for 24 months after the last vaccination. One patient exhibited a tumor-specific interleukin 5 response to an autologous tumor cell line. This immunization strategy proved to be safe and feasible, and induced tumor-specific immune responses in a minority of patients; however, no objective tumor regressions were observed. C1 Providence Portland Med Ctr, Earle A Chiles Res Inst, Robert W Franz Canc Res Ctr, Portland, OR 97213 USA. Oregon Grad Inst Sci & Technol, Dept Biochem & Mol Biol, Portland, OR 97239 USA. Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97239 USA. Providence Portland Med Ctr, Dept Pathol, Portland, OR 97213 USA. Providence Portland Med Ctr, Dept Surg, Portland, OR 97213 USA. Providence Portland Med Ctr, Oregon Hematol Oncol Associates, Portland, OR 97213 USA. NCI, Frederick Canc Res & Dev Ctr, Comp & Stat Serv, Frederick, MD 21702 USA. RP Urba, WJ (reprint author), 4805 NE Glisan St, Portland, OR 97213 USA. FU NCI NIH HHS [R03 CA 70299-02] NR 20 TC 41 Z9 45 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD JUL PY 2003 VL 14 IS 11 BP 1117 EP 1123 DI 10.1089/104303403322124828 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 702BW UT WOS:000184205600007 PM 12885350 ER PT J AU Boyadjiev, SA Justice, CM Eyaid, W McKusick, VA Lachman, RS Chowdry, AB Jabak, M Zwaan, J Wilson, AF Jabs, EW AF Boyadjiev, SA Justice, CM Eyaid, W McKusick, VA Lachman, RS Chowdry, AB Jabak, M Zwaan, J Wilson, AF Jabs, EW TI A novel dysmorphic syndrome with open calvarial sutures and sutural cataracts maps to chromosome 14q13-q21 SO HUMAN GENETICS LA English DT Article ID MULTILOCUS LINKAGE ANALYSIS; HOMEOBOX GENE; OSTEOBLAST DIFFERENTIATION; CLEIDOCRANIAL DYSPLASIA; OSSIFICATION DEFECTS; SKULL OSSIFICATION; PARIETAL FORAMINA; PEDIGREE ANALYSIS; FACTOR RUNX2; HAPLOINSUFFICIENCY AB We describe a new dysmorphic syndrome in an inbred Saudi Arabian family with 21 members. Five males and one female have similar craniofacial features including wide open calvarial sutures with large and late-closing anterior fontanels, frontal bossing, hyperpigmentation with capillary hemangioma of the forehead, significant hypertelorism, and a broad and prominent nose. In addition, these individuals have Y-shaped sutural cataracts diagnosed by 1-2 years of age. No chromosomal or biochemical abnormalities were identified. A genome-wide scan was performed, and two-point LOD score analysis, assuming autosomal recessive inheritance, detected linkage to chromosome 14q13-q21. The highest LOD scores were obtained for marker GATA136A04 (LOD=4.58 at theta=0.00) and for the adjacent telomeric marker D14S1048 (LOD=4.32 at theta=0.00). Multipoint linkage analysis resulted in a maximum LOD score of 5.44 between markers D14S1048 and GATA136A04. Model independent analysis by SIBPAL confirmed linkage to the same chromosomal region. Haplotype analysis indicated that all affected individuals were homozygous for the interval on chromosome 14q13-q21 with two recombinants for D14S1014 (centromeric) and one recombinant for D14S301 (telomeric). These recombinations limit the disease locus to a region of approximately 7.26 Mb. Candidate genes localized to this region were identified, and analysis of PAX9 did not identify mutations in these patients. The unique clinical phenotype and the mapping data suggest that this family represents a novel autosomal recessive syndrome. C1 Johns Hopkins Univ, Sch Med, Ctr Craniofacial Dev & Disorders, McKusick Nathans Inst Genet Med,Dept Pediat, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Dept Med, Baltimore, MD 21287 USA. Johns Hopkins Univ Sch Med, Ctr Craniofacial Dev & Disorders, McKusick Nathans Inst Genet Med, Dept Plast Surg, Baltimore, MD 21287 USA. NHGRI, Genometr Sect, Inherited Dis Res Branch, NIH, Baltimore, MD 21224 USA. King Fahad Hosp, Dept Pediat, Riyadh 11426, Saudi Arabia. Univ Calif Los Angeles, Cedars Sinai Med Ctr, Sch Med, Int Skeletal Dysplasia Registry, Los Angeles, CA 90048 USA. King Khalid Eye Specialist Hosp, Div Pediat Ophthalmol, Riyadh 11462, Saudi Arabia. Univ Texas, Hlth Sci Ctr, Dept Ophthalmol, San Antonio, TX 78229 USA. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. RP Boyadjiev, SA (reprint author), Johns Hopkins Univ, Sch Med, Ctr Craniofacial Dev & Disorders, McKusick Nathans Inst Genet Med,Dept Pediat, Baltimore, MD 21287 USA. RI Wilson, Alexander/C-2320-2009; OI Jabs, Ethylin/0000-0001-8983-5466 FU NCRR NIH HHS [1P41 RR03655, M01 RR00052]; NHGRI NIH HHS [N01-HG-65403]; NICHD NIH HHS [R01 HD24061]; NIDCR NIH HHS [K23 DE00462, P60 DE13087]; NIGMS NIH HHS [T32 GM7471] NR 46 TC 26 Z9 26 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD JUL PY 2003 VL 113 IS 1 BP 1 EP 9 DI 10.1007/s00439-003-0932-6 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 693NH UT WOS:000183723300001 PM 12677423 ER PT J AU Anderson, PD Huizing, M Claassen, DA White, J Gahl, WA AF Anderson, PD Huizing, M Claassen, DA White, J Gahl, WA TI Hermansky-Pudlak syndrome type 4 (HPS-4): clinical and molecular characteristics SO HUMAN GENETICS LA English DT Article ID LOCUS HETEROGENEITY; PULMONARY FIBROSIS; VESICLE FORMATION; BETA-3A SUBUNIT; PROTEIN COMPLEX; GENE; MUTATIONS; ADAPTER; AP-3; FORM AB Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder of oculocutaneous albinism and bleeding attributable to storage-pool-deficient platelets. Although at least 14 mouse models of HPS exist, the human disorders that comprise HPS, i.e., HPS-1, HPS-2, HPS-3, and HPS-4, are recognized to result from mutations in four genes, viz., HPS1, ADMA, HPS3, and HPS4, respectively. To characterize further the recently identified HPS-4 disease on molecular and clinical grounds, we first identified the genomic organization of HPS4, located on chromosome 22q11.2-q12.2, including its intron/exon boundaries. We found that HPS4 produces at least two alternatively spliced mRNA transcripts that differ at their 5'-ends. Next, we performed an extensive analysis of 22 unassigned HPS patients (i.e., not having HPS-1, HPS-2, or HPS-3 disease). Using single-strand conformation polymorphism, we determined that seven of the 22 patients had HPS-4. In these seven individuals, we identified five different HPS4 mutations, including one frameshift insertion, one missense, and three nonsense mutations. Three alleles in two patients contained the previously reported Q698insAAGCA frameshift. Three HPS4 mutations were newly described. Four alleles in three patients contained R217X, and two siblings were compound heterozygotes for E138X and E222X. Clinically, our HPS-4 patients exhibited iris transillumination, variable hair and skin pigmentation, absent platelet dense bodies, and occasional pulmonary fibrosis and gramilomatous colitis, a severe phenotype similar to that of patients with HPS-1. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Dept Lab Med, Minneapolis, MN 55455 USA. RP Gahl, WA (reprint author), NHGRI, Med Genet Branch, NIH, MSC 1851,Bldg 10,Room 10C-103,10 Ctr Dr, Bethesda, MD 20892 USA. NR 30 TC 66 Z9 68 U1 1 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD JUL PY 2003 VL 113 IS 1 BP 10 EP 17 DI 10.1007/s00439-003-0933-5 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 693NH UT WOS:000183723300002 PM 12664304 ER PT J AU Schell-Apacik, C Rivero, M Knepper, JL Roessler, E Muenke, M Ming, JE AF Schell-Apacik, C Rivero, M Knepper, JL Roessler, E Muenke, M Ming, JE TI SONIC HEDGEHOG mutations causing human holoprosencephaly impair neural patterning activity SO HUMAN GENETICS LA English DT Article ID PROGENITOR-CELL IDENTITY; NERVOUS-SYSTEM; MOTOR-NEURON; POLARIZING ACTIVITY; GENE-FUNCTION; OF-FUNCTION; INDUCTION; FOREBRAIN; SHH; SPECIFICATION AB Holoprosencephaly (HPE) is a common fore-brain malformation associated with mental retardation and craniofacial anomalies. Multiple lines of evidence indicate that loss of ventral neurons is associated with HPE. The condition is etiologically heterogeneous, and abnormalities in any of several genes can cause human HPE. Among these genes, mutations in SONIC HEDGEHOG (SHH) are the most commonly identified single gene defect causing human HPE. SHH mediates a number of processes in central nervous system development and is required for the normal induction of ventral cell types in the brain and spinal cord. Although a number of missense mutations in SHH have been identified in patients with HPE, the functional significance of these mutations has not yet been determined. We demonstrate that two SHH mutations that cause human HPE result in decreased in vivo activity of SHH in the developing nervous system. These mutant forms of SHH fail to regulate genes properly that are normally responsive to SHH signaling and do not induce ventrally expressed genes. In addition, the immunoreactivity of the mutant proteins is altered, suggesting that the conformation of the SHH protein has been disrupted. These studies are the first demonstration that mutations in SHH associated with human HPE perturb the in vivo patterning function of SHH in the developing nervous system. C1 Childrens Hosp Philadelphia, Dept Pediat, Div Human Genet & Mol Biol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Ming, JE (reprint author), Childrens Hosp Philadelphia, Dept Pediat, Div Human Genet & Mol Biol, 3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA. FU NICHD NIH HHS [HD01218, HD29862] NR 55 TC 32 Z9 33 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD JUL PY 2003 VL 113 IS 2 BP 170 EP 177 DI 10.1007/s00439-003-0950-4 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 703FZ UT WOS:000184270500009 PM 12709790 ER PT J AU Robinson-White, A Hundley, TR Shiferaw, M Bertherat, J Sandrini, F Stratakis, CA AF Robinson-White, A Hundley, TR Shiferaw, M Bertherat, J Sandrini, F Stratakis, CA TI Protein kinase-A activity in PRKAR1A-mutant cells, and regulation of mitogen-activated protein kinases ERK1/2 SO HUMAN MOLECULAR GENETICS LA English DT Article ID EPSTEIN-BARR VIRUS; SCHWANNOMAS CARNEY COMPLEX; SPOTTY SKIN PIGMENTATION; CYCLIC-AMP; B-RAF; MAP KINASE; DIFFERENTIAL REGULATION; ENDOCRINE OVERACTIVITY; LYSOPHOSPHATIDIC ACID; COLORIMETRIC ASSAY AB Carney complex (CNC) is caused by PRKAR1A-inactivating mutations. PRKAR1A encodes the regulatory subunit type I-alpha (RIalpha) of the cAMP-dependent kinase (PKA) holoenzyme; how RIalpha insufficiency leads to tumorigenesis remains unclear. In many cells PKA inhibits the extracellular receptor kinase (ERK1/2) cascade of the mitogen-activated protein kinase (MAPK) pathway leading to inhibition of cell proliferation. We investigated whether the PKA-mediated inhibitory effect on ERK1/2 is affected in CNC cells that carry germline PRKAR1A mutations. PKA activity both at baseline and after stimulation with cAMP was augmented in cells carrying mutations. Quantitative message analysis showed that the main PKA subunits expressed were type I (RIalpha and RIbeta) but RIalpha was decreased in mutant cells. Immunoblot assays of ERK1/2 phosphorylation by the cell- and pathway-specific stimulant lysophosphatidic acid (LPA) showed activation of this pathway in a time- and concentration-dependent manner that was prevented by a specific inhibitor. There was a greater rate of growth in mutant cells; forskolin and isoproterenol inhibited LPA-induced ERK1/2 phosphorylation in normal but not in mutant cells. Forskolin inhibited LPA-induced cell proliferation and metabolism in normal cells, but stimulated these parameters in mutant cells. These data were also replicated in a pituitary tumor cell line carrying the most common PRKAR1A mutation (c.578del TG), and an in vitro construct of mutant PRKAR1A that was recently shown to lead to augmented PKA-mediated phosphorylation. We conclude that PKA activity in CNC cells is increased and that its stimulation by forskolin or isoproterenol increases LPA-induced ERK1/2 phosphorylation, cell metabolism and proliferation. Reversal of PKA-mediated inhibition of this MAPK pathway in CNC cells may contribute to tumorigenesis in this condition. C1 NICHD, Sect Endocrinol & Genet, DEB, NIH, Bethesda, MD 20892 USA. NHLBI, LMI, NIH, Bethesda, MD 20892 USA. Univ Paris 05, CNRS, Dept Endocrinol, Inst Cochin,INSERM,U576,UMR 8104,IFR116, F-75270 Paris, France. RP Stratakis, CA (reprint author), NICHD, Sect Endocrinol & Genet, DEB, NIH, Bldg 10,Room 10N262,10 Ctr Dr MSC1862, Bethesda, MD 20892 USA. NR 53 TC 53 Z9 55 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUL 1 PY 2003 VL 12 IS 13 BP 1475 EP 1484 DI 10.1093/hmg/ddg160 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 692MA UT WOS:000183663800002 PM 12812976 ER PT J AU Rapic-Otrin, V Navazza, V Nardo, T Botta, E McLenigan, M Bisi, DC Levine, AS Stefanini, M AF Rapic-Otrin, V Navazza, V Nardo, T Botta, E McLenigan, M Bisi, DC Levine, AS Stefanini, M TI True XP group E patients have a defective UV-damaged DNA binding protein complex and mutations in DDB2 which reveal the functional domains of its p48 product SO HUMAN MOLECULAR GENETICS LA English DT Article ID NUCLEOTIDE-EXCISION-REPAIR; PIGMENTOSUM GROUP-E; COMPLEMENTATION GROUP-E; GROUP-E CELLS; XERODERMA-PIGMENTOSUM; ITALIAN PATIENTS; COCKAYNE-SYNDROME; PRIMATE CELLS; GROUP-F; GENE AB Xeroderma pigmentosum (XP) is a skin cancer-prone autosomal recessive disease characterized by inability to repair UV-induced DNA damage. The major form of XP is defective in nucleotide excision repair (NER) and comprises seven complementation groups (A-G). The genes defective in all groups have been identified unambiguously with the exception of group E. The cells of some XP-E patients are deficient in a protein complex (consisting of two subunits: p127/DDBI and p48/DDB2) which binds to UV-damaged DNA (UV-DDB) and is specifically involved in the removal of photoproducts from the non-transcribed regions of the genome. However, other XP-E patients have been reported not to lack UV-damaged DNA binding activity (DDB+). Here we describe several genetically unrelated XP-E patients, not previously analyzed in depth, each carrying two mutated alleles for DDB2, causing either a single amino acid change or a protein truncation or internal deletion. These defects result in a severe decrease of detectable p48 protein, abolish interaction with the p127 subunit, and produce a deficiency in UV-DDB binding activity (DDB-). The role of p48 in the repair defect of these patients was demonstrated in vivo and in vitro. Investigation of four DDB+ cell strains from patients previously assigned to XP-E, allowed us to reclassify all of them into other groups and to show that they do not share the molecular and biochemical features typical for XP-E. Besides confirming that the true XP-E phenotype is DDB-, resulting from defects in a single gene, DDB2, our results identify the functional domains of the corresponding p48 protein. C1 Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Pittsburgh Canc Inst, Pittsburgh, PA 15213 USA. CNR, Ist Genet Mol, I-27100 Pavia, Italy. NICHHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. RP Levine, AS (reprint author), Univ Pittsburgh, Scaife Hall,Suite 401,3550 Terrace St, Pittsburgh, PA 15261 USA. RI Botta, Elena/B-9065-2015; OI BOTTA, ELENA/0000-0003-2060-0110 NR 59 TC 68 Z9 70 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUL 1 PY 2003 VL 12 IS 13 BP 1507 EP 1522 DI 10.1093/hmg/ddg174 PG 16 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 692MA UT WOS:000183663800005 PM 12812979 ER PT J AU Morris, JA Kandpal, G Ma, L Austin, CP AF Morris, JA Kandpal, G Ma, L Austin, CP TI DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation SO HUMAN MOLECULAR GENETICS LA English DT Article ID MICROTUBULE-ASSOCIATED PROTEINS; LONG-TERM FACILITATION; TRANSCRIPTION FACTORS; SCHIZOPHRENIA; BINDING; SYNAPSES; DYNEIN; TAU; LOCALIZATION; ORGANIZATION AB Disrupted-In-Schizophrenia 1 (DISC1) is a novel gene associated with schizophrenia by multiple genetic studies. In order to determine how mutations in DISC1 might cause susceptibility to schizophrenia, we undertook a comprehensive study of the cellular biology of DISC1 in its full-length and disease-associated mutant forms. DISC1 interacts by yeast two-hybrid, mammalian two-hybrid, and co-immunoprecipitation assays with multiple proteins of the centrosome and cytoskeletal system, including MIPT3, MAP1A and NUDEL; proteins which localize receptors to membranes, including alpha-actinin2 and beta4-spectrin; and proteins which transduce signals from membrane receptors, including ATF4 and ATF5. Truncated mutant DISC1 fails to interact with ATF4, ATF5 or NUDEL. Deletion mapping demonstrated that DISC1 has distinct interaction domains: MAP1A interacts via its LC2 domain with the N-terminus of DISC1, whereas MIPT3 and NUDEL bind via their C-terminal domains to the central coiled-coil domain of DISC1, and ATF4/5 bind via their C-terminal domains to the C-terminus of DISC1. In its full-length form, DISC1 protein localizes to predominantly perinuclear punctate structures which extend into neurites in some cells; mutant truncated DISC1, by contrast, is seen in a diffuse pattern throughout the cytoplasm and abundantly in neurites. Both forms co-localize with the centrosomal complex, although truncated less abundantly than full-length DISC1. Although both full-length and mutant DISC1 are found in microtubule fractions, neither form of DISC1 appears to bind directly to microtubules, but rather do so in a MIPT3-dependent fashion that is stabilized by taxol. Based on these data, we propose that DISC1 is a multifunctional protein whose truncation contributes to schizophrenia susceptibility by disrupting intracellular transport, neurite architecture and/or neuronal migration, all of which have been hypothesized to be pathogenic in the schizophrenic brain. C1 Merck Res Labs, Dept Neurosci, W Point, PA 19486 USA. RP Austin, CP (reprint author), NHGRI, NIH, Bldg 31,Room 4B09,31 Ctr Dr, Bethesda, MD 20892 USA. NR 57 TC 265 Z9 275 U1 3 U2 18 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUL 1 PY 2003 VL 12 IS 13 BP 1591 EP 1608 DI 10.1093/hmg/ddg162 PG 18 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 692MA UT WOS:000183663800012 PM 12812986 ER PT J AU Krakowiak, PA Wassif, CA Kratz, L Cozma, D Kovarova, M Harris, G Grinberg, A Yang, YZ Hunter, AGW Tsokos, M Kelley, RI Porter, FD AF Krakowiak, PA Wassif, CA Kratz, L Cozma, D Kovarova, M Harris, G Grinberg, A Yang, YZ Hunter, AGW Tsokos, M Kelley, RI Porter, FD TI Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency SO HUMAN MOLECULAR GENETICS LA English DT Article ID LEMLI-OPITZ-SYNDROME; SONIC-HEDGEHOG; STEROL BIOSYNTHESIS; TERATOGENIC ACTION; PLASMA-MEMBRANE; MOUSE MODEL; MUTATIONS; GENE; INHIBITION; EMBRYO AB Lathosterol 5-desaturase catalyzes the conversion of lathosterol to 7-dehydrocholesterol in the next to last step of cholesterol synthesis. Inborn errors of cholesterol synthesis underlie a group of human malformation syndromes including Smith-Lemli-Opitz syndrome, desmosterolosis, CHILD syndrome, CDPX2 and lathosterolosis. We disrupted the lathosterol 5-desaturase gene (Sc5d ) in order to further our understanding of the pathophysiological processes underlying these disorders and to gain insight into the corresponding human disorder. Sc5d(-/-) pups were stillborn, had elevated lathosterol and decreased cholesterol levels, had craniofacial defects including cleft palate and micrognathia, and limb patterning defects. Many of the malformations found in Sc5d(-/-) mice are consistent with impaired hedgehog signaling, and appear to be a result of decreased cholesterol rather than increased lathosterol. A patient initially described as atypical SLOS with mucolipidosis was shown to have lathosterolosis by biochemical and molecular analysis. We identified a homozygous mutation of SC5D (137A>C, Y46S) in this patient. An unique aspect of the lathosterolosis phenotype is the combination of a malformation syndrome with an intracellular storage defect. C1 NICHHD, Unit Mol Dysmorphol, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Kennedy Krieger Inst, Baltimore, MD 21205 USA. Acad Sci Czech Republ, Inst Mol Genet, CR-14220 Prague, Czech Republic. NIAMSD, Mol Inflammat Sect, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Childrens Hosp Eastern Ontario, Genet Patient Serv Unit, Ottawa, ON K1H 8L1, Canada. NCI, NIH, Bethesda, MD 20892 USA. RP Porter, FD (reprint author), NICHD, HDB, NIH, Bld 10,Rm 9S241,10 Ctr Dr, Bethesda, MD 20892 USA. OI Wassif, Christopher/0000-0002-2524-1420 NR 50 TC 81 Z9 84 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUL 1 PY 2003 VL 12 IS 13 BP 1631 EP 1641 DI 10.1093/hmg/ddg172 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 692MA UT WOS:000183663800015 PM 12812989 ER PT J AU Vahratian, A Schieve, LA Reynolds, MA Jeng, G AF Vahratian, A Schieve, LA Reynolds, MA Jeng, G TI Live-birth rates and multiple-birth risk of assisted reproductive technology pregnancies conceived using thawed embryos, USA 1999-2000 SO HUMAN REPRODUCTION LA English DT Article DE assisted reproductive technology; embryo cryopreservation; multiple birth; thawed embryo transfer ID IN-VITRO FERTILIZATION; INTRACYTOPLASMIC SPERM INJECTION; CRYOPRESERVED EMBRYOS; INVITRO FERTILIZATION; TWIN PREGNANCIES; IMPLANTATION; CYCLE; IVF AB BACKGROUND: Increasing use of assisted reproductive technology treatments has been associated with the current rise in multiple births in the USA. Embryo cryopreservation and subsequent thawed embryo transfer may favourably impact the multiple-birth risk by relieving some pressure that patients and providers may feel to transfer several embryos in a single cycle. The study objective was to examine both live-birth rates and multiple-birth risk in thawed cycles. METHODS: The authors used a population-based sample of 21555 assisted reproductive technology procedures performed in US clinics in 1999 and 2000 that used thawed embryos derived from the patient's oocytes. RESULTS: Both patient age and the number of embryos transferred were independent predictors of live birth. Even among women aged 20-29 years, the transfer of three embryos resulted in an increase in the live-birth rate compared with cycles in which one or two embryos were transferred. This increase in success was accompanied by an increased multiple-birth risk. In all age groups up to 40 years, the transfer of just two embryos resulted in a multiple-birth risk of 16-17%. The multiple-birth risk increased with the number of embryos transferred. CONCLUSIONS: Patient age and the number of embryos transferred significantly affect live-birth and multiple-birth rates among women who use thawed embryos. C1 Ctr Dis Control & Prevent, Div Reprod Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. RP Vahratian, A (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, 6100 Execut Blvd,Room 7B03, Bethesda, MD 20892 USA. RI Vahratian, Anjel/A-1182-2011 NR 32 TC 10 Z9 12 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD JUL PY 2003 VL 18 IS 7 BP 1442 EP 1448 DI 10.1093/humrep/deg284 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 701BD UT WOS:000184144900014 PM 12832370 ER PT J AU Sharabi, Y Dendi, R Holmes, C Goldstein, DS AF Sharabi, Y Dendi, R Holmes, C Goldstein, DS TI Baroreflex failure as a late sequela of neck irradiation SO HYPERTENSION LA English DT Article DE baroreflex; irradiation; carotid sinus; autonomic nervous system; hypertension, secondary; norepinephrine; Valsalva maneuver ID CAROTID-ARTERY; HODGKINS-DISEASE; MALIGNANT VAGOTONIA; RADIATION-THERAPY; HYPERTENSION; SENSITIVITY; THROMBOSIS; CATECHOLS AB Combined chemotherapy and radiotherapy increase long-term survival in patients with head and neck tumors. Late complications of treatment, however, are being recognized increasingly. Surgery or radiotherapy of the carotid sinuses or brain stem can evoke labile hypertension and orthostatic intolerance from acute or subacute baroreflex failure. Here we report cases in which chronic baroreflex failure appeared to develop as a late sequela of neck irradiation. Three patients referred for autonomic nervous system function testing had labile blood pressure and chronic orthostatic intolerance that developed years after neck irradiation for cancer. In each patient, heart rate remained constant during performance of the Valsalva maneuver, suggesting baroreflex-cardiovagal failure. All 3 patients had virtually zero baroreflex-cardiovagal gain, quantified by interbeat interval-systolic blood pressure relationships after intravenous phenylephrine or nitroglycerine. Ambulatory blood pressure monitoring revealed highly variable blood pressure, with sudden pressor and depressor episodes, a characteristic feature of baroreflex failure. Cardiovagal efferent function, assessed by power spectral analysis of heart rate variability during slow, deep respiration, was normal. Sympathetic noradrenergic efferent function, assessed by cold pressor testing and plasma catecholamine levels during supine rest and orthostasis, was also normal or increased. These findings indicated a primarily afferent lesion. Carotid ultrasonography revealed intimal thickening and atheromatous plaques in all 3 patients. We propose that labile hypertension and orthostatic intolerance can develop as a late sequela of neck irradiation, due to chronic carotid baroreflex failure, which in turn is due to radiation-induced accelerated development of carotid arteriosclerosis. Splinting of carotid sinus mechanoreceptors in rigidified arterial walls would impede detection of alterations in blood pressure and thereby disrupt baroreflex regulation of cardiovagal and sympathetic outflows. C1 NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Sharabi, Y (reprint author), NINDS, Clin Neurocardiol Sect, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. NR 26 TC 42 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 JUL PY 2003 VL 42 IS 1 BP 110 EP 116 DI 10.1161/01.HYP.0000077441.45309.08 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 697NP UT WOS:000183949900018 PM 12782644 ER PT J AU Basser, PJ Pajevic, S AF Basser, PJ Pajevic, S TI A normal distribution for tensor-valued random variables: Applications to diffusion tensor MRI SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article; Proceedings Paper CT IEEE International Symposium on Biomedical Imaging: Macro to Nano CY 2002 CL WASHINGTON, D.C. SP IEEE DE covariance; distribution; experimental design; fourth-order; Gaussian; normal; precision; probability; random variable; second-order; strain-energy; tensor ID ACQUISITION SCHEMES; ANISOTROPY; SPECTROSCOPY; NOISE AB Diffusion tensor magnetic resonance imaging (DT-MRI) provides a statistical estimate of a symmetric, second-order diffusion tensor of water, D, in each voxel within an imaging volume. We propose a new normal distribution, p(D) proportional to exp(-1/2 D : A : D), which describes the variability of D in an ideal DT-MRI experiment. The scalar invariant, D : A : D, is the contraction of a positive definite symmetric, fourth-order precision tensor, A, and D. A correspondence is established between D: A: D and the elastic strain energy density function in continuum mechanics-specifically between D and the second-order infinitesimal strain tensor, and between A and the fourth-order tensor of elastic coefficients. We show that A can be further classified according to different classical elastic symmetries (i.e., isotropy, transverse isotropy, orthotropy, planar symmetry, and anisotropy). When A is an isotropic fourth-order tensor, we derive an explicit analytic expression for p(D), and for the distribution of the three eigenvalues of D, p(gamma(1), gamma(2), gamma(3)), which are confirmed by Monte Carlo simulations. We show how A can be estimated from either real or synthetic DT-MRI data for any given experimental design. Here we propose a new criterion for an optimal experimental design: that A be an isotropic fourth-order tensor. This condition ensures that the statistical properties of D (and quantities derived from it) are rotationally invariant. We also investigate the degree of isotropy of several DT-MRI experimental designs. Finally, we show that the univariate and multivariate distributions are special cases of the more general tensor-variate normal distribution, and suggest how to generalize p(D) to treat normal random tensor variables that are of third- (or higher) order. We expect that this new distribution, p(D), should be useful in feature extraction; in developing a hypothesis testing framework for segmenting and classifying noisy, discrete tensor data; and in designing experiments to measure tensor quantities. C1 NICHD, STBB, LIMB, NIH, Bethesda, MD 20892 USA. NIH, MSCL, CIT, Bethesda, MD 20892 USA. RP Basser, PJ (reprint author), NICHD, STBB, LIMB, NIH, Bldg 13,Rm 3W16,13 S Dr, Bethesda, MD 20892 USA. RI Basser, Peter/H-5477-2011 NR 29 TC 50 Z9 52 U1 0 U2 5 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD JUL PY 2003 VL 22 IS 7 BP 785 EP 794 DI 10.1109/TMI.2003.815059 PG 10 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 706FX UT WOS:000184443900001 PM 12906233 ER PT J AU Yim, PJ Vasbinder, GBC Ho, VB Choyke, PL AF Yim, PJ Vasbinder, GBC Ho, VB Choyke, PL TI Isosurfaces as deformable models for magnetic resonance angiography SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article; Proceedings Paper CT SPIE Medical Imaging Conference CY FEB 23-28, 2002 CL SAN DIEGO, CALIFORNIA SP SPIE DE carotid artery; deformable model; magnetic resonance angiography; renal artery ID SURFACE RECONSTRUCTION; MR-ANGIOGRAPHY; IMAGES; SEGMENTATION; EXPERIENCE; ARTERIES; CT AB Vascular disease produces changes in lumenal shape evident in magnetic resonance angiography (MRA). However, quantification of vascular shape from MRA is problematic due to image artifacts. Prior deformable models for vascular surface reconstruction primarily resolve problems of initialization of the surface mesh. However, initialization can be obtained in a trivial manner for MRA using isosurfaces. We propose a methodology for deforming the isusurface to conform to the boundaries of objects in the image with minimal a priori assumptions of object shape. As in conventional methods, external forces attract the surface toward edges in the image. However, smoothing is produced by a moment that aligns the normals of adjacent surface triangles. Notably, the moment produces no translational motion of surface triangles. The deformable isosurface was applied to a digital phantom of a stenotic artery, to MRA of three renal arteries with atherosclerotic disease and MRA of one carotid artery with atherosclerotic disease. Results of the surface reconstruction from the deformable model were compared with conventional X-ray angiography for the renal arteries. Measurement of the degree of stenosis of the renal arteries was within 12% +/- 6%. The deformable model provided improvements over the isosurface in all cases in terms of measurement of the degree of stenosis or improving the surface smoothness. C1 Univ Med & Dent New Jersey, Dept Radiol, New Brunswick, NJ 08903 USA. Maastricht Univ Hosp, NL-6202 AZ Maastricht, Netherlands. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Yim, PJ (reprint author), Univ Med & Dent New Jersey, Dept Radiol, New Brunswick, NJ 08903 USA. NR 25 TC 33 Z9 35 U1 0 U2 5 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD JUL PY 2003 VL 22 IS 7 BP 875 EP 881 DI 10.1109/TMI.2003.815056 PG 7 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 706FX UT WOS:000184443900009 PM 12906241 ER PT J AU Marsh, SGE Parham, P Dupont, B Geraghty, DE Trowsdale, J Middleton, D Vilches, C Carrington, M Witt, C Guethlein, LA Shilling, H Garcia, CA Hsu, KC Wain, H AF Marsh, SGE Parham, P Dupont, B Geraghty, DE Trowsdale, J Middleton, D Vilches, C Carrington, M Witt, C Guethlein, LA Shilling, H Garcia, CA Hsu, KC Wain, H TI Killer-cell immunoglobulin-like receptor (KIR) nomenclature report, 2002 SO IMMUNOGENETICS LA English DT Article ID INHIBITORY RECEPTORS; ALLELIC POLYMORPHISM; GENOMIC ORGANIZATION; GENE CONTENT; HLA-C; NK; DOMAINS; HAPLOTYPES; DIVERSITY; VARIANTS AB During discussion at the WHO Nomenclature Committee for Factors of the HLA System meeting in Victoria, Canada in May 2002, it was decided to form a subcommittee to co-ordinate the naming of alleles of the genes encoding the killer-cell immunoglobulin-like receptors KIR) (Marsh et al. 2002). These genes are encoded on chromosome 19 (19q13.4) and have varying degrees of polymorphism. The receptors encoded by the KIR genes are expressed by natural killer (NK) cells and a subset of T cells and some of them have been shown to have specificity for determinants of HLA class I molecules. The extracellular ligand-binding part of KIR consists of two or three immunoglobulin-( Ig-) like domains. The discussions which took place in Victoria are further to earlier discussions on KIR nomenclature at the NK Polymorphism meeting ( 27 - 29 July 2001) in Cambridge, UK. In addition a request has been made by the International Union of Immunological Societies (IUIS) to provide a standardised nomenclature for the expressed protein products of the KIR genes. C1 Royal Free Hosp, Anthony Nolan Res Inst, London NW3 2QG, England. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Sloan Kettering Inst Canc Res, New York, NY USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Cambridge, Cambridge, England. No Ireland Tissue Typing Lab, Belfast, Antrim, North Ireland. Hosp Puerta Hierro, Madrid, Spain. Frederick Canc Res & Dev Ctr, Frederick, MD USA. Royal Perth Hosp, Perth, WA, Australia. Univ Washington, Seattle, WA 98195 USA. Anthony Nolan Res Inst, London, England. UCL, HUGO Gene Nomenclature Comm, London, England. RP Marsh, SGE (reprint author), Royal Free Hosp, Anthony Nolan Res Inst, Pond St, London NW3 2QG, England. EM marsh@ebi.ac.uk RI Vilches, Carlos/G-1471-2012 OI Vilches, Carlos/0000-0002-0300-9225 NR 36 TC 54 Z9 58 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0093-7711 J9 IMMUNOGENETICS JI Immunogenetics PD JUL PY 2003 VL 55 IS 4 BP 220 EP 226 DI 10.1007/s00251-003-0571-z PG 7 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 704NH UT WOS:000184345400004 PM 12838378 ER PT J AU Singh, SP Williams, YU Miller, S Nikaido, H AF Singh, SP Williams, YU Miller, S Nikaido, H TI The c-terminal domain of Salmonella enterica serovar Typhimurium OmpA is an immunodominant antigen in mice but appears to be only partially exposed on the bacterial cell surface SO INFECTION AND IMMUNITY LA English DT Article ID OUTER-MEMBRANE PROTEIN; LIPID BILAYER-MEMBRANES; GRAM-NEGATIVE BACTERIA; ESCHERICHIA-COLI; PSEUDOMONAS-AERUGINOSA; MONOCLONAL-ANTIBODIES; SYNTHETIC PEPTIDES; TYPHOID-FEVER; PORIN; LIPOPOLYSACCHARIDE AB We examined the way the major outer membrane protein OmpA of Salmonella enterica serovar Typhimurium is recognized by the mouse immune system, by raising a panel of 12 monoclonal antibodies (MAbs) against this protein. Interaction between OmpA and these MAbs is competitively inhibited with several-hundredfold dilutions of mouse polyclonal sera obtained by immunization with live or heat-killed whole cells, suggesting that OmpA is one of the immunodominant antigens of serovar Typhimurium. All of the MAbs were specific for an identical epitope(s) located on the C-terminal domain of OmpA, as indicated by the use of OmpA fragments generated by protease or cyanogen bromide treatment and by competitive inhibition enzyme-linked immunosorbent assay. This epitope was highly conserved within (but not outside) the family Enterobacteriaceae. The strong immunogenicity of this epitope was surprising because the C-terminal domain of OmpA, usually thought to be located in the periplasm, is not expected to be exposed on the bacterial cell surface. A MAb, however, reacted in a cytofluorometry assay more strongly with outer-membrane-permeabilized cells than with untreated cells, a result supporting the predominantly periplasmic localization of the epitope. Significant, though low-level, reactivity of intact cells nevertheless suggests that in some cells the C-terminal domain of OmpA is exposed on the surface, a result consistent with the proposal that OmpA can fold into one of the two alternate conformations. C1 Alabama State Univ, Biomed Res & Training Programs, Montgomery, AL 36101 USA. Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. RP Singh, SP (reprint author), Natl Inst Gen Med Sci, Off Sci Review, NIH, 45 Ctr Dr,Room 3AN-12, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [GM 08219, S06 GM008219] NR 52 TC 40 Z9 41 U1 0 U2 3 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 JUL PY 2003 VL 71 IS 7 BP 3937 EP 3946 DI 10.1128/IAI.71.7.3937-3946.2003 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 694WB UT WOS:000183797200034 PM 12819080 ER PT J AU Valenzuela, JG Francischetti, IMB Pham, VM Garfield, MK Ribeiro, JMC AF Valenzuela, JG Francischetti, IMB Pham, VM Garfield, MK Ribeiro, JMC TI Exploring the salivary gland transcriptome and proteome of the Anopheles stephensi mosquito SO INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE salivary glands; proteome; electrophoresis; hematophagy; sialome ID AEDES-AEGYPTI; MALARIA VECTOR; GERMLINE TRANSFORMATION; DROSOPHILA-MELANOGASTER; LUTZOMYIA-LONGIPALPIS; IXODES-SCAPULARIS; TRYPANOSOMA-CRUZI; FEMALE MOSQUITO; BINDING PROTEIN; HIGH-AFFINITY AB Anopheles stephensi is the main urban mosquito vector of malaria in the Indian subcontinent, and belongs to the same subgenus as Anopheles gambiae, the main malaria vector in Africa. Recently the genome and proteome sets of An. gambiae have been described, as well as several protein sequences expressed in its salivary glands, some of which had their expression confirmed by ammo terminal sequencing. In this paper, we randomly sequenced a full-length cDNA library of An. stephensi and performed Edman degradation of polyvinylidene difluoride (PVDF)-transferred protein bands from salivary homogenates. Twelve of 13 proteins found by aminoterminal degradation were found among the cDNA clusters of the library. Thirty-three full-length novel cDNA sequences are reported, including a novel secreted galectin; the homologue of anophelin, a thrombin inhibitor; a novel trypsin/chymotrypsin inhibitor; an apyrase; a lipase; and several new members of the D7 protein family. Most of the novel proteins have no known function. Comparison of the putatively secreted and putatively housekeeping proteins of An. stephensi with An. gambiae proteins indicated that the salivary gland proteins are at a faster evolutionary pace. The possible role of these proteins in blood and sugar feeding by the mosquito is discussed. The electronic tables and supplemental material are available at http://www.ncbi.nlm.nih.gov/projects/Mosquito/A_stephensi_sialome/. C1 NIAID, Med Entomol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Ribeiro, JMC (reprint author), NIAID, Med Entomol Sect, Parasit Dis Lab, NIH, Bldg 4,Room 126,4 ctr Dr,MSC 0425, Bethesda, MD 20892 USA. OI Ribeiro, Jose/0000-0002-9107-0818 NR 60 TC 136 Z9 140 U1 1 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0965-1748 J9 INSECT BIOCHEM MOLEC JI Insect Biochem. Mol. Biol. PD JUL PY 2003 VL 33 IS 7 BP 717 EP 732 DI 10.1016/S0965-1748(03)00067-5 PG 16 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 699RQ UT WOS:000184070100007 PM 12826099 ER PT J AU Engels, EA Pfeiffer, RM AF Engels, EA Pfeiffer, RM TI Malignant thymoma in the United States: Demographic patterns in incidence and associations with subsequent malignancies SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE thymoma; demography; multiple primary neoplasms; non-Hodgkin's lymphoma ID CANCER; NEOPLASMS; SURVIVAL; RISK AB The cause of thymoma is unknown. No population-based study has described demographic patterns of thymoma incidence. Previous reports have linked thymoma with diverse subsequent malignancies, but these associations are uncertain. We used Surveillance, Epidemiology and End Results (SEER) data to study the incidence of malignant thymoma by sex, age and race in the United States (1973-1998). Incidence was modeled with joinpoint regression (for age) and Poisson regression. We also used SEER data to compare malignancies following thymoma diagnosis with those expected from general population rates, calculating the standardized incidence ratio (SIR, observed/expected cases) to measure risk. The overall incidence of malignant thymoma was 0.15 per 100,000 person-years (849 cases). Thymoma incidence increased into the 8th decade of age and then decreased. Incidence was higher in males than females (p=0.007) and was highest among Asians/Pacific Islanders (0.49 per 100,000 person-years). Following thymoma, there were 66 malignancies (SIR 1.5, 95%CI 1.2-1.9). The most notable excess risk for subsequent malignancy was for non-Hodgkin's lymphoma (B immunophenotype) where the SIR was 4.7 (95%CI 1.9-9.6, 7 cases). There were also excess digestive system cancers (SIR 1.8, 95%CI 1.1-2.9) and soft tissue sarcomas (SIR 11.1, 1.3-40.1). No other cancers were increased after thymoma. In conclusion, malignant thymoma is extremely rare. The peak in late adulthood deserves further study. Variation in incidence by race suggests a role for genetic factors. Our study did not demonstrate broadly increased risk for malignancies following thymoma. (C) 2003 Wiley-Liss, Inc. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Rockville, MD 20892 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Rockville, MD USA. RP Engels, EA (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 8010, Rockville, MD 20892 USA. NR 25 TC 188 Z9 193 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 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUL 1 PY 2003 VL 105 IS 4 BP 546 EP 551 DI 10.1002/ijc.11099 PG 6 WC Oncology SC Oncology GA 680EH UT WOS:000182963000017 PM 12712448 ER PT J AU Park, SW Durkin, ME Thorgeirsson, SS Popescu, NC AF Park, SW Durkin, ME Thorgeirsson, SS Popescu, NC TI DNA variants of DLC-1, a candidate tumor suppressor gene in human hepatocellular carcinoma SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE DLC-1 tumor suppressor gene; hepatocellular carcinoma ID CANCER; IDENTIFICATION; DELETION; LINKAGE; RHOGAP; GTPASE AB The DLC-1 gene encoding a regulator of the Rho family of small GTPases is altered in breast, prostate, colon, and liver cancer and has several characteristics of a tumor suppressor gene. DLC-1 overexpression causes inhibition of in vitro growth of liver tumor cells and complete suppression of in vivo tumorigenicity of breast tumor cells. Inactivation and aberrant expression of DLC-1 in human hepatocellular carcinoma (HCC) is frequently associated with hemizygous and homozygous genomic deletion and promoter methylation. Since inactivation of tumor suppressor genes in cancer cells is also commonly associated with point mutation, we evaluated the incidence of mutation of the DLC-1 gene by PCR-SSCP in 17 primary HCC and 18 HCC cell lines. One missense mutation was detected at codon 991 of exon 12 (C-->T transition, Val-->Ile) in an HCC cell line. In addition, two types of polymorphisms were identified: a G-->T at codon 745 of exon 9, a T-C at 17 by downstream of exon 2. While the pathogenic relevance of the intronic polymorphism is not known, the low rate of mutation of the DLC-1 gene in HCC implies that genomic deletion and promoter methylation primarily account for the altered expression and tumor suppressive inactivation of the DLC-1 gene. C1 NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Popescu, NC (reprint author), NCI, Expt Carcinogenesis Lab, Bldg 37,Room 4128B,37 Convent Dr,MSC 4262, Bethesda, MD 20892 USA. NR 18 TC 16 Z9 18 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD JUL PY 2003 VL 23 IS 1 BP 133 EP 137 PG 5 WC Oncology SC Oncology GA 688BL UT WOS:000183412300015 PM 12792785 ER PT J AU De Graff, WG Myers, LS Mitchell, JB Hahn, SM AF De Graff, WG Myers, LS Mitchell, JB Hahn, SM TI Protection against Adriamycin (R) cytotoxicity and inhibition of DNA topoisomerase II activity by 3,4-dihydroxybenzoic acid SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE adriamycin; topoisomerase II; dihydroxybenzoic acid; cytotoxicity; free radicals ID COMPOUND PROTOCATECHUIC ACID; SUPEROXIDE-DISMUTASE; CYTO-TOXICITY; INDUCED CARDIOTOXICITY; OXIDATIVE DESTRUCTION; RADICAL FORMATION; IRON COMPLEX; DOXORUBICIN; CELLS; ANTHRACYCLINE AB The mechanism of Adriamycin (ADR) induced cytotoxicity is not completely understood. While a variety of mechanisms have been proposed, the production of free radicals by redox cycling of the semiquinone has been implicated in cytotoxicity, specifically for cardiotoxicity. To determine whether a scavenger of free radicals would modify the cytotoxicity of ADR, the benzoic acid derivative 3,4-dihydroxybenzoic acid (DHB) was investigated for its ability to protect against: ADR-induced cytotoxicity and DNA double strand breaks in Chinese hamster V79 cells. V79 cells were treated with ADR, or its non-redox cycling analog iminodaunomycin, in the presence or absence of DHB. DHB provided significant protection (dose-modifying factor greater than 2.5 for ADR, and nearly 2 for iminodaunomycin) and also caused a dose-dependent decrease in DNA double strand breaks as measured by pulsed field gel electrophoresis. Assays of topoisomerase II activity showed that DHB inhibited topoisomerase II in a concentration-dependent manner, but did not inhibit topoisomerase I. Another non-toxic topoisomerase II inhibitor, the radioprotector WR-1065, also protected against ADR-induced cytotoxicity. These data identify DHB as a non-toxic inhibitor of DNA topoisomerase II and suggest that much of the cytotoxicity of ADR in actively growing V79 cells is due to mechanisms other than redox cycling by the semiquinone. C1 NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. RP De Graff, WG (reprint author), NCI, Radiat Biol Branch, Bldg 10,Room B3-B69,10 Ctr Dr, Bethesda, MD 20892 USA. NR 43 TC 14 Z9 14 U1 0 U2 2 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD JUL PY 2003 VL 23 IS 1 BP 159 EP 163 PG 5 WC Oncology SC Oncology GA 688BL UT WOS:000183412300019 PM 12792789 ER PT J AU Ingjaldsson, JT Thayer, JF Laberg, JC AF Ingjaldsson, JT Thayer, JF Laberg, JC TI Craving for alcohol and pre-attentive processing of alcohol stimuli SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Article DE pre-attentive processing; craving; cue reactivity; visual masking; alcohol dependence ID HEART-RATE-VARIABILITY; GENERALIZED ANXIETY DISORDER; NEUROVISCERAL CONCOMITANTS; INDIVIDUAL-DIFFERENCES; ABSTINENT ALCOHOLICS; DRUG CUES; REACTIVITY; DRINKING; URGES; MODEL AB The present study was designed to test the hypothesis of unconscious attending to alcohol-related information in alcoholics experiencing a high level of craving for alcohol. Subjects included a group of alcoholics (n = 34) divided by a median split on a craving measure into two groups labeled as 'high craving' (n = 18) and 'low craving' (n = 16) alcoholics, and a non-alcoholic control group (n = 39). The cardiovascular reactions of these groups were compared after their exposure to masked and unmasked alcohol and control stimuli. As expected the 'high craving' alcoholics showed an immediate heart rate deceleration after exposure to masked and non-consciously accessible alcohol pictures. The 'high craving' alcoholics reported a small but significant increase in difficulty resisting a drink after exposure to masked alcohol pictures. When the alcohol pictures were presented unmasked a significant increase was found in both high and low craving alcoholics on consciously expressed urges, fidgeting and reduced coping with temptation to drink. The 'high craving' alcoholics had lower tonic heart rate variability compared to the control group and the level of craving was positively associated with salivation during the exposure to all picture types. The findings generally support the psychobiological theory of craving, which suggests that the uncontrollability of the craving experience is rooted in unconscious processing of drug-related information. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Univ Bergen, Dept Psychosocial Sci, N-5015 Bergen, Norway. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Ingjaldsson, JT (reprint author), Univ Bergen, Dept Psychosocial Sci, Christiesgate 12, N-5015 Bergen, Norway. NR 67 TC 31 Z9 31 U1 2 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD JUL PY 2003 VL 49 IS 1 BP 29 EP 39 DI 10.1016/S0167-8760(03)00075-8 PG 11 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 705WQ UT WOS:000184419400003 PM 12853128 ER PT J AU Shiramizu, B Theodore, T Bassett, R Coel, M Sherman, KE Glesby, IJ Chow, D Alston, B Colquhoun, D Merigan, TC Reichman, TC Berggren, R Burning, WJ Brobst, S AF Shiramizu, B Theodore, T Bassett, R Coel, M Sherman, KE Glesby, IJ Chow, D Alston, B Colquhoun, D Merigan, TC Reichman, TC Berggren, R Burning, WJ Brobst, S CA Adult AIDS Clinical Trials Grp 509 TI Correlation of single photon emission computed tomography parameters as a noninvasive alternative to liver biopsies in assessing liver involvement in the setting of HIV and hepatitis C virus coinfection: A multicenter trial of the adult AIDS clinical trials group SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE hepatitis C virus; HIV; single photon emission computed tomograph (SPECT); liver biopsy alternatives ID HUMAN-IMMUNODEFICIENCY-VIRUS; BIOCHEMICAL MARKERS; INFECTED PATIENTS; FIBROSIS; SPECT; DISEASE; HCV; PREVALENCE; CIRRHOSIS AB Performing a liver biopsy in patients infected with HIV and hepatitis C virus (HCV) is considered the standard of practice to assess hepatic involvement but carries risks to patients. This pilot study was designed to identify single photon emission computed tomography (SPECT) parameters that correlate with liver disease stage. HIV-coinfected and HCV-coinfected individuals undergoing a liver biopsy had a SPECT scan performed. The results showed that a number of SPECT parameters were associated with histologic changes in architecture, fibrosis, and cirrhosis, of which two SPECT parameters, the minimum pixel count for spleen region of interest and maximum pixel count for right hepatic lobe, correctly classified 39 of 46 SPECT/biopsy pairs. In conclusion, this pilot trial identified SPECT parameters that correlated with liver histology changes. A larger study is needed to demonstrate whether SPECT parameters alone or with other markers can provide information on fibrosis with the clinical significance obtained through liver biopsy. C1 Univ Hawaii, Honolulu, HI 96822 USA. Univ N Carolina, Chapel Hill, NC USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Univ Cincinnati, Med Ctr, Cincinnati, OH 45267 USA. Cornell Univ, New York, NY USA. NIH, Bethesda, MD 20892 USA. Frontier Sci & Technol Res, Amherst, NY USA. Stanford Univ, Med Ctr, Stanford, CA 94305 USA. Univ Rochester, Med Ctr, Rochester, NY 14642 USA. Tulane Univ, New Orleans, LA 70118 USA. Social & Sci Syst, Silver Spring, MD USA. RP Shiramizu, B (reprint author), 3675 Kilauea Ave,Young Bldg,5th Floor, Honolulu, HI 96816 USA. FU NIAID NIH HHS [AI-25987, 5U01 AI-27666-16, 5UO1AI46376-03, AI-38858, AI-38855, 5UO1AI25868-16, AI-34853-10, AI-27658/RR00044, AI-49508] NR 31 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2003 VL 33 IS 3 BP 329 EP 335 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 699VT UT WOS:000184077200006 PM 12843743 ER PT J AU Van Veldhuisen, PC Walters, M Sawada, T Levine, PH Wilks, R Hanchard, B Hisada, M AF Van Veldhuisen, PC Walters, M Sawada, T Levine, PH Wilks, R Hanchard, B Hisada, M TI Seroincidence of human T-lymphotropic virus type I infection and characterization of seroconverters in Jamaican food handlers SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HTLV-1; seroincidence; provirus load; antibody titer; anti-tax; Jamaica ID CELL LEUKEMIA-VIRUS; POLYMERASE-CHAIN-REACTION; HTLV-I; RISK-FACTORS; CLINICAL ENTITY; GENE-EXPRESSION; PROVIRAL DNA; TRANSMISSION; ANTIBODY; TRANSFUSION AB In a prospective study of food handlers in Jamaica, we estimated the age- and sex-specific seroincidence of human T-lymphotropic virus type I (HTLV-I) infection. Of 682 sexually active adults (132 males and 550 females) who were initially seronegative, 12 (1 male and 11 females) seroconverted over 8 years of follow-up. The seroincidence was 1.2 per 1,000 person-years for males and 3.2 per 1,000 person-years for females. The age-standardized incidence was 1.8 times higher for females than for males (P = 0.55). Within a median of 4 years after seroconversion, the median HTLV-I provirus load was 500 copies/10(5) cells, and the median antibody titer was 1:3109. Four of 12 seroconverters developed antibody to the Tax regulatory protein. HTLV-I infection in this population occurred at a rate comparable with that described for a Japanese cohort. Provirus load, titer and appearance of antibody to the Tax regulatory protein were typical of chronic carriers within a few years of seroconversion. C1 NCI, Div Canc Epidemiol & Genet, Viral Epidemiol Branch, Rockville, MD 20852 USA. George Washington Univ, Sch Publ Hlth & Hlth Serv, Washington, DC USA. EMMES Corp, Rockville, MD USA. NCI Frederick, Sci Applicat Int Corp, Viral Epidemiol Sect, Frederick, MD USA. Eisai & Co Ltd, Tsukuba Res Labs, Tsukuba, Ibaraki 30026, Japan. Univ W Indies, Res Inst Trop Med, Kingston 7, Jamaica. Univ W Indies, Dept Pathol, Kingston 7, Jamaica. RP Van Veldhuisen, PC (reprint author), NCI, Div Canc Epidemiol & Genet, Viral Epidemiol Branch, 6120 Execut Blvd,EPS 8008, Rockville, MD 20852 USA. NR 39 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2003 VL 33 IS 3 BP 387 EP 392 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 699VT UT WOS:000184077200014 PM 12843751 ER PT J AU Morey, MC Dubbert, PM Doyle, ME MacAller, H Crowley, GM Kuchibhatla, M Schenkman, M Horner, RD AF Morey, MC Dubbert, PM Doyle, ME MacAller, H Crowley, GM Kuchibhatla, M Schenkman, M Horner, RD TI From supervised to unsupervised exercise: Factors associated with exercise adherence SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Article DE patient compliance; aging; health behavior; chronic disease; comorbidity ID PHYSICAL-ACTIVITY; OLDER PERSONS; SELF-EFFICACY; HEALTH; MAINTENANCE; ADULTS; TRIAL; PARTICIPATION; DETERMINANTS; ADOPTION AB Getting older adults to initiate and maintain long-term exercise is an important public health mandate. This study is an analysis of a clinical trial of 112 sedentary adults, age 65-90 years, randomly assigned to 1 of 2 exercise interventions. We examined predictors and patterns of adherence of the 6-month home-based component of the trial. Telephone follow-up and diaries were used to assess adherence. Adherence to weekend exercise during the supervised phase of the program was the strongest predictor of subsequent home-based adherence. Adherence appeared stable throughout the intervention, indicating that adherence or nonadherence was established from the outset. The authors conclude that nonadherence can be identified early in the behavioral-change process. Future studies should focus on developing strategies for adults with chronic illnesses, depressive symptoms, and functional limitations who are nonadherent early on as they initiate and attempt to maintain exercise. C1 Duke Univ, Med Ctr, Claude D Pepper Older Amer Independence Ctr, Ctr Aging, Durham, NC 27710 USA. Duke Univ, Sch Nursing, Med Ctr, Durham, NC 27710 USA. Duke Univ, Sch Nursing, Dept Phys Therapy, Durham, NC 27710 USA. Dept Vet Affairs Med Ctr, Mental Hlth Serv, Jackson, MS 39216 USA. Univ Colorado, Hlth Sci Ctr, Dept Rehabil Med, Denver, CO 80262 USA. NINDS, Off Minor Hlth & Res, Rockville, MD 20852 USA. RP Morey, MC (reprint author), Duke Univ, Med Ctr, Claude D Pepper Older Amer Independence Ctr, Ctr Aging, Durham, NC 27710 USA. NR 34 TC 25 Z9 26 U1 5 U2 10 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1063-8652 J9 J AGING PHYS ACTIV JI J. Aging Phys. Act. PD JUL PY 2003 VL 11 IS 3 BP 351 EP 368 PG 18 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 702QG UT WOS:000184234100006 ER PT J AU Iwasaki, M Saito, K Takemura, M Sekikawa, K Fuji, H Yamada, Y Wada, H Mizuta, K Seishima, M Ito, Y AF Iwasaki, M Saito, K Takemura, M Sekikawa, K Fuji, H Yamada, Y Wada, H Mizuta, K Seishima, M Ito, Y TI TNF-alpha contributes to the development of allergic rhinitis in mice SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE TNF-alpha; TNF-alpha-deficient mice; adhesion molecule; allergic rhinitis; IgE ID TUMOR-NECROSIS-FACTOR; EOTAXIN MESSENGER-RNA; ADHESION MOLECULES; AIRWAY HYPERRESPONSIVENESS; ENDOTHELIAL-CELLS; NASAL-MUCOSA; MAST-CELLS; TH2 CELLS; INDUCTION; ASTHMA AB Background: Allergic rhinitis is an inflammation involving T(H)2-type cytokine production, with pathologic eosinophil infiltration in the nasal mucosa. Although TNF-alpha is thought to be a pro-inflammatory cytokine, the relationship between TNF-alpha and allergic rhinitis has not been clarified. Objectives: The role of TNF-alpha in a murine model of ovalbumin (OVA)-sensitized allergic rhinitis was investigated by using mice deficient in the gene encoding TNF-alpha (TNF-alpha(-/-) mice). Methods: Both wild-type (TNF-alpha(+/+)) and TNF-alpha(-/-) mice were sensitized with OVA by means of intraperitoneal injection. They were then challenged with intranasal OVA, and various allergic responses were assessed. Results: The production of OVA-specific IgE in the serum (P < .05) and the frequency of sneezes (P < .05) and nasal rubs (P < .05) decreased significantly in TNF-α(-/-) mice after OVA sensitization compared with that in TNF-α(+/+) mice (P < .05). The mRNA expression of IL-4, IL-10, and eotaxin in nasal mucosa in TNF-alpha(-/-) mice was also significantly suppressed compared with that in TNF-alpha(+/+) mice after OVA sensitization (P < .05). Furthermore, the expression of both endothelial-leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1 mRNA in the nasal mucosa was significantly suppressed (P < .05), although intercellular adhesion molecule 1 mRNA expression did not decrease significantly in TNF-alpha(-/-) mice compared with that in TNF-alpha(+/+) mice after OVA sensitization. In addition, the effect of TNF-alpha on endothelial-leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1 expression by means of Western blot analysis was compatible with the mRNA results. Pathologically, eosinophil infiltration in nasal mucosa was significantly restricted in TNF-alpha(-/-) mice compared with in TNF-alpha(+/+) mice after OVA sensitization (P < .05). Conclusion: TNF-α is necessary for antigen-specific IgE production and for the induction of T(H)2-type cytokines and chemokines. Furthermore, TNF-α might be important for the expression of adhesion molecules to recruit eosinophils to the allergic inflammatory site. We conclude that the lack of TNF-α inhibited the development of allergic rhinitis. C1 NIMH, LNT, Bethesda, MD 20892 USA. Gifu Univ, Sch Med, Dept Otorhinolaryngol, Gifu 500, Japan. Gifu Univ, Sch Med, Dept Clin Lab Med, Gifu 500, Japan. Natl Inst Anim Hlth, Dept Immunol, Tsukuba, Ibaraki 305, Japan. RP Saito, K (reprint author), NIMH, LNT, Bldg 10 Room 3D42,MSC 1262,10 Ctr Dr, Bethesda, MD 20892 USA. NR 33 TC 62 Z9 66 U1 1 U2 5 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 JUL PY 2003 VL 112 IS 1 BP 134 EP 140 DI 10.1067/mai.2003.1554 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 698QQ UT WOS:000184010600021 PM 12847490 ER PT J AU Koenig, BW Rogowski, M Louis, JM AF Koenig, BW Rogowski, M Louis, JM TI A rapid method to attain isotope labeled small soluble peptides for NMR studies SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE E. coli; fusion protein; isotope labeling; NMR; recombinant peptide ID NUCLEAR-MAGNETIC-RESONANCE; BACTERIALLY EXPRESSED PEPTIDE; RESIDUAL DIPOLAR COUPLINGS; CARTILAGE MATRIX PROTEIN; RECEPTOR-BINDING DOMAIN; ESCHERICHIA-COLI; MULTIDIMENSIONAL NMR; SECONDARY STRUCTURE; BACKBONE DYNAMICS; STRAIN PAK AB A widely applicable strategy is presented for efficient and rapid production of small water soluble peptides expressed as fusion proteins with the immunoglobulin-binding domain of streptococcal protein G. A simple extraction and purification scheme that includes a protease cleavage step to release the target peptide is described. The yield of authentic target peptide exceeds 10 mg per liter of culture. Production of U-C-13, N-15 and highly deuterated U-C-13, N-15 isotope labeled peptide is demonstrated for the 11 residue S2 peptide, corresponding to the C-terminus of the alpha-subunit of transducin, and the coiled coil trimerization domain from cartilage matrix protein (CMPcc), respectively. Heteronuclear two-dimensional NMR spectra are used for initial peptide characterization. C1 Res Ctr Julich, Inst Biol Struct, IBI 2, D-52425 Julich, Germany. Univ Dusseldorf, Inst Phys Biol, D-40225 Dusseldorf, Germany. Univ Basel, Dept Biol Struct, Biozentrum, CH-4056 Basel, Switzerland. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Koenig, BW (reprint author), Res Ctr Julich, Inst Biol Struct, IBI 2, D-52425 Julich, Germany. RI Koenig, Bernd/B-4315-2008 OI Koenig, Bernd/0000-0002-5300-6276 NR 47 TC 35 Z9 36 U1 0 U2 7 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 JUL PY 2003 VL 26 IS 3 BP 193 EP 202 DI 10.1023/A:1023887412387 PG 10 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 681NA UT WOS:000183041200001 PM 12766417 ER PT J AU Corsi, A Collins, MT Riminucci, M Howell, PGT Boyde, A Robey, PG Bianco, P AF Corsi, A Collins, MT Riminucci, M Howell, PGT Boyde, A Robey, PG Bianco, P TI Osteomalacic and hyperparathyroid changes in fibrous dysplasia of bone: Core biopsy studies and clinical correlations SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE fibrous dysplasia; bone pathology; bone turnover; hyperparathyroidism; osteomalacia; histology; backscattered electron imaging ID MCCUNE-ALBRIGHT SYNDROME; ACTIVATING G(S)ALPHA MUTATION; RENAL TUBULAR REABSORPTION; TUMOR-INDUCED OSTEOMALACIA; STIMULATORY G-PROTEIN; GENE; PHOSPHATE; HISTOMORPHOMETRY; DYSFUNCTION; CHILDREN AB Deposition, mineralization, and resorption of FD bone compared with unaffected bone from FD patients was investigated in iliac crest biopsy specimens from 13 patients. Compared with unaffected bone, lesional FD bone seemed to be very sensitive to the effects of PTH and renal phosphate wasting, which respectively bring about hyperparathyroid or osteomalacic changes in the lesional bone. Introduction: Fibrous dysplasia is a genetic noninherited disease caused by activating mutations of the GNAS1 gene, resulting in the deposition of qualitatively abnormal bone and marrow. This study was designed to learn more about the local processes of bone deposition, mineralization, and resorption within lesional fibrous dysplasia (FD) bone compared with unaffected bone of FD patients. Methods: Histology, histomorphometry, and quantitative back-scattered electron imaging (qBSE) analysis was conducted on affected and unaffected biopsy specimens from 13 patients and correlated to markers of bone metabolism. Results and Conclusions: There was a marked excess of unmineralized osteoid with a nonlamellar structure and a reduced mineral content in mineralized bone within FD lesions (p < 0.001). A negative correlation (p = 0.05) between osteoid thickness (O.Th) and renal tubular phosphate reabsorption (measured as TmP/GFR) was observed for lesional bone, but not for unaffected bone, in which no histological or histomorphometric evidence of osteomalacia was observed in patients with renal phosphate wasting. Histological and histomorphometric evidence of increased bone resorption was variable in lesional bone and correlated with serum levels of parathyroid hormone (PTH). Hyperparathyroidism-related histological changes were observed in fibrous dysplastic bone, but not in the unaffected bone, of patients with elevated serum PTH secondary to vitamin D deficiency. Our data indicate that, compared with unaffected bone, lesional FD bone is very sensitive to the effects of PTH and renal phosphate wasting, which, respectively, bring about hyperparathyroid or osteomalacic changes in the lesional bone. Osteomalacic and hyperparathyroid changes, which emanate from distinct metabolic derangements (which superimpose on the local effects of GNAS1 mutations in bone), influence, in turn, the severity and type of skeletal morbidity in FD. 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 USA. Parco Sci Biomed San Raffaele, Rome, Italy. UCL, Eastman Dent Inst, London, England. UCL, Dept Anat & Dev Biol, London, England. RP Bianco, P (reprint author), Univ Roma La Sapienza, Dipartimento Med Sperimentale & Patol, Viale Regina Elena 324, I-00161 Rome, Italy. EM p.bianco@flashnet.it RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Telethon [E.1029] NR 28 TC 48 Z9 52 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUL PY 2003 VL 18 IS 7 BP 1235 EP 1246 DI 10.1359/jbmr.2003.18.7.1235 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 692GD UT WOS:000183652200008 PM 12854833 ER PT J AU Santel, A Frank, S Gaume, B Herrier, M Youle, RJ Fuller, MT AF Santel, A Frank, S Gaume, B Herrier, M Youle, RJ Fuller, MT TI Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells SO JOURNAL OF CELL SCIENCE LA English DT Article DE mitochondria; fusion; fission; Fzo; GTPase; organelle; human; mtDNA ID TRANSMEMBRANE GTPASE; OUTER-MEMBRANE; COMPLEMENTATION; FISSION; YEAST; APOPTOSIS; DIVISION; DYNAMICS; MICE; P21 AB Mitochondrial fusion may regulate mitochondrial morphogenesis and underlie complementation between mitochondrial genomes in mammalian cells. The nuclear encoded mitochondrial proteins Mfn1 and Mfn2 are human homologues of the only known protein mediators of mitochondrial fusion, the Drosophila Fzo GTPase and Saccharomyces cerevisiae yFzo1p. Although the Mfn1 and Mfn2 genes were broadly expressed, the two genes showed different levels of mRNA expression in different tissues. Two Mfn1 transcripts were detected at similar levels in a variety of human tissues and were dramatically elevated in heart, while Mfn2 mRNA was abundantly expressed in heart and muscle tissue but present only at low levels in many other tissues. Human Mfn1 protein localized to mitochondria and participated in a high molecular weight, detergent extractable protein complex. Forced expression of Mfn1 in cultured cells caused formation of characteristic networks of mitochondria. Introduction of a point mutation in the conserved G1 region of the predicted GTPase domain (Mfn1(K88T)) dramatically decreased formation of mitochondrial networks upon Mfn1 overexpression, suggesting that network formation required completion of the Mfn1 GTPase cycle. Conversely, a protein variant carrying a point mutation in the G2 motif of the Mfn1 GTPase domain acted as a dominant negative: overexpression of Mfn1(T109A) resulted in fragmentation of mitochondria. We propose that Mfn1(T109A) interferes with fusion activity of endogenous Mfn1 protein, possibly by binding necessary cofactors, so to allow unopposed mitochondrial fission. Thus, Mfn1 appears to be a key player in mediating mitochondrial fusion and morphology in mammalian cells. C1 Stanford Univ, Sch Med, Dept Child Dev, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. CLONTECH, BD Biosci, Palo Alto, CA 94303 USA. Univ Bonn, Dept Neuropathol, D-53105 Bonn, Germany. RP Fuller, MT (reprint author), Stanford Univ, Sch Med, Dept Child Dev, Stanford, CA 94305 USA. OI Fuller, Margaret T/0000-0002-3804-4987 FU NICHD NIH HHS [HD29194] NR 40 TC 188 Z9 197 U1 0 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JUL 1 PY 2003 VL 116 IS 13 BP 2763 EP 2774 DI 10.1242/jcs.00479 PG 12 WC Cell Biology SC Cell Biology GA 700DF UT WOS:000184096800015 PM 12759376 ER PT J AU Derfoul, A Lin, FJ Awumey, EM Kolodzeski, T Hall, DJ Tuan, RS AF Derfoul, A Lin, FJ Awumey, EM Kolodzeski, T Hall, DJ Tuan, RS TI Estrogenic endocrine disruptive components interfere with calcium handling and differentiation of human trophoblast cells SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE Ca transport; DDT; endocrine disruption; methoxychlor; placenta; trophoblast; 17 beta-estradiol ID MOUSE CHORIOALLANTOIC PLACENTA; SMOOTH-MUSCLE CELLS; DEVELOPMENTAL EXPRESSION; DIETHYLSTILBESTROL DES; HUMAN CHORIOCARCINOMA; BINDING PROTEIN; FUNCTIONAL-DIFFERENTIATION; POLYCHLORINATED-BIPHENYLS; PROGESTERONE-RECEPTOR; GENE-EXPRESSION AB During development, calcium (Ca) is actively transported by placental trophoblasts to meet fetal nutritional and the skeletal mineralization needs. Maternal exposure to estrogenic pesticides, such as 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT) and methoxychlor (MTC), has been shown to result in reproductive disorders and/or abnormal fetal development. In this study, we have examined the effects of exposure of trophoblastic cells to MTC and DTT, in comparison to 17beta-estradiol (E2) and diethylstilbestrol (DES), to test the hypothesis that cellular Ca handling is a target for these endocrine disruptive components. Treatment with DDT, MTC, DES, or E2 increased cellular Ca uptake, and the expression of trophoblast-specific human Ca binding protein (HCaBP) was down-regulated by both MTC and DDT. Treatment with MTC, DDT, and DES inhibited cell proliferation, induced apoptosis, and suppressed expression of several trophoblast differentiation marker genes. These effects were reversed by overexpression of metallothionein IIa, a gene highly responsive to cadmium and other metals. These results strongly suggest that trophoblast Ca handling functions are endocrinally modulated, and that their alteration by candidate endocrine disruptors, such as MTC and DDT, constitutes a possible pathway of the harmful effects of these components on fetal development. Published 2003 Wiley-Liss, Inc.(dagger) 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, 50 Ctr Dr,Rm 1503,MSC 8022, Bethesda, MD 20892 USA. FU NICHD NIH HHS [HD 29937]; NIDCR NIH HHS [DE 11327]; NIEHS NIH HHS [ES 07005, T32 ES07282] NR 78 TC 18 Z9 18 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD JUL 1 PY 2003 VL 89 IS 4 BP 755 EP 770 DI 10.1002/jeb.10558 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 695FB UT WOS:000183819500011 PM 12858341 ER PT J AU Ying, YLM Shen, DW Liang, XJ Gottesman, MM AF Ying, YLM Shen, DW Liang, XJ Gottesman, MM TI Codominance of cisplatin resistance in somatic cell hybrids SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID BINDING-PROTEINS; CROSS-RESISTANCE; DNA-REPAIR; LINES; ACCUMULATION; SENSITIVITY; CIS-DIAMMINEDICHLOROPLATINUM(II); MODULATION; REMOVAL AB Intrinsic or acquired resistance to cisplatin in cancer cells remains a major obstacle to successful chemotherapy. The clinically relevant genetic and molecular mechanisms of resistance have not yet been identified. Cisplatin-resistant (CP-r) human KB epidermoid carcinoma cell lines (HeLa) resistant to varying levels of cisplatin after single and multiple selection steps are cross-resistant to other platinum compounds and to methotrexate. Intraspecies hybrids of the sensitive and KB CP-r cells were fused with HeLa D98(OR) CP-s, hypoxanthine-aminopterin-thymidine (HAT) sensitive, ouabain resistant, to determine whether cisplatin resistance is dominant or recessive. Cell-cell hybridization between the sensitive cells and single-step or two-step KB CP-r cells both indicated codominance of cisplatin resistance compared to hybrids between sensitive cell lines (D98(OR)xKB). The hybrids between sensitive cell lines (D98xKB) and a single-step CP-r KB cell line (D98xKB-CP.5) also were cross-resistant to carboplatin and methotrexate. In addition, the relatively slower growth rate of CP-r cells appears to be dominant. In the two-step CP-r KB cell line, KB-CP1, resistance is no more dominant than in the single-step CP-r KB cell line, KB-CP.5, suggesting that one of the two steps of resistance in KB-CP1 may not be dominant. These dominance data suggest that it might be possible to identify one or more genes responsible for cisplatin resistance by gene transfer from a resistant cell line to a sensitive cell line. (C) 2003 Wiley-Liss, Inc. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr,Room 1A09, Bethesda, MD 20892 USA. NR 26 TC 3 Z9 3 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD JUL PY 2003 VL 196 IS 1 BP 63 EP 69 DI 10.1002/jcp.10320 PG 7 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 687DX UT WOS:000183361700007 PM 12767041 ER PT J AU Bonavita, S Virta, A Jeffries, N Goldin, E Tedeschi, G Schiffmann, R AF Bonavita, S Virta, A Jeffries, N Goldin, E Tedeschi, G Schiffmann, R TI Diffuse neuroaxonal involvement in mucolipidosis IV as assessed by proton magnetic resonance spectroscopic imaging SO JOURNAL OF CHILD NEUROLOGY LA English DT Article ID N-ACETYLASPARTATE; IN-VIVO; BRAIN; IDENTIFICATION; CHANNEL; DEGENERATION; ENDOCYTOSIS; METABOLISM; MUTATIONS; PROTEIN AB Mucolipidosis IV is an autosomal recessive disorder caused by mutations in MCOLN1, which codes for mucolipin, a transient receptor potential protein. In order to investigate brain metabolic abnormalities in mucolipidosis IV, we studied 14 patients (11 children, 3 adults) by proton magnetic resonance spectroscopic imaging. The ratios of N-acetylaspartate/ creatine-phosphocreatine and N-acetylaspartate/choline-containing compounds in patients with mucolipidosis IV were significantly reduced in all regions of interest except the parietal gray matter and thalamus. The ratios of choline-containing compounds/creatine-phosphocreatine was not significantly reduced in patients compared with controls. The ratio of N-acetylaspartate/creatine-phosphocreatine were significantly lower (P =.005) in the more neurologically impaired patients compared with the least impaired. For every region of interest, except for parietal gray matter, the ratio of N-acetylaspartate/creatine-phosphocreatine was lower in the more motorically impaired patient group. There was no difference for the ratio of N-acetylaspartate/creatine-phosphocreatine between younger and older patients. These findings suggest that mucolipidosis IV is largely a static developmental encephalopathy associated with diffuse neuronal and axonal damage or dysfunction. Mucolipin deficiency impairs motor more than sensory central nervous system pathways. C1 Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Naples 2, Div Neurol 2, Naples, Italy. Natl Inst Neurol Disorders & Stroke, Neuroimaging Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, Biometry & Field Studies Branch, NIH, Bethesda, MD 20892 USA. RP Schiffmann, R (reprint author), Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, NIH, Bldg 10,Rm 3D03,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 31 TC 9 Z9 10 U1 0 U2 0 PU B C DECKER INC PI HAMILTON PA 20 HUGHSON ST SOUTH, PO BOX 620, L C D 1, HAMILTON, ONTARIO L8N 3K7, CANADA SN 0883-0738 J9 J CHILD NEUROL JI J. Child Neurol. PD JUL PY 2003 VL 18 IS 7 BP 443 EP 449 DI 10.1177/08830738030180070701 PG 7 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 710QY UT WOS:000184692000001 PM 12940649 ER PT J AU Inoff-Germain, G Rodriguez, RS Torres-Alcantara, S Diaz-Jimenez, MJ Swedo, SE Rapoport, JL AF Inoff-Germain, G Rodriguez, RS Torres-Alcantara, S Diaz-Jimenez, MJ Swedo, SE Rapoport, JL TI An immunological marker (D8/17) associated with rheumatic fever as a predictor of childhood psychiatric disorders in a community sample SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY AND ALLIED DISCIPLINES LA English DT Article DE autoimmunity; depression; monoclonal antibody D8/17; obsessive-compulsive disorder; streptococcal infection; tics ID OBSESSIVE-COMPULSIVE DISORDER; AUTOIMMUNE NEUROPSYCHIATRIC DISORDERS; DIAGNOSTIC INTERVIEW SCHEDULE; CHILDREN VERSION-2.3 DISC-2.3; LYMPHOCYTE ANTIGEN D8/17; B-CELL MARKER; TOURETTES-SYNDROME; SYDENHAMS CHOREA; STREPTOCOCCAL INFECTIONS; CLINICAL DESCRIPTION AB Background: Previous studies have documented that various behavioral disturbances accompany Sydenham's chorea, a neurologic variant of rheumatic fever. Further, an immunological marker associated with rheumatic fever (monoclonal antibody D8/17) has been reported to be elevated in several neuropsychiatric disorders, most frequently tics and obsessive-compulsive disorder. We examined this association in a community sample of children previously identified as being D8/17 positive or negative. It was hypothesized that D8/17 positivity would predict increased rates of tics and obsessive-compulsive disorder, even in the absence of Sydenham's chorea. Possible associations with other disorders accompanying Sydenham's chorea - hyperactivity, anxiety, and depression, also were explored. Method: From 1991 to 1995, 2631 children (mean age = 9.6 +/- 1.6 years) from a low socioeconomic area of Mexico City were screened for the D8/17 marker. In a 2- to 5-year follow-up of 240 of these children (108 positive and 132 negative), structured psychiatric interviews and rating scales were administered to the child and main caretaker. Assessments were conducted and scored blind to the child's D8/17 status. Results: No association was seen between D8/17 positivity and tics or OCD. Conclusion: This study failed to provide support for the generalized use of D8/17 as a marker of susceptibility to tics and OCD in a community sample. C1 NIMH, NIH, DHHS, Bethesda, MD 20892 USA. Hosp Infantil Mexico Feder Gomez, Mexico City, DF, Mexico. RP Inoff-Germain, G (reprint author), NIMH, NIH, DHHS, Bethesda, MD 20892 USA. NR 69 TC 20 Z9 22 U1 3 U2 4 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry Allied Discip. PD JUL PY 2003 VL 44 IS 5 BP 782 EP 790 DI 10.1111/1469-7610.00163 PG 9 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 691RR UT WOS:000183619700013 PM 12831121 ER PT J AU Roca, CA Schmidt, PJ Altemus, M Deuster, P Danaceau, MA Putnam, K Rubinow, DR AF Roca, CA Schmidt, PJ Altemus, M Deuster, P Danaceau, MA Putnam, K Rubinow, DR TI Differential menstrual cycle regulation of hypothalamic-pituitary-adrenal axis in women with premenstrual syndrome and controls SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; GONADAL-STEROIDS; CHRONIC ESTROGEN; ADRENOCORTICOTROPIN RESPONSES; M-CHLOROPHENYLPIPERAZINE; ARGININE-VASOPRESSIN; DYSPHORIC DISORDER; STRESS RESPONSES; FEMALE RATS; SECRETION AB Previous studies in animals indicate that reproductive steroids are potent modulators of the hypothalamic-pituitary-adrenal (HPA) axis, a physiologic system that is typically dysregulated in affective disorders, such as major depression. Determination of the role of reproductive steroids in HPA axis regulation in humans is of importance when attempting to understand the pathophysiology of premenstrual syndrome (PMS), a disorder characterized by affective symptoms during the luteal phase of the menstrual cycle. We performed two studies using treadmill exercise stress testing to determine the effect of menstrual cycle phase and diagnosis on the HPA axis in women with PMS and controls and the role of gonadal steroids in HPA axis modulation in control women. The results of these studies indicate that women with PMS fail to show the normal increased HPA axis response to exercise during the luteal phase and that progesterone, not estradiol, produces increased HPA axis response to treadmill stress testing in control women. These data demonstrate that women with PMS, when symptomatic, appear to have an abnormal response to progesterone and, furthermore, do not display the HPA axis abnormalities characteristic of major depression. C1 NIMH, Behav Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIMH, Geriatr Psychiat Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Nursing, Bethesda, MD 20892 USA. Cornell Univ, Weill Med Coll, Dept Psychiat, Dept Hlth & Human Serv, New York, NY 10021 USA. Uniformed Serv Univ Hlth Sci, Dept Mil & Emergency Med, Bethesda, MD 20814 USA. RP Roca, CA (reprint author), Bldg 10,Room 3N242,10 Ctr Dr MSC 1277, Bethesda, MD 20892 USA. EM rocac@intra.nimh.nih.gov RI Deuster, Patricia/G-3838-2015 OI Deuster, Patricia/0000-0002-7895-0888 NR 53 TC 77 Z9 80 U1 4 U2 11 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 JUL PY 2003 VL 88 IS 7 BP 3057 EP 3063 DI 10.1210/jc.2002-021570 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 697DE UT WOS:000183926300016 PM 12843143 ER PT J AU Vozarova, B Weyer, C Snitker, S Gautier, JF Cizza, G Chrousos, G Ravussin, E Tataranni, PA AF Vozarova, B Weyer, C Snitker, S Gautier, JF Cizza, G Chrousos, G Ravussin, E Tataranni, PA TI Effect of cortisol on muscle sympathetic nerve activity in Pima Indians and Caucasians SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; BODY-WEIGHT GAIN; BLOOD-PRESSURE; OBESITY; SYSTEM; GLUCOCORTICOIDS; SUPPRESSION; INSULIN; HUMANS; HYPERTENSION AB The hypothalamo-pituitary-adrenal axis and sympathetic nervous system (SNS) interact to maintain cardiovascular and metabolic homeostasis, especially during stress. Pima Indians have a low SNS activity, which may contribute to both their increased risk of obesity and reduced risk of hypertension. Although glucocorticoids inhibit SNS activity, Pima Indians are not hypercortisolemic compared with Caucasians. This does not exclude the possibility that the SNS is more responsive to an inhibitory effect of cortisol in the former than in the latter group. We measured fasting plasma ACTH and cortisol and muscle SNS activity [muscle sympathetic nervous system activity (MSNA), microneurography] in 58 males [27 Pimas/31 Caucasians]. Seven Pimas and 12 Caucasians were randomized to a double-blind, placebo-controlled, cross-over study to examine the effect of overnight partial chemical adrenalectomy (metyrapone) followed by cortisol replacement (hydrocortisone) on plasma ACTH, cortisol, and MSNA. There were no ethnic differences in fasting plasma ACTH or cortisol, but MSNA adjusted for percent body fat was lower in Pimas than in Caucasians (P < 0.006). No correlation was found between fasting cortisol and basal MSNA. Administration of metyrapone did not lead to significant changes in MSNA. In response to a hydrocortisone infusion, MSNA decreased in Pima Indians (P = 0.03) but not in Caucasians (P = 0.7). Our data indicate that the low SNS activity that predisposes Pima Indians to obesity is not due to a tonic inhibitory effect of cortisol. However, an acute release of cortisol is likely to more effectively contain sympathoexcitation during stress in Pima Indians than in Caucasians, which may be an important mechanism of cardioprotection in this Native American population. C1 NIDDKD, Clin Diabet & Nutr Sect, Dept Human Serv, NIH, Phoenix, AZ 85016 USA. Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21210 USA. Hop St Louis, Serv Diabetol, F-75010 Paris, France. NIMH, NIH, Bethesda, MD 20892 USA. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. RP Vozarova, B (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Dept Human Serv, NIH, 4212 N 16Th St,Room 5-41, Phoenix, AZ 85016 USA. EM bvozarov@mail.nih.gov OI de Courten, Barbora/0000-0001-8760-2511 NR 33 TC 6 Z9 6 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 JUL PY 2003 VL 88 IS 7 BP 3218 EP 3226 DI 10.1012/jc.2002-021818 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 697DE UT WOS:000183926300041 PM 12843168 ER PT J AU Leitner, WW Restifo, NP AF Leitner, WW Restifo, NP TI DNA vaccines and apoptosis: to kill or not to kill? SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID DENDRITIC CELLS; GENE GUN; ANTIGEN; ENHANCEMENT; IMMUNIZATION; MATURATION; TOLERANCE; IMMUNITY; CASPASES; DELIVERY AB The apoptotic machinery has become the latest target of vaccinologists attempting to improve the efficacy of DNA vaccines. While workers have previously sought to induce apoptotic death in transfected DCs as a means to activate immunity, a new approach (see related article on pages 109-117) instead seeks to delay apoptosis in host DCs after DNA vaccination. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B46, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; Leitner, Wolfgang/F-5741-2011; OI Leitner, Wolfgang/0000-0003-3125-5922; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 24 TC 18 Z9 20 U1 0 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 JUL PY 2003 VL 112 IS 1 BP 22 EP 24 DI 10.1172/JCI200319069 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 697DJ UT WOS:000183926700005 PM 12840054 ER PT J AU Santos, N Soares, CC Volotao, EM Albuquerque, MCM Hoshino, Y AF Santos, N Soares, CC Volotao, EM Albuquerque, MCM Hoshino, Y TI Surveillance of rotavirus strains in Rio de Janeiro, Brazil, from 1997 to 1999 SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID POLYMERASE CHAIN-REACTION; P-TYPE; PROBE HYBRIDIZATION; INFANTILE DIARRHEA; NORTHERN BRAZIL; UNITED-STATES; 3-YEAR PERIOD; CHILDREN; G9; IDENTIFICATION AB One hundred fifty-seven (23%; n = 678) rotavirus-positive stool samples were collected between March 1997 and December 1999 in the cites of Rio de Janeiro and Niteroi. Rotaviruses in 143 (91%) samples were genotyped by reverse transcription-PCR for G and/or P specificity. Rotaviruses in the majority of G-P-typeable samples (73.3%; 74 of 101) were identified as having globally common genotypes GIP[8], G2P[4], G3P[8], and G4P [8]. Unusual strains such as GIP [9], G2 [P8], G3P [9], and G9P [4] strains were detected in 8.9% (9 of 101) of the samples. Genotypes G9P[8], G9P[6], and a mixture of G9 and other G or P types represented 15.9% (25 of 157) of the isolates. Mixed infections were detected in 25 (15.9%) samples, and rotaviruses in 15 samples (9.6%) were not typed. C1 Univ Fed Rio de Janeiro, Inst Microbiol, Dept Virol, BR-21941590 Rio De Janeiro, Brazil. Natl Inst Hlth, Infect Dis Lab, Bethesda, MD 20892 USA. RP Santos, N (reprint author), Univ Fed Rio de Janeiro, Inst Microbiol, Dept Virol, Cidade Univ,CCS-Bl 1, BR-21941590 Rio De Janeiro, Brazil. RI Santos, Norma/H-6986-2015 OI Santos, Norma/0000-0002-5123-9172 NR 42 TC 25 Z9 26 U1 0 U2 0 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 JUL PY 2003 VL 41 IS 7 BP 3399 EP 3402 DI 10.1128/JCM.41.7.3399-3402.2003 PG 4 WC Microbiology SC Microbiology GA 701MF UT WOS:000184170800100 PM 12843103 ER PT J AU Lang, FF Bruner, JM Fuller, GN Aldape, K Prados, MD Chang, S Berger, MS McDermott, MW Kunwar, SM Junck, LR Chandler, W Zwiebel, JA Kaplan, RS Yung, WKA AF Lang, FF Bruner, JM Fuller, GN Aldape, K Prados, MD Chang, S Berger, MS McDermott, MW Kunwar, SM Junck, LR Chandler, W Zwiebel, JA Kaplan, RS Yung, WKA TI Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: Biological and clinical results SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID WILD-TYPE P53; CELL LUNG-CANCER; BRAIN-TUMORS; MALIGNANT GLIOMAS; ANTICANCER AGENTS; GLIAL NEOPLASMS; MUTATIONS; SUPPRESSOR; VIVO; EXPRESSION AB Purpose : Advances in brain tumor biology indicate that transfer of p53 is an alternative therapy for human gliomas. Consequently, we undertook a phase I clinical trial of p53 gene therapy using an adenovirus vector (Ad-p53, INGN 201). Materials and Methods: To obtain molecular information regarding the transfer and distribution of exogenous p53 into gliomas after intratumoral injection and to determine the toxicity of intracerebrally injected Ad-p53, patients underwent a two-stage approach. In stage 1, Ad-p53 was stereotactically injected intratumorally via an implanted catheter. In stage 2, the tumor-catheter was resected en bloc, and the postresection cavity was treated with Ad-p53. This protocol provided intact Ad-p53-treated biologic specimens that could be analyzed for molecular end points, and because the resection cavity itself was injected with Ad-p53, patients could be observed for clinical toxicity. Results: Of fifteen patients enrolled, twelve underwent both treatment stages. In all patients, exogenous p53 protein was detected within the nuclei of astrocytic tumor cells. Exogenous p53 transactivated p21(CIP/WAF) and induced apoptosis. However, transfected cells resided on average within 5 mm of the injection site. Clinical toxicity was minimal and a maximum-tolerated dose was not reached. Although anti-adenovirus type 5 (Ad5) titers increased in most patients, there was no evidence of systemic viral dissemination. Conclusion: Intratumoral injection of Ad-p53 allowed for exogenous transfer of the p53 gene and expression of functional p53 protein. However, at the dose and schedule evaluated, transduced cells were only found within a short distance of the injection site. Although toxicity was minimal, widespread distribution of this agent remains a significant goal. (C) 2003 by American Society of Clinical Oncology. C1 Univ Texas, MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94143 USA. Univ Michigan, Dept Neurooncol, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Neurosurg, Ann Arbor, MI 48109 USA. N Amer Brain Tumor Consortium, Bethesda, MD USA. NCI, Div Canc Therapy & Diagnosis, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Lang, FF (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Neurosurg, 1515 Holcombe Blvd,Unit 442, Houston, TX 77030 USA. OI Fuller, Gregory/0000-0001-9447-2647 FU NCI NIH HHS [CA62399, CA62422, CA16672, CA62412]; NCRR NIH HHS [M01-RR00042, M01-RR00079] NR 50 TC 239 Z9 247 U1 4 U2 9 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2003 VL 21 IS 13 BP 2508 EP 2518 DI 10.1200/JCO.2003.11.138 PG 11 WC Oncology SC Oncology GA 695EU UT WOS:000183818800011 PM 12839017 ER PT J AU Meropol, NJ Weinfurt, KP Burnett, CB Balshem, A Benson, AB Castel, L Corbett, S Diefenbach, M Gaskin, D Li, Y Manne, S Marshall, J Rowland, JH Slater, E Sulmasy, DP Van Echo, D Washington, S Schulman, KA AF Meropol, NJ Weinfurt, KP Burnett, CB Balshem, A Benson, AB Castel, L Corbett, S Diefenbach, M Gaskin, D Li, Y Manne, S Marshall, J Rowland, JH Slater, E Sulmasy, DP Van Echo, D Washington, S Schulman, KA TI Perceptions of patients and physicians regarding phase I cancer clinical trials: Implications for physician-patient communication SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 38th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 18-21, 2002 CL ORLANDO, FLORIDA SP Amer Soc Clin Oncol ID TREATMENT PREFERENCES; TREATMENT DECISIONS; BREAST-CANCER; OLDER WOMEN; OF-LIFE; HEALTH; CARE; PREDICTIONS; KNOWLEDGE; QUALITY AB Purpose : To describe and compare the perceptions of cancer patients and their physicians regarding phase I clinical trials. Methods : Eligible patients had been offered phase I trial participation and had decided to participate but had not yet begun treatment. Each patient's physician also served as a study subject. Patients and physicians completed questionnaires with domains including perceptions of potential benefit and harm from treatment (experimental and standard), relative value of quality and length of life, and perceived content of patient-physician consultations. Results: Three hundred twenty-eight patients and 48 physicians completed surveys. Patients had high expectations regarding treatment outcomes (eg, median 60% benefit from experimental therapy), with those choosing to participate in a phase I trial being more optimistic than those declining phase I participation. Patients predicted a higher likelihood of both benefit and adverse reactions from treatment (experimental and standard) than their physicians (P < .0001 for all comparisons). Although 95% of patients reported that quality of life was at least as important as length of life, only 28% reported that changes in quality of life with treatment were discussed with their physicians. In contrast, 73% of physicians reported that this topic was discussed (P < .0001). Conclusion: Cancer patients offered phase I trial participation have expectations for treatment benefit that exceed those of their physicians. The discordant perceptions of patients and physicians may possibly be explained by patient optimism and confidence; however, the discrepancies in reports of consultation content, particularly given patients' stated values regarding quality of life, raise the possibility that communication in this context is suboptimal. (C) 2003 by American Society of Clinical Oncology. C1 Fox Chase Canc Ctr, Div Med Sci, Philadelphia, PA 19111 USA. Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. Duke Univ, Durham, NC USA. Georgetown Univ, Washington, DC USA. Northwestern Univ, Chicago, IL 60611 USA. Univ Maryland, Baltimore, MD 21201 USA. NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. St Vincents Catholic Med Ctr, New York, NY USA. RP Meropol, NJ (reprint author), Fox Chase Canc Ctr, Div Med Sci, 7701 Burholme Ave, Philadelphia, PA 19111 USA. RI Castel, Liana/E-7343-2011 FU NCI NIH HHS [R01 CA82085] NR 27 TC 110 Z9 110 U1 0 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2003 VL 21 IS 13 BP 2589 EP 2596 DI 10.1200/JCO.2003.10.072 PG 8 WC Oncology SC Oncology GA 695EU UT WOS:000183818800022 PM 12829680 ER PT J AU Kaufmann, M von Minckwitz, G Smith, R Valero, V Gianni, L Eiermann, W Howell, A Costa, SD Beuzeboc, P Untch, M Blohmer, JU Sinn, HP Sittek, R Souchon, R Tulusan, AH Volm, T Senn, HJ AF Kaufmann, M von Minckwitz, G Smith, R Valero, V Gianni, L Eiermann, W Howell, A Costa, SD Beuzeboc, P Untch, M Blohmer, JU Sinn, HP Sittek, R Souchon, R Tulusan, AH Volm, T Senn, HJ TI International expert panel on the use of primary (Preoperative) systemic treatment of operable breast cancer: Review and recommendations SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID NEOADJUVANT CHEMOTHERAPY; INDUCTION CHEMOTHERAPY; RANDOMIZED TRIALS; PRIMARY TUMOR; PATHOLOGICAL RESPONSE; RESIDUAL TUMOR; DOUBLE-BLIND; THERAPY; RADIOTHERAPY; DOXORUBICIN AB Primary systemic therapy (PST) represents the standard of care in patients with locally advanced breast cancer. In addition, there is increasing information on PST in operable breast disease that supports the use of PST in routine practice. However, current regimens and techniques vary. To address this concern, a group of representatives from breast cancer clinical research groups in France, Germany, Italy, the United Kingdom, and the United States reviewed all available data on prospective randomized trials in this setting. Recommendations are made regarding terminology, indications, regimen, diagnosis before treatment, monitoring of efficacy, tumor localization, surgery, pathologic evaluation, and postoperative treatment. (C) 2003 by American Society of Clinical Oncology. C1 Univ Frankfurt, Klin Gynakol & Geburtshilfe, D-60590 Frankfurt, Germany. Univ Grosshadern, Res Cross Gynecol Hosp, Munich, Germany. Charite Hosp, Berlin, Germany. Univ Heidelberg, Heidelberg, Germany. Gen Hosp, Hagen, Germany. Gen Hosp, Bayreuth, Germany. Univ Hosp, Ulm, Germany. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Natl Canc Inst, I-20133 Milan, Italy. Christie Hosp NHS Trust, Manchester, Lancs, England. Ctr Tumor Prevent, St Gallen, Switzerland. Inst Curie, Paris, France. RP Kaufmann, M (reprint author), Univ Frankfurt, Klin Gynakol & Geburtshilfe, Theodor Stern Kai 7, D-60590 Frankfurt, Germany. RI Sinn, Hans-Peter/C-5661-2008; OI Howell, Anthony/0000-0002-6233-719X NR 53 TC 193 Z9 204 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2003 VL 21 IS 13 BP 2600 EP 2608 DI 10.1200/JCO.2003.01.136 PG 9 WC Oncology SC Oncology GA 695EU UT WOS:000183818800024 PM 12829681 ER PT J AU Lugo, TG Braun, S Cote, RJ Pantel, K Rusch, V AF Lugo, TG Braun, S Cote, RJ Pantel, K Rusch, V TI Detection and measurement of occult disease for the prognosis of solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BREAST-CANCER PATIENTS; CELL LUNG-CANCER; BONE-MARROW; LYMPH-NODES; IMMUNOHISTOCHEMICAL DETECTION; CARCINOMA-CELLS; PRIMARY SURGERY; BLOOD; METASTASES; MICROMETASTASES C1 NCI, Canc Diag Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. Leopold Franzens Univ, Univ Klinikum Frauenheilkunde, Innsbruck, Austria. Univ So Calif, Keck Sch Med, Los Angeles, CA USA. Univ Klinikum Hamburg, Hamburg, Germany. Cornell Univ, Med Ctr, Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Lugo, TG (reprint author), NCI, Canc Diag Program, Div Canc Treatment & Diag, 6130 Execut Blvd,Room EPN 6035A, Bethesda, MD 20892 USA. NR 30 TC 58 Z9 59 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2003 VL 21 IS 13 BP 2609 EP 2615 DI 10.1200/JCO.2003.01.153 PG 7 WC Oncology SC Oncology GA 695EU UT WOS:000183818800025 PM 12829682 ER PT J AU Corina, DP Jose-Robertson, LS Guillemin, A High, J Braun, AR AF Corina, DP Jose-Robertson, LS Guillemin, A High, J Braun, AR TI Language lateralization in a bimanual language SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID WORD-FORM AREA; POSITRON EMISSION TOMOGRAPHY; INFERIOR PREFRONTAL CORTEX; FUNCTIONAL-ANATOMY; SENTENCE COMPREHENSION; CEREBRAL ORGANIZATION; VERB GENERATION; FRONTAL-CORTEX; SIGN LANGUAGE; TASK AB Unlike spoken languages, sign languages of the deaf make use of two primary articulators, the right and left hands, to produce signs, This situation has no obvious parallel in spoken languages, in which speech articulation is carried out by symmetrical unitary midline vocal structures. This arrangement affords a unique opportunity to examine the robustness of linguistic systems that underlie language production in the face of contrasting articulatory demands and to chart the differential effects of handedness for highly skilled movements. Positron emission tomography (PET) technique was used to examine brain activation in 16 deaf users of American Sign Language (ASL) while subjects generated verb signs independently with their right dominant and left nondominant hands (compared to the repetition of noun signs), Nearly identical patterns of left inferior frontal and right cerebellum activity were observed. This pattern of activation during signing is consistent with patterns that have been reported for spoken languages including evidence for specializations of inferior frontal regions related to lexical-semantic processing, search and retrieval, and phonological encoding. These results indicate that lexical-semantic processing in production relies upon left-hemisphere regions regardless of the modality in which a language is realized, and that this left-hemisphere activation is stable, even in the face of conflicting articulatory demands. in addition, these data provide evidence for the role of the right posterolateral cerebellum in linguistic-cognitive processing and evidence of a left ventral fusiform contribution to sign language processing. C1 Univ Washington, Dept Psychol, Seattle, WA 98195 USA. NIH, Bethesda, MD 20892 USA. RP Corina, DP (reprint author), Univ Washington, Dept Psychol, Seattle, WA 98195 USA. FU NIDCD NIH HHS [R29 DC03099] NR 62 TC 61 Z9 64 U1 4 U2 7 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD JUL 1 PY 2003 VL 15 IS 5 BP 718 EP 730 DI 10.1162/jocn.2003.15.5.718 PG 13 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 703FV UT WOS:000184270100009 PM 12965045 ER PT J AU Clay, JR AF Clay, JR TI A novel mechanism for irregular firing of a neuron in response to periodic stimulation: Irregularity in the absence of noise SO JOURNAL OF COMPUTATIONAL NEUROSCIENCE LA English DT Article DE stochastic resonance; action potentials; ionic conductances; computational models ID SQUID GIANT-AXONS; HODGKIN-HUXLEY EQUATIONS; CAT NEOCORTICAL NEURONS; SUBTHRESHOLD DYNAMICS; NERVE MEMBRANE; CHANNEL; FLUCTUATIONS; EXCITATION; POTENTIALS; SYNCHRONY AB Irregular firing of action potentials (AP's) is a characteristic feature of neurons in the brain. The variability has been attributed to noise from various sources. This study illustrates an alternative mechanism, namely, deterministic irregularity within a model of ionic conductances. Specifically, a model based on modern measurements of the Na+ and K+ current components from the squid giant axon fires irregularly in response to a continuous train of near-threshold current pulses. The interspike interval histogram from these simulations is multi-modal, a result which in other systems has been attributed to stochastic resonance. Moreover, the simulations exhibited short burst of spikes followed by relatively long quiescent periods, a result suggestive of patterned input to the model even though the input consisted of a train of regularly spaced current pulses. The variability of firing is attributable to variations in AP parameters, in particular AP amplitude. The action potential for squid giant axons is not all-or-none. Rather, it is fundamentally a continuous function of stimulus amplitude. That is, the membrane lacks a threshold. Variation in AP amplitude, and to a lesser extent, AP duration, can produce variations in the time to a subsequent AP, which represents a paradigm shift for understanding irregular neuronal firing. The emphasis is not as much on events prior to an AP as it is on the AP's themselves. C1 Natl Inst Neurol Disorders & Stroke, Ion Channel Biophys Unit, NIH, Bethesda, MD 20892 USA. RP Natl Inst Neurol Disorders & Stroke, Ion Channel Biophys Unit, NIH, Bethesda, MD 20892 USA. EM jrclay@ninds.nih.gov NR 36 TC 14 Z9 14 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5313 EI 1573-6873 J9 J COMPUT NEUROSCI JI J. Comput. Neurosci. PD JUL-AUG PY 2003 VL 15 IS 1 BP 43 EP 51 DI 10.1023/A:1024470718603 PG 9 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA 695MP UT WOS:000183834900004 PM 12843694 ER PT J AU Hosokawa, R Nonaka, K Morifuji, M Shum, L Ohishi, M AF Hosokawa, R Nonaka, K Morifuji, M Shum, L Ohishi, M TI TGF-beta decreases type I collagen and scarring after labioplasty SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE cleft lip; CL/Fraser mouse; mesenchymal cells; myofibroblast; matrix metalloproteinase-9 ID GROWTH-FACTOR-BETA; CLEFT-LIP; CRANIOFACIAL DEVELOPMENT; DIFFERENTIAL EXPRESSION; MATRIX; REPAIR; FIBROBLASTS; TISSUE; SKIN; LOCALIZATION AB Cleft lip is a common congenital malformation, and labioplasty performed on infants to repair such defects often results in severe scar formation. Since TGF-beta3 has been implicated in wound healing, we therefore hypothesized that TGF-beta3 functions to reduce scarring after cleft lip repair. In this investigation, we demonstrated that exogenous TGF-beta3 reduced scar formation in an incised and sutured mouse lip in vivo. During labioplasty, endogenous TGF-beta3 expression was also elevated. In vitro experiments showed that exogenous TGF-beta3 reduced type I collagen accumulation. Furthermore, TGF-beta3 inhibited alpha-smooth-muscle actin expression, a marker for myofibroblasts. In tandem, TGF-beta3 induced the expression and activity of MMP-9. Analysis of our data suggests that TGF-beta3 is normally secreted following labioplastic wound healing. An elevated level of TGF-beta3 reduces type I collagen deposition by restricting myofibroblast differentiation and thereby collagen synthesis, and by promoting collagen degradation by MMP-9. In combination, these events lead to TGF-beta3-mediated reduced scar formation. C1 Kyushu Univ, Fac Dent Sci, Div Maxillofacial Diagnost & Surg Sci, Higashi Ku, Fukuoka 8128582, Japan. Kyushu Univ, Fac Dent Sci, Div Oral Hlth Growth & Dev, Higashi Ku, Fukuoka 8128582, Japan. Kyushu Univ, Fac Dent Sci, Grad Sch Dent sci, Higashi Ku, Fukuoka 8128582, Japan. NIH, Cartilage Biol & Orthopaed Branch, Bethesda, MD USA. RP Ohishi, M (reprint author), Kyushu Univ, Fac Dent Sci, Div Maxillofacial Diagnost & Surg Sci, Higashi Ku, Maidashi 3-1-1, Fukuoka 8128582, Japan. NR 30 TC 27 Z9 34 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUL PY 2003 VL 82 IS 7 BP 558 EP 564 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 693MM UT WOS:000183721400014 PM 12821719 ER PT J AU Dimmock, JR Jha, A Zello, GA Sharma, RK Shrivastav, A Selvakumar, P Allen, TM Santos, CL Balzarini, J De Clercq, E Manavathu, EK Stables, JP AF Dimmock, JR Jha, A Zello, GA Sharma, RK Shrivastav, A Selvakumar, P Allen, TM Santos, CL Balzarini, J De Clercq, E Manavathu, EK Stables, JP TI 3,5-bis(phenylmethylene)-1-(N-arylmaleamoyl)-4-piperidones: A novel group of cytotoxic agents SO JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY LA English DT Article DE 4-piperidones; maleamic acids; cytotoxicity; molecular modeling; human N-myristoyltransferase ID PROTEIN N-MYRISTOYLTRANSFERASE; MYRISTOYL-COA; TRANSFERASE; DRUGS; ASSAY AB A series of novel 3,5-bis(phenylmethylene)-1-(N-arylmaleamoyl)-4-piperidones 3 have been synthesized which displayed potent cytotoxicity towards human Molt 4/C8 and CEM T-lymphocytes as well as murine P388 and L1210 leukemic cells. In contrast, the related N-arylmaleamic acids 4 possessed little or no cytotoxicity in these four screens. Molecular modeling revealed certain interplanar and bond angles and interatomic distances which were perceived to contribute to the observed bioactivity as well as providing suggestions for future structural modifications of the piperidones 3 . Evaluation of representative compounds in series 3 and 4 on the activity of human N-myristoyltransferase revealed that, at the maximum concentration utilized, namely 250 muM, only weak inhibiting properties were displayed by some of the compounds in series 4 . Various members of series 3 and 4 were well tolerated in mice. C1 Univ Saskatchewan, Coll Pharm & Nutr, Saskatoon, SK S7N 5C9, Canada. Saskatoon Canc Ctr, Canc Res Unit, Saskatoon, SK S7N 4H4, Canada. Saskatoon Canc Ctr, Coll Med, Dept Pathol, Saskatoon, SK S7N 4H4, Canada. Univ Alberta, Dept Pharmacol, Edmonton, AB T6G 2H7, Canada. Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium. Wayne State Univ, Dept Med, Detroit, MI 48201 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Dimmock, JR (reprint author), Univ Saskatchewan, Coll Pharm & Nutr, Saskatoon, SK S7N 5C9, Canada. EM dimmock@skyway.usask.ca RI Jha, Amitabh/B-5452-2010 OI Jha, Amitabh/0000-0002-6305-0721 NR 30 TC 25 Z9 26 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1475-6366 J9 J ENZYM INHIB MED CH JI J. Enzym. Inhib. Med. Chem. PD JUL PY 2003 VL 18 IS 4 BP 325 EP 332 DI 10.1080/1475636031000121938 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 701QV UT WOS:000184179800006 PM 14567547 ER PT J AU Cocco, P Broccia, G Aru, G Casula, P Muntoni, S Cantor, KP Ward, MH AF Cocco, P Broccia, G Aru, G Casula, P Muntoni, S Cantor, KP Ward, MH TI Nitrate in community water supplies and incidence of non-Hodgkin's lymphoma in Sardinia, Italy SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Article ID DRINKING-WATER; RISK C1 Univ Cagliari, Dept Publ Hlth, Occupat Hlth Sect, I-09124 Cagliari, Italy. ASL 8, Oncol Hosp, Div Haematol, Cagliari, Italy. Univ Cagliari, Dept Biomed Sci & Biotechnol, I-09124 Cagliari, Italy. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Cocco, P (reprint author), Univ Cagliari, Dept Publ Hlth, Occupat Hlth Sect, Via San Giorgio 12, I-09124 Cagliari, Italy. NR 5 TC 4 Z9 5 U1 0 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD JUL PY 2003 VL 57 IS 7 BP 510 EP 511 DI 10.1136/jech.57.7.510 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 693CY UT WOS:000183698700013 PM 12821696 ER PT J AU Sechena, R Liao, S Lorenzana, R Nakano, C Polissar, N Fenske, R AF Sechena, R Liao, S Lorenzana, R Nakano, C Polissar, N Fenske, R TI Asian American and Pacific Islander seafood consumption - a community-based study in King County, Washington SO JOURNAL OF EXPOSURE ANALYSIS AND ENVIRONMENTAL EPIDEMIOLOGY LA English DT Article DE seafood consumption; Asian American and Pacific Islanders; community-university partnerships; fish; shellfish ID JAPANESE-AMERICAN; KOREAN-AMERICANS; FOOD-HABITS; FISH; CALIFORNIA; REFUGEES; PATTERNS; BAY AB This paper describes and quantifies seafood consumption rates, and acquisition and preparation habits of 202 first-and second-generation Asian American and Pacific Islanders (AAPI) from 10 ethnic groups (Cambodian, Chinese, Filipino, Hmong, Japanese, Korean, Laotian, Mien, Samoan, and Vietnamese) in King County, Washington in 1997. Participants were all seafood consumers. Average and median seafood consumption rates were 117.2 and 89 g/day, respectively, based on the average body weight (62 kg) of participants. Shellfish comprised 45.9% and "all finfish'' 43.3% of all seafood consumed. Consumption rates varied significantly between ethnic groups with Vietnamese (2.63 g/kg/day) and Japanese (2.18 g/kg/day) having the highest average consumption rates, and Mien (0.58 g/kg/day) and Hmong (0.59 g/kg/day) the lowest. The most frequently consumed finfish and invertebrates were salmon (93% of respondents), tuna (86%), shrimp (98%), crab (96%), and squid (82%). Fish fillets were eaten with the skin 55%, and the head, bones, eggs, and/or other organs 20% of the time. Crabmeat including the hepatopancreas (accumulates lipophilic chemicals such as organochlorine compounds) was consumed 43% of the time. This paper was a product of a Community-University Partnership. Community guidance in study design and data collection was essential for successful participation by the AAPI Community. Data reported here not only will provide risk assessors with AAPI-specific seafood consumption rates but with insights into cultural consumption/acquisition habits that may alter risk assessment assumptions for the AAPI Community. C1 US EPA, Reg 10, Seattle, WA 98101 USA. Univ Washington, NIEHS, Ctr Ecogenet & Environm Hlth, Seattle, WA 98105 USA. Statpro Consultants, Seattle, WA USA. Refugee Federat Serv Ctr, Seattle, WA USA. Mt Whisper Light Stat Consulting, Seattle, WA USA. Univ Washington, Dept Environm Hlth, Seattle, WA 98195 USA. RP Lorenzana, R (reprint author), US EPA, Reg 10, 1200 6th Ave,OEA-095, Seattle, WA 98101 USA. NR 37 TC 37 Z9 38 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1053-4245 J9 J EXPO ANAL ENV EPID JI J. Expo. Anal. Environ. Epidemiol. PD JUL PY 2003 VL 13 IS 4 BP 256 EP 266 DI 10.1038/sj.jea.7500274 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 702KZ UT WOS:000184224200002 PM 12923552 ER PT J AU Boese, SH Aziz, O Simmons, NL Gray, MA AF Boese, SH Aziz, O Simmons, NL Gray, MA TI Intracellular Ca2+ directly regulates the Ca2+-activated Cl- conductance in mouse inner medullary collecting duct cells SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-of-General-Physiologists CY SEP 03-07, 2003 CL MARINE BIOL LAB, WOODS HOLE, MASSACHUSETTS SP Soc Gen Physiol HO MARINE BIOL LAB C1 Univ Newcastle Upon Tyne, Sch Med, Sch Cell & Mol Biosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. Univ Potsdam, Inst Biochem & Biol, D-14471 Potsdam, Germany. NIEH, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD JUL PY 2003 VL 122 IS 1 MA 87 BP 37A EP 38A PG 2 WC Physiology SC Physiology GA 699ZJ UT WOS:000184087600098 ER PT J AU Zhou, J Brum, G Gonzalez, A Launikonis, BS Stern, MD Rios, E AF Zhou, J Brum, G Gonzalez, A Launikonis, BS Stern, MD Rios, E TI Ca2+ sparks and embers of mammalian muscle. - Properties of the sources SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article DE sarcoplasmic reticulum; intracellular channels; excitation-contraction coupling; ryanodine receptors ID FROG SKELETAL-MUSCLE; SARCOPLASMIC-RETICULUM; CALCIUM-RELEASE; RYANODINE RECEPTOR; ELEMENTARY EVENTS; FIBERS; CHANNELS; MODEL; TRANSIENTS; SIMULATION AB Ca2+ sparks of membrane-pcrmeabilized rat muscle cells were analyzed to derive properties of their sources. Most events identified in longitudinal confocal line scans looked like sparks, but 23% (1,000 out of 4,300) were followed by long-lasting embers. Some were preceded by embers, and 48 were "lone embers." Average spatial width was similar to2 mum in the rat and 1.5 mum in frog events in analogous solutions. Amplitudes were 33% smaller and rise times 50% greater in the rat. Differences were highly significant. The greater spatial width was not a consequence of greater open time of the rat source, and was greatest at the shortest rise times, suggesting a wider Ca2+ source. In the rat, but not the frog, spark width was greater in scans transversal to the fiber axis. These features suggested that rat spark sources were elongated transversally. Ca2+ release was calculated in averages of sparks with long embers. Release current during the averaged ember started at 3 or 7 pA (depending on assumptions), whereas in lone embers it was 0.7 or 1.3 pA, which suggests that embers that trail sparks start with five open channels. Analysis of a spark with leading ember yielded a current ratio ranging from 37 to 160 in spark and ember, as if 37-160 channels opened in the spark. In simulations, 25-60 pA of Ca2+ current exiting a point source was required to reproduce frog sparks. 130 pA, exiting a cylindric source of 3 mum, qualitatively reproduced rat sparks. In conclusion, sparks of rat muscle require a greater current than frog sparks, exiting a source elongated transversally to the fiber axis, constituted by 35-260 channels. Not infrequently, a few of those remain open and produce the trailing ember. C1 Rush Univ, Sch Med, Dept Physiol & Mol Biophys, Chicago, IL 60612 USA. Univ Republica, Fac Med, Dept Biofis, Montevideo, Uruguay. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Rios, E (reprint author), Rush Univ, Sch Med, Dept Physiol & Mol Biophys, 1750 W Harrison St,Suite 1279JS, Chicago, IL 60612 USA. RI Launikonis, Bradley/K-6256-2015 FU NIAMS NIH HHS [R01 AR032808] NR 52 TC 56 Z9 57 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD JUL PY 2003 VL 122 IS 1 BP 95 EP 114 DI 10.1085/jgp.200308796 PG 20 WC Physiology SC Physiology GA 699ZJ UT WOS:000184087600009 PM 12835473 ER PT J AU Pratt, CA Ha, L Levine, SR Pratt, CB AF Pratt, CA Ha, L Levine, SR Pratt, CB TI Stroke knowledge and barriers to stroke prevention among African Americans: Implications for health communication SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article; Proceedings Paper CT American-Heart-Association 25th International Stroke Conference CY FEB 10-12, 2000 CL NEW ORLEANS, LOUISIANA SP Amer Heart Assoc ID RISK-FACTORS; CARDIOVASCULAR-DISEASE; UNITED-STATES; HIV/AIDS; SYMPTOMS; TRENDS; SIGNS AB Stroke is a major cause of death and disability, especially among African Americans. Yet research on stroke knowledge and barriers to stroke prevention among African Americans is limited. This study used a 50-item questionnaire to conduct structured telephone interviews with 379 African American adults, 50 Years or older. The questionnaire included questions on stroke knowledge, stroke risk behaviors, and barriers to stroke prevention. A stroke knowledge score was computed by assigning points for correct responses on knowledge items. The average stroke knowledge score of participants was 10.9, out of a maximum possible score of 27. Stroke knowledge was significantly related to the presence of hypertension, heart disease, diabetes, and family history of stroke. College education was significantly associated with older respondents' stroke knowledge. Younger college-educated respondents had more knowledge about the risky behaviors that lead to stroke than those with less education. Respondents preferred hospitals to churches or senior centers for receiving stroke information and for learning about stroke from their physicians. Stress and poor financial status were most frequently reported as barriers to stroke prevention. These findings have implications for developing more effective strategies for educating African Americans about stroke prevention. C1 NHLBI, NIH, Bethesda, MD 20892 USA. Bowling Green State Univ, Bowling Green, OH 43403 USA. NYU, Mt Sinai Sch Med, New York, NY USA. Michigan State Univ, E Lansing, MI 48824 USA. RP Pratt, CA (reprint author), 6701 Rockledge Dr,Room 8134,MSC 7936, Bethesda, MD 20892 USA. FU NIA NIH HHS [AG15286]; NINDS NIH HHS [3P01 NS23393-12SI] NR 20 TC 21 Z9 21 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1081-0730 J9 J HEALTH COMMUN JI J. Health Commun. PD JUL-AUG PY 2003 VL 8 IS 4 BP 369 EP 381 DI 10.1080/10810730390222380 PG 13 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA 721MN UT WOS:000185320300005 PM 12907401 ER PT J AU Magai, C Kerns, MD Gillespie, M Huang, B AF Magai, C Kerns, MD Gillespie, M Huang, B TI Anger experience and anger inhibition in sub-populations of African American and European American older adults and relation to circulatory disease SO JOURNAL OF HEALTH PSYCHOLOGY LA English DT Article DE African American; anger experience; anger inhibition; circulatory disease; West Indian ID CORONARY HEART-DISEASE; BLOOD-PRESSURE; COMPREHENSIVE ASSESSMENT; INTERVIEW SCHEDULE; INDICATOR SCALES; PHYSICAL HEALTH; EXPRESSION; HOSTILITY; STRESS; BEHAVIOR AB This study examined ethnic differences in the link between anger experience and anger inhibition and that of circulatory disease (CD). To ascertain the effects of anger inhibition in older persons, health data from groups of African American, African Caribbean, Eastern European and European American adults were collected. Experienced anger and anger inhibition were significant predictors of CD only for the African American group and the relation between experienced anger and CD was mediated by anger inhibition. The data suggest that cultural factors play a role in the development of an anger-inhibitory style and that this trait may pose a serious risk factor for circulatory disease. C1 Long Isl Univ, Ctr Studies Ethnic & Human Dev, Brooklyn, NY 11201 USA. NIA, NIH, Bethesda, MD 20892 USA. Univ Alberta, Edmonton, AB T6G 2M7, Canada. Univ Washington, Sch Social Work, Seattle, WA 98195 USA. Univ Alberta, Edmonton, AB T6G 2M7, Canada. RP Magai, C (reprint author), Long Isl Univ, Ctr Studies Ethnic & Human Dev, 1 Univ Plaza, Brooklyn, NY 11201 USA. FU NIA NIH HHS [K07 AG00921]; NIGMS NIH HHS [S06 GM54650] NR 67 TC 3 Z9 3 U1 2 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 6 BONHILL STREET, LONDON EC2A 4PU, ENGLAND SN 1359-1053 J9 J HEALTH PSYCHOL JI J. Health Psychol. PD JUL PY 2003 VL 8 IS 4 BP 413 EP 432 DI 10.1177/13591053030084002 PG 20 WC Psychology, Clinical SC Psychology GA 713AD UT WOS:000184831000002 PM 19127709 ER PT J AU Scuteri, A Stuehlinger, MC Cooke, JP Wright, JG Lakata, EG Anderson, DE Fleg, JL AF Scuteri, A Stuehlinger, MC Cooke, JP Wright, JG Lakata, EG Anderson, DE Fleg, JL TI Nitric oxide inhibition as a mechanism for blood pressure increase during salt loading in normotensive postmenopausal women SO JOURNAL OF HYPERTENSION LA English DT Article DE arginine; endothelium; nitric oxide; postmenopausal women; salt sensitivity; vasodilation ID ENDOTHELIUM-DEPENDENT VASODILATION; HORMONE REPLACEMENT THERAPY; END-TIDAL CO2; ESSENTIAL-HYPERTENSION; L-ARGININE; SENSITIVE HYPERTENSION; HEART-DISEASE; ESTROGEN; RATS; DYSFUNCTION AB Objectives Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO), which plays an important role in natriuresis. We determined whether changes in endothelium-dependent vasodilation (EDD) and plasma ADMA predict changes in blood pressure (BP) after salt loading in normotensive postmenopausal women (PMW). Methods In 15 normotensive PMW (age 50-60 years), not receiving estrogen, ambulatory 24-h BP, plasma lipids, and ADMA were measured after 4 days of a low-salt diet (70 mEq/day) and following 7 days of high-salt intake (260 mEq/day). Brachial artery diameter at rest, during reactive hyperemia, i.e. EDD, and after sublingual nitroglycerin, i.e. non-EDD, were measured by ultrasound. The 24-h urinary NO metabolite (NOx) was measured by Griess reaction. Plasma ADMA was measured by high-pressure liquid chromatography. Results During low-salt, 24-h BP levels averaged 121 +/- 11 and 69 +/- 7 mmHg for systolic BP (SBP) and diastolic BP (DBP), respectively. After salt loading, average 24-h BP increases were: 7.6 mmHg for SBP, 2.2 mmHg for DBP, and 5.5 mmHg for pulse pressure (PP). Increases of 24-h SBP and 24-h PP after salt loading correlated directly with changes in ADMA (partial R-2 = 0.16 for 24-h SBP and 0.17 for 24-h PP, P < 0.05 for both) and inversely with changes in EDD (partial R-2 = 0.13, P = 0.09 for 24 h SBP and partial R-2 = 0.15, P = 0.07 for 24-h PP), after adjustment for age and cholesterol. Conclusions Inhibition of NO bioavailability by ADMA and a subsequent reduction in EDD contribute to the increase in BP during high-salt intake in normotensive PMW not receiving estrogen. C1 NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. INRCA, UO Geriatria, Rome, Italy. Stanford Univ, Sch Med, Dept Cardiovasc Med, Falk Cardiovasc Res Ctr, Stanford, CA 94305 USA. Univ Klin Innere Med, Innsbruck, Austria. RP Scuteri, A (reprint author), NIA, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Cooke, John/0000-0003-0033-9138 FU NHLBI NIH HHS [R01 HL-63685, R01 HL-58638] NR 37 TC 39 Z9 40 U1 0 U2 0 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 JUL PY 2003 VL 21 IS 7 BP 1339 EP 1346 DI 10.1097/01.hjh.0000059082.43904.02 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 703KF UT WOS:000184278000023 PM 12817182 ER PT J AU Edwards, AD Chaussabel, D Tomlinson, S Schulz, O Sher, A Sousa, CRE AF Edwards, AD Chaussabel, D Tomlinson, S Schulz, O Sher, A Sousa, CRE TI Relationships among murine CD11c(high) dendritic cell subsets as revealed by baseline gene expression patterns SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MOUSE LYMPHOID ORGANS; CD4 T-CELLS; IN-VIVO; CROSS-PRESENTATION; IFN-GAMMA; B-CELLS; SURFACE PHENOTYPE; CD8-ALPHA(+); CD8(+); MATURATION AB The functional relationships and properties of different subtypes of dendritic cells (DC) remain largely undefined. To better characterize these cells, we used global gene analysis to determine gene expression patterns among murine CD11c(high) DC subsets. CD4(+), CD8alpha(+), and CD8alpha(-) CD4(-) (double negative (DN)) DC were purified from spleens of normal C57/BL6 mice and analyzed using Affymetrix microarrays. The CD4(+) and CD8alpha(+) DC subsets showed distinct basal expression profiles differing by >200 individual genes. These included known DC subset markers as well as previously unrecognized, differentially expressed CD Ags such as CD1d, CD5, CD22, and CD72. Flow cytometric analysis confirmed differential expression in nine of nine cases, thereby validating the microarray analysis. Interestingly, the microarray expression profiles for DN cells strongly resembled those of CD4(+) DC, differing from them by <25 genes. This suggests that CD4(+) and DN DC are closely related phylogenetically, whereas CD8a+ DC represent a more distant lineage, supporting the historical distinction between CD8alpha(+) and CD8alpha(-) DC. However, staining patterns revealed that in contrast to CD4(+) DC, the DN subset is heterogeneous and comprises at least two subpopulations. Gene Ontology and literature mining analyses of genes expressed differentially among DC subsets indicated strong associations with immune response parameters as well as cell differentiation and signaling. Such associations offer clues to possible unique functions of the CD11c(high) DC subsets that to date have been difficult to define as rigid distinctions. C1 Canc Res UK, London Res Inst, Immunobiol Lab, Lincolns Inn Fields Labs, London WC2A 3PX, England. Canc Res UK, London Res Inst, Computat Genome Anal Lab, London WC2A 3PX, England. NIAID, Immunobiol Sect, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. RP Sousa, CRE (reprint author), Canc Res UK, London Res Inst, Immunobiol Lab, Lincolns Inn Fields Labs, 44 Lincolns Inn Fields, London WC2A 3PX, England. RI Edwards, Alexander/F-7440-2010; OI Edwards, Alexander/0000-0003-2369-989X; Chaussabel, Damien/0000-0002-6131-7242 NR 68 TC 90 Z9 91 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2003 VL 171 IS 1 BP 47 EP 60 PG 14 WC Immunology SC Immunology GA 692RQ UT WOS:000183674400009 PM 12816982 ER PT J AU Geiszt, M Lekstrom, K Brenner, S Hewitt, SM Dana, R Malech, HL Leto, TL AF Geiszt, M Lekstrom, K Brenner, S Hewitt, SM Dana, R Malech, HL Leto, TL TI NAD(P)H oxidase 1, a product of differentiated colon epithelial cells, can partially replace glycoprotein 91(phox) in the regulated production of superoxide by phagocytes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; INFLAMMATORY-BOWEL-DISEASE; SMOOTH-MUSCLE CELLS; NADPH OXIDASE; VITAMIN-D; GENE-TRANSFER; EXPRESSION; GP91(PHOX); APOPTOSIS; NOX1 AB Reactive oxygen species (ROS) serve several physiological functions; in some settings they act in host defense, while in others they function in cellular signaling or in biosynthetic reactions. We studied the expression and function of a recently described source of ROS, NAD(P)H oxidase 1 or Nox1, which has been associated with cell proliferation. In situ hybridization in mouse colon revealed high Nox1 expression within the lower two-thirds of colon crypts, where epithelial cells undergo proliferation and differentiation. Human multitumor tissue array analysis confirmed colon-specific Nox1 expression, predominantly in differentiated epithelial tumors. Differentiation of Caco2 and HT29 cells with 1alpha,25-dihydroxyvitamin D-3 or IFN-gamma enhances Nox1 expression and decreases cell proliferation, suggesting that Nox1 does not function as a mitogenic oxidase in colon epithelial cells. Transduction with retrovirus encoding Nox1 restored activation and differentiation-dependent superoxide production in gp91(phox)-deficient PLB-985 cells, indicating close functional similarities to the phagocyte oxidase (phox). Furthermore, coexpression of cytosolic components, p47(phox) and p67(phox) , augments Nox1 activity in reconstituted K562 cells. Finally, Nox1 partially restores superoxide production in neutrophils differentiating ex vivo from gp91(phox)-deficient CD34(+) peripheral blood-derived stem cells derived from patients with X-linked chronic granulomatous disease. These studies demonstrate a significant functional homology (cofactor-dependent and activation-regulated superoxide production) between Nox1 and its closest homologue, gp91(phox), suggesting that targeted up-regulation of Nox1 expression in phagocytic cells could provide a novel approach in the molecular treatment of chronic granulomatous disease. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, Bethesda, MD 20892 USA. Semmelweis Univ, Dept Physiol, Fac Med, Budapest, Hungary. RP Leto, TL (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 11N106, Bethesda, MD 20892 USA. RI Brenner, Sebastian/D-7456-2013; OI Hewitt, Stephen/0000-0001-8283-1788 NR 35 TC 128 Z9 134 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2003 VL 171 IS 1 BP 299 EP 306 PG 8 WC Immunology SC Immunology GA 692RQ UT WOS:000183674400038 PM 12817011 ER PT J AU Liu, GT Khong, TT Wheeler, CJ Yu, JS Black, KL Ying, H AF Liu, GT Khong, TT Wheeler, CJ Yu, JS Black, KL Ying, H TI Molecular and functional analysis of tyrosinase-related protein (TRP)-2 as a cytotoxic T lymphocyte target in patients with malignant glioma SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE cytotoxic T lymphocyte; dendritic cells; glioblastoma multiforme; TRP-2; tumor antigen ID TUMOR-INFILTRATING LYMPHOCYTES; MELANOMA ANTIGEN; DENDRITIC CELLS; BRAIN-TUMORS; B16 MELANOMA; IMMUNE-RESPONSES; IN-VITRO; IMMUNOTHERAPY; CANCER; IDENTIFICATION AB Tyrosinase-related protein (TRP)-2 is an immunogenic antigen in melanoma. The authors sought to investigate whether TRP-2 could be a potential target for patients with malignant glioma. RT-PCR analysis demonstrated that TRP-2 was present in 51.2% of primary tumor cell lines derived from patients with glioblastoma multiforme (GBM). The percentage of TRP-2-6b, TRP-2-INT2, TRP-2-LT, and TRP-2-8b isoform expression in all tested GBM cells was 13.9%, 34.9%, 41.9%, and 39.5%, respectively. TRP-2 protein expression was detected in GBM cells and tumor tissues by Western blot and immunohistochemistry. In addition, an HLA-A2-restricted cytotoxic T cell clone that recognizes the TRP-2(180-188) peptide (SVYDFFVWL) specifically lysed the TRP-2 positive GBM cells in a HLA-A2 restricted manner. In addition, the level of TRP-2 mRNA expression, as determined by real-time quantitative RT-PCR, correlated with the level of CTL recognition as measured by IFN-gamma secretion (R = 0.90; p < 0.01). To further test the immunogenicity of TRP-2 in glioma, PBMCs from a healthy donor were primed in vitro using autologous dendritic cells (DCs) pulsed with irradiated GBM cells. These in vitro generated T cells specifically lysed T2 cells pulsed with TRP-2(180-188) peptide and TRP-2 positive GBM cell lines. Most importantly, TRP-2180-188 specific CTL frequency in four patients' PBMC who were both HLA-A2 and TRP-2 positive was significantly (p < 0.01) increased, respectively, after vaccinations with DCs pulsed with autologous tumor lysate. The authors' studies demonstrate that TRP-2 could be a useful antigen target for monitoring or developing immunotherapeutic strategies for glioma patients. C1 Cedars Sinai Med Ctr, Maxine Dunitz Neurosurg Inst, Los Angeles, CA 90048 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Liu, GT (reprint author), Berlex Biosci, 2600 Hilltop Dr, Richmond, CA 94804 USA. NR 47 TC 46 Z9 50 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD JUL-AUG PY 2003 VL 26 IS 4 BP 301 EP 312 DI 10.1097/00002371-200307000-00002 PG 12 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 698EV UT WOS:000183985400002 PM 12843792 ER PT J AU Dudley, ME Wunderlich, JR Shelton, TE Even, J Rosenberg, SA AF Dudley, ME Wunderlich, JR Shelton, TE Even, J Rosenberg, SA TI Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE adoptive cell transfer; tumor-infiltrating lymphocyte; melanoma; tumor antigen; immunotherapy ID T-CELL CLONES; METASTATIC MELANOMA; IDENTIFICATION; PEPTIDE AB The generation of T lymphocytes with specific reactivity against tumor antigens is a prerequisite for effective adoptive transfer therapies. Melanoma-specific lymphocyte cultures can be established from tumor infiltrating lymphocytes (TILs) by in vitro culture in high levels of IL-2. We have optimized methods for generating melanoma-reactive TIL cultures from small resected tumor specimens. We report a retrospective analysis of 860 attempted TIL cultures from 90 sequential melanoma biopsy specimens from 62 HLA-A2(+) patients. Multiple independent TIL derived from a single tumor often exhibited substantial functional and phenotypic variation. Tumor specific activity was detected in TIL from 29 (81%) of 36 patients screened. TIL cultures selected for high activity were generally capable of large numerical expansion using a single round of a rapid expansion protocol. Limited clonal T-cell populations in an oligoclonal TIL culture could confer specific tumor recognition in these highly selected, highly expanded TIL cultures. These methods were efficient at generating TILs suitable for adoptive transfer therapy. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Dudley, ME (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B-08,10 Ctr Dr, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 SC003811-32] NR 18 TC 285 Z9 297 U1 3 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD JUL-AUG PY 2003 VL 26 IS 4 BP 332 EP 342 DI 10.1097/00002371-200307000-00005 PG 11 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 698EV UT WOS:000183985400005 PM 12843795 ER PT J AU Phan, GQ Touloukian, CE Yang, JC Restifo, NP Sherry, RM Hwu, P Topalian, SL Schwartzentruber, DJ Seipp, CA Freezer, LJ Morton, KE Mavroukakis, SA White, DE Rosenberg, SA AF Phan, GQ Touloukian, CE Yang, JC Restifo, NP Sherry, RM Hwu, P Topalian, SL Schwartzentruber, DJ Seipp, CA Freezer, LJ Morton, KE Mavroukakis, SA White, DE Rosenberg, SA TI Immunization of patients with metastatic melanoma using both class I- and class II-restricted peptides from melanoma-associated antigens SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE gp100; MART-1; CD4(+) T cell; CD8(+) T cell; CD4(+)CD25(+) T cell ID T-CELL RESPONSES; RECOMBINANT INTERLEUKIN-2 THERAPY; HIGH-DOSE INTERLEUKIN-2; EFFECTOR FUNCTION; VITRO; IDENTIFICATION; LYMPHOCYTES; IMMUNITY; INHIBIT; HELP AB Cancer vaccines targeting CD8(+) T cells have been successful in eliciting immunologic responses but disappointing in inducing clinical responses. Strong evidence supports the importance of CD4(+) T cells in "helping" cytotoxic CD8(+) cells in antitumor immunity. We report here on two consecutive clinical trials evaluating the impact of immunization with both human leukocyte antigen class I- and class II-restricted peptides from the gp100 melanoma antigen. In Protocol 1, 22 patients with metastatic melanoma were immunized with two modified class I A*0201-restricted peptides, gp100:209-217(210M) and MART-1:26-35(27L). In Protocol 2, 19 patients received the same class I-restricted peptides in combination with a class 11 DRB1*0401-restricted peptide, gp100:44-59. As assessed by in vitro sensitization assays using peripheral blood mononuclear cells (PBMC) against the native ap100:209-217 peptide, 95% of patients in Protocol I were successfully immunized after two vaccinations in contrast to 50% of patients in Protocol 2 (P-2 < 0.005). Furthermore, the degree of sensitization was significantly lower in patients in Protocol 2 (P = 0.01). Clinically, one patient in Protocol 2 had an objective response, and none did in Protocol 1. Thus, the addition of the class II-restricted peptide gp100:44-59 did not improve clinical response but might have diminished the immunologic response of circulating PBMC to the class I-restricted peptide gp100:209-217. The reasons for this decreased immune reactivity are unclear but may involve increased CD4(+)CD25(+) regulatory T-cell activity, increased apoptosis of activated CD8(+) T cells, or the trafficking of sensitized CD8(+) reactive cells out of the peripheral blood. Moreover, the sequential, nonrandomized nature of patient enrollment for the two trials may account for the differences in immunologic response. C1 NCI, Surg Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, Canc Res Ctr, NIH, Bldg 10,Room 2B42,10 Ctr Dr, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 24 TC 86 Z9 89 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD JUL-AUG PY 2003 VL 26 IS 4 BP 349 EP 356 DI 10.1097/00002371-200307000-00007 PG 8 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 698EV UT WOS:000183985400007 PM 12843797 ER PT J AU Agrawal, AG Petersen, LR AF Agrawal, AG Petersen, LR TI Human immunoglobulin as a treatment for West Nile virus infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID INTRAVENOUS IMMUNOGLOBULIN; ALPHAVIRUS INFECTION; ENCEPHALITIS-VIRUS; GAMMA-GLOBULIN; ANTIBODIES; EFFICACY; MODEL; RIBAVIRIN; OUTBREAK; NEURONS C1 Ctr Dis Control & Prevent, Div Vector Borne Infect Dis, Ctr Infect Dis, Ft Collins, CO 80522 USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Petersen, LR (reprint author), Ctr Dis Control & Prevent, Div Vector Borne Infect Dis, Ctr Infect Dis, POB 2087,Foothills Campus, Ft Collins, CO 80522 USA. NR 38 TC 51 Z9 54 U1 0 U2 0 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 JUL 1 PY 2003 VL 188 IS 1 BP 1 EP 4 DI 10.1086/376871 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 696UK UT WOS:000183905800001 PM 12825164 ER PT J AU Pfeiffer, RM Tanaka, Y Yeo, AET Umemura, T Seal, KH Shih, JWK Alter, HJ Edlin, BR O'Brien, TR AF Pfeiffer, RM Tanaka, Y Yeo, AET Umemura, T Seal, KH Shih, JWK Alter, HJ Edlin, BR O'Brien, TR TI Prevalence of SEN viruses among injection drug users in the San Francisco Bay area SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HEPATITIS-C; INFECTION; RISK AB SEN viruses (SENVs) are newly discovered bloodborne viruses that may play a role in liver disease. SENV strain prevalence was examined in a race/ethnicity-stratified sample of 531 injection drug users (IDUs) from the San Francisco Bay area. Weighted prevalences were as follows: SENV-A, 45.7%; SENV-C/H, 35.6%; and SENV-D, 10.3%. Infection was associated with a longer duration of injection drug use. SENV-A was more common in black subjects (adjusted odds ratio [ORa], 4.37; 95% confidence interval [CI], 2.65-7.21) and Hispanic subjects (ORa, 2.30; 95% CI, 1.38-3.85) than in white and non-Hispanic subjects, and the pattern was similar for SENV-C/H. For SENV-D, prevalence was similar in black and white subjects, but lower in Hispanic subjects; infection was less common among women than men (ORa, 0.32; 95% CI, 0.15-0.71) and more common among men with at least 1 recent male sex partner than among heterosexual men (ORa, 7.05; 95% CI, 2.62-18.95). SENV strains are common among San Francisco Bay area IDUs, and prevalence varies demographically within this group. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. Univ Calif San Francisco, Urban Hlth Study, San Francisco, CA 94143 USA. RP O'Brien, TR (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,Rm 8016, Rockville, MD 20852 USA. RI Pfeiffer, Ruth /F-4748-2011; OI Edlin, Brian/0000-0001-8172-8797 NR 17 TC 5 Z9 6 U1 0 U2 0 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 JUL 1 PY 2003 VL 188 IS 1 BP 13 EP 18 DI 10.1086/375740 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 696UK UT WOS:000183905800003 PM 12825166 ER PT J AU Vgontzas, AN Bixler, EO Chrousos, GP AF Vgontzas, AN Bixler, EO Chrousos, GP TI Metabolic disturbances in obesity versus sleep apnoea: the importance of visceral obesity and insulin resistance SO JOURNAL OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT International Symposium on Sleep as Restitution CY AUG, 2002 CL STOCKHOLM, SWEDEN DE sleep apnoea; visceral obesity; insulin resistance; interleukin-6; tumour necrosis factor-alpha; daytime sleepiness ID POLYCYSTIC-OVARY-SYNDROME; EXCESSIVE DAYTIME SLEEPINESS; SUBCUTANEOUS ADIPOSE-TISSUE; AIRWAY PRESSURE TREATMENT; PITUITARY-ADRENAL AXIS; BODY-FAT DISTRIBUTION; NECROSIS-FACTOR-ALPHA; RISK FACTOR; BREATHING DISORDERS; GLUCOSE-TOLERANCE AB Obstructive sleep apnoea (OSA) is a very prevalent disorder particularly amongst middle-aged, obese men, although its existence in women as well as in lean individuals is increasingly recognized. Despite the early recognition of the strong association between OSA and obesity, and OSA and cardiovascular problems, sleep apnoea has been treated as a 'local abnormality' of the respiratory track rather than as a 'systemic illness'. In 1997, we first reported that the pro-inflammatory cytokines interleukin (IL)-6 and tumour necrosis factor-alpha (TNFalpha ) were elevated in patients with disorders of excessive daytime sleepiness (EDS) and proposed that these cytokines were mediators of daytime sleepiness. Also, we reported a positive correlation between IL-6 or TNFalpha plasma levels and the body mass index (BMI). In subsequent studies, we showed that IL-6, TNFalpha , leptin and insulin levels were elevated in sleep apnoea independently of obesity and that visceral fat, was the primary parameter linked with sleep apnoea. The association of OSA with insulin resistance and diabetes type 2 has been confirmed since then in several epidemiological and clinical studies. Furthermore, our findings that women with polycystic ovary syndrome (PCOS, a condition associated with hyperandrogenism and insulin resistance) were much more likely than controls to have sleep disordered breathing (SDB) and daytime sleepiness support the pathogenetic role of insulin resistance in OSA. Other findings that support the view that sleep apnoea and sleepiness may be manifestations of a serious metabolic disorder, namely the Metabolic or Visceral Obesity Syndrome, include: obesity without sleep apnoea is associated with daytime sleepiness; PCOS and diabetes type 2 are independently associated with EDS after controlling for SDB, obesity and age; and increased prevalence of sleep apnoea in postmenopausal women, with hormonal replacement therapy associated with a significantly reduced risk for OSA. In conclusion, accumulating evidence provides support to our model of the bi-directional, feedforward, pernicious association between sleep apnoea, sleepiness, inflammation and insulin resistance, all promoting atherosclerosis and cardiovascular disease. C1 Penn State Coll Med, Dept Psychiat, Hershey, PA 17033 USA. NIH, Pediat & Reprod Endocrinol Branch, Bethesda, MD 20892 USA. RP Vgontzas, AN (reprint author), Penn State Coll Med, Dept Psychiat, 500 Univ Dr, Hershey, PA 17033 USA. FU NHLBI NIH HHS [HL40916, HL51931, HL64415] NR 98 TC 166 Z9 178 U1 1 U2 7 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUL PY 2003 VL 254 IS 1 BP 32 EP 44 DI 10.1046/j.1365-2796.2003.01177.x PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 691AX UT WOS:000183583600005 PM 12823641 ER PT J AU Zerhouni, EA AF Zerhouni, EA TI The JIM interview SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Zerhouni, EA (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B C DECKER INC PI HAMILTON PA 20 HUGHSON ST SOUTH, PO BOX 620, L C D 1, HAMILTON, ONTARIO L8N 3K7, CANADA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD JUL PY 2003 VL 51 IS 4 BP 173 EP 176 PG 4 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 700VT UT WOS:000184132400001 PM 12929731 ER PT J AU Spiegel, AM AF Spiegel, AM TI G protein-regulated signaling dysfunction in human disease: A personal historical perspective - Foreword SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Editorial Material C1 NIDDK, NIH, Bethesda, MD 20892 USA. RP Spiegel, AM (reprint author), NIDDK, NIH, Bldg 31,Room 9A52,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B C DECKER INC PI HAMILTON PA 20 HUGHSON ST SOUTH, PO BOX 620, L C D 1, HAMILTON, ONTARIO L8N 3K7, CANADA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD JUL PY 2003 VL 51 IS 4 BP 192 EP 193 DI 10.2310/6650.2003.38931 PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 700VT UT WOS:000184132400010 ER PT J AU Simonds, WF AF Simonds, WF TI G protein-regulated signaling dysfunction in human disease SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Review ID THYROTROPIN RECEPTOR GENE; DOMINANT RETINITIS-PIGMENTOSA; STATIONARY NIGHT BLINDNESS; NEPHROGENIC DIABETES-INSIPIDUS; STIMULATORY G-PROTEIN; LUTEINIZING-HORMONE RECEPTOR; SECRETING PITUITARY-ADENOMAS; GTPASE-ACTIVATING PROTEIN; HETEROTRIMERIC G-PROTEINS; CGMP-GATED CHANNEL C1 NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Simonds, WF (reprint author), NIDDK, Metab Dis Branch, NIH, Bldg 10 Room 8C-101,10 Ctr Dr,MSC 1752, Bethesda, MD 20892 USA. NR 215 TC 6 Z9 6 U1 0 U2 0 PU B C DECKER INC PI HAMILTON PA 20 HUGHSON ST SOUTH, PO BOX 620, L C D 1, HAMILTON, ONTARIO L8N 3K7, CANADA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD JUL PY 2003 VL 51 IS 4 BP 194 EP 214 DI 10.2310/6650.2003.39183 PG 21 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 700VT UT WOS:000184132400011 PM 12929736 ER PT J AU Bacot, SM Lenz, P Frazier-Jessen, MR Feldman, GM AF Bacot, SM Lenz, P Frazier-Jessen, MR Feldman, GM TI Activation by prion peptide PrP106-126 induces a NF-kappa B-driven proinflammatory response in human monocyte-derived dendritic cells SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE TSE; cell signaling; inflammation ID CENTRIFUGAL ELUTRIATION CCE; CENTRAL-NERVOUS-SYSTEM; SCRAPIE-INFECTED MICE; NECROSIS-FACTOR-ALPHA; PROTEIN-FRAGMENT; MICROGLIAL CELLS; NEUROLOGICAL DISEASE; ENRICHED FRACTIONS; IL-4 RECEPTOR; IN-VITRO AB Specific prion peptides have been shown to mimic the pathologic isoform of the prion protein (PrP) and to induce a neurotoxic effect in vitro and in vivo. As monocytic cells are thought to play a role in the transmission and pathogenesis of prion disease, the use of these peptides in regulating monocytic cell function is under intense investigation. In the current study, we characterize the ability of prion peptide PrP106-126 to activate specific signaling pathways in human monocyte-derived dendritic cells (DCs). Electrophoretic mobility shift assays establish the activation of transcription factor nuclear factor-kappaB within 15 min of exposure, with as little as 25 muM peptide. This signaling cascade results in the up-regulation of inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha (TNF-alpha) at the mRNA and protein levels. Phenotypic activation of DCs exposed to PrP106-126 is partly a result of an antocrine TNF-alpha response and results in an increased ability of these cells to induce lymphocyte proliferation. The effects of PrP106-126 on DCs were elicited through a receptor complex distinct from that used by human monocytes, demonstrating the ability of this peptide to interact with a multiplicity of receptors on various cell types. Together, these data suggest an involvement of DCs in prion disease pathogenesis. C1 US FDA, Div Monoclonal Antibodies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Feldman, GM (reprint author), US FDA, Div Monoclonal Antibodies, Ctr Biol Evaluat & Res, HFB-564,Bldg 29A,Rm 3C24,29 Lincoln Dr, Bethesda, MD 20892 USA. NR 53 TC 17 Z9 18 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUL PY 2003 VL 74 IS 1 BP 118 EP 125 DI 10.1189/jlb.1102521 PG 8 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 755FB UT WOS:000187367800016 PM 12832450 ER PT J AU Strott, CA Higashi, Y AF Strott, CA Higashi, Y TI Cholesterol sulfate in human physiology: what's it all about? SO JOURNAL OF LIPID RESEARCH LA English DT Review DE sterol; sulfonation sulfoconjugation; sulfotransferase; signal transduction ID X-LINKED ICHTHYOSIS; SIDE-CHAIN CLEAVAGE; HYDROXYSTEROID SULFOTRANSFERASE SULT2B1; STRATUM-CORNEUM LIPIDS; PROTEIN-KINASE-C; CULTURED HUMAN KERATINOCYTES; LOW-DENSITY LIPOPROTEINS; DEHYDROEPIANDROSTERONE SULFOTRANSFERASE; STEROID-SULFATASE; HUMAN-PLASMA AB Cholesterol sulfate is quantitatively the most important known sterol sulfate in human plasma, where it is present in a concentration that overlaps that of the other abundant circulating steroid sulfate, dehydroepiandrosterone (DMA) sulfate. Although these sulfolipids have similar production and metabolic clearance rates, they arise from distinct sources and are metabolized by different pathways. While the function of DHEA sulfate remains an enigma, cholesterol sulfate has emerged as an important regulatory molecule. Cholesterol sulfate is a component of cell membranes where it has a stabilizing role, e.g., protecting erythrocytes from osmotic lysis and regulating sperm capacitation. It is present in platelet membranes where it supports platelet adhesion. Cholesterol sulfate can regulate the activity of serine proteases, e.g., those involved in blood clotting, fibrinolysis, and epidermal cell adhesion. As a result of its ability to regulate the activity of selective protein kinase C isoforms and modulate the specificity of phosphatidylinositol 3-kinase, cholesterol sulfate is involved in signal transduction. Cholesterol sulfate functions in keratinocyte differentiation, inducing genes that encode for key components involved in development of the barrier. EM The accumulating evidence demonstrating a regulatory function for cholesterol sulfate appears solid; the challenge now is to work out the molecular mechanisms whereby this interesting molecule carries out its various roles. C1 NICHHD, Sect Steroid Regulat, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Strott, CA (reprint author), NICHHD, Sect Steroid Regulat, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. NR 131 TC 98 Z9 99 U1 3 U2 15 PU LIPID RESEARCH INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD JUL PY 2003 VL 44 IS 7 BP 1268 EP 1278 DI 10.1194/jlr.R300005-JLR200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 701YF UT WOS:000184196000002 PM 12730293 ER PT J AU Shen, J AF Shen, J TI Slice-selective J-coupled coherence transfer using symmetric linear phase pulses: applications to localized GABA spectroscopy SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE rotator symmetry; spectral editing; spatial localization; GABA; in vivo magnetic resonance spectroscopy ID DOUBLE-QUANTUM FILTER; GAMMA-AMINOBUTYRIC-ACID; IN-VIVO DETECTION; HUMAN BRAIN; NMR-SPECTROSCOPY; EXCITATION; INVERSION; LACTATE; ECHO AB Symmetric, linear phase, slice-selective RF pulses were analyzed theoretically for performing slice-selective coherence transfer. It was shown using numerical simulations of product operators that, when a prefocusing gradient of the same area as that of the refocusing gradient is added, these pulses become slice-selective universal rotator pulses, therefore, capable of performing slice-selective coherence transfer. As an example, a slice-selective universal rotator pulse based on a seven-lobe hamming-filtered sinc pulse was applied to in vivo single-shot simultaneous spectral editing and spatial localization of neurotransmitter GABA in the human brain. Published by Elsevier Science (USA). C1 NIMH, Mol Imaging Branch, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Shen, J (reprint author), NIMH, Mol Imaging Branch, Mood & Anxiety Disorders Program, Rm 2D51A,Bldg 10,9000 Rockville Pike,MSC 1527, Bethesda, MD 20892 USA. NR 29 TC 12 Z9 12 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD JUL PY 2003 VL 163 IS 1 BP 73 EP 80 DI 10.1016/S1090-7807(03)00112-5 PG 8 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 703KM UT WOS:000184278600009 PM 12852909 ER PT J AU Fargiano, AA Desai, KV Green, JE AF Fargiano, AA Desai, KV Green, JE TI Interrogating mouse mammary cancer models: Insights from gene expression profiling SO JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA LA English DT Article DE transgenic mouse models; breast cancer; gene expression profiling; oncogenic signaling pathways; microarrays; oncogenes ID HUMAN-BREAST-CANCER; LASER CAPTURE MICRODISSECTION; C-MYC GENE; TRANSGENIC MICE; MICROARRAY DATA; NEU ONCOGENE; NEU/ERBB-2 ONCOGENE; TISSUE MICROARRAYS; METASTATIC-DISEASE; ACTIVATED NEU AB Numerous mouse models for mammary cancer have been developed and characterized based upon their biological, molecular, and histopathological features. In an effort to dissect the molecular anatomy of such models and compare their gene expression profiles to those of human breast cancer, six models representing various oncogenic pathways have been investigated using cDNA microarray technology. Results of these analyses are presented and discussed in the context of technological challenges presented by analyzing data on such a large scale. Further expression profiling coupled with emerging proteomic technologies will more completely define and distinguish mouse models of mammary cancer from each other and provide a comprehensive basis for comparing such models with the human disease they are intended to represent. C1 NCI, TRansgen Oncogenesis Grp, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Green, JE (reprint author), NCI, TRansgen Oncogenesis Grp, Lab Cell Regulat & Carcinogenesis, NIH, 41 Lib Dr,Room C629, Bethesda, MD 20892 USA. NR 90 TC 8 Z9 10 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1083-3021 J9 J MAMMARY GLAND BIOL JI J. Mammary Gland Biol. Neoplasia PD JUL PY 2003 VL 8 IS 3 BP 321 EP 334 DI 10.1023/B:JOMG.0000010032.05234.6f PG 14 WC Oncology; Endocrinology & Metabolism; Physiology SC Oncology; Endocrinology & Metabolism; Physiology GA 757EH UT WOS:000187535500006 PM 14973376 ER PT J AU McShane, LM Shih, JH Michalowska, AM AF McShane, LM Shih, JH Michalowska, AM TI Statistical issues in the design and analysis of gene expression microarray studies of animal models SO JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA LA English DT Article DE gene expression profiling; animal models of cancer; statistics; study design; analysis of microarray data ID PROBE LEVEL DATA; CLASS PREDICTION; CLASS DISCOVERY; CLASSIFICATION; PATTERNS; CANCER; NORMALIZATION; SUMMARIES AB Appropriate statistical design and analysis of gene expression microarray studies is critical in order to draw valid and useful conclusions from expression profiling studies of animal models. In this paper, several aspects of study design are discussed, including the number of animals that need to be studied to ensure sufficiently powered studies, usefulness of replication and pooling, and allocation of samples to arrays. Data preprocessing methods for both cDNA dual-label spotted arrays and Affymetrix-style oligonucleotide arrays are reviewed. High-level analysis strategies are briefly discussed for each of the types of study aims, namely class comparison, class discovery, and class prediction. For class comparison, methods are discussed for identifying genes differentially expressed between classes while guarding against unacceptably high numbers of false positive findings. Various clustering methods are discussed for class discovery aims. Class prediction methods are briefly reviewed, and reference is made to the importance of proper validation of predictors. C1 NCI, Biometr Res Branch, DCDT, Bethesda, MD 20892 USA. RP McShane, LM (reprint author), NCI, Biometr Res Branch, DCDT, Room 8126,Execut Plaza N,MSC 7434,6130 Execut Blv, Bethesda, MD 20892 USA. EM lm5h@nih.gov NR 49 TC 25 Z9 27 U1 0 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1083-3021 J9 J MAMMARY GLAND BIOL JI J. Mammary Gland Biol. Neoplasia PD JUL PY 2003 VL 8 IS 3 BP 359 EP 374 DI 10.1023/B:JOMG.0000010035.57912.5a PG 16 WC Oncology; Endocrinology & Metabolism; Physiology SC Oncology; Endocrinology & Metabolism; Physiology GA 757EH UT WOS:000187535500009 PM 14973379 ER PT J AU Newman, DJ Cragg, GM Snader, KM AF Newman, DJ Cragg, GM Snader, KM TI Natural products as sources of new drugs over the period 1981-2002 SO JOURNAL OF NATURAL PRODUCTS LA English DT Review ID II RECEPTOR ANTAGONISTS; POTENT ANTIHYPERTENSIVES; COMBINATORIAL SYNTHESIS; GENOME SEQUENCE; MARKET; DISCOVERY; TARGETS; MALARIA; PEPTIDOMIMETICS; PHOSPHATASES AB This review is an updated and expanded version of a paper that was published in this journal in 1997. The time frame has been extended in both directions to include the 22 years from 1981 to 2002, and a new secondary subdivision related to the natural product source but applied to formally synthetic compounds has been introduced, using the concept of a "natural product mimic" or "NM" to join the original primary divisions. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, the percentage of small molecule, new chemical entities that are nonsynthetic has remained at 62% averaged over the whole time frame. In other areas, the influence of natural product structures is quite marked, particularly in the antihypertensive area, where of the 74 formally synthetic drugs, 48 can be traced to natural product structures/mimics. Similarly, with the 10 antimigraine drugs, seven are based on the serotonin molecule or derivatives thereof. Finally, although combinatorial techniques have succeeded as methods of optimizing structures and have, in fact, been used in the optimization of a number of recently approved agents, we have not been able to identify a de novo combinatorial compound approved as a drug in this time frame. C1 NCI, Div Canc Treatment & Diag, Nat Prod Branch, Dev Therapeut Program, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Pharmaceut Resources Branch, Dev Therapeut Program, Bethesda, MD 20892 USA. RP NCI Frederick, POB B, Frederick, MD 21702 USA. EM newmand@mail.nih.gov NR 68 TC 1468 Z9 1566 U1 24 U2 190 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 EI 1520-6025 J9 J NAT PROD JI J. Nat. Prod. PD JUL PY 2003 VL 66 IS 7 BP 1022 EP 1037 DI 10.1021/np030096l PG 16 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 705UE UT WOS:000184412800027 PM 12880330 ER PT J AU Sgambato, V Minassian, R Nairn, AC Hyman, SE AF Sgambato, V Minassian, R Nairn, AC Hyman, SE TI Regulation of ania-6 splice variants by distinct signaling pathways in striatal neurons SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE cyclin; dopamine; glutamate; signaling; splicing; striatum ID CA2+/CALMODULIN-DEPENDENT PROTEIN-KINASE; TRANSCRIPTION FACTOR CREB; CYCLIN-DEPENDENT KINASES; C-FOS TRANSCRIPTION; GENE-EXPRESSION; MAP-KINASE; MEMBRANE DEPOLARIZATION; MOLECULAR-MECHANISMS; SELECTIVE INHIBITOR; SYNAPTIC ACTIVITY AB The striatum is a brain region involved in motor control and in diverse forms of implicit memory. It is also involved in the pathogenesis of many significant human disorders, including drug addiction, that are thought to involve adaptive changes in gene expression. We have previously shown that the cyclin L, ania-6, is expressed as at least two splice forms, which are differentially regulated in striatal neurons by different neurotransmitters. Here, we report that ania-6 transcription is mostly regulated via cAMP response element binding protein (CREB), but that signaling pathways that converge on CREB at the transcriptional level produce different effects on splicing and neuronal gene expression. Glutamate induced a long ania-6 mRNA that encodes a truncated form of the cyclin. This effect depended on the activation of NMDA receptors but was independent of both calcium/calmodulin-dependent protein kinases (CaMK) and extracellular regulated kinase (ERK). Forskolin or brain-derived neurotropic factor (BDNF) induced a short ania-6 mRNA, that encodes the full-length cyclin, and this induction depended on ERK. However, KCl-mediated induction of ania-6 short mRNA, which required activation of L-type calcium channels, was independent of ERK but depended on CaMK. These data suggest that different neuronal signals can differentially regulate splicing and that different intracellular pathways can be recruited to yield a given splice variant. C1 NINDS, Mol Plast Sect, Bethesda, MD 20892 USA. Rockefeller Univ, Mol & Cellular Neurosci Lab, New York, NY 10021 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. Harvard Univ, Cambridge, MA 02138 USA. RP Sgambato, V (reprint author), INSERM, U318, Lab Neurosci Preclin, CHU Pavillon B,BP217, F-38000 Grenoble, France. EM Veronique.Sgambato@ujf-grenoble.fr OI Nairn, Angus/0000-0002-7075-0195 FU NIDA NIH HHS [P01 DA010044]; NIMH NIH HHS [MH40899] NR 51 TC 23 Z9 26 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUL PY 2003 VL 86 IS 1 BP 153 EP 164 DI 10.1046/j.1471-4159.2003.01816.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 690AY UT WOS:000183526200017 PM 12807435 ER PT J AU Montanez, S Owens, WA Gould, GG Murphy, DL Daws, LC AF Montanez, S Owens, WA Gould, GG Murphy, DL Daws, LC TI Exaggerated effect of fluvoxamine in heterozygote serotonin transporter knockout mice SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE chronoamperometry; hippocampus; serotonin clearance rates; serotonin transporter; serotonin transporter knockout mice; norepinephrine transporter ID RECEPTOR-MEDIATED REGULATION; IN-VIVO; ANTIDEPRESSANT RESPONSE; DOPAMINE CLEARANCE; DORSAL RAPHE; UPTAKE SITES; RAT-BRAIN; GENE; POLYMORPHISM; PROMOTER AB Clearance rates for serotonin (5-HT) in heterozygote (+/-) and homozygote (-/-) serotonin transporter (5-HTT) knockout (KO) mice have not been determined in vivo . Moreover, the effect of selective serotonin reuptake inhibitors (SSRIs) on 5-HT clearance in these mice has not been examined. In this study, the rate of clearance of exogenously applied 5-HT was measured in the CA3 region of the hippocampus of anesthetized mice using high-speed chronoamperometry. Compared with wild-type mice, the maximal rate of 5-HT clearance from extracellular fluid (ECF) was decreased in heterozygotes and more markedly so in KO mice. Heterozygote mice were more sensitive to the 5-HT uptake inhibitor, fluvoxamine, resulting in longer clearance times for 5-HT than in wild-type mice; as expected, the KO mice were completely unresponsive to fluvoxamine. There were no associated changes in norepinephrine transporter density, nor was there an effect of the norepinephrine uptake inhibitor, desipramine, on 5-HT clearance in any genotype. Thus, adaptive changes in the norepinephrine transport system do not occur in the CA3 region of hippocampus as a consequence of 5-HTT KO. These data highlight the potential of the heterozygote 5-HTT mutant mice to model the dynamic in vivo consequences of the human 5-HTT polymorphism. C1 Univ Texas, Hlth Sci Ctr, Dept Psychiat, Div Alcohol & Drug Addict, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Pharmacol, Div Alcohol & Drug Addict, San Antonio, TX 78284 USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Daws, LC (reprint author), Univ Texas, Hlth Sci Ctr, Dept Psychiat, Div Alcohol & Drug Addict, Mail Code 7792,7703 Floyd Curl Dr, San Antonio, TX 78284 USA. OI Gould, Georgianna/0000-0002-5470-8763 FU NIMH NIH HHS [MH64489] NR 39 TC 72 Z9 73 U1 2 U2 6 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 JUL PY 2003 VL 86 IS 1 BP 210 EP 219 DI 10.1046/j.1471-4159.2003.01836.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 690AY UT WOS:000183526200022 PM 12807440 ER PT J AU Tonelli, LH Maeda, S Rapp, KL Sternberg, EM AF Tonelli, LH Maeda, S Rapp, KL Sternberg, EM TI Differential induction of interleukin-I beta mRNA in the brain parenchyma of Lewis and Fischer rats after peripheral injection of lipopolysaccharides SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE hypothalamus; circumventricular organs; cerebral cortex; cytokines; inbred rats ID CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; PRO-INFLAMMATORY CYTOKINES; CELL-MEDIATED-IMMUNITY; NITRIC-OXIDE SYNTHASE; RECEPTOR ANTAGONIST; GENE-EXPRESSION; PATHOPHYSIOLOGICAL IMPLICATIONS; TNF-ALPHA; LEUKOCYTE TRAFFICKING AB The expression of interleukin-1 beta (IL-1beta) mRNA was compared in the brain of inflammatory susceptible LEW/N and resistant F344/N rats at 3, 6, and 12 It after peripheral administration of lipopolysaccharide (LPS) or saline. No differences between strains were observed in the circumventricular organs (CVOs) and choroid plexus. At 12 It after LPS administration, increased IL-1beta mRNA expression was detected in the hypothalamus of LEW/N rats. In contrast, increased IL-1beta mRNA expression was detected in the cerebral cortex of F344/N rats. These data show region-specific differences of IL-1beta mRNA expression in the brain of these rat strains that differ in their susceptibility to inflammation. Published by Elsevier B.V. C1 NIMH, Sect Neuroendocrine Immunol & Behav, NIH, DHHS, Bethesda, MD 20892 USA. RP Sternberg, EM (reprint author), NIMH, Sect Neuroendocrine Immunol & Behav, NIH, DHHS, 36 Convent Dr,MSC 4020,Bldg 36,Room 1A23, Bethesda, MD 20892 USA. NR 45 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD JUL PY 2003 VL 140 IS 1-2 BP 126 EP 136 DI 10.1016/S0165-5728(03)00171-1 PG 11 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 709DZ UT WOS:000184610600014 PM 12864980 ER PT J AU Dhib-Jalbut, S Chen, M Said, A Zhan, M Johnson, KP Martin, R AF Dhib-Jalbut, S Chen, M Said, A Zhan, M Johnson, KP Martin, R TI Glatiramer acetate-reactive peripheral blood mononuclear cells respond to multiple myelin antigens with a Th2-biased phenotype SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE multiple sclerosis; glatiramer acetate; Copaxone (R); myelin; immunotherapy ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; PLACEBO-CONTROLLED TRIAL; PHASE-III MULTICENTER; REDUCES RELAPSE RATE; BASIC-PROTEIN; COPOLYMER 1; DOUBLE-BLIND; SYNTHETIC COPOLYMER-1; T-CELLS; OLIGODENDROCYTE GLYCOPROTEIN AB One favored mechanism of action of glatiramer acetate (GA) in multiple sclerosis (MS) involves the induction of GA-reactive Th2 cells that are believed to enter the central nervous system and mediate bystander suppression in response to cross-reactive myelin antigens. To test this hypothesis, we examined the proliferative response and cytokine release from peripheral blood mononuclear cells (PBMCs) of 12 p MS patients treated with GA, in response to 16 myelin peptides that were previously described as immunodominant or encephalitogenic and a tetanus peptide as a control antigen. lnterferon-gamma (IFN-gamma) and IL-5 (markers of Th1 and Th2 responses, respectively) were assayed by enzyme-linked immunosorbent assay (ELISA). GA-stimulated PBMCs from 9 of 12 patients (75%) proliferated to one or more myelin peptides. Anions! the 16 peptides tested, GA-stimulated PBMCs from the majority of the patients proliferated in response to MOG(21-44). PBMCs from two thirds of the patients produced IL-5 in response to myelin peptides, while half of them produced IFN-gamma. Th1/Th0/Th2 cytokine phenotypes demonstrated that responses from 10 of 12 patients were either Th0- or Th2-biased. Responses from two patients, p were Th1-biased. Conversely, some myelin-specific T-cell lines (TCLs) responded to GA by proliferation (3 of 21 TCLs), IL-5 release (11 of 21 TCLs), and IFN-gamma release (3 of 21 TCLs). These results indicate that GA-reactive TCLs can respond to a spectrum of myelin peptides in a Th2-biased fashion, which is consistent with the concept of bystander suppression. Furthermore, some myelin-specific TCLs are able to recognize GA. with a tendency to produce more IL-5 than IFN-gamma, which would suggest a systemic modulatory effect of the drug. (C) 2003 Elsevier B.V. All rights reserved. C1 Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Baltimore VA Med Ctr, Baltimore, MD 21201 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Dhib-Jalbut, S (reprint author), Univ Maryland Hosp, Dept Neurol, Room N4W46,22 S Greene St, Baltimore, MD 21201 USA. FU NINDS NIH HHS [K-24-NS02082] NR 38 TC 39 Z9 40 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD JUL PY 2003 VL 140 IS 1-2 BP 163 EP 171 DI 10.1016/S0165-5728(03)00170-X PG 9 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 709DZ UT WOS:000184610600019 PM 12864985 ER PT J AU Wartenburger, I Heekeren, HR Burchert, F De Bleser, R Villringer, A AF Wartenburger, I Heekeren, HR Burchert, F De Bleser, R Villringer, A TI Grammaticality judgments on sentences with and without movement of phrasal constituents - an event-related fMRI study SO JOURNAL OF NEUROLINGUISTICS LA English DT Article DE agrammatism; Broca's area; event-related functional magnetic resonance imaging; grammaticality judgments; syntactic traces; Trace Deletion Hypothesis ID BROCAS-AREA; LANGUAGE COMPREHENSION; SYNTAX; BRAIN; ACTIVATION; COMPONENTS; NEUROLOGY; APHASICS; DEFICITS; DESIGNS AB One of the leading neurolinguistic theories of syntactic comprehension disorders in agrammatic aphasic subjects-the Trace Deletion Hypothesis-postulates a specific impairment in processing syntactic chains, and that this function is mediated by Broca's area. The aim of this study was to investigate whether the specific involvement of Broca's area in processing syntactic traces can be verified using functional brain imaging. We used event-related functional magnetic resonance imaging (fMRI) while healthy subjects were asked to judge the grammaticality of visually presented sentences with and without movement of phrasal constituents. During both kinds of sentences, fMRI showed activation in language-related brain regions. Comparing both kinds of sentences did not result in differential brain activation of left frontal or temporal regions. In particular, Broca's area was similarly activated in processing both moved and nonmoved sentences. Thus, Broca's area seems to be involved in general syntactic processing as required by grammaticality judgments rather than having a specific function in transmitting syntactic relations. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Humboldt Univ, Dept Neurol, Clin Res Grp, Charite, D-10117 Berlin, Germany. Univ Potsdam, Dept Patholinguist, D-14415 Potsdam, Germany. NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Wartenburger, I (reprint author), Humboldt Univ, Dept Neurol, Clin Res Grp, Charite, Schumannstr 20-21, D-10117 Berlin, Germany. RI Heekeren, Hauke/B-7739-2008; Wartenburger, Isabell/A-2820-2013; OI Heekeren, Hauke/0000-0001-7912-6826; Burchert, Frank/0000-0002-5470-1588 NR 34 TC 8 Z9 8 U1 3 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0911-6044 J9 J NEUROLINGUIST JI J. Neurolinguist. PD JUL-SEP PY 2003 VL 16 IS 4-5 BP 301 EP 314 DI 10.1016/S0911-6044(03)00028-9 PG 14 WC Linguistics; Neurosciences; Psychology, Experimental SC Linguistics; Neurosciences & Neurology; Psychology GA 703UZ UT WOS:000184301000004 ER PT J AU Sohn, YH Kaelin-Lang, A Hallett, M AF Sohn, YH Kaelin-Lang, A Hallett, M TI The effect of transcranial magnetic stimulation on movement selection SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID SEQUENCES; COMPLEX AB Objective: To attempt to replicate previous findings that showed an influence of transcranial magnetic stimulation of the cortical motor areas on the selection of motor programmes on the contralateral side. Methods: Healthy volunteers were asked to choose to make a right or left index finger extension movement freely after hearing the click produced by transcranial magnetic stimulation. The stimulation was applied to the motor areas (test), including the motor cortex, vertex, and prefrontal cortex, and in the air (control). Results: There was no preference for choosing the hand contralateral to the stimulation site, in either test or control trials. Conclusions: Previous results could not be reproduced. Simple magnetic stimulation of the motor areas is insufficient to affect voluntary selection of movement. C1 Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, NIH, Bethesda, MD USA. Natl Inst Neurol Disorders & Stroke, Human Cort Physiol Sect, Bethesda, MD USA. RP Hallett, M (reprint author), Bldg 10,Rm 5N226,10 Ctr Dr, Bethesda, MD 20892 USA. NR 5 TC 6 Z9 6 U1 0 U2 3 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD JUL PY 2003 VL 74 IS 7 BP 985 EP 987 DI 10.1136/jnnp.74.7.985 PG 3 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 690JB UT WOS:000183543800042 PM 12810802 ER PT J AU Peng, YB Ling, QD Ruda, MA Kenshalo, DR AF Peng, YB Ling, QD Ruda, MA Kenshalo, DR TI Electrophysiological changes in adult rat dorsal horn neurons after neonatal peripheral inflammation SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID SPINOTHALAMIC TRACT NEURONS; PRIMARY AFFERENT-FIBERS; PRIMARY SENSORY NEURONS; NOXIOUS HEAT STIMULI; SPINAL-CORD NEURONS; NERVE INJURY; RECEPTOR ANTAGONISTS; ACUTE ARTHRITIS; NMDA RECEPTOR; PAIN HYPERSENSITIVITY AB Neonatal peripheral inflammation has been shown to produce profound anatomical changes in the dorsal horn of adult rats. In this study, we explored whether parallel physiological changes exist. Neonatal rats were injected with complete Freund's adjuvant (CFA) into the left hind paw. At 8-10 wk of age, single dorsal horn neurons were recorded in response to graded intensities of mechanical stimuli delivered to the receptive field. In addition, cord dorsum potentials, produced by electrical stimuli delivered to the left sciatic nerve at 2.5X threshold, were recorded bilaterally from L2 to S3. There were significant increases in background activity and responses to brush and pinch in neonatal rats that were treated with CFA, as compared with control rats. Further analysis showed similar significant changes when dorsal horn neurons were categorized into wide dynamic range (WDR), high-threshold (HT), and low-threshold (LT) groups. The receptive field was significantly larger in neonatally treated rats as compared with control rats. Additionally, there was a significant increase in the response to a 49degreesC heat stimulus in neonatally treated rats as compared with control rats. There was also a trend for the amplitudes of N1, N2, and P waves of the cord dorsum potential to increase and latencies to decrease in neonatally treated rats, but no significant differences were detected between different levels of the spinal cord ( L2 to S3). These data further support the notion that anatomical and physiological plasticity changes occurred in the spinal cord following early neonatal CFA treatment. C1 Univ Texas, Dept Psychol, Arlington, TX 76019 USA. NIDCR, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, Dept Psychol, Arlington, TX 76019 USA. NIH, Ctr Sci Review, Bethesda, MD 20814 USA. Cathay Gen Hosp, Cell Biol & Anat Lab, Taipei 221, Taiwan. RP Peng, YB (reprint author), Univ Texas, Dept Psychol, POB 19528,501 S Nedderman Dr, Arlington, TX 76019 USA. NR 68 TC 35 Z9 35 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 JUL PY 2003 VL 90 IS 1 BP 73 EP 80 DI 10.1152/jn.01019.2002 PG 8 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 697JZ UT WOS:000183940600010 PM 12634281 ER PT J AU Cheng, CM Mervis, RF Niu, SL Salem, N Witters, LA Tseng, V Reinhardt, R Bondy, CA AF Cheng, CM Mervis, RF Niu, SL Salem, N Witters, LA Tseng, V Reinhardt, R Bondy, CA TI Insulin-like growth factor 1 is essential for normal dendritic growth SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE cholesterol; synaptogenesis; phospholipid; cdc42; synaptotagmin; cholesterol; mental retardation ID ACTIVATED PROTEIN-KINASE; CENTRAL-NERVOUS-SYSTEM; FACTOR-I; POSTNATAL-DEVELOPMENT; NEURITE GROWTH; RHO GTPASES; IGF-I; NEURONS; BRAIN; CHOLESTEROL AB This study evaluated somatic and dendritic growth of neurons in the frontoparietal cortex of Igf1-/- brains. Pyramidal neuron density was increased by similar to25% (P = .005) and soma size reduced by similar to10% (P < .001). Golgi staining revealed that cortical layer II-III neurons exhibited a significant reduction in dendritic length and complexity in Igf1 null mice. Dendritic spine density and presumably synaptic contacts were reduced by 16% (P = .002). Similar findings were obtained for cortical layer V and piriform cortex pyramids. Supporting a reduction in synapses, synaptotagmin levels were reduced by 30% (P < .02) in the Igf1 null brain. Investigation of factors critically involved in dendritic growth and synaptogenesis showed an similar to50% reduction in cortical CDC42 protein expression (P < .001) and an similar to10% reduction in brain cholesterol levels (P < .01) in Igf1 null mice. Evidence is presented that Igf1 deletion causes disruptions in lipid and microtubule metabolism, leading to impaired neuronal somatic and dendritic growth. Published 2003 Wiley-Liss, Inc. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Neurostruct Res Labs, Columbus, OH USA. NIAAA, Lab Membrane Biophys & Biochem, NIH, Bethesda, MD USA. Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Med & Biochem, Hanover, NH 03756 USA. RP Cheng, CM (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10-10N262,10 Ctr Dr, Bethesda, MD 20892 USA. NR 34 TC 82 Z9 84 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUL 1 PY 2003 VL 73 IS 1 BP 1 EP 9 DI 10.1002/jnr.10634 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 696FG UT WOS:000183875800001 PM 12815703 ER PT J AU Lanuza, MA Garcia, N Gonzalez, CM Santafe, MM Nelson, PG Tomas, J AF Lanuza, MA Garcia, N Gonzalez, CM Santafe, MM Nelson, PG Tomas, J TI Role and expression of thrombin receptor PAR-1 in muscle cells and neuromuscular junctions during the synapse elimination period in the neonatal rat SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE polyneuronal innervation; PAR-1; thrombin ID PROTEIN-KINASE-C; NERVOUS-SYSTEM DEVELOPMENT; SKELETAL-MUSCLE; IN-VITRO; POSTNATAL MATURATION; NEURITE RETRACTION; HUMAN PLATELETS; ADULT-RAT; NEXIN-I; MOUSE AB A role for thrombin and its receptor (ThR) during mammalian skeletal muscle cell differentiation and neuromuscular junction (NMJ) formation has been suggested. Previously, we found that the synapse elimination process in the neonatal rat muscle was accelerated by thrombin and blocked by hirudin, its specific inhibitor (Lanuza et al. [2001] J. Neurosci. Res. 63:330-340). To test whether this process resulted from a signal transduction cascade initiated by activation of ThR, in particular PAR-1, we applied to the levator auris longus (LAL) muscle of newborn rats two synthetic peptides (SFLL and FSLL). SFLL is a potent specific agonist for activation of PAR-1, whereas FSLL is an inactive peptide. We have demonstrated that the activation of PAR-1 by SFLL produced acceleration of the presynaptic loss of connections and the postsynaptic maturation of NMJs. Moreover, Western blot analysis showed that PAR-1 was present in the skeletal muscle, and by immunohistochemistry we detected PAR-1 in muscle fibers concentrated in the synaptic area but also in satellite cells. Several lines of evidence suggested that PAR-1 is localized in the postsynaptic membrane: PAR-1 immunofluorescence was concentrated at denervated synaptic sites and was present in the myotube membrane in vitro in the absence of neurons and in dissociated single muscle fibers from which nerve terminals and Schwann cells had been removed. Taken together, these results indicate that thrombin mediates certain stages of activity-dependent synapse elimination in the skeletal muscle and does so through its action on the thrombin receptor PAR-1 localized, at least in part, on the postsynaptic membrane. (C) 2003 Wiley-Liss, Inc. C1 Univ Rovira & Virgili, Unitat Histol & Neurobiol, Fac Med & Ciencies Salut, Reus 43201, Tarragona, Spain. NICHD, Dev Neurobiol Lab, NIH, Bethesda, MD USA. RP Lanuza, MA (reprint author), Univ Rovira & Virgili, Unitat Histol & Neurobiol, Fac Med & Ciencies Salut, Sant Llorenc 21, Reus 43201, Tarragona, Spain. OI Santafe, Manel/0000-0002-5462-5108 NR 51 TC 16 Z9 17 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUL 1 PY 2003 VL 73 IS 1 BP 10 EP 21 DI 10.1002/jnr.10576 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 696FG UT WOS:000183875800002 PM 12815704 ER PT J AU Lonser, RR Wait, SD Butman, JA Vortmeyer, AO Walther, MM Governale, LS Oldfield, EH AF Lonser, RR Wait, SD Butman, JA Vortmeyer, AO Walther, MM Governale, LS Oldfield, EH TI Surgical management of lumbosacral nerve root hemangioblastomas in von Hippel-Lindau syndrome SO JOURNAL OF NEUROSURGERY LA English DT Article DE hemangioblastoma; microsurgery; neoplasm; nerve root; von Hippel-Lindau syndrome ID CAUDA-EQUINA ANATOMY; SPINAL-CORD; DISEASE; SYSTEM; IDENTIFICATION; SURGERY; TUMORS AB Object. Hemangioblastomas in the lumbosacral region are rare, and the authors of prior reports have not defined the surgical management, histopathological features, or outcome in a group of patients after resection of these tumors. To identify features that will help guide the operative and clinical management of these lesions, the authors reviewed data obtained in a series of patients with von Hippel-Lindau syndrome who underwent resection of lumbosacral nerve root hemangioblastomas. Methods. Six consecutive patients (three men and three women; mean age at surgery 39 years [range 31-48 years]) who underwent operations for resection of lumbosacral nerve root hemangioblastomas were included in this study. The mean follow-up period was 23 months (range 6-45 months). Data derived from examination, hospital charts, operative findings, histopathological analysis, and magnetic resonance imaging were used to analyze surgical management and clinical outcome. The resected tumors were located in the lumbar (five cases) or sacral (one case) regions; the mean tumor size was 2728 mm(3) (range 80-15,022 mm(3)). Consistent with central nervous system (CNS) regional variation of space available to accommodate the neural compressive effect of the hemangioblastoma size, the mean tumor volume (2728 mm(3)) of these symptomatic lesions was much larger than that of symptomatic hemangioblastomas resected in the other regions of the CNS. Histopathological examination showed infiltration of the associated nerve root by the hemangioblastoma in each case. In five of the six patients complete resection was achieved, and in one patient intradural exploration of two hemangioblastomas was performed, but resection was not achieved because of motor root involvement. In all cases involving complete resections the patients experienced symptomatic improvement. Conclusions. Lumbosacral nerve root hemangioblastomas can be safely removed in most patients with von Hippel-Lindau syndrome. Generally, hemangioblastomas of the lumbosacral nerve roots should be resected when they become symptomatic. Because these neoplasms appear to originate from the nerve root, it is necessary to sacrifice the nerve root from which the hemangioblastoma originates to achieve complete resection. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Lonser, RR (reprint author), NINDS, Surg Neurol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 5D37, Bethesda, MD 20892 USA. RI Butman, John/A-2694-2008; OI Butman, John/0000-0002-1547-9195 NR 34 TC 27 Z9 28 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD JUL PY 2003 VL 99 IS 1 SU S BP 64 EP 69 DI 10.3171/spi.2003.99.1.0064 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 699AP UT WOS:000184034000015 PM 12859062 ER PT J AU Kremer, MA Fruin, A Larson, TC Roll, J Weil, RJ AF Kremer, MA Fruin, A Larson, TC Roll, J Weil, RJ TI Vertebroplasty in focal Paget disease of the spine - Case report SO JOURNAL OF NEUROSURGERY LA English DT Article DE Paget disease; vertebroplasty; back pain; methylmethacrylate; biphosphonates ID BODY COMPRESSION FRACTURES; PERCUTANEOUS VERTEBROPLASTY; POLYMETHYLMETHACRYLATE; METASTASES; INJECTION; BONE AB Paget disease is an idiopathic metabolic disease of bone that may involve the axial and appendicular skeleton. In up to one third of patients there may be pagetoid involvement of the spine, which can cause back pain and vertebral collapse, with instability or myeloradiculopathy. Although medical therapy is the mainstay of treatment, decompressive surgery or stabilization may be required. The authors report on a case of localized Paget disease of the spine treated successfully by performing percutaneous vertebroplasty. They propose this procedure as a useful intervention that can be undertaken safely in patients with spinal Paget disease, in whom acquisition of a transpedicular biopsy sample is required as part of diagnosis. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Sch Med, Dept Neurosurg, Nashville, TN 37212 USA. Vanderbilt Univ, Sch Med, Dept Radiol, Nashville, TN 37212 USA. RP Weil, RJ (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 5D37,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 15 TC 10 Z9 12 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD JUL PY 2003 VL 99 IS 1 SU S BP 110 EP 113 DI 10.3171/spi.2003.99.1.0110 PG 4 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 699AP UT WOS:000184034000023 PM 12859070 ER PT J AU Mitchell, P Lee, FT Hall, C Rigopoulos, A Smyth, FE Hekman, AM van Schijndel, GM Powles, R Brechbiel, MW Scott, AM AF Mitchell, P Lee, FT Hall, C Rigopoulos, A Smyth, FE Hekman, AM van Schijndel, GM Powles, R Brechbiel, MW Scott, AM TI Targeting primary human Ph+ B-cell precursor leukemia-engrafted SCID mice using radiolabeled anti-CD19 monoclonal antibodies SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE monoclonal antibody; CD19; Philadelphia chromosome-positive acute lympoblastic leukemia; severe combined immunodeficient mouse strain ID ACUTE LYMPHOBLASTIC-LEUKEMIA; NON-HODGKINS-LYMPHOMA; TYROSINE KINASE; CD19; APOPTOSIS; RADIONUCLIDES; IMMUNOTHERAPY; ACTIVATION; TRANSPORT; RETENTION AB The Philadelphia chromosome translocation (Ph+) confers a poor prognosis in patients with acute lymphocytic leukemia (ALL). CD19 is highly expressed (CD19(+)) on ALL cells and is an attractive target for antibody-based therapies. CLB-CD19 is an IgG1kappa murine monoclonal antibody (mAb) directed against an epitope on the CD19 antigen. Methods: Radiolabeled CLB-CD19 antibody was evaluated for targeting ALL in a severe combined immunodeficient (SCID) mouse model engrafted with primary human leukemia cells. Lodgment of CD19(+) ALL cells in spleen and liver was confirmed using immunohistochemistry analyses. Circulating CD19(+) ALL cells in blood were also detected by flow cytometry. Results: Antibody was labeled directly with the radiohalogen I-125 and radiometal In-111 via the bifunctional metal ion chelate CHX-A"-diethylenetriaminepentaacetic acid (DTPA) with retention of immunoreactivities. After intravenous injection of radioconjugates, biodistribution studies showed rapid localization of the In-111-conjugate to leukemia-infiltrated spleen, reaching a maximum (mean +/- SD) of 72.78 +/- 13.67 % injected dose per gram of tissue (%ID/g) by 24 h after injection. In contrast, peak localization of coinjected I-125-CLB-CD19 occurred by 4 h and was significantly lower (11.41 +/- 12.79 %ID/g) (P < 0.001). Uptake of In-111-conjugate in the liver containing tumor was also evident but not in other normal tissues. Uptake of radiolabeled CLB-CD19 in tumor-bearing organs was specific, as uptake of radiolabeled isotype-matched antibody control was low. Gamma-camera imaging detected the uptake of In-111-CHX-A"-DTPA CLB-CD19 in enlarged tumor-bearing spleen of engrafted mice. A single injection of 32 jig CLB-CD19 mAb had a delayed suppressive effect on the level of circulatory leukemia cells in surviving mice and extended the median survival from 48.5 to 58 d (n = 8; P = 0.03). Conclusion: The radiolabeled anti-CD19 antibody showed specific targeting and rapid internalization in ALL cell-engrafted SCID mice and may also be used for selective intracellular delivery of cytotoxic radionuclides with β-, Auger, or α-emissions. C1 Austin & Repatriat Med Ctr, Ludwig Med Oncol Unit, Ludwig Inst Canc Res, Melbourne Tumour Biol Branch, Melbourne, Vic, Australia. Austin & Repatriat Med Ctr, Tumour Targeting Program, Ludwig Inst Canc Res, Melbourne Tumour Biol Branch, Melbourne, Vic, Australia. Netherlands Canc Inst, Dept Immunol, Amsterdam, Netherlands. Univ Amsterdam, Sanquin Res & Landsteiner Lab, Amsterdam, Netherlands. Royal Marsden Hosp, Leukemia Unit, Surrey, England. NCI, Radioimmune & Inorgan Chem Sect, NIH, Bethesda, MD 20892 USA. Austin & Repatriat Med Ctr, Dept Nucl Med, Melbourne, Vic, Australia. Austin & Repatriat Med Ctr, Ctr PET, Melbourne, Vic, Australia. RP Lee, FT (reprint author), Austin & Repatriat Med Ctr, Ludwig Inst Canc Res, 145-163 Studley Rd, Heidelberg, Vic 3084, Australia. NR 24 TC 10 Z9 10 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD JUL PY 2003 VL 44 IS 7 BP 1105 EP 1112 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 700GJ UT WOS:000184104000030 PM 12843229 ER PT J AU Davis, CD Uthus, EO AF Davis, CD Uthus, EO TI Does dietary selenium affect plasma homocysteine concentrations in humans? SO JOURNAL OF NUTRITION LA English DT Letter ID ABERRANT CRYPT FORMATION; DNA METHYLATION; CELLS; COLON; RATS C1 NCI, Nutr Sci Res Grp, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. USDA, Grand Forks Human Nutr Res Ctr, Grand Forks, ND 58203 USA. RP Davis, CD (reprint author), NCI, Nutr Sci Res Grp, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. NR 5 TC 3 Z9 3 U1 0 U2 0 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUL PY 2003 VL 133 IS 7 BP 2392 EP 2392 PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 699BW UT WOS:000184036900050 PM 12840211 ER PT J AU Kim, YS Milner, JA AF Kim, YS Milner, JA TI Nutritional Genomics and proteomics in cancer prevention - Proceedings of the Conference Held September 5-6, 2002 in Bethesda, MD - Introduction SO JOURNAL OF NUTRITION LA English DT Editorial Material C1 NCI, Nutr Sci Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. RP Kim, YS (reprint author), NCI, Nutr Sci Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 1 U2 1 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUL PY 2003 VL 133 IS 7 SU S BP 2399S EP 2399S PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 701HY UT WOS:000184163200001 ER PT J AU Kavanaugh, C Green, JE AF Kavanaugh, C Green, JE TI The use of genetically altered mice for breast cancer prevention studies SO JOURNAL OF NUTRITION LA English DT Article; Proceedings Paper CT Conference on Nutritional Genomics and Proteomics in Cancer Prevention CY SEP 05-06, 2002 CL BETHESDA, MARYLAND SP NCI, Ctr Canc Res, NCI, Div Canc Prevent, Natl Ctr Complementary & Alternat Med, Amer Soc Nutr Sci DE genetically engineered mice; chemoprevention; breast cancer ID ANTIGEN-TRANSGENIC MICE; SUPPRESSES MAMMARY-CANCER; VITAMIN-D; 1-ALPHA-HYDROXYVITAMIN D-5; TUMOR PROGRESSION; SODIUM-BUTYRATE; MOUSE MODEL; TUMORIGENESIS; GENISTEIN; CHEMOPREVENTION AB Chemoprevention through nutritional and dietary changes may offer an important means of inhibiting the development and progression of breast cancer, which would have a major impact on public health. Studies to assess the efficacy of potential chemopreventive compounds are difficult to perform in large human populations, whereas the use of genetically engineered mice (GEM) for preclinical testing offers several advantages. GEM models can be utilized to assess the inhibitory effects of nutritional and chemopreventive agents on well-defined oncogenic signaling pathways. Because several transgenic mouse models progress through a well-defined temporal series of stages leading to invasive carcinoma formation, they may be particularly useful for determining cancer stage-specific responses to nutritional and chemopreventive agents. The C3(1)SV40 T/t-antigen transgenic mouse mammary cancer model has been utilized for chemopreventive research in which mammary tumors develop over a well-characterized time course. Several compounds have been shown to inhibit mammary tumor development in this model, including retinoids, di-fluoromethylornithine (DFMO), dehydroepiandrosterone (DHEA), antiangiogenic compounds and nonsteroidal anti-inflammatory drugs (NSAID). All of the chemopreventive agents used in the C3(1)Tag mammary mouse model appear to affect the promotion stage of tumorigenesis, suggesting that these agents may be useful in inhibiting the transition of human ductal carcinoma in situ (DCIS) to invasive carcinoma. Selective combinations of chemopreventive agents may be particularly useful for targeting multiple signaling pathways involved in cancer development and progression leading to improved clinical responses. The application of gene expression profiling to chemopreventive studies will aid in the selection of appropriate models for preclinical testing and further define mechanisms of action. C1 NCI, Lab Cellular Regulat & Carcinogenesis, Bethesda, MD 20892 USA. NCI, Div Prevent Oncol, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. RP Green, JE (reprint author), NCI, Lab Cellular Regulat & Carcinogenesis, Bethesda, MD 20892 USA. NR 43 TC 13 Z9 15 U1 0 U2 3 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUL PY 2003 VL 133 IS 7 SU S BP 2404S EP 2409S PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 701HY UT WOS:000184163200003 PM 12840216 ER PT J AU Petricoin, EF Liotta, LA AF Petricoin, EF Liotta, LA TI Clinical applications of proteomics SO JOURNAL OF NUTRITION LA English DT Article; Proceedings Paper CT Conference on Nutritional Genomics and Proteomics in Cancer Prevention CY SEP 05-06, 2002 CL BETHESDA, MARYLAND SP NCI, Ctr Canc Res, NCI, Div Canc Prevent, Natl Ctr Complementary & Alternat Med, Amer Soc Nutr Sci DE proteomics; pattern diagnostics; SELDI; protein microarrays; cell signaling ID PROTEIN IDENTIFICATION TECHNOLOGY; LASER CAPTURE MICRODISSECTION; ARTIFICIAL NEURAL NETWORKS; TYROSINE KINASE INHIBITOR; IMMOBILIZED PH GRADIENTS; HUMAN PROSTATE-CANCER; B-CELL LYMPHOMA; OVARIAN-CANCER; MASS-SPECTROMETRY; BREAST-CANCER AB Proteomics, the systematic evaluation of changes in the protein constituency of a cell, is more than just the generation of lists of proteins that increase or decrease in expression as a cause or consequence of disease. The ultimate goal is to characterize the information flow through protein pathways that interconnect the extracellular microenvironment with the control of gene transcription. The nature of this information can be a cause or a consequence of disease processes. Clinical applications of proteomics involve the use of proteomic technologies at the bedside. The analysis of human cancer as a model for how proteomics can have an impact at the bedside is now employing several new proteomic technologies that are being developed for early detection, therapeutic targeting and finally, patient-tailored therapy. C1 US FDA, Natl Canc Inst, Ctr Biol Evaluat & Res, Clin Proteom Program, Rockville, MD 20852 USA. NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Petricoin, EF (reprint author), US FDA, Natl Canc Inst, Ctr Biol Evaluat & Res, Clin Proteom Program, Rockville, MD 20852 USA. NR 82 TC 61 Z9 62 U1 0 U2 1 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUL PY 2003 VL 133 IS 7 SU S BP 2476S EP 2484S PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 701HY UT WOS:000184163200014 PM 12840227 ER PT J AU Moustafa, ME Kumaraswamy, E Zhong, NX Rao, M Carlson, BA Hatfield, DL AF Moustafa, ME Kumaraswamy, E Zhong, NX Rao, M Carlson, BA Hatfield, DL TI Models for assessing the role of selenoproteins in health SO JOURNAL OF NUTRITION LA English DT Article; Proceedings Paper CT Conference on Nutritional Genomics and Proteomics in Cancer Prevention CY SEP 05-06, 2002 CL BETHESDA, MARYLAND SP NCI, Ctr Canc Res, NCI, Div Canc Prevent, Natl Ctr Complementary & Alternat Med, Amer Soc Nutr Sci DE conditional knockout mice; selenium; selenocysteine; selenocysteine tRNA; transgenic mice ID SELENOCYSTEINE TRANSFER-RNA; GENE TRSP; SELENIUM; PROTEIN; MICE; CODE AB Two model systems for examining the role of selenoproteins in health are discussed. One utilizes transgenic mice that carry mutant selenocysteine (Sec) tRNA transgenes that result in the reduction of selenoprotein expression in a protein- and tissue-specific manner. The other utilizes loxP-Cre technology to selectively remove the Sec tRNA gene in mammary epithelium that results in the reduction of only certain selenoproteins in this tissue. Both approaches provide important tools for examining the role of selenoproteins in health. C1 NCI, Sect Mol Biol Selenium, Basic Res Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Hatfield, DL (reprint author), NCI, Sect Mol Biol Selenium, Basic Res Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NR 22 TC 16 Z9 16 U1 0 U2 0 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUL PY 2003 VL 133 IS 7 SU S BP 2494S EP 2496S PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 701HY UT WOS:000184163200016 PM 12840229 ER PT J AU Wang, ML Tuli, R Manner, PA Sharkey, PF Hall, DJ Tuan, RS AF Wang, ML Tuli, R Manner, PA Sharkey, PF Hall, DJ Tuan, RS TI Direct and indirect induction of apoptosis in human mesenchymal stem cells in response to titanium particles SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE mesenchymal stem cell; apoptosis; wear particles; titanium; zirconia ID TOTAL HIP-ARTHROPLASTY; OSTEOBLAST-LIKE CELLS; WEAR DEBRIS; BONE-MARROW; IN-VITRO; CANINE MODEL; DIFFERENTIATION; OSTEOLYSIS; DEATH; ALLOY AB The most frequent complication of total joint arthroplasty is periprosthetic osteolysis initiated by an inflammatory response to orthopaedic wear debris, which if left untreated, can result in implant instability and failure, eventually requiring revision surgery. We have previously reported that osteogenic differentiation of human marrow stroma-derived mesenchymal stem cells (hMSCs) is suppressed upon exposure to titanium particles, accompanied by reduced bone sialoprotein (BSP) gene expression, diminished production of collagen type I and BSP, decreased cellular viability and proliferation, and inhibition of extracellular matrix mineralization. In this study, we have further investigated hMSC cytotoxicity upon exposure to submicron particles of commercially pure titanium (cpTi) and zirconium oxide (ZrO2). Our results showed that direct exposure to cpTi and ZrO2 particles compromises cell viability through the induction of apoptosis, eliciting increased levels of the tumor suppressor proteins p53 and p73, in a manner dependent on material composition, particle dosage, and time. Additionally, conditioned medium collected from hMSCs exposed to cpTi particles, but not to ZrO2 particles, is cytotoxic to hMSCs, inducing apoptosis in the absence of particles. These findings demonstrate that exposure to orthopaedically derived wear particles can compromise hMSC viability through the direct and indirect induction of apoptosis. Thus, prolonged in vivo exposure of marrow-derived hMSCs to implant-derived wear debris is likely to reduce the population of viable osteoprogenitor cells, and may contribute to poor periprosthetic bone quality and implant loosening. Published by Elsevier Science Ltd. on behalf of Orthopaedic Society. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Dept Orthopaed Surg, Philadelphia, PA 19107 USA. George Washington Univ, Dept Orthopaed Surg, Washington, DC 20037 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bldg 50,Room 1503,50 S Dr,MSC 8022, Bethesda, MD 20892 USA. NR 43 TC 73 Z9 76 U1 0 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0736-0266 J9 J ORTHOPAED RES JI J. Orthop. Res. PD JUL PY 2003 VL 21 IS 4 BP 697 EP 707 DI 10.1016/S0736-0266(02)00241-3 PG 11 WC Orthopedics SC Orthopedics GA 694UD UT WOS:000183792200018 PM 12798071 ER PT J AU Engbring, JA Kleinman, HK AF Engbring, JA Kleinman, HK TI The basement membrane matrix in malignancy SO JOURNAL OF PATHOLOGY LA English DT Review DE basement membrane; extracellular matrix; laminin; metastasis ID LAMININ-A CHAIN; CAPILLARY-LIKE STRUCTURES; AMINO-ACID-SEQUENCE; EXTRACELLULAR-MATRIX; TUMOR-GROWTH; ENDOTHELIAL-CELLS; EMBRYONIC VASCULOGENESIS; CANCER METASTASIS; SCATTER FACTOR; IN-VIVO AB Cancer is the second most common cause of death among Americans, although for several age groups it ranks first. Most of these deaths are not due to the primary tumour but rather to tumour cell metastases to distant organs. There are many steps that lead to metastasis, all of which are being studied with the goal of preventing these fatalities. Normally, cells attach to the extracellular matrix to maintain tissue integrity. During cancer progression, cells become more motile and acquire invasive qualities. Tumour cells move along blood and lymph vessels or invade into them to travel to distant sites. Then, the tumour cells must attach to the vessel wall, extravasate from the vessel, invade the new tissue, proliferate, and form a secondary tumour. Angiogenesis, the formation of new blood vessels, is critical to survival of these cells at the new site and is also important for primary tumour growth and spread. Tumour cell metastasis is a complex cascade of sequential steps, each of which is not yet fully understood. Progress has been made in identifying several key activators, one of which is the extracellular matrix. A major tumour promoter is the glycoprotein laminin, which is predominantly found in the extracellular matrix produced by endothelial and epithelial cells. This review will follow the metastatic process with particular attention to the effect of laminin on tumour cells. Copyright (C) 2003 John Wiley Sons, Ltd. C1 NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Kleinman, HK (reprint author), NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Dept Hlth & Human Serv, 30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. NR 74 TC 137 Z9 147 U1 2 U2 7 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0022-3417 J9 J PATHOL JI J. Pathol. PD JUL PY 2003 VL 200 IS 4 BP 465 EP 470 DI 10.1002/path.1396 PG 6 WC Oncology; Pathology SC Oncology; Pathology GA 697CY UT WOS:000183925700005 PM 12845613 ER PT J AU Kimberlin, DW Lin, CY Sanchez, PJ Demmler, GJ Dankner, W Shelton, M Jacobs, RF Vaudry, W Pass, RF Kiell, JM Soong, SJ Whitley, RJ AF Kimberlin, DW Lin, CY Sanchez, PJ Demmler, GJ Dankner, W Shelton, M Jacobs, RF Vaudry, W Pass, RF Kiell, JM Soong, SJ Whitley, RJ CA Natl Inst Allergy Infect Dis Colla TI Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: A randomized, controlled trial SO JOURNAL OF PEDIATRICS LA English DT Article; Proceedings Paper CT 40th Interscience Conference on Antimicrobial Agents and Chemotherapy CY SEP 17-21, 2000 CL TORONTO, CANADA SP NIH ID DAY-CARE-CENTER; MOLECULAR EPIDEMIOLOGY; VIRAL TRANSMISSION; INCLUSION DISEASE; INFECTION; CHILDREN; PARENTS; PHARMACOKINETICS; NEWBORNS; CENTERS AB Objective To evaluate the efficacy and safety of gancielovir therapy in neonates with congenital cytomegalovirus (CMV) disease. Study design Neonates with symptomatic CMV disease involving the central nervous system were randomly assigned to receive 6 weeks of intravenous gancielovir versus no treatment. The primary end point was improved brainstem-evoked response (BSER) between baseline and 6-month follow-up (or, for patients with normal baseline hearing, normal BSER at both time points). Results From 1991 to 1999, 100 patients were enrolled. Of these, 42 patients had both a baseline and 6-month follow-up BSER audiometric examination and thus were evaluable for the primary end point. Twenty-one (84%) of 25 gancielovir recipients had improved hearing or maintained normal hearing between baseline and 6 months versus 10 (59%) of 17 control patients (P = .06). None (0%) of 25 gancielovir recipients bad worsening in hearing between baseline and 6 months versus 7 (41%) of 17 control patients (P < .01). A total of 43 patients had a BSER at both baseline and at I year or beyond. Five (21%) of 24 gancielovir recipients had worsening of hearing between baseline and greater than or equal to 1 year versus 13 (68%) of 19 control patients (P <.01). A total of 89 patients had absolute neutrophil counts determined during the course of the study; 29 (63%) of 46 ganciclovir-treated patients had grade 3 or 4 neutropenia during treatment versus 9 (21%) of 43 control patients (P <.01). Conclusions Ganciclovir therapy begun in the neonatal period in symptomatically infected infants with CMV infection involving the central nervous system prevents hearing deterioration at 6 months and may prevent hearing deterioration at ! I year. Almost two thirds of treated infants have significant neutropenia during therapy. C1 NIAID, Collaborat Antiviral Study Grp, Bethesda, MD USA. RP Kimberlin, DW (reprint author), NIAID, Collaborat Antiviral Study Grp, Bethesda, MD USA. EM dkimberlin@peds.uab.edu FU NCRR NIH HHS [RR-032]; NIAID NIH HHS [N01-AI-15113, N01-AI-62554] NR 33 TC 341 Z9 362 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JUL PY 2003 VL 143 IS 1 BP 16 EP 25 DI 10.1016/S0022-3476(03)00192-6 PG 10 WC Pediatrics SC Pediatrics GA 708DZ UT WOS:000184553000008 PM 12915819 ER PT J AU Cai, Q Dmitrieva, NI Michea, LF Rocha, G Ferguson, D Burg, MB AF Cai, Q Dmitrieva, NI Michea, LF Rocha, G Ferguson, D Burg, MB TI Toxicity of acetaminophen, salicylic acid, and caffeine for first-passage rat renal inner medullary collecting duct cells SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; DNA-DAMAGE; HYPERTONIC STRESS; KINASE-ACTIVITY; HISTONE H2AX; PROLIFERATION; PARACETAMOL; INHIBITION; APOPTOSIS; GROWTH AB Chronic excess ingestion of nonsteroid anti-inflammatory drugs causes renal medullary necrosis. Previously, using an immortalized line of mouse inner medullary collecting ducts cells (mIMCD3), we found that acetaminophen, salicylic acid, and caffeine are toxic, and the effects of acetaminophen and caffeine are strongly additive. Furthermore, toxicity was greater in proliferating than in nonproliferating cells. Important limitations were that mIMCD3 cells do not readily tolerate the high concentrations of salt and urea normally present in renal inner medullas and proliferate much more rapidly than inner medullary cells in vivo. Thus, these cells may not serve as an appropriate model for the in vivo IMCD. The present studies address these limitations by using passage-1 rat inner medullary collecting duct (p1rIMCD) cells, which tolerate high salt and urea and become contact inhibited when confluent. At 640 mOsmol/kg (the lowest normal inner medullary osmolality), the drugs, singly and in combination, reduce the number of proliferating (i.e., subconfluent) p1rIMCD cells more than they do confluent cells. Effects of acetaminophen and caffeine are strongly additive. Addition of as little as 0.1 mM caffeine significantly enhances the toxicity of acetaminophen plus salicylic acid. With confluent cells at 640 mOsmol/kg and very slowly growing cells at 1370 mOsmol/kg, combinations of drugs that include acetaminophen increase proliferation, accompanied by DNA damage and apoptosis. We conclude that these drugs are toxic to renal inner medullary collecting duct cells under the conditions of high osmolality normally present in the inner medulla, that combinations of the drugs are more toxic than are the drugs individually, and that the toxicity includes induction of proliferation of these cells that are otherwise quiescent in the presence of high osmolality. C1 NHLBI, Kidney & Electrolyte Metab Lab, US Dept HHS, NIH, Bethesda, MD 20892 USA. RP Burg, MB (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, US Dept HHS, NIH, Bethesda, MD 20892 USA. RI Dmitrieva, Natalia/A-2924-2013 OI Dmitrieva, Natalia/0000-0001-8074-6950 NR 39 TC 4 Z9 4 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUL PY 2003 VL 306 IS 1 BP 35 EP 42 DI 10.1124/jpet.102.047431 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 691NW UT WOS:000183613200005 PM 12663684 ER PT J AU Solinas, M Panlilio, LV Antoniou, K Pappas, LA Goldberg Sr AF Solinas, M Panlilio, LV Antoniou, K Pappas, LA Goldberg, SR TI The cannabinoid CB1 antagonist N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole -3-carboxamide (SR-141716A) differentially alters the reinforcing effects of heroin under continuous reinforcement, fixed ratio, and progressive ratio schedules of drug self-administration in rats SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID RECEPTOR KNOCKOUT MICE; INVERSE AGONIST; G-PROTEINS; MORPHINE; BRAIN; LOCALIZATION; COCAINE; OPIATE; REWARD; WITHDRAWAL AB Activation or blockade of cannabinoid CB1 receptors markedly alters many effects of opioids. In the present study, we investigated whether the cannabinoid antagonist (N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR-141716A) could alter the reinforcing effects of heroin in rats. A Delta(9)-tetrahydrocannabinol (THC) drug-discrimination procedure was first used to determine effective CB1 antagonist doses of SR-141716A and optimal pretreatment times for self-administration studies. Subsequently, Sprague-Dawley rats learned to self-administer heroin under three different schedules of intravenous drug injection: a continuous reinforcement schedule [fixed ratio (FR)1], a five-response, fixed ratio schedule (FR5), and a progressive ratio schedule. Then, SR-141716A (1 mg/kg i.p.) was administered 60 min before the start of the session for three consecutive daily sessions. SR-141716A markedly decreased heroin self-administration under the progressive ratio schedule at heroin doses ranging from 12.5 to 100 mug/kg/injection. In contrast, SR-141716A had no effect on heroin self-administration under the FR1 schedule at heroin doses of 50 or 100 mug/kg/injection, but produced small decreases in self-administration at lower doses (25 and 12.5 mug/kg/injection). Consistent with a behavioral economics evaluation, SR-141716A produced a small but significant decrease in self-administration of the higher 50 mug/kg/injection dose of heroin when the fixed ratio requirement was raised to five (FR5). Thus, blockade of CB1 receptors differentially decreased the reinforcing efficacy of heroin depending on the number of responses required for each injection (price). These findings indicate a facilitatory modulation of opioid reward by endogenous cannabinoid activity and provide support for the use of cannabinoid CB1 antagonists as medications for heroin addiction. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch,Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. Univ Athens, Sch Med, Dept Pharmacol, Goudi, Greece. RP Goldberg Sr (reprint author), NIDA, Preclin Pharmacol Sect, Neurosci Res Branch,Div Intramural Res, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sgoldber@intra.nida.nih.gov RI Solinas, Marcello/M-3500-2016 OI Solinas, Marcello/0000-0002-0664-5964 NR 39 TC 113 Z9 120 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUL PY 2003 VL 306 IS 1 BP 93 EP 102 DI 10.1124/jpet.102.047928 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 691NW UT WOS:000183613200012 PM 12660305 ER PT J AU Varga, EV Rubenzik, MK Stropova, D Sugiyama, M Grife, V Hruby, VJ Rice, KC Roeske, WR Yamamura, HI AF Varga, EV Rubenzik, MK Stropova, D Sugiyama, M Grife, V Hruby, VJ Rice, KC Roeske, WR Yamamura, HI TI Converging protein kinase pathways mediate adenylyl cyclase superactivation upon chronic delta-opioid agonist treatment SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID HAMSTER OVARY CELLS; CHRONIC MORPHINE; BETA-GAMMA; RECEPTOR; ACTIVATION; DEPENDENCE; MU; PHOSPHORYLATION; CALMODULIN; TOLERANCE/DEPENDENCE AB Adenylyl cyclase (AC) superactivation is thought to play an important role in opioid tolerance, dependence, and withdrawal. In the present study, we investigated the involvement of protein kinases in chronic delta-opioid agonist-mediated AC superactivation in Chinese hamster ovary (CHO) cells stably expressing the human delta-opioid receptor (hDOR/CHO). Maximal forskolin-stimulated cAMP formation in hDOR/CHO cells increased by 472 +/- 91, 399 +/- 2, and 433 +/- 73% after chronic treatment with the delta-opioid agonists (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N,N-diethyl benzamide (SNC 80), [D-Pen(2),D-Pen(5)]-enkephalin, and deltorphin II, respectively. Concurrently, chronic SNC 80 (1 muM, 4-h) treatment augmented P-32 incorporation into a 200-kDa protein immunoreactive with the ACV/VI antibody by 300 +/- 60% in hDOR/CHO cell lysates. The calmodulin antagonist calmidazolium significantly attenuated chronic deltorphin II-mediated AC superactivation. Tyrosine kinase (genistein) and protein kinase C (chelerythrine) inhibitors individually had minimal effect on chronic delta-opioid agonist-mediated AC superactivation. Conversely, simultaneous treatment with both genistein and chelerythrine significantly attenuated AC superactivation. Because we showed previously that the Raf-1 inhibitor 3-(3,5-dibromo-4-hydroxybenzylidene-5-iodo-1,3-dihydro-indol-2-one (GW5074) attenuates AC superactivation, we hypothesize that parallel calmidazolium-, chelerythrine-, and genistein-sensitive pathways converge at Raf-1 to mediate AC superactivation by phosphorylating AC VI in hDOR/CHO cells. C1 Univ Arizona, Hlth Sci Ctr, Coll Med, Dept Pharmacol, Tucson, AZ 85724 USA. Univ Arizona, Hlth Sci Ctr, Dept Biochem & Psychiat, Tucson, AZ 85724 USA. Univ Arizona, Hlth Sci Ctr, Dept Med, Tucson, AZ 85724 USA. Univ Arizona, Hlth Sci Ctr, Dept Chem, Tucson, AZ 85724 USA. Univ Arizona, Hlth Sci Ctr, Sarver Heart Ctr, Tucson, AZ 85724 USA. NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Yamamura, HI (reprint author), Univ Arizona, Hlth Sci Ctr, Coll Med, Dept Pharmacol, Tucson, AZ 85724 USA. NR 30 TC 37 Z9 39 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUL PY 2003 VL 306 IS 1 BP 109 EP 115 DI 10.1124/jpet.103.049643 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 691NW UT WOS:000183613200014 PM 12660310 ER PT J AU Burrowes, JD Larive, B Cockram, DB Dwyer, J Kusek, JW McLeroy, S Poole, D Rocco, MV AF Burrowes, JD Larive, B Cockram, DB Dwyer, J Kusek, JW McLeroy, S Poole, D Rocco, MV CA Hemodialysis Study Grp TI Effects of dietary intake, appetite, and eating habits on dialysis and non-dialysis treatment days in hemodialysis patients: Cross-sectional results from the HEMO study SO JOURNAL OF RENAL NUTRITION LA English DT Article ID MAINTENANCE HEMODIALYSIS; NUTRITIONAL-STATUS; DISEASE AB Objective: To evaluate differences between dietary energy intake (DEI), dietary protein intake (DPI), appetite, dietary patterns, and eating habits during dialysis treatment days (DID) and non-dialysis treatment days (NDD) in 1,901 adults receiving maintenance hemodialysis who were enrolled in the baseline phase of the National Institutes of Health-sponsored Hemodialysis (HEMO) study. Design: A cross-sectional analysis of participants at baseline (before randomization). Setting: Fifteen clinical centers across the United States. Measurements: DEI, DPI, and self-reported assessment of appetite, dietary patterns, and eating habits. Results: For the entire study cohort, total mean (+/- SD) DEI (1,566 +/- 636 kcal/day) and weight-adjusted DEI (23.2 +/- 9.5 kcal/kg/day) were significantly higher (P < .0001) on NDD than on DD (1,488 +/- 620 kcal/day and 22.2 +/- 9.6 kcal/kg/day), respectively. Similarly, DPI was significantly higher (P < .0001) on NDD (65.0 +/- 29.0 g/day and 0.96 +/- 0.43 g/kg/day) than on DID (60.2 +/- 26.5 g/day and 0.90 +/- 0.41 g/kg/day). On DID and NDD, the mean weight-adjusted DEI for the entire cohort was less than the HEMO study standard of care (SOC) of greater than or equal to28 kcal/kg/day, whereas on NDD, several subgroups reported dietary protein intakes that were closer to the study's SOC. These included men, patients under 50 years of age, nonblack participants, those without diabetes, those with a normal or mild Index of Co-Existing Disease score, and those on dialysis for more than 5 years. Protein and energy intakes declined with worsening self-reported appetites in both DID and NDD after adjusting for other subgroup effects. Conclusion: Dietary energy and protein intakes of HEMO study participants were lower on DID than on NDD, and also lower than the SOC on both days, particularly with regard to energy intake. People receiving maintenance hemodialysis should be counseled to consume adequate amounts of energy and protein daily, especially on DID. Practitioners should monitor closely those patients who report poor appetite and should intervene appropriately. (C) 2003 by the National Kidney Foundation, Inc. C1 Beth Israel Med Ctr, Div Nephrol & Hypertens, New York, NY 10003 USA. Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. Abbott Labs, Ross Prod Div, Columbus, OH USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. Tufts Univ, Sch Nutr, Boston, MA 02111 USA. Tufts Univ New England Med Ctr, Frances Stern Nutr Ctr, Boston, MA 02111 USA. NIDDKD, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Med Ctr, Div Nephrol, Nashville, TN USA. Piedmont Dialysis Ctr, Winston Salem, NC USA. Wake Forest Univ, Sch Med, Nephrol Sect, Winston Salem, NC 27109 USA. RP Burrowes, JD (reprint author), Long Isl Univ, Dept Nutr, CW Post Campus,720 No Blvd, Greenvale, NY 11548 USA. OI Dwyer, Johanna/0000-0002-0783-1769 NR 17 TC 73 Z9 75 U1 1 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 1051-2276 J9 J RENAL NUTR JI J. Renal Nutr. PD JUL PY 2003 VL 13 IS 3 BP 191 EP 198 DI 10.1016/S1051-2276(03)00069-4 PG 8 WC Nutrition & Dietetics; Urology & Nephrology SC Nutrition & Dietetics; Urology & Nephrology GA 705LR UT WOS:000184397000004 PM 12874743 ER PT J AU Talbot, LA Gaines, JM Ling, SM Metter, EJ AF Talbot, LA Gaines, JM Ling, SM Metter, EJ TI A home-based protocol of electrical muscle stimulation for quadriceps muscle strength in older adults with osteoarthritis of the knee SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE electrical muscle stimulation; muscle strength; physical activity; functional performance; knee osteoarthritis ID PHYSICAL-ACTIVITY; HEALTH-STATUS; DISABILITY; QUESTIONNAIRE; ARTHRITIS; PAIN; WEAKNESS; EXERCISE; PROGRAM AB Objective. To determine whether home-based neuromuscular electrical stimulation (NMES) applied to the quadriceps femoris (QF) muscle increases strength, physical activity, and physical performance in older adults with knee osteoarthritis (OA). Methods. Thirty-four adults (> 60 yrs) with radiographically confirmed symptomatic knee OA were randomized to NMES plus education. or education only (EDU). The primary outcome was isometric QF peak torque (PTIso), with secondary outcomes of daily step counts, total activity vector magnitude, 100-foot walk-turn-walk, timed stair climb, chair rise, and pain. The NMES group used a portable electrical muscle stimulator 3 days a week for unilateral QF training with incremental increases in the intensity of isometric contraction to 30-40% of maximum over 12 weeks. Both groups received the 12-week Arthritis Self-Management course and were followed an additional 12 weeks. Results. The stimulated knee-extensor showed a 9.1% increase in 120degrees PTIso. compared to a 7% loss in the EDU group (time x group interaction for 120degrees PTIso; p = 0.04). The chair rise time decreased by 11% in the NMES group, whereas the EDU group saw a 7% reduction (p = 0.01, time; p = 0.9, group). Similarly, both groups improved their walk time by similar to7% (p = 0.02, time; p = 0.61 group). Severity, of pain reported following intervention did not differ between groups. Conclusion. In older adults with knee OA, a home-based NMES protocol appears to be a promising therapy for increasing QF strength in adults with knee OA without exacerbating painful symptoms. C1 Johns Hopkins Univ, Sch Nursing, Baltimore, MD 21205 USA. Gerontol Res Ctr, Natl Inst Aging, Baltimore, MD USA. Erickson Fdn, Baltimore, MD USA. RP Talbot, LA (reprint author), Johns Hopkins Univ, Sch Nursing, 5825 N Wolfe St,Rm 445, Baltimore, MD 21205 USA. NR 26 TC 53 Z9 58 U1 0 U2 10 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD JUL PY 2003 VL 30 IS 7 BP 1571 EP 1578 PG 8 WC Rheumatology SC Rheumatology GA 699MT UT WOS:000184061100031 PM 12858461 ER PT J AU Lewis, MK Nahirney, PC Chen, V Adhikari, BB Wright, J Reedy, MK Bass, AH Wang, K AF Lewis, MK Nahirney, PC Chen, V Adhikari, BB Wright, J Reedy, MK Bass, AH Wang, K TI Concentric intermediate filament lattice links to specialized Z-band junctional complexes in sonic muscle fibers of the type I male midshipman fish SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE sonic muscle fiber; midshipman fish; cytoskeleton; wide Z band; Z corset; Z bar; alpha-actinin; desmin; plectin; confocal microscopy; superfast muscle ID MAMMALIAN SKELETAL-MUSCLE; MICE LACKING DESMIN; FAST-TWITCH MUSCLE; 3-DIMENSIONAL STRUCTURE; SARCOPLASMIC-RETICULUM; PORICHTHYS-NOTATUS; SARCOMERE MATRIX; ALPHA-ACTININ; TELEOST FISH; OPSANUS-TAU AB Type I male midshipman fish produce high-frequency hums for prolonged durations using sonic muscle fibers, each of which contains a hollow tube of radially oriented thin and flat myofibrils that display extraordinarily wide (similar to 1.2 mum) Z bands. We have revealed an elaborate cytoskeletal network of desmin filaments associated with the contractile cylinder that form interconnected concentric ring structures in the core and periphery at the level of the Z bands. Stretch and release of single fibers revealed reversible length changes in the elastic desmin lattice. This lattice is linked to Z bands via novel intracellular desmosome-like junctional complexes that collectively form a ring, termed the "Z corset," around the periphery and within the core of the cylinder. The junctional complex consists of regularly spaced parallel similar to900-nm-long cytoskeletal rods, or "Z bars," interconnected with slender (3-4 nm) plectin-positive filaments. Z bars are linked to the Z band by plectin filaments and on the opposite side to a dense mesh of desmin filaments. Adjacent Z bands are linked by slender filaments that appear to suspend sarcotubules. We propose that the highly reinforced elastic desmin cytoskeleton and the unique Z band junctions are structural adaptations that enable the muscles' high-frequency and high-endurance activity. Published by Elsevier Science Inc. C1 NIAMSD, Muscle Proteom & Nanotechnol Sect, Muscle Biol Lab, NIH,DHHS, Bethesda, MD 20892 USA. Univ Texas, Cell Res Inst, Dept Chem & Biochem, Austin, TX 78712 USA. Cornell Univ, Dept Neurobiol & Behav, Ithaca, NY 14853 USA. Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. RP Wang, K (reprint author), NIAMS, Muscle Biol Lab, NIH, Bldg 50,Room 1140, Bethesda, MD 20892 USA. NR 56 TC 18 Z9 20 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 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD JUL PY 2003 VL 143 IS 1 BP 56 EP 71 DI 10.1016/S1047-8477(03)00121-7 PG 16 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 712CJ UT WOS:000184778500006 PM 12892726 ER PT J AU Harris, CR Albaugh, B Goldman, D Enoch, MA AF Harris, CR Albaugh, B Goldman, D Enoch, MA TI Neurocognitive impairment due to chronic alcohol consumption in an American Indian community SO JOURNAL OF STUDIES ON ALCOHOL LA English DT Article ID NEUROPSYCHOLOGICAL PERFORMANCE; FEMALE ALCOHOLICS; WAIS-R; DRINKING; DEFICITS; GENDER; WOMEN; AGE; DYSFUNCTION; DEPENDENCE AB Objective: Studies have shown that clinically ascertained alcoholics tend to have lower scores than nonalcoholics on cognitive performance tests, particularly the Block Design (BD) and Digit Symbol (DS) tests of the Weschler Adult Intelligence Scale-Revised (WAIS-R). The aim of this study was to determine whether similar differences are found in a community sample of Plains Indian men and women with an episodic pattern of drinking and a high lifetime prevalence of alcoholism (71% for men, 44% for women). Method: We administered a truncated form of the WAIS-R to 334 members of a Plains Indian tribe (197 women and 137 men). Blind-rated psychiatric diagnoses were assigned according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III-R) criteria and based on the Schedule for Affective Disorders, Lifetime Version (SADS-L) interview. We compared 68 currently drinking alcoholics (38 men and 30 women), 116 abstaining alcoholics (59 men and 57 women) and 150 nonalcoholics (40 men and 110 women). Results: Current and past heavy drinking had no impact on WAIS-R scores in women. Male alcoholics who were abstinent greater than or equal to2years had similar scores to nonalcoholic men. Male current drinkers showed a trend for lower overall verbal and performance (PIQ) scores and BD performance subtest. Further analysis showed that drinking for a 15 years was significantly associated with reduced DS in male current drinkers. Conclusions: These findings suggest that for the men in this community sample, the impact on PIQ is due to the direct effect of chronic alcohol consumption on cognitive performance and is at least partially reversible after 2 years of abstinence. C1 NIAAA, DICBR, LNG, NIH, Bethesda, MD 20892 USA. RP Harris, CR (reprint author), NIAAA, DICBR, LNG, NIH, 124020 Parktown Dr,Pk 5 Bldg,Room 451,MSC 8110, Bethesda, MD 20892 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 48 TC 9 Z9 9 U1 0 U2 2 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 0096-882X J9 J STUD ALCOHOL JI J. Stud. Alcohol PD JUL PY 2003 VL 64 IS 4 BP 458 EP 466 PG 9 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 705TP UT WOS:000184411400003 PM 12921187 ER PT J AU Lenczowski, JM Cassarino, DS Jain, A Turner, ML AF Lenczowski, JM Cassarino, DS Jain, A Turner, ML TI Disseminated vascular papules in an nodeficient patient being treated with granulocyte colony-stimulating factor SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID HEMANGIOMA PYOGENIC GRANULOMA; HYPER-IGM SYNDROME; JUVENILE HEMANGIOMAS; ENDOTHELIAL-CELLS C1 NCI, Ctr Canc Res, Dermatol Branch, Bethesda, MD 20892 USA. NCI, Pathol Branch, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Dermatol Branch, Bethesda, MD 20892 USA. RP Turner, ML (reprint author), NCI, Ctr Canc Res, Dermatol Branch, Bldg 10 Rm 12N238,10 Ctr Dr MSC 1908, Bethesda, MD 20892 USA. NR 16 TC 3 Z9 3 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUL PY 2003 VL 49 IS 1 BP 105 EP 108 DI 10.1067/mjd.2003.306 PG 4 WC Dermatology SC Dermatology GA 700WW UT WOS:000184135000014 PM 12833018 ER PT J AU Kronsberg, SS Obarzanek, E Affenito, SG Crawford, PB Sabry, ZI Schmidt, M Striegel-Moore, R Kim, SYS Barton, BA AF Kronsberg, SS Obarzanek, E Affenito, SG Crawford, PB Sabry, ZI Schmidt, M Striegel-Moore, R Kim, SYS Barton, BA TI Macronutrient intake of black and white adolescent girls over 10 years: The NHLBI Growth and Health Study SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID CARDIOVASCULAR RISK-FACTORS; BLOOD-INSTITUTE GROWTH; YOUNG-ADULTS; PHYSICAL-ACTIVITY; US CHILDREN; FAT INTAKE; BODY-FAT; DISEASE; OBESITY; DIETARY AB Objective To compare age-related changes in macronutrient and cholesterol intake between black and white girls, compare intakes with National Cholesterol Education Program (NCEP) recommendations, and examine sociodemographic associations with macronutrient intake. Design Cohort study with 3-day food records collected over 10 years. Subjects 2,379 girls, 1,166 white and 1,213 black, age 9 to 10 years at baseline, recruited from three geographic locations. Statistical analysis Longitudinal generalized estimating equation (GEE) regression models examined the relationships of age, ethnicity, and sociodemographic factors with macronutrient and cholesterol intake and with percentage of girls meeting NCEP recommendations. Results Total and saturated fat intakes decreased with age, more in white girls than black girls, from 35.1% and 13.6% kcal at age 9 to 29.3% and 10.4% at age 19 for white girls and from 36.5% and 13.4% kcal at age 9 to 35.1% and 11.7% kcal at age 19 for black girls. Dietary cholesterol decreased with age, but decreased more in white girls than black girls (range 95 to 119 mg/1,000 kcal for white girls and 119 to 132 mg/ 1,000 kcal for black girls). Depending on age, 7% to 51% of white girls and 8% to 26% of black girls met NCEP recommendations for total fat (less than or equal to30% kcal) and saturated fat (<10% kcal). About 85% of white and 75% of black girls met NCEP recommendation for dietary cholesterol (<300 mg/ day). Lower parental education was associated with increased fat and cholesterol and decreased carbohydrate in-take. Applications Nutrition counseling and health promotion endeavors should make efforts to promote nutritional heart-healthy messages to adolescents, particularly black girls. C1 Maryland Med Res Inst, Baltimore, MD 21210 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. St Joseph Coll, Dept Nutr & Family Studies, Hartford, CT USA. Univ Calif Berkeley, Ctr Weight & Hlth, Berkeley, CA USA. Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. Dietary Data Entry Ctr, Growth & Hlth Study, Cincinnati, OH USA. Wesleyan Univ, Dept Psychol, Middletown, CT USA. Univ Pittsburgh, Sch Med, Dept Family Med, Pittsburgh, PA USA. RP Kronsberg, SS (reprint author), Maryland Med Res Inst, 600 Wyndhurst Ave, Baltimore, MD 21210 USA. OI Barton, Bruce/0000-0001-7878-8895 NR 41 TC 16 Z9 16 U1 0 U2 0 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD JUL PY 2003 VL 103 IS 7 BP 852 EP 860 DI 10.1053/jada.2003.50169 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 697DF UT WOS:000183926400016 PM 12830023 ER PT J AU Appel, LJ Middleton, J Miller, ER Lipkowitz, M Norris, K Agodoa, LY Bakris, G Douglas, JG Charleston, J Gassman, J Greene, T Jamerson, K Kusek, JW Lewis, JA Phillips, RA Rostand, SG Wright, JT AF Appel, LJ Middleton, J Miller, ER Lipkowitz, M Norris, K Agodoa, LY Bakris, G Douglas, JG Charleston, J Gassman, J Greene, T Jamerson, K Kusek, JW Lewis, JA Phillips, RA Rostand, SG Wright, JT CA African Amer Study TI The rationale and design of the AASK Cohort Study SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article; Proceedings Paper CT 1st International Summit on Kidney Disease Prevention CY JUL 25-27, 2002 CL SINGAPORE ID HYPERTENSIVE NEPHROSCLEROSIS; TRIAL AB Hypertensive kidney disease commonly progresses. The primary objective of the AASK (African American Study of Kidney Disease and Hypertension) Cohort Study is to determine prospectively the course of kidney function and risk factors for kidney disease progression in African Americans with hypertensive kidney disease who receive recommended anti-hypertensive therapy. The AASK Cohort Study is a prospective, observational study that is an extension of the AASK trial. The AASK trial tested the effects of three medications used as initial anti-hypertensive therapy (ramipril, metoprolol, and amlodipine) and two levels of BP control. Of the 1094 trial participants, approximately 650 to 700 individuals who have not reached ESRD will likely enroll in the Cohort Study. Risk factors to be studied include environmental, genetic, physiologic, and socioeconomic variables. The primary renal outcome is a composite clinical outcome defined by doubling of serum creatinine, ESRD, or death. Medication treatment for hypertension, beginning with the angiotensin converting enzyme inhibitor ramipril, is offered to all participants. In this fashion, the study directly controls two of the major determinants of kidney disease progression: treatment of hypertension and use of renoprotective, anti-hypertensive medication. The minimum duration of follow-up in the Cohort Study is 5 yr (total of 9 to 12 yr, including the period of the AASK trial). Ultimately, data from the AASK Cohort Study should enhance our understanding of the risk factors and processes that determine the progression of kidney disease. Such results might eventually lead to new strategies that delay or prevent ESRD. C1 Johns Hopkins Med Inst, Welsh Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. Univ Texas, SW Med Ctr, Dept Internal Med, Div Nephrol, Dallas, TX USA. Mount Sinai Sch Med, Div Nephrol, Dept Med, New York, NY USA. NYU, Sch Med, Lenox Hill Hosp, New York, NY USA. Charles R Drew Univ, Dept Internal Med, Los Angeles, CA USA. NIDDKD, NIH, Bethesda, MD 20892 USA. Rush Presbyterian St Lukes Med Ctr, Dept Prevent Med, Chicago, IL 60612 USA. Case Western Reserve Univ, Dept Med, Div Hypertens, Sch Med, Cleveland, OH 44106 USA. Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. Univ Michigan Hlth Syst, Dept Med, Ann Arbor, MI USA. Vanderbilt Univ, Dept Med, Div Nephrol, Nashville, TN USA. Univ Alabama, Dept Med, Div Nephrol, Birmingham, AL 35294 USA. RP Appel, LJ (reprint author), Johns Hopkins Med Inst, Welsh Ctr Prevent Epidemiol & Clin Res, 2024 E Monument St,Suite 2-645, Baltimore, MD 21205 USA. FU NCRR NIH HHS [RR-00032, RR-00071, RR-00052, RR-00827, RR-11104, RR-11145]; NIDDK NIH HHS [DK-2818] NR 5 TC 54 Z9 54 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2003 VL 14 IS 7 SU 2 BP S166 EP S172 DI 10.1097/01.ASN.0000070081.15137.C0 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 696RH UT WOS:000183900700020 PM 12819323 ER PT J AU Gassman, JJ Greene, T Wright, JT Agodoa, L Bakris, G Beck, GJ Douglas, J Jamerson, K Lewis, J Kutner, M Randall, OS Wang, SR AF Gassman, JJ Greene, T Wright, JT Agodoa, L Bakris, G Beck, GJ Douglas, J Jamerson, K Lewis, J Kutner, M Randall, OS Wang, SR CA AASK Grp TI Design and statistical aspects of the African American Study of Kidney Disease and Hypertension (AASK) SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article; Proceedings Paper CT 1st International Summit on Kidney Disease Prevention CY JUL 25-27, 2002 CL SINGAPORE ID BLOOD-PRESSURE CONTROL; STAGE RENAL-DISEASE; CONVERTING ENZYME-INHIBITION; ANTIHYPERTENSIVE TREATMENT; DIABETIC-NEPHROPATHY; CLINICAL-TRIALS; PROGRESSION; BLACK; INSUFFICIENCY; INTERVENTION AB The African American Study of Kidney Disease and Hypertension (AASK) is a multicenter randomized clinical trial designed to test the effectiveness of three anti-hypertensive drug regimens and two levels of BP control on the progression of hypertensive kidney disease. Participants include African-American men and women aged 18 to 70 yr who have hypertensive kidney disease and GFR between 20 and 65 ml/min per 1.73 m(2). The three anti-hypertensive drug regimens include an angiotensin converting enzyme inhibitor (ramipril), a dihydropyridine calcium channel blocker (amlodipine) or a beta-blocker (metoprolol) as initial therapy. The BP control levels are a lower goal (mean arterial pressure, less than or equal to92 mmHg) and a usual goal (mean arterial pressure, 102 to 107 mmHg inclusive). The primary outcome is rate of change in renal function as measured by GFR, assessed by I-125-iothalamate clearance. The main secondary patient outcome is a composite including the following events: (1) reduction in GFR by 50%, (2) end-stage renal disease, or (3) death. C1 Cleveland Clin Fdn, Dept Biostat, Cleveland, OH 44195 USA. Case Western Reserve Univ, Sch Med, Cleveland, OH USA. Univ Hosp, Cleveland, OH USA. NIDDK, NIH, Bethesda, MD USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL USA. Univ Michigan, Ann Arbor, MI 48109 USA. Vanderbilt Univ, Sch Med, Dept Internal Med, Nashville, TN 37212 USA. Howard Univ, Washington, DC 20059 USA. RP Gassman, JJ (reprint author), Cleveland Clin Fdn, Dept Biostat, 9500 Euclid Ave,WB-4, Cleveland, OH 44195 USA. FU NCRR NIH HHS [RR11104, M01 RR000032, M01 RR000052, M01 RR000071, M01 RR000080, M01 RR000827, P20 RR011104, P20 RR011145, RR-00071, RR-00080, RR00032, RR00052, RR00827, RR11145]; NIDDK NIH HHS [DK 2818, K24 DK002818, U01 DK048643] NR 56 TC 37 Z9 38 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2003 VL 14 IS 7 SU 2 BP S154 EP S165 DI 10.1097/01.ASN.0000070080.21682.CB PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 696RH UT WOS:000183900700019 PM 12819322 ER PT J AU Hostetter, TH AF Hostetter, TH TI Prevention of the development and progression of renal disease SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article; Proceedings Paper CT 1st International Summit on Kidney Disease Prevention CY JUL 25-27, 2002 CL SINGAPORE ID RANDOMIZED CONTROLLED TRIAL; CONVERTING ENZYME-INHIBITORS; DIABETIC-NEPHROPATHY; COST-EFFECTIVENESS; TYPE-2 DIABETES/; LIFE-STYLE; COMPLICATIONS; HYPERTENSION; METAANALYSIS; IRBESARTAN AB Prevention of the major causes of ESRD, hypertension, and diabetes, is possible. Careful glycemic control can prevent diabetes nephropathy. BP control can likely prevent the large majority of hypertensive renal disease. Testing for diabetic renal disease is well founded. In contrast, screening for hypertensive kidney disease is less well defined. Most established renal disease can be treated with glycemic control in the case of diabetes, BP treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and dietary protein restriction. Other therapeutic targets have been proposed, but are not well established. Future research should focus on defining the high risk patients, developing better markers of risk, and designing additional therapies. C1 NIDDKD, Natl Kidney Dis Educ Program, NIH, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. RP Hostetter, TH (reprint author), NIDDKD, Natl Kidney Dis Educ Program, NIH, Div Kidney Urol & Hematol Dis, 6707 Democracy Blvd,MSC 5458, Bethesda, MD 20892 USA. NR 23 TC 30 Z9 33 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2003 VL 14 IS 7 SU 2 BP S144 EP S147 DI 10.1097/01.ASN.0000070150.60928.06 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 696RH UT WOS:000183900700017 PM 12819320 ER PT J AU Hostetter, TH Lising, M AF Hostetter, TH Lising, M TI National Kidney Disease Education Program SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article; Proceedings Paper CT 1st International Summit on Kidney Disease Prevention CY JUL 25-27, 2002 CL SINGAPORE ID RENAL-DISEASE; PREVENTION; TRIAL AB The National Kidney Disease Education Program (NDKEP) is a program of the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health. It seeks to increase awareness of CKD among high risk groups and primary care providers. The NKDEP is a response to the rapidly escalating incidence of ESRD in the United States in the face of new treatment to prevent and mitigate CKD. The hope is that awareness will lead to action, testing, and treatment. C1 NIH, Natl Kidney Dis Educ Program, Bethesda, MD 20892 USA. RP Hostetter, TH (reprint author), NIDDKD, NIH, 6707 Democracy Blvd,MSC 5458, Bethesda, MD 20892 USA. NR 9 TC 35 Z9 35 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2003 VL 14 IS 7 SU 2 BP S114 EP S116 DI 10.1097/01.ASN.0000070156.78824.C7 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 696RH UT WOS:000183900700011 PM 12819314 ER PT J AU Molitch, ME Fujimoto, W Hamman, RF Knowler, WC AF Molitch, ME Fujimoto, W Hamman, RF Knowler, WC CA Diabet Prevention Program Res Grp TI The Diabetes Prevention Program and its global implications SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article; Proceedings Paper CT 1st International Summit on Kidney Disease Prevention CY JUL 25-27, 2002 CL SINGAPORE ID IMPAIRED GLUCOSE-TOLERANCE; LIFE-STYLE; MICROVASCULAR COMPLICATIONS; COST-EFFECTIVENESS; MELLITUS; NIDDM; RISK; HEALTH; PREVALENCE; REDUCTION AB Type 2 diabetes affects over 150 million adults worldwide and this figure is expected to double over the next 25 yr. This increase will be accompanied by a marked increase in the number of patients with ESRD due to diabetes. We hypothesized that a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7% weight loss and at least 150 min of physical activity per week. The mean age of the participants was 51 yr, and the mean body mass index was 34.0 kg/m(2); 68% were women, and 45% were members of non-Caucasian racial/ethnic groups. The average follow-up was 2.8 yr. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence of diabetes by 58% (95% CI: 48 to 66%) and metformin by 31% (95% CI: 17 to 43%), compared with placebo; the lifestyle intervention was significantly more effective than metformin. In conclusion, lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk and the lifestyle intervention was more effective than metformin. Because the lifestyle changes worked equally in all racial/ethnic groups in the Diabetes Prevention Program, they should be applicable to high-risk populations worldwide and may be able to reduce the projected progressive rise in the incidence of diabetes and the expected increase in ESRD. C1 Northwestern Univ, Feinberg Sch Med, Ctr Endocrinol Metab & Mol Sci, Evanston, IL 60208 USA. Northwestern Univ, Ctr Endocrinol Metab & Mol Med, Chicago, IL USA. Univ Washington, Sch Med, Dept Med, Seattle, WA USA. Univ Colorado, Hlth Sci Ctr, Dept Prevent Med & Biometr, Denver, CO 80262 USA. NIDDK, Diabet & Arthrit Epidemiol Sect, Phoenix, AZ USA. RP Molitch, ME (reprint author), George Washington Univ, Ctr Biostat, Diabet Prevent Program Coordinating Ctr, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. FU NIDDK NIH HHS [U01 DK048489, U01 DK048489-06] NR 26 TC 19 Z9 21 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2003 VL 14 IS 7 SU 2 BP S103 EP S107 DI 10.1097/01.ASN.0000070140.62190.97 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 696RH UT WOS:000183900700009 PM 12819312 ER PT J AU von Eschenbach, AC AF von Eschenbach, AC TI NCI sets goal of eliminating suffering and death due to cancer by 2015 SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP von Eschenbach, AC (reprint author), NCI, Bethesda, MD 20892 USA. EM avonesch@mail.nih.gov NR 0 TC 16 Z9 16 U1 0 U2 0 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD JUL PY 2003 VL 95 IS 7 BP 637 EP 639 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 836HY UT WOS:000222547700015 PM 12911262 ER PT J AU Lau, DTY Ma, H Lemon, SM Doo, E Ghany, MG Miskovsky, E Woods, GL Park, Y Hoofnagle, JH AF Lau, DTY Ma, H Lemon, SM Doo, E Ghany, MG Miskovsky, E Woods, GL Park, Y Hoofnagle, JH TI A rapid immunochromatographic assay for hepatitis B virus screening SO JOURNAL OF VIRAL HEPATITIS LA English DT Article DE diagnosis; enzyme immunoassays; hepatitis B; immunochromatographic assay ID SURFACE-ANTIGEN; BLOOD; TESTS; RISK AB Simple, rapid and accurate assays for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) are helpful for clinical diagnosis and field epidemiological surveys. A commercially developed, rapid immunochromatographic test for simultaneous detection of HBsAg and HBeAg was evaluated using a total of 2463 selected samples (827 frozen sera, 1011 fresh sera, and 625 whole blood samples). Results of the rapid test were compared with standard enzyme immunoassay (EIA) methods for HBsAg and HBeAg detection. The accuracy of the rapid test was excellent and was similar for frozen sera, fresh sera and whole blood. The overall sensitivity and specificity for the detection of HBsAg were 95 and 100%, and the corresponding positive and negative predictive values were 100 and 99.7%, respectively. The sensitivity and specificity for the detection of HBeAg were slightly less than that for HBsAg, and were 80 and 98%, with positive and negative predictive values of 91 and 94%, respectively. Thus, compared with the EIA method, the rapid test was highly sensitive and accurate for the detection of HBsAg although somewhat less sensitive and specific for detection of HBeAg. Because of its speed, simplicity and flexibility, the rapid test is ideally suited for HBsAg and HBeAg screening in population-based epidemiological studies and in low risk populations, particularly in regions of the world where hepatitis B is endemic. C1 Univ Texas, Med Branch, Dept Internal Med, Div Gastroenterol & Hepatol, Galveston, TX 77555 USA. Univ Texas, Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. NIDDKD, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. Univ Texas, Med Branch, Dept Pathol, Galveston, TX 77550 USA. RP Lau, DTY (reprint author), Univ Texas, Med Branch, Dept Internal Med, Div Gastroenterol & Hepatol, 4-106 McCullough Bldg,301 Univ Blvd, Galveston, TX 77555 USA. NR 12 TC 13 Z9 13 U1 1 U2 4 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1352-0504 J9 J VIRAL HEPATITIS JI J. Viral Hepatitis PD JUL PY 2003 VL 10 IS 4 BP 331 EP 334 DI 10.1046/j.1365-2893.2003.00418.x PG 4 WC Gastroenterology & Hepatology; Infectious Diseases; Virology SC Gastroenterology & Hepatology; Infectious Diseases; Virology GA 692XK UT WOS:000183685400014 PM 12823602 ER PT J AU Kovacs, GR Parks, CL Vasilakis, N Udem, SA AF Kovacs, GR Parks, CL Vasilakis, N Udem, SA TI Enhanced genetic rescue of negative-strand RNA viruses: use of an MVA-T7 RNA polyrnerase vector and DNA replication inhibitors SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE vaccinia virus; T7 RNA polymerase; measles virus ID RESPIRATORY SYNCYTIAL VIRUS; CANINE-DISTEMPER VIRUS; CLONED CDNA; MESSENGER-RNA; FOREIGN GENE; EXPRESSION; RECOVERY; SYSTEM; GENERATION; PROMOTER AB A modified cDNA rescue system that improves recovery of recombinant nonsegmented, negative-strand RNA viruses from cloned DNAs is described. Rescue systems based on vaccinia virus-T7 RNA polymerase vectors have been used to derive many negative-strand viruses; however, some strains can be recalcitrant to rescue possibly because of the simultaneous replication of the vaccinia virus-T7 vector. Our goal was to engineer a system where replication of the vaccinia virus-T7 vector could be blocked, yet allow for sufficient T7 RNA polymerase expression to enable genetic rescue. To that end, a recombinant modified vaccinia virus Ankara (MVA) was engineered that contained the bacteriophage T7 gene-1 under the control of a strong early promoter that would enable T7 RNA polymerase expression in the absence of MVA DNA replication. The new T7 helper, MVAGKT7, was then utilized successfully for the genetic rescue of a measles virus minigenome and full-length cDNAs, in the presence of DNA synthesis inhibitors. In addition to blocking completely MVAGKT7 replication, AraC treatment was found to enhance minigenome-encoded gene expression and the efficiency of measles virus rescue. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Wyeth Res, Viral Vaccine Discovery, Pearl River, NY 10965 USA. RP Kovacs, GR (reprint author), NIAID, Off Biodefense Res Affairs, NIH, 6610 Rockledge Dr,Room 5121, Bethesda, MD 20892 USA. NR 24 TC 21 Z9 23 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD JUL PY 2003 VL 111 IS 1 BP 29 EP 36 DI 10.1016/S0166-0934(03)00132-0 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 699WT UT WOS:000184079600004 PM 12821194 ER PT J AU Gibbs, JS Malide, D Hornung, F Bennink, JR Yewdell, JW AF Gibbs, JS Malide, D Hornung, F Bennink, JR Yewdell, JW TI The influenza A virus PB1-F2 protein targets the inner mitochondrial membrane via a predicted basic amphipathic helix that disrupts mitochondrial function SO JOURNAL OF VIROLOGY LA English DT Article ID P13(II) PROTEIN; CELL-DEATH; APOPTOSIS; IMPORT; RECEPTORS; TYPE-1 AB The 11th influenza A virus gene product is an 87-amino-acid protein provisionally named PB1-F2 (because. it is encoded by an open reading frame overlapping the PB1 open reading frame). A significant fraction of PB1-F2 localizes to the inner mitochondrial membrane in influenza A virus-infected cells. PB1-F2 appears to enhance virus-induced cell death in a cell type-dependent manner. For the present communication we have identified and characterized a region near the COOH terminus of PB1-F2 that is necessary and sufficient for its inner mitochondrial membrane localization, as determined by transient expression of chimeric proteins consisting of elements of PB1-F2 genetically fused to enhanced green fluorescent protein (EGFP) in HeLa cells. Targeting of EGFP to mitochondria by this sequence resulted in the loss of the inner mitochondrial membrane potential, leading to cell death. The mitochondrial targeting sequence (MTS) is predicted to form a positively charged amphipathic et-helix and, as such, is similar to the MTS of the p13(II) protein of human T-cell leukemia virus type 1. We formally demonstrate the functional interchangeability of the two sequences for mitochondrial localization of PB1-F2. Mutation analysis of the putative amphipathic helix in the PB1-F2 reveals that replacement of five basic amino acids with Ala abolishes mitochondrial targeting, whereas mutation of two highly conserved Leu to Ala does not. These findings demonstrate that PB1-F2 possesses an MTS similar to other viral proteins and that this MTS, when fused to EGFP, is capable of independently compromising mitochondrial function and cellular viability. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Heinrich Pette Inst, Hamburg, Germany. RP Bennink, JR (reprint author), NIAID, Viral Dis Lab, NIH, Bldg 4,Room 211,4 Ctr Dr, Bethesda, MD 20892 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 17 TC 143 Z9 161 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2003 VL 77 IS 13 BP 7214 EP 7224 DI 10.1128/JVI.77.13.7214-7224.2003 PG 11 WC Virology SC Virology GA 691GX UT WOS:000183598600007 PM 12805420 ER PT J AU Hermankova, M Siliciano, JD Zhou, Y Monie, D Chadwick, K Margolick, JB Quinn, TC Siliciano, RF AF Hermankova, M Siliciano, JD Zhou, Y Monie, D Chadwick, K Margolick, JB Quinn, TC Siliciano, RF TI Analysis of human immunodeficiency virus type 1 gene expression in latently infected resting CD4(+) T lymphocytes in vivo SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; LONG TERMINAL REPEAT; BLOOD MONONUCLEAR-CELLS; TUMOR NECROSIS FACTOR; REV TRANS-ACTIVATOR; HIV-1 INFECTION; TRANSACTIVATOR GENE; HTLV-III; TAT GENE; REPLICATION AB In individuals with human immunodeficiency virus type 1 (HIV-1) infection, a small reservoir of resting memory CD4(+) T lymphocytes carrying latent, integrated provirus persists even in patients treated for prolonged periods with highly active antiretroviral therapy (HAART). This reservoir greatly complicates the prospects for eradicating HIV-1 infection with antiretroviral drugs. Therefore, it is critical to understand how HIV-1 latency is established and maintained. In particular, it is important to determine whether transcriptional or posttranscriptional mechanisms are involved. Therefore, HIV-1 DNA and mRNAs were measured in highly purified populations of resting CD4(+) T lymphocytes from the peripheral blood of patients on long-term HAART. In such patients, the predominant form of persistent HIV-1 is latent integrated provirus. Typically, 100 HIV-1 DNA molecules were detected per 10(6) resting CD4(+) T cells. Only very low levels of unspliced HIV-1 RNA (similar to50 copies/10(6) resting CD4(+) T cells) were detected using a reverse transcriptase PCR assay capable of detecting a single molecule of RNA standard. Levels of multiply spliced HIV-1 RNA were below the limit of detection (<50 copies/10(6) Cells). Only 1% of the HIV-1 DNA-positive lymphocytes in this compartment could be induced to up-regulate HIV-1 mRNAs after cellular activation, indicating that most of the proviral DNA in resting CD4(+) T cells either carries intrinsic defects precluding transcription or is subjected to transcriptional control mechanisms that preclude high-level production of multiply spliced mRNAs. Nevertheless, by inducing T-cell activation, it is possible to isolate replication-competent virus from resting CD4(+) T lymphocytes of all infected individuals, including those on prolonged HAART. Thus, a subset of integrated proviruses (1%) remains competent for high-level mRNA production after cellular activation, and a subset of these can produce infectious virus. Measurements of steady-state levels of multiply spliced and unspliced HIV-1 RNA prior to cellular activation suggest that infected resting CD4(+) T lymphocytes in blood synthesize very little viral RNA and are unlikely to be capable of producing virus. In these cells, latency appears to reflect regulation at the level of mRNA production rather than at the level of splicing or nuclear export of viral mRNAs. C1 Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Siliciano, RF (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. FU NIAID NIH HHS [AI43222, R01 AI051178, AI51178, R01 AI043222, R37 AI051178] NR 58 TC 105 Z9 108 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2003 VL 77 IS 13 BP 7383 EP 7392 DI 10.1128/JVI.77.13.7383-7392.2003 PG 10 WC Virology SC Virology GA 691GX UT WOS:000183598600024 PM 12805437 ER PT J AU Post, K Guo, JH Howard, KJ Powell, MD Miller, JT Hizi, A Le Grice, SFJ Levin, JG AF Post, K Guo, JH Howard, KJ Powell, MD Miller, JT Hizi, A Le Grice, SFJ Levin, JG TI Human immunodeficiency virus type 2 reverse transcriptase activity in model systems that mimic steps in reverse transcription SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-1 NUCLEOCAPSID PROTEIN; POLYPURINE TRACT PRIMER; RIBONUCLEASE-H ACTIVITY; ZINC-FINGER STRUCTURES; PLUS-STRAND TRANSFER; STRONG-STOP DNA; RNASE-H; NONNUCLEOSIDE INHIBITORS; MINUS-STRAND; ESCHERICHIA-COLI AB Human immunodeficiency virus type 2 (HIV-2) infection is a serious problem in West Africa and Asia. However, there have been relatively few studies of HIV-2 reverse transcriptase (RT), a potential target for antiviral therapy. Detailed knowledge of HIV-2 RT activities is critical for development of specific high-throughput screening assays of potential inhibitors. Here, we have conducted a systematic evaluation of HIV-2 RT function, using assays that model specific steps in reverse transcription. Parallel studies were performed with HIV-1 RT. In general, under standard assay conditions, the polymerase and RNase H activities of the two enzymes were comparable. However, when the RT concentration was significantly reduced, HIV-2 RT was less active than the HIV-1 enzyme. HIV-2 RT was also impaired in its ability to catalyze secondary RNase H cleavage in assays that mimic tRNA primer removal during plus-strand transfer and degradation of genomic RNA fragments during minus-strand DNA synthesis. In addition, initiation of plus-strand DNA synthesis was much less efficient with HIV-2 RT than with HIV-1 RT. This may reflect architectural differences in the primer grip regions in the p66 (HIV-1) and p68 (HIV-2) palm subdomains of the two enzymes. The implications of our findings for antiviral therapy are discussed. C1 NICHHD, Mol Genet Lab, Bethesda, MD 20892 USA. Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA. Morehouse Sch Med, Dept Microbiol Biochem & Immunol, Atlanta, GA 30310 USA. NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Dept Cell Biol & Histol, IL-69978 Tel Aviv, Israel. RP Levin, JG (reprint author), NICHD, Mol Genet Lab, NIH, Bldg 6B,Room 216, Bethesda, MD 20892 USA. NR 74 TC 12 Z9 12 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2003 VL 77 IS 13 BP 7623 EP 7634 DI 10.1128/JVI.77.13.7623-7634.2003 PG 12 WC Virology SC Virology GA 691GX UT WOS:000183598600049 PM 12805462 ER PT J AU Permar, SR Moss, WJ Ryon, JJ Douek, DC Monze, M Griffin, DE AF Permar, SR Moss, WJ Ryon, JJ Douek, DC Monze, M Griffin, DE TI Increased thymic output during acute measles virus infection SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL HOMEOSTASIS; SCID-HU MOUSE; LYMPHOID-TISSUES; ANTIRETROVIRAL THERAPY; EXCISION CIRCLES; IMMUNE-RESPONSES; EPITHELIAL-CELLS; IN-VIVO; LYMPHOCYTES AB Measles virus infects thymic epithelia, induces a transient lymphopenia, and impairs cell-mediated immunity, but thymic function during measles has not been well characterized. Thirty Zambian children hospitalized with measles were studied at entry, hospital discharge, and at 1-month follow-up and compared to 17 healthy children. During hospitalization, percentages of naive (CD62L(+), CD45RA(+)) CD4(+) and CD8(+) T lymphocytes decreased (P = 0.01 for both), and activated (HLA-DR+, CD25(+), or CD69(+)) CD4(+) and CD8(+) T lymphocytes increased (P = 0.02 and 0.03, respectively). T-cell receptor rearrangement excision circles (TRECs) in measles patients were increased in CD8(+) T cells at entry compared to levels at hospital discharge (P = 0.02) and follow-up (P = 0.04). In CD4(+) T cells, the increase in TRECS occurred later but was more sustained. At discharge, TRECs in CD4(+) T cells (P = 0.05) and circulating levels of interleukin-7 (P = 0.007) were increased compared to control values and remained elevated for 1 month, similar to observations in two measles virus-infected rhesus monkeys. These findings suggest that a decrease in thymic output is not the cause of the lymphopenia and depressed cellular immunity associated with measles. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21205 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Teaching Hosp, Virol Lab, Lusaka, Zambia. RP Griffin, DE (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, 615 N Wolfe St, Baltimore, MD 21205 USA. FU NIAID NIH HHS [R01 AI023047, AI 23047] NR 48 TC 23 Z9 26 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2003 VL 77 IS 14 BP 7872 EP 7879 DI 10.1128/JVI.77.14.7872-7879.2003 PG 8 WC Virology SC Virology GA 696QX UT WOS:000183899200019 PM 12829827 ER PT J AU Liu, SL Lerman, MI Miller, AD AF Liu, SL Lerman, MI Miller, AD TI Putative phosphatidylinositol 3-kinase (PI3K) binding motifs in ovine betaretrovirus Env proteins are not essential for rodent fibroblast transformation and PI3K/Akt activation SO JOURNAL OF VIROLOGY LA English DT Article ID JAAGSIEKTE SHEEP RETROVIRUS; ENZOOTIC NASAL TUMOR; RECEPTOR TYROSINE KINASE; APE LEUKEMIA-VIRUS; ONCOGENIC TRANSFORMATION; PULMONARY ADENOMATOSIS; NUCLEOTIDE-SEQUENCE; MAMMALIAN-CELLS; LUNG-CANCER; GENE AB Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV) are simple betaretroviruses that cause epithelial cell tumors in the lower and upper airways of sheep and goats. The envelope (Env) glycoproteins of both viruses can transform rodent and chicken fibroblasts, indicating that they play an essential role in oncogenesis. Previous studies found that a YXXM motif in the Env cytoplasmic tail, a putative docking site for phosphatidylinositol 3-kinase (PI3K) after tyrosine phosphorylation, was necessary for rodent cell transformation but was not required for transformation of DF-1 chicken fibroblasts. Here we show that JSRV and ENTV Env proteins with tyrosine or methionine mutations in the YXXM motif can still transform rodent fibroblasts, albeit with reduced efficiency. Akt was activated in cells transformed by JSRV or ENTV Env proteins and in cells transformed by the proteins with tyrosine mutations. Furthermore, the PI3K-specific inhibitor LY294002 could inhibit Akt activation and cell transformation in all cases, indicating that Akt activation and transformation is PI3K dependent. However, we could not detect tyrosine phosphorylation of JSRV or ENTV Env proteins or an interaction between the Env proteins and PI3K in the transformed cells. We found no evidence for mitogen-activated protein kinase activation in cells that were transformed by the JSRV or ENTV Env proteins. We conclude that ovine betaretrovirus Env proteins transform the rodent fibroblasts by indirectly activating the PI3K/Akt pathway. C1 Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. Univ Washington, Dept Pathol, Seattle, WA 98195 USA. NCI, Canc Res Ctr, Immunobiol Lab, Frederick, MD 21702 USA. RP Miller, AD (reprint author), Fred Hutchinson Canc Res Ctr, Div Human Biol, 1100 Fairview Ave N,Room C2-105, Seattle, WA 98109 USA. RI Liu, Shan-Lu/L-5923-2016; OI Liu, Shan-Lu/0000-0003-1620-3817; Miller, Dusty/0000-0002-3736-3660 FU NCI NIH HHS [CO 65000, T32 CA 09437, T32 CA009437]; NHLBI NIH HHS [HL 66947, HL 54881, P50 HL054881, U01 HL066947]; NIDDK NIH HHS [DK 47754, P30 DK047754] NR 41 TC 51 Z9 58 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2003 VL 77 IS 14 BP 7924 EP 7935 DI 10.1128/JVI.77.14.7924-7935.2003 PG 12 WC Virology SC Virology GA 696QX UT WOS:000183899200024 PM 12829832 ER PT J AU Bouma, P Leavitt, M Zhang, PF Sidorov, IA Dimitrov, DS Quinnan, GV AF Bouma, P Leavitt, M Zhang, PF Sidorov, IA Dimitrov, DS Quinnan, GV TI Multiple interactions across the surface of the gp120 core structure determine the global neutralization resistance phenotype of human immunodeficiency virus type 1 SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODY; CD4 BINDING-SITE; HIV TYPE-1; ENVELOPE GLYCOPROTEIN; POINT MUTATION; SOLUBLE CD4; RECEPTOR-BINDING; HIGH INFECTIVITY; FAB FRAGMENTS; V3 REGION AB Resistance to neutralization is an important characteristic of primary isolates of human immunodeficiency virus type 1 (HIV-1) that relates to the potential for successful vaccination to prevent infection and use of immunotherapeutics for treatment of established infection. In order to further elucidate mechanisms responsible for neutralization resistance, we studied the molecular mechanisms that determine the resistance of the primary virus isolate of the strain HIV-1 MN to neutralization by soluble CD4 (sCD4). As is the case for the global neutralization resistance phenotype, sCD4 resistance depended upon sequences in the amino-terminal heptad repeat region of gp41 (HR1), as well as on multiple functional interactions within the envelope complex. The functional interactions that determined the resistance included interactions between the variable loop 1 and 2 (V1/V2) region and sequences in or near the CD4 binding site (CD4bs) and with the V3 loop. Additionally, the V3 loop region was found to interact functionally with sequences in the outer domain of gp120, distant from the CD4bs and coreceptor-binding site, as well as with a residue thought to be located centrally in the coreceptor-binding site. These and previous results provide the basis for a model by which functional signals that determine the neutralization resistance, high-infectivity phenotype depend upon interactions occurring across the surface of the gp120 core structure and involving variable loop structures and gp41. This model should be useful in efforts to define epitopes that may be important for primary virus neutralization. C1 Uniformed Serv Univ Hlth Sci, PMB, Dept Prevent Med & Biometr, Div Trop Publ Hlth, Bethesda, MD 20814 USA. NCI, Lab Expt & Computat Biol, NIH, Frederick, MD 21701 USA. RP Quinnan, GV (reprint author), Uniformed Serv Univ Hlth Sci, PMB, Dept Prevent Med & Biometr, Div Trop Publ Hlth, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. OI Sidorov, Igor/0000-0001-6519-4983 FU NIAID NIH HHS [AI 37438, AI 48280, P01 AI048280, R01 AI037438, R21 AI037438] NR 50 TC 18 Z9 21 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2003 VL 77 IS 14 BP 8061 EP 8071 DI 10.1128/JVI.77.14.8061-8071.2003 PG 11 WC Virology SC Virology GA 696QX UT WOS:000183899200037 PM 12829845 ER PT J AU Whitby, D Stossel, A Gamache, C Papin, J Bosch, M Smith, A Kedes, DH White, G Kennedy, R Dittmer, DP AF Whitby, D Stossel, A Gamache, C Papin, J Bosch, M Smith, A Kedes, DH White, G Kennedy, R Dittmer, DP TI Novel Kaposi's sarcoma-associated herpesvirus homolog in baboons SO JOURNAL OF VIROLOGY LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; TIME QUANTITATIVE PCR; EPSTEIN-BARR-VIRUS; OLD-WORLD PRIMATES; MOTHER-TO-CHILD; B-CELL; CYNOMOLGUS MONKEYS; HUMAN-HERPESVIRUS-8 INFECTION; RETROPERITONEAL FIBROMATOSIS; MACAQUE RHADINOVIRUS AB Kaposi's sarcoma (KS) and lymphoproliferative diseases induced by KS-associated herpesvirus (KSHV/ human herpesvirus 8) cause substantial morbidity and mortality in human immunodeficiency virus-infected individuals. To understand KSHV biology it is useful to investigate closely related rhadinoviruses naturally occurring in nonhuman primates. Here we report evidence for a novel KSHV homolog in captive baboon species (Papio anubis and other). Using degenerate PCR we identified a novel rhadinovirus, PapRV2, that has substantial sequence identity to two essential KSHV genes, the viral polymerase and thymidylate synthase. A subset of animals exhibited detectable PapRV2 viral load in peripheral blood mononuclear cells. Extensive serological analysis of nearly 200 animals in the colony demonstrated that the majority carried cross-reacting antibodies that recognize KSHV or macaque rhadinovirus antigens. Seroreactivity increased with age, similar to the age-specific prevalence of KSHV in the human population. This establishes baboons as a novel resource to investigate rhadinovirus biology, which can be developed into an animal model system for KSHV-associated human diseases, vaccine development, and therapy evaluation. C1 Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. Univ Oklahoma, Hlth Sci Ctr, Dept Lab Anim Sci, Oklahoma City, OK 73104 USA. NCI, SAIC Frederick, AIDS Vaccine Program, Viral Epidemiol Sect, Frederick, MD 21702 USA. NW Hosp, Seattle, WA USA. Univ Virginia, Dept Microbiol, Charlottesville, VA 22908 USA. Univ Virginia, Dept Internal Med, Charlottesville, VA 22908 USA. Texas Tech, Dept Microbiol & Immunol, Lubbock, TX USA. RP Dittmer, DP (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, 940 Stanton L Young Blvd, Oklahoma City, OK 73104 USA. FU NCI NIH HHS [N01 CO 12400, R21 CA097951, N01CO12400, CA 97951]; NCRR NIH HHS [RR 12317-04, P40 RR012317, RR 1555777]; NIAID NIH HHS [T32 AI007364, AI 07364]; NIBIB NIH HHS [EB 53309] NR 58 TC 20 Z9 22 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2003 VL 77 IS 14 BP 8159 EP 8165 DI 10.1128/JVI.77.14.8159-8165.2003 PG 7 WC Virology SC Virology GA 696QX UT WOS:000183899200047 PM 12829855 ER PT J AU Harris, TB AF Harris, TB TI Commentary - Aging well and aging poorly: Primary and secondary low blood pressure SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Editorial Material ID HYPERTENSION; OLD C1 NIA, Geriatr Epidemiol Sect, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. RP Harris, TB (reprint author), NIA, Geriatr Epidemiol Sect, Lab Epidemiol Demog & Biometry, Intramural Res Program, 7201 Wisconsin Ave,3C-309, Bethesda, MD 20892 USA. NR 7 TC 4 Z9 4 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2003 VL 58 IS 7 BP 662 EP 664 PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 702RH UT WOS:000184236700016 PM 12865487 ER PT J AU Jo, SK Hu, XZ Kobayashi, H Lizak, M Miyaji, T Koretsky, A Star, RA AF Jo, SK Hu, XZ Kobayashi, H Lizak, M Miyaji, T Koretsky, A Star, RA TI Detection of inflammation following renal ischemia by magnetic resonance imaging SO KIDNEY INTERNATIONAL LA English DT Article DE renal ischemia; inflammation; magnetic resonance imaging; contrast agent; USPIO particles; macrophages ID SUPERPARAMAGNETIC IRON-OXIDE; REPERFUSION INJURY; CONTRAST-AGENT; RAT-KIDNEY; CELL BIOLOGY; FAILURE; PARTICLES; PROTECTS; MRI; INTERLEUKIN-10 AB Background. Determining the disease culprits in human acute renal failure (ARF) has been difficult because of the paucity of renal biopsies and the lack of noninvasive methods to determine the location or cause of renal injury. Recently, ultrasmall superparamagnetic iron oxide (USPIO) particles have been used to detect inflammation in animal models. Therefore, we tested if USPIO enhanced magnetic resonance imaging (MRI) could detect inflammation in ischemic ARF in rats. Methods. Rats were subjected to 40 or 60 minutes of bilateral ischemia or injected with mercuric chloride. MR images were obtained before and 24 hours after USPIO injection, and the signal intensity decrease in the outer medulla was measured. Cells containing iron particles were identified by iron staining and transmission electron microscopy (TEM). Leukocytes were identified by ED-1 and chloracetate esterase staining. Results. Injection of USPIO particles caused a black band to appear in the outer medulla at 48, 72, and 120 hours after ischemia. This band was not detected in normal animals, 24 hours after ischemia, or 48 hours after mercuric chloride injection. The signal intensity change in the outer medulla correlated with serum creatinine and the number of iron particle containing cells. Most infiltrating cells were macrophages, and iron particles were present inside lysosomes of macrophages. USPIO injection did not alter renal function in normal or ischemic animals. Conclusion. USPIO-enhanced MRI could detect inflammation noninvasively from 48 hours after 40 or 60 minutes of renal ischemia in rats. This method might be useful to understand the pathogenesis of human ARF and to evaluate the effectiveness of anti-inflammatory agents. C1 NIDDKD, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NINDS, NIH, MRI Res Facil, Bethesda, MD 20892 USA. NINDS, NIH, Mouse Imaging Facil, Bethesda, MD 20892 USA. RP Star, RA (reprint author), NIDDKD, Renal Diagnost & Therapeut Unit, NIH, Bldg 10,Room 3N108,10 Ctr Dr,MSC 1268, Bethesda, MD 20892 USA. EM Robert_Star@nih.gov RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS003047-01] NR 46 TC 38 Z9 39 U1 0 U2 4 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUL PY 2003 VL 64 IS 1 BP 43 EP 51 DI 10.1046/j.1523-1755.2003.00048.x PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 690KH UT WOS:000183547500007 PM 12787394 ER PT J AU Stiles, KP Moffatt, MJ Agodoa, LY Swanson, SJ Abbott, KC AF Stiles, KP Moffatt, MJ Agodoa, LY Swanson, SJ Abbott, KC TI Renal cell carcinoma as a cause of end-stage renal disease in the United States: Patient characteristics and survival SO KIDNEY INTERNATIONAL LA English DT Article DE renal cell carcinoma; nephrectomy; Caucasian; male; transplantation; complications; dialysis; USRDS; age ID POLYCYSTIC KIDNEY-DISEASE; RADICAL NEPHRECTOMY; PROGNOSTIC-SIGNIFICANCE; BILATERAL-NEPHRECTOMY; TRANSPLANTATION; DIALYSIS; CANCER; ERYTHROPOIETIN; GRADE; PREDICTION AB Background. The patient characteristics and mortality associated with renal cell carcinoma (RCC) as a cause of end-stage renal disease (ESRD) have not been characterized for a national population. Methods. An historical cohort study of renal cell carcinoma (RCC) was conducted from April 1, 1995, to December 31, 1999. Included were 360,651 patients in the United States Renal Data System (USRDS) who were initiated on ESRD therapy with valid causes of ESRD. Results. Of the study population, 1646 patients (0.5%) had RCC. The mean age of patients with RCC was 66.8 +/- 14.6 years versus 61.3 +/- 16.4 years for patients with other causes of ESRD (P < 0.01 by Student t test). The unadjusted 3-year survival (censored at the date of renal transplantation) of patients with RCC during the study period was 23% versus 36% in all other patients [adjusted hazard ratio (AHR), 1.10, 95% confidence interval (CI) 1.02-1.19, P = 0.019 by Cox regression]. However, patients with RCC who underwent nephrectomy (bilateral or unilateral) had significantly better survival compared to RCC patients who did not (AHR, 0.73, 95% Cl, 0.63-0.85, P < 0.01), and their survival was not significantly different in comparison with nondiabetic ESRD patients. Bilateral nephrectomy (vs. unilateral) was not associated with any difference in adjusted mortality. Conclusion. Among patients with ESRD, the demographics of those with RCC were similar to those of patients with RCC in the general population. Overall, patients with RCC had decreased survival compared to patients with other causes of ESRD; those who underwent nephrectomy had significantly better survival than those who did not, with survival comparable to patients with nondiabetic ESRD. C1 Madigan Army Med Ctr, Serv Nephrol, Ft Lewis, WA USA. Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. NIDDK, Bethesda, MD USA. NIH, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Organ Transplant Serv, Washington, DC USA. RP Abbott, KC (reprint author), Walter Reed Army Med Ctr, MC Nephrol Serv, Washington, DC 20307 USA. OI Abbott, Kevin/0000-0003-2111-7112 NR 44 TC 12 Z9 14 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUL PY 2003 VL 64 IS 1 BP 247 EP 253 DI 10.1046/j.1523-1755.2003.00060.x PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 690KH UT WOS:000183547500029 PM 12787416 ER PT J AU Brindle, TJ Mattacola, C McCrory, J AF Brindle, TJ Mattacola, C McCrory, J TI Electromyographic changes in the gluteus medius during stair ascent and descent in subjects with anterior knee pain SO KNEE SURGERY SPORTS TRAUMATOLOGY ARTHROSCOPY LA English DT Article DE kinetic chain; electromyography; temporal patterns; patellofemoral pain; kinematics ID VASTUS MEDIALIS OBLIQUE; LATERALIS MUSCLE-ACTIVITY; PATELLOFEMORAL PAIN; PATELLAR KINEMATICS; ONSET; AMBULATION; KINETICS; POSITION; INJURY; GAIT AB Ascending and descending stairs is a provocative activity for anterior knee pain (AKP) patients. The gluteus medius (GM) acts on the lower extremity in the frontal plane and can affect forces at the knee. Determining activation patterns of the GM in patients with AKP can help identify efficacy of training the GM in this population. This study examined electromyographic (EMG) firing patterns in lower extremity muscles in subjects with AKP while ascending and descending stairs. Subjects in the AKP group (n=16) demonstrated general AKP for at least 2 months compared to the control group (n=12); neither group had any history of knee trauma. Subjects were instrumented with EMG electrodes on the vastus medialis oblique (VMO), vastus lateralis (VL), and GM. Retroreflective markers were placed on lower extremities to determine knee flexion angle, and frontal plane pelvis orientation at toe contact. Subjects then performed a series of five stair (height=18 cm) ascent and descent trials. Repeated measures analyses of variance were performed on EMG and kinematic variables, between the two groups and between the symptomatic and asymptomatic sides. In the AKP group the GM demonstrated delayed onset and shorter durations for stair ascent and shorter duration during descent. There were no significant differences between sides in the AKP group. Consistent with previous studies, subjects in the AKP group demonstrated no difference in the VMO onsets relative to VL onsets compared to the control group. Changes in neuromuscular activity patterns may be a result of a compensations strategy due to AKP. Training of GM and other hip muscles is warranted during rehabilitation of AKP patients. C1 NICHHD, Phys Disabil Branch, Dept Rehabil Med, Warren Grant Magnuson Clin Ctr,NIH, Bethesda, MD 20892 USA. Univ Kentucky, Div Athlet Training, Lexington, KY 40506 USA. Univ Pittsburgh, Neuromuscular Res Lab, Pittsburgh, PA USA. RP Brindle, TJ (reprint author), NICHHD, Phys Disabil Branch, Dept Rehabil Med, Warren Grant Magnuson Clin Ctr,NIH, Bethesda, MD 20892 USA. NR 28 TC 85 Z9 86 U1 1 U2 11 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0942-2056 J9 KNEE SURG SPORT TR A JI Knee Surg. Sports Traumatol. Arthrosc. PD JUL PY 2003 VL 11 IS 4 BP 244 EP 251 DI 10.1007/s00167-003-0353-z PG 8 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA 713JQ UT WOS:000184854700008 PM 12695878 ER PT J AU Herring, JM Lyons, HA Ahalt, MM Bullock, JA AF Herring, JM Lyons, HA Ahalt, MM Bullock, JA TI Wire mesh reasoning SO LAB ANIMAL LA English DT Editorial Material C1 NCI, LAM, Frederick, MD 21701 USA. RP Herring, JM (reprint author), NCI, LAM, Frederick, MD 21701 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD JUL-AUG PY 2003 VL 32 IS 7 BP 18 EP 19 DI 10.1038/laban0803-18b PG 2 WC Veterinary Sciences SC Veterinary Sciences GA 697RC UT WOS:000183956200005 PM 19877305 ER PT J AU Valent, P Akin, C Sperr, WR Escribano, L Arock, M Horny, HP Bennett, JM Metcalfe, DD AF Valent, P Akin, C Sperr, WR Escribano, L Arock, M Horny, HP Bennett, JM Metcalfe, DD TI Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria SO LEUKEMIA RESEARCH LA English DT Article DE aggressive systematic mastocytosis; classification; therapy; interferon-alpha; response criteria ID C-KIT; INTERFERON-ALPHA; SMOLDERING MASTOCYTOSIS; HEMATOLOGIC DISORDER; ACTIVATING MUTATION; CATALYTIC DOMAIN; DISEASE; BLOOD; CLASSIFICATION; LEUKEMIA AB Aggressive systemic mastocytosis (ASM) is a clonal mast cell disease characterized by progressive growth of neoplastic cells in diverse organs leading to organopathy. The organ-systems most frequently affected are the bone marrow, skeletal system, liver, spleen, and the gastrointestinal tract. Respective clinical findings (so called C-Findings) include cytopenias, osteolysis (or osteoporosis) with pathologic fractures, hepatosplenomegaly with impaired liver function and ascites, and malabsorption. During the past decade several treatment strategies for ASM have been proposed. One promising approach may be combination treatment with interferon-alpha (IFN-alpha) and glucocorticoids. This concept has been based on the notion that systemic mastocytosis involves multilineage hematopoietic progenitors indicating a relationship with myeloproliferative disorders. However, relatively little is known about the quality of responses to IFN-alpha in ASM and the actual response rates. This may be due in part to the fact that disease criteria for ASM have only recently been established, and no response criteria are available. In the current article, we propose surrogate markers and treatment response criteria for patients with ASM. In addition, we have applied these criteria retrospectively to ASM patients described in the available literature. In these analyses, the calculated rate of major response (= complete resolution of C-Findings) in patients treated with IFN-alpha (with or without additional glucocorticoids) amounts to approximately 21%. This confirms clinical activity in some patients for this drug-combination, but also points to the need to search for more effective strategies in the treatment of patients with aggressive mast cell disorders. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Univ Vienna, Div Hematol & Hemostaseol, Dept Internal Med 1, A-1090 Vienna, Austria. NIAID, Lab Allerg Dis, NIH, Bethesda, MD USA. Hosp Ramon y Cajal, Unidad Mastocitosis, Serv Hematol, E-28034 Madrid, Spain. Fac Pharm, Lab Hematol Cellulaire & Mol, Paris, France. Med Univ Lubeck, Inst Pathol, Lubeck, Germany. Univ Rochester, Ctr Med, Ctr Canc, Rochester, NY USA. RP Valent, P (reprint author), Univ Vienna, Div Hematol & Hemostaseol, Dept Internal Med 1, Waehringer Guertel 18-20, A-1090 Vienna, Austria. OI Akin, Cem/0000-0001-6301-4520 NR 51 TC 127 Z9 129 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD JUL PY 2003 VL 27 IS 7 BP 635 EP 641 DI 10.1016/S0145-2126(02)00168-6 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 685DE UT WOS:000183244900010 PM 12681363 ER PT J AU Marcus, PM AF Marcus, PM TI Conflicting evidence in lung cancer screening: randomized controlled trials versus case-control studies SO LUNG CANCER LA English DT Editorial Material ID PREFECTURE; JAPAN; BIAS; EFFICACY C1 NCI, US Dept HHS, NIH, Bethesda, MD 20892 USA. RP Marcus, PM (reprint author), NCI, US Dept HHS, NIH, 9000 Wisconsin Ave, Bethesda, MD 20892 USA. NR 22 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0169-5002 J9 LUNG CANCER-J IASLC JI Lung Cancer PD JUL PY 2003 VL 41 IS 1 BP 37 EP 39 DI 10.1016/S0169-5002(03)00200-9 PG 3 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 699NY UT WOS:000184063900005 PM 12826310 ER PT J AU Hautaniemi, S Yli-Harja, O Astola, J Kauraniemi, P Kallioniemi, A Wolf, M Ruiz, J Mousses, S Kallioniemi, OP AF Hautaniemi, S Yli-Harja, O Astola, J Kauraniemi, P Kallioniemi, A Wolf, M Ruiz, J Mousses, S Kallioniemi, OP TI Analysis and visualization of gene expression microarray data in human cancer using self-organizing maps SO MACHINE LEARNING LA English DT Article DE bioinformatics; gene expression in human cancer; self-organizing map ID BREAST-CANCER; CLUSTERING METHODS; CDNA MICROARRAYS; COPY-NUMBER; PATTERNS; AMPLICON AB cDNA microarrays permit massively parallel gene expression analysis and have spawned a new paradigm in the study of molecular biology. One of the significant challenges in this genomic revolution is to develop sophisticated approaches to facilitate the visualization, analysis, and interpretation of the vast amounts of multi-dimensional gene expression data. We have applied self-organizing map (SOM) in order to meet these challenges. In essence, we utilize U-matrix and component planes in microarray data visualization and introduce general procedure for assessing significance for a cluster detected from U-matrix. Our case studies consist of two data sets. First, we have analyzed a data set containing 13,824 genes in 14 breast cancer cell lines. In the second case we show an example of the SOM in drug treatment of prostate cancer cells. Our results indicate that ( 1) SOM is capable of helping finding certain biologically meaningful clusters, ( 2) clustering algorithms could be used for finding a set of potential predictor genes for classification purposes, and ( 3) comparison and visualization of the effects of different drugs is straightforward with the SOM. In summary, the SOM provides an excellent format for visualization and analysis of gene microarray data, and is likely to facilitate extraction of biologically and medically useful information. C1 Tampere Univ Technol, Inst Signal Proc, FIN-33101 Tampere, Finland. Tampere Univ, Canc Genet Lab, Inst Med Technol, FIN-33520 Tampere, Finland. Tampere Univ Hosp, FIN-33520 Tampere, Finland. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. VTT Tech Res Ctr Finland, Med Biotechnol Grp, Turku 20521, Finland. Univ Turku, Turku 20521, Finland. RP Hautaniemi, S (reprint author), Tampere Univ Technol, Inst Signal Proc, POB 553, FIN-33101 Tampere, Finland. RI Hautaniemi, Sampsa/A-3122-2009; Kallioniemi, Olli/H-5111-2011; Kallioniemi, Olli/H-4738-2012; Astola, Jaakko/G-4297-2014; OI Hautaniemi, Sampsa/0000-0002-7749-2694; Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Anne/0000-0003-3552-8158; Yli-Harja, Olli/0000-0001-8581-4414; Astola, Jaakko/0000-0002-2750-5311 NR 30 TC 27 Z9 28 U1 0 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0885-6125 J9 MACH LEARN JI Mach. Learn. PD JUL-AUG PY 2003 VL 52 IS 1-2 BP 45 EP 66 DI 10.1023/A:1023941307670 PG 22 WC Computer Science, Artificial Intelligence SC Computer Science GA 684HT UT WOS:000183199900004 ER PT J AU Datta, A Choudhary, A Bittner, ML Dougherty, ER AF Datta, A Choudhary, A Bittner, ML Dougherty, ER TI External control in Markovian Genetic Regulatory Networks SO MACHINE LEARNING LA English DT Article DE gene regulatory network; Markov chain; optimal control; dynamic programming ID PROBABILISTIC BOOLEAN NETWORKS; MELANOMA AB Probabilistic Boolean Networks (PBN's) have been recently introduced as a rule-based paradigm for modeling gene regulatory networks. Such networks, which form a subclass of Markovian Genetic Regulatory Networks, provide a convenient tool for studying interactions between different genes while allowing for uncertainty in the knowledge of these relationships. This paper deals with the issue of control in probabilistic Boolean networks. More precisely, given a general Markovian Genetic Regulatory Network whose state transition probabilities depend on an external ( control) variable, the paper develops a procedure by which one can choose the sequence of control actions that minimize a given performance index over a finite number of steps. The procedure is based on the theory of controlled Markov chains and makes use of the classical technique of Dynamic Programming. The choice of the finite horizon performance index is motivated by cancer treatment applications where one would ideally like to intervene only over a finite time horizon, then suspend treatment and observe the effects over some additional time before deciding if further intervention is necessary. The undiscounted finite horizon cost minimization problem considered here is the simplest one to formulate and solve, and is selected mainly for clarity of exposition, although more complicated costs could be used, provided appropriate technical conditions are satisfied. C1 Texas A&M Univ, Dept Elect Engn, College Stn, TX 77843 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. RP Datta, A (reprint author), Texas A&M Univ, Dept Elect Engn, College Stn, TX 77843 USA. NR 14 TC 154 Z9 155 U1 1 U2 14 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0885-6125 J9 MACH LEARN JI Mach. Learn. PD JUL-AUG PY 2003 VL 52 IS 1-2 BP 169 EP 191 DI 10.1023/A:1023909812213 PG 23 WC Computer Science, Artificial Intelligence SC Computer Science GA 684HT UT WOS:000183199900009 ER PT J AU Peters, DC Derbyshire, JA McVeigh, ER AF Peters, DC Derbyshire, JA McVeigh, ER TI Centering the projection reconstruction trajectory: Reducing gradient delay errors SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE projection reconstruction; radial imaging; gradient errors; gradient delay; compensation blips; reference scans; echo-planar imaging; magnitude back projection; linear phase ID ECHO; MRI AB The projection reconstruction (PR) trajectory was investigated for the effect of gradient timing delays between the actual and requested start time of each physical gradient. Radial trajectories constructed with delayed gradients miss the center of k-space in an angularly dependent manner, causing effective echo times to vary with projection angle. The gradient timing delays were measured in phantoms, revealing delays on the x, y, and z gradients which differed by as much as 5 musec. Using this one-time calibration measurement, the trajectories were corrected for gradient delays by addition of compensatory gradient areas to the prephasers of the logical x and y readout gradients. Effective projection-to-projection echo time variability was reduced to less than 1 musec for all imaging orientations. Using corrected trajectories, artifacts were reduced in phantom images and in volunteer studies. This correction should potentiate greater clinical use of the PR trajectory. Magn Reson Med 50:1-6, 2003. Published 2003 Wiley-Liss, lnc. C1 NHLBI, Cardiac Energet Lab, DHHS, NIH, Bethesda, MD 20892 USA. RP Peters, DC (reprint author), NHLBI, Cardiac Energet Lab, DHHS, NIH, 10 Ctr Dr,Bldg 10B1D416, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 HL004608-08] NR 10 TC 68 Z9 69 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUL PY 2003 VL 50 IS 1 BP 1 EP 6 DI 10.1002/mrm.10501 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 697UN UT WOS:000183961800001 PM 12815671 ER PT J AU Aoki, I Ebisu, T Tanaka, C Katsuta, K Fujikawa, A Umeda, M Fukunaga, M Takegami, T Shapiro, EM Naruse, S AF Aoki, I Ebisu, T Tanaka, C Katsuta, K Fujikawa, A Umeda, M Fukunaga, M Takegami, T Shapiro, EM Naruse, S TI Detection of the anoxic depolarization of focal ischemia using manganese-enhanced MRI SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE manganese enhanced MRI; anoxic depolarization; focal ischemia; penumbra ID DIFFUSION-WEIGHTED MRI; BLOOD-BRAIN-BARRIER; MAGNETIC-RESONANCE; CEREBRAL-ISCHEMIA; CA CHANNELS; STROKE; RAT; CALCIUM; TISSUE; CHLORIDE AB Mismatch between diffusion- and perfusion-weighted MRI was used to indicate a treatable area following focal ischemia, called the penumbra. Activity-induced manganese contrast MRI has been reported as a new visualization method for neural activation using manganese ions as a depolarization-dependent contrast agent. It is well known that energy failure induced by cerebral ischemia produces anoxic depolarization. The purpose of this study was to detect manganese accumulation caused by permanent middle cerebral artery occlusion (MCAO) of rat brain and to compare regional differences between manganese accumulation and decreased apparent diffusion coefficient (ADC). The ratios of signal intensity of manganese-enhanced MRI in the ipsilateral cortex to that in the contralateral cortex were 171.0 +/- 17.5% in MCAO group and 108.4 +/- 13.2% in the sham group. In addition, the enhanced region was much smaller than the area which was detected as having a reduced ADC. Magn Reson Med 50:7-12,2003. (C) 2003 Wiley-Liss, Inc. C1 Meiji Univ Oriental Med, Med MR Ctr, Dept Med Informat, Kyoto 6290392, Japan. Meiji Univ Oriental Med, Dept Neurosurg, Kyoto, Japan. Fujisawa Pharmaceut Co Ltd, Osaka 532, Japan. Kyoto Prefectural Univ Med, Dept Neurosurg, Kyoto 602, Japan. NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. Kyoto Prefectural Univ Med, Dept Radiol, Kyoto, Japan. RP Aoki, I (reprint author), Meiji Univ Oriental Med, Med MR Ctr, Dept Med Informat, Hiyoshi Cho, Kyoto 6290392, Japan. RI Aoki, Ichio/G-2529-2011; Fukunaga, Masaki/F-6441-2013 OI Aoki, Ichio/0000-0002-4429-5053; Fukunaga, Masaki/0000-0003-1010-2644 NR 30 TC 38 Z9 39 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUL PY 2003 VL 50 IS 1 BP 7 EP 12 DI 10.1002/mrm.10528 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 697UN UT WOS:000183961800002 PM 12815672 ER PT J AU St Lawrence, KS Ye, FQ Lewis, BK Frank, JA McLaughlin, AC AF St Lawrence, KS Ye, FQ Lewis, BK Frank, JA McLaughlin, AC TI Measuring the effects of indomethacin on changes in cerebral oxidative metabolism and cerebral blood flow during sensorimotor activation SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article ID FUNCTIONAL MRI; OXYGEN-CONSUMPTION; BOLD FMRI; VISUAL-STIMULATION; WORKING-MEMORY; HUMAN BRAIN; SIGNAL; SENSITIVITY; REDUCTION; CONTRAST AB The work presented here uses combined blood oxygenation level-dependent (BOLD) and arterial spin tagging (AST) approaches to study the effect of indomethacin on cerebral blood flow (CBF) and oxygen consumption (CMRO2) increases during motor activation. While indomethacin reduced the CBF increase during activation, it did not significantly affect the CMRO2 increase during activation. The ratio of the activation-induced CBF increase in the presence and absence of indomethacin was 0.54 +/- 0.08 (+/-SEM, n = 8, P < 0.001), while the ratio of the CMRO2 increase in the presence and absence of the drug was 1.02 +/- 0.08 (+/-SEM, N = 8, ns). Potential difficulties in estimating CMRO2 changes from combined BOLD/AST data are discussed. Magn Reson Med 50:99-106, 2003. Published 2003 Wiley-Liss, lnc. C1 Natl Inst Hlth, Ctr Clin, Lab Diagnost Radiol Res, Bethesda, MD USA. NIMH, DIRP, NIH, Bethesda, MD 20892 USA. NIAAA, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. RP St Lawrence, KS (reprint author), St Josephs Hlth Care London, Lawson Hlth Res Inst, 268 Grosvenor St, London, ON N6A 4V2, Canada. RI St. Lawrence, Keith/B-5726-2015 NR 40 TC 39 Z9 39 U1 0 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUL PY 2003 VL 50 IS 1 BP 99 EP 106 DI 10.1002/mrm.10502 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 697UN UT WOS:000183961800014 PM 12815684 ER PT J AU Sampath, S Derbyshire, JA Atalar, E Osman, NF Prince, JL AF Sampath, S Derbyshire, JA Atalar, E Osman, NF Prince, JL TI Real-time imaging of two-dimensional cardiac strain using a harmonic phase magnetic resonance imaging (HARP-MRI) pulse sequence SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE real-time imaging; magnetic resonance tagging; harmonic phase; cardiac motion; myocardial strain; FastHARP ID MOTION TRACKING; MYOCARDIAL MOTION; HUMAN-HEART; CONTRAST; IMAGES; ACQUISITION; DENSE AB The harmonic phase (HARP) method provides automatic and rapid analysis of tagged magnetic resonance (MR) images for quantification and visualization of myocardial strain. In this article, the development and implementation of a pulse sequence that acquires HARP images in real time are described. In this pulse sequence, a CINE sequence of images with 1-1 spatial modulation of magnetization (SPAMM) tags are acquired during each cardiac cycle, alternating between vertical and horizontal tags in successive heartbeats. An incrementing train of imaging RF flip angles is used to compensate for the decay of the harmonic peaks due to both T-1 relaxation and the applied imaging pulses. The magnitude images displaying coarse anatomy are automatically reconstructed and displayed in real time after each heartbeat. HARP strain images are generated off line at a rate of four images per second; real-time processing should be possible with faster algorithms or computers. A comparison of myocardial contractility in non-breath-hold and breath-hold experiments in normal humans is presented. (C) 2003 Wiley-Liss, Inc. C1 Johns Hopkins Univ, Dept Elect & Comp Engn, Image Anal & Commun Lab, Baltimore, MD 21218 USA. NHLBI, Cardiac Energet Lab, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Radiol, Baltimore, MD 21218 USA. RP Prince, JL (reprint author), Johns Hopkins Univ, Dept Elect & Comp Engn, Image Anal & Commun Lab, 307 Barton Hall, Baltimore, MD 21218 USA. EM prince@jhu.edu RI Prince, Jerry/A-3281-2010; Atalar, Ergin/D-3184-2012 OI Prince, Jerry/0000-0002-6553-0876; Atalar, Ergin/0000-0002-6874-6103 FU NHLBI NIH HHS [R01HL47405] NR 29 TC 44 Z9 44 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUL PY 2003 VL 50 IS 1 BP 154 EP 163 DI 10.1002/mrm.10509 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 697UN UT WOS:000183961800020 PM 12815690 ER PT J AU Bulte, JWM Ben-Hur, T Miller, BR Mizrachi-Kol, R Einstein, O Reinhartz, E Zywicke, HA Douglas, T Frank, JA AF Bulte, JWM Ben-Hur, T Miller, BR Mizrachi-Kol, R Einstein, O Reinhartz, E Zywicke, HA Douglas, T Frank, JA TI MR microscopy of magnetically labeled neurospheres transplanted into the Lewis EAE rat brain SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MR microscopy; transplantation; iron oxide MR contrast agent; neurospheres; experimental autoimmune encephalomyelitis ID EMBRYONIC STEM-CELLS; GLIAL-CELLS; OLIGODENDROCYTE PROGENITORS; SCHWANN-CELLS; SPINAL-CORD; IN-VIVO; PRECURSORS; MIGRATION; MYELIN; TRACKING AB Stem cell transplantation is being explored as a new paradigm for the treatment of demyelinating diseases. Magnetically labeled multipotential neural precursor cells were transplanted into the ventricles of rats with acute experimental allergic encephalomyelitis (EAE) and high-resolution (microscopic) MR images were obtained ex vivo. Migration patterns of live cells into periventricular white matter structures could be easily visualized, with a good correlation of the corresponding histopathology. The present results confirm that MR cell tracking can be used to guide the development of successful transplantation protocols. (C) 2003 Wiley-Liss, Inc. C1 Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD 21205 USA. NIH, Ctr Clin, Expt Neuroimaging Sect, Bethesda, MD USA. Hadassah Univ Hosp, Agnes Ginges Ctr Human Neurogenet, Dept Neurol, IL-91120 Jerusalem, Israel. Montana State Univ, Dept Chem & Biochem, Bozeman, MT 59717 USA. RP Bulte, JWM (reprint author), Johns Hopkins Univ, Sch Med, Dept Radiol, 217 Taylor Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. RI Bulte, Jeff/A-3240-2008; Douglas, Trevor/F-2748-2011; Miller, Bradley/G-7426-2014 OI Bulte, Jeff/0000-0003-1202-1610; FU NINDS NIH HHS [R01 NS45062] NR 20 TC 100 Z9 111 U1 0 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUL PY 2003 VL 50 IS 1 BP 201 EP 205 DI 10.1002/mrm.10511 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 697UN UT WOS:000183961800026 PM 12815696 ER PT J AU Aviv, A Levy, D Mangel, M AF Aviv, A Levy, D Mangel, M TI Growth, telomere dynamics and successful and unsuccessful human aging SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE telomeres; aging; growth; somatic cells; replication ID CORONARY HEART-DISEASE; HUMAN FIBROBLASTS; PULSE PRESSURE; SHORT-TERM; VASCULAR-DISEASE; GENE-EXPRESSION; ADIPOSE-TISSUE; HUMAN-CELLS; LENGTH; CANCER AB This paper links mass trajectories with telomere dynamics to construct theoretical models of successful and unsuccessful aging in human beings. It couples parameters of telomere length in somatic cells, as expressed by the terminal restriction fragment (TRF), at birth and the rate of telomere attrition thereafter with nonlinear models of somatic growth to predict the probability of surviving disease free, based on the assumption that telomere length in replicating somatic cells is a surrogate indicator of aging determinants in humans. The models capture aspects of individual variation in successful and unsuccessful aging and the long-term consequences of rapid growth early in life. (C) 2003 Elsevier Ireland Ltd. All rights reserved. C1 Univ Med & Dent New Jersey, New Jersey Med Sch, Cardiovasc Res Inst, Hypertens Res Ctr, Newark, NJ 07103 USA. NHLBI, Framingham, MA USA. Framingham Heart Dis Epidemiol Study, Framingham, MA USA. Univ Calif Santa Cruz, Jack Baskin Sch Engn, Dept Appl Math & Stat, Santa Cruz, CA 95064 USA. RP Aviv, A (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Cardiovasc Res Inst, Hypertens Res Ctr, 185 S Orange Ave,Room F-464, Newark, NJ 07103 USA. NR 66 TC 38 Z9 41 U1 2 U2 7 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD JUL PY 2003 VL 124 IS 7 BP 829 EP 837 DI 10.1016/S0047-6374(03)00143-X PG 9 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 708MR UT WOS:000184571800006 PM 12875746 ER PT J AU Coleman, CM Tuan, RS AF Coleman, CM Tuan, RS TI Functional role of growth/differentiation factor 5 in chondrogenesis of limb mesenchymal cells SO MECHANISMS OF DEVELOPMENT LA English DT Article DE growth/differentiation factor 5; chondrogenesis; cell condensation; limb development; gap junction ID GROWTH-FACTOR-BETA; GAP-JUNCTIONAL COMMUNICATION; BONE MORPHOGENETIC PROTEIN-2; N-CADHERIN EXPRESSION; CHICK LIMB; TGF-BETA; IN-VITRO; CARTILAGE DIFFERENTIATION; MOUSE LIMB; COLORIMETRIC ASSAY AB Growth/Differentiation Factor 5 (GDF5) plays an important role in limb mesenchymal cell condensation and chondrogenesis. Here we demonstrate, using high density cultures of chick embryonic limb mesenchyme, that GDF5 misexpression increased condensation of chondroprogenitor cells and enhanced chondrogenic differentiation. These effects were observed in the absence of altered cellular viability or biosynthetic activity, suggesting that GDF5 action might be directed at the level of cellular adhesion or cell-cell communication. GDF5-enhanced condensation occurred independent of cell density or N-cadherin mediated adhesion and signaling, but was inhibited upon interference of gap junction mediated communication. p38 MAP kinase signaling was required for the GDF5 effect on chondrocyte differentiation, but not for mesenchymal condensation. These findings suggest gap junction involvement in the action of GDF5 in developmental chondrogenesis. (C) 2003 Elsevier Ireland Ltd. All rights reserved. C1 Natl Inst Arthritis & Musculoskeletal & Skin Dis, Cartilage Biol & Orthopaed Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Dept Orthopaed Surg, Philadelphia, PA 19107 USA. RP Tuan, RS (reprint author), Natl Inst Arthritis & Musculoskeletal & Skin Dis, Cartilage Biol & Orthopaed Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. NR 66 TC 34 Z9 49 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD JUL PY 2003 VL 120 IS 7 BP 823 EP 836 DI 10.1016/S0925-4773(03)00067-4 PG 14 WC Developmental Biology SC Developmental Biology GA 716VH UT WOS:000185049900007 PM 12915232 ER PT J AU Dimitrakakis, C Zhou, J Wang, J Belanger, A LaBrie, F Cheng, C Powell, D Bondy, C AF Dimitrakakis, C Zhou, J Wang, J Belanger, A LaBrie, F Cheng, C Powell, D Bondy, C TI A physiologic role for testosterone in limiting estrogenic stimulation of the breast SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE breast cancer; estrogen; androgen; proliferation; estrogen receptor ID ANDROGEN RECEPTOR GENE; C-MYC; CANCER RISK; REPLACEMENT THERAPY; BETA EXPRESSION; CAG REPEAT; PROLIFERATION; GYNECOMASTIA; WOMEN; POLYMORPHISM AB Objective: The normal ovary produces abundant testosterone in addition to estradiol (E-2) and progesterone, but usually only the latter two hormones are "replaced" in the treatment of ovarian failure and menopause. Some clinical and genetic evidence suggests, however, that endogenous androgens normally inhibit estrogen-induced mammary epithelial proliferation (MEP) and thereby may protect against breast cancer. Design: To investigate the role of endogenous androgen in regulating mammary epithelial proliferation, nonnal-cycling rhesus monkeys were treated with flutamide, an androgen receptor antagonist. To evaluate the effect of physiological testosterone (T) supplementation of estrogen replacement therapy, ovariectomized monkeys were treated with E-2, E-2 plus progesterone, E-2 plus T, or vehicle. Results: We show that androgen receptor blockade in normal female monkeys results in a more than twofold increase in MEP, indicating that endogenous androgens normally inhibit MEP. Moreover, we show that addition of a small, physiological dose of T to standard estrogen therapy almost completely attenuates estrogen-induced increases in MEP in the ovariectomized monkey, suggesting that the increased breast cancer risk associated with estrogen treatment could be reduced by T supplementation. Testosterone reduces mammary epithelial estrogen receptor (ER) alpha and increases ERbeta expression, resulting in a marked reversal of the ERalpha/beta ratio found in the estrogen-treated monkey. Moreover, T treatment is associated with a significant reduction in mammary epithelial MYC expression, suggesting that T's antiestrogenic effects at the mammary gland involve alterations in ER signaling to MYC. Conclusions: These findings suggest that treatment with a balanced formulation including all ovarian hormones may prevent or reduce estrogenic cancer risk in the treatment of girls and women with ovarian failure. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Quebec, Ctr Hosp, Res Ctr, Quebec City, PQ, Canada. NIH, Vet Res Branch, Off Res Serv, Bethesda, MD 20892 USA. RP Bondy, C (reprint author), Bldg 10-10N262,10 Ctr Dr, Bethesda, MD 20892 USA. NR 39 TC 105 Z9 107 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD JUL-AUG PY 2003 VL 10 IS 4 BP 292 EP 298 DI 10.1097/01.GME.0000055522.67459.89 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 702WG UT WOS:000184247300006 PM 12851512 ER PT J AU Marmorstein, AD Peachey, NS Csaky, KG AF Marmorstein, AD Peachey, NS Csaky, KG TI In vivo gene transfer as a means to study the physiology and morphogenesis of the retinal pigment epithelium in the rat SO METHODS LA English DT Article DE adenovirus; retina; photoreceptor; retinal pigment epithelium; retinal degeneration; gene therapy; electroretinogram ID CHOROIDAL NEOVASCULARIZATION; ADENOASSOCIATED VIRUS; EXPRESSION; ADENOVIRUS; POLARITY; VECTOR; SUPPRESSION; MECHANISMS; MEMBRANE; THERAPY AB Our understanding of the morphogenesis of epithelial phenotypes has been greatly advanced by the use of in vitro cell culture systems. However, cell cultures often do not faithfully reconstitute many of the differentiated properties of the cell from which they are derived and cannot be used to examine complex physiologic interactions between adjacent tissues. This is particularly true of the retinal pigment epithelium (RPE). Many plasma membrane proteins, in vivo, exhibit a reversed polarity with respect to other epithelia, and RPE-derived cell lines seldom exhibit these same polarity properties. Furthermore, the interaction between the RPE cell and the neuorsensory retina, or the underlying blood supply, the choroid, is absent in cell culture. Most epithelia are difficult to isolate and study in vivo. The RPE is an exception to this. We have explored several aspects of RPE protein transport properties, vision-related physiology, and disease-related pathophysiology in the eye using in vivo gene transfer and electrophysiologic techniques. By injecting replication-defective adenoviruses into the subretinal space of rat eyes, we have been able to easily direct the expression of a test protein and follow its sorting and physiologic effects on RPE cells and adjacent tissues. Due to binding and internalization of adenoviral vectors to integrins found on the RPE apical plasma membrane, expression in a healthy eye is essentially confined to the RPE cell, even under control of a cytomegalovirus promotor. The use of varying amounts of adenoviral vector allows for determination of dose-responsive effects and the comparison of multiple mutants of a protein. In addition, there are substantial savings with respect to time and money in comparison to standard transgenic approaches. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Cleveland Clin Fdn, Cole Eye Inst, Dept Ophthalm Res, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Lerner Res Inst, Dept Cell Biol, Cleveland, OH 44195 USA. Vet Adm Med Ctr, Res Serv, Cleveland, OH 44106 USA. NEI, Bethesda, MD 20892 USA. RP Marmorstein, AD (reprint author), Cleveland Clin Fdn, Cole Eye Inst, Dept Ophthalm Res, I31,9500 Euclid Ave, Cleveland, OH 44195 USA. RI Peachey, Neal/G-5533-2010 FU NEI NIH HHS [EY13160] NR 32 TC 5 Z9 5 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 1046-2023 J9 METHODS JI Methods PD JUL PY 2003 VL 30 IS 3 BP 277 EP 285 DI 10.1016/S1046-2023(03)00034-3 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 690AZ UT WOS:000183526300011 PM 12798142 ER PT J AU Carroll, JA Stewart, PE Rosa, P Elias, AF Garon, CF AF Carroll, JA Stewart, PE Rosa, P Elias, AF Garon, CF TI An enhanced GFP reporter system to monitor gene expression in Borrelia burgdorferi SO MICROBIOLOGY-SGM LA English DT Article ID GREEN FLUORESCENT PROTEIN; LYME-DISEASE SPIROCHETE; IN-VITRO; DIFFERENTIAL EXPRESSION; MEMBRANE-PROTEIN; INFECTIVITY; PH; POPULATIONS; MUTAGENESIS; TEMPERATURE AB Borrelia burgdorferi regulates genes in response to a number of environmental signals such as temperature and pH. A green fluorescent protein (GFP) reporter system using the ospC, ospA and flaB promoters from B. burgdorferi B31 was introduced into infectious clonal isolates of strains B31 and N40 to monitor and compare gene expression in response to pH and temperature in vitro. GFP could be assayed by epifluorescence microscopy, immunoblotting or spectrofluorometry and was an accurate reporter of target gene expression. It was determined that only 179 bp 5' of ospC was sufficient to regulate the reporter gfp in vitro in response to pH and temperature in B. burgdorferi B31. The loss of linear plasmid (Ip) 25, Ip28-1, Ip36 and Ip56 had no effect on the ability of B. burgdorferi B31 to regulate ospC in response to pH or temperature. The amount of OspC in N40 transformants was unaffected by changes in pH or temperature of the culture medium. This suggests that regulation of gene expression in response to pH and temperature may vary between these two B. burgdorferi strains. C1 NIAID, Rocky Mt Labs, Rocky Mt Microscopy Branch, NIH, Hamilton, MT 59840 USA. NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. Charite Univ Klinikum, Inst Mikrobiol & Hyg, D-10117 Berlin, Germany. RP Carroll, JA (reprint author), Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, E1240 Biomed Sci Tower, Pittsburgh, PA 15261 USA. NR 36 TC 37 Z9 38 U1 0 U2 1 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 1350-0872 J9 MICROBIOL-SGM JI Microbiology-(UK) PD JUL PY 2003 VL 149 BP 1819 EP 1828 DI 10.1099/mic.0.26165-0 PN 7 PG 10 WC Microbiology SC Microbiology GA 702DA UT WOS:000184209000021 PM 12855733 ER PT J AU Salcedo, R Oppenheim, JJ AF Salcedo, R Oppenheim, JJ TI Role of chemokines in angiogenesis: CXCL12/SDF-1 and CXCR4 interaction, a key regulator of endothelial cell responses SO MICROCIRCULATION LA English DT Article DE angiogenic factors; chemokines; chemokine receptors; endothelial cells; stromal-cell derived factor-1/CXCL12 ID FIBROBLAST-GROWTH-FACTOR; HEMATOPOIETIC PROGENITOR CELLS; MESSENGER-RNA EXPRESSION; NECROSIS IN-VIVO; INTERFERON-GAMMA; MOLECULAR-MECHANISMS; CANCER METASTASIS; TUMOR PROGRESSION; RECEPTOR CXCR4; LUNG-CARCINOMA AB Chemokines are small proteins that act as cell attractants via the activation of G protein-coupled receptors. Chemokines play an important role in several pathophysiological processes such as inflammation and immunity. Many proinflammatory chemokines also support the development of vascular blood supply at the site of inflammation. Similarly, tumor-generated chemokines can contribute to tumor growth by promoting angiogenesis. Recently, significant advances have been made in understanding the contribution of chemokines to the angiogenesis process. This review will discuss first the evidence supporting the direct contribution of different chemokine subfamily members, including CC, CXC, and CX3C chemokines, as positive or negative regulators of the angiogenesis process based on the expression of their cognate receptors on endothelial cells. Additionally, the relationship between classic angiogenic factors and chemokine receptor expression on endothelial cells, and the implications of chemokine production by cancer cells will be analyzed with particular emphasis on the CXCL12/stromal-cell derived factor-1 interaction with CXCR4. C1 NCI, Mol Immunoregulat Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Oppenheim, JJ (reprint author), NCI, Mol Immunoregulat Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr, Bldg 560,Room 21-89A, Frederick, MD 21702 USA. NR 88 TC 181 Z9 191 U1 0 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1073-9688 J9 MICROCIRCULATION JI Microcirculation PD JUL PY 2003 VL 10 IS 3-4 BP 359 EP 370 DI 10.1038/sj.mn.7800200 PG 12 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 699QW UT WOS:000184068300012 PM 12851652 ER PT J AU Palacios, J Sarrio, D Garcia-Macias, MC Bryant, B Sobel, ME Merino, MJ AF Palacios, J Sarrio, D Garcia-Macias, MC Bryant, B Sobel, ME Merino, MJ TI Frequent E-cadherin gene inactivation by loss of heterozygosity in pleomorphic lobular carcinoma of the breast SO MODERN PATHOLOGY LA English DT Article DE E-cadherin; loss of heterozygosity; microdissection; pleomorphic lobular breast carcinoma ID IN-SITU; HUMAN CANCER; EXPRESSION; FEATURES; TUMORIGENESIS; MUTATIONS; LESIONS; REGIONS; COMPLEX; TUMORS AB Pleomorphic lobular carcinoma of the breast is a variant of infiltrating lobular carcinoma that has poor prognosis. The pleomorphic appearance of this variant hinders its correct identification and differentiation from ductal carcinoma. The analysis of E-cadherin glycoprotein expression is a powerful tool for distinguishing lobular from ductal carcinomas, because complete loss of E-cadherin expression occurs in most infiltrating lobular tumors and lobular carcinomas in situ but not in ductal tumors. In the present study, we have evaluated E-cadherin expression by immunohistochemistry in a series of 29 pleomorphic lobular breast carcinomas, including 7 cases with an in situ component. Complete loss of E-cadherin expression was observed in all the cases (29/29, 100%), invasive and in situ components. To understand better the mechanisms underlying E-cadherin inactivation in this tumor type, the frequency of loss of heterozygosity at the E-cadherin gene locus (16q22.1) was analyzed. All informative tumors (27/27, 100%) showed loss of heterozygosity, thus implying a strong association between loss of E-cadherin expression and loss of heterozygosity at 16q22.1. Moreover, loss of heterozygosity was detected in all in situ components analyzed. These results imply that in terms of E-cadherin inactivation, pleomorphic lobular tumors are identical to classic infiltrating lobular carcinomas and distinct from ductal tumors, and therefore they should be considered a variant of lobular carcinoma of the breast, despite their aggressive behavior. C1 Ctr Nacl Invest Oncol, Programa Patol Mol, Lab Breast & Gynecol Canc, Madrid 28029, Spain. Hosp Clin Univ, Serv Pathol, Salamanca, Spain. NCI, Dept Pathol, NIH, Bethesda, MD 20892 USA. RP Palacios, J (reprint author), Ctr Nacl Invest Oncol, Programa Patol Mol, Lab Breast & Gynecol Canc, C Melchor Fernandez Almagro 3, Madrid 28029, Spain. NR 34 TC 54 Z9 54 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD JUL PY 2003 VL 16 IS 7 BP 674 EP 678 DI 10.1097/01.MP.0000073974.42583.F7 PG 5 WC Pathology SC Pathology GA 703MT UT WOS:000184284000008 PM 12861063 ER PT J AU Frazar, TF Weisbein, JL Anderson, SM Cline, AP Garrett, LJ Felsenfeld, G Gallagher, PG Bodine, DM AF Frazar, TF Weisbein, JL Anderson, SM Cline, AP Garrett, LJ Felsenfeld, G Gallagher, PG Bodine, DM TI Variegated expression from the murine band 3 (AE1) promoter in transgenic mice is associated with mRNA transcript initiation at upstream start sites and can be suppressed by the addition of the chicken beta-globin 5 ' HS4 insulator element SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MEMBRANE SKELETAL PROTEINS; ENHANCER-BLOCKING ACTIVITY; ERYTHROCYTE-MEMBRANE; ANION-EXCHANGER; CHROMATIN INSULATOR; CYTOPLASMIC DOMAIN; GENE; CELLS; STABILITY; POSITION AB The anion exchanger protein 1 (AE1; band 3) is an abundant erythrocyte transmembrane protein that regulates chloride-bicarbonate exchange and provides an attachment site for the erythrocyte membrane skeleton on the cytoplasmic domain. We analyzed the function of the erythroid AE1 gene promoter by using run-on transcription, RNase protection, transient transfection, and transgenic mouse assays. AE1 mRNA was transcribed at a higher level and maintained at a higher steady-state level than either ankyrin or beta-spectrin in mouse fetal liver cells. When linked to a human gamma-globin gene, two different AE1 promoters directed erythroid-specific expression of gamma-globin mRNA in 18 of 18 lines of transgenic mice. However, variegated expression of gamma-globin was observed in 14 of 18 lines. While there was a significant correlation between transgene copy number and the amount of gamma-globin mRNA in all 18 lines, the transgene mRNAs initiated upstream of the start site of the endogenous AE1 mRNA. Addition of the insulator element from 5'HS4 of the chicken beta-globin cluster to the AE1/gamma-globin transgene allowed position-independent, copy-number-dependent expression at levels similar to the AE1 transcription rate in six of six lines of transgenic mice. The mRNA from the insulated AE1/gamma-globin transgene mapped to the start site of the endogenous AE1 mRNA, and gamma-globin protein was expressed in 100% of erythrocytes in all lines. We conclude that the chicken beta-globin 5'HS4 element is necessary for full function of the AE1 promoter and that position effect variegation is associated with RNA transcription from the upstream start sites. C1 NHGRI, Hematopoiesis Sect, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. NHGRI, Transgen Mouse Core Facil, Genet Dis Res Branch, Bethesda, MD 20892 USA. NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. Yale Univ, Dept Pediat, New Haven, CT 06520 USA. RP Bodine, DM (reprint author), NHGRI, Hematopoiesis Sect, Genet & Mol Biol Branch, 49 Convent Dr,MSC 4442,Bldg 49,Rm 3A14, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [R01 HL065448, HL65448] NR 43 TC 18 Z9 19 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2003 VL 23 IS 14 BP 4753 EP 4763 DI 10.1128/MCB.23.14.4753-4763.2003 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 697RY UT WOS:000183958100002 PM 12832463 ER PT J AU Figueroa, A Cuadrado, A Fan, J Atasoy, U Muscat, GE Munoz-Canoves, P Gorospe, M Munoz, A AF Figueroa, A Cuadrado, A Fan, J Atasoy, U Muscat, GE Munoz-Canoves, P Gorospe, M Munoz, A TI Role of HuR in skeletal myogenesis through coordinate regulation of muscle differentiation genes SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MESSENGER-RNA STABILITY; AU-RICH ELEMENTS; BINDING PROTEIN; IN-VIVO; CELL ACTIVATION; POLY(A) TAIL; ELAV PROTEIN; UV-LIGHT; STABILIZATION; EXPRESSION AB In this report, we investigate the role of the RNA-binding protein HuR during skeletal myogenesis. At the onset of myogenesis in differentiating C2C12 myocytes and in vivo in regenerating mouse muscle, HuR cytoplasmic abundance increased dramatically, returning to a predominantly nuclear presence upon completion of myogenesis. mRNAs encoding key regulators of myogenesis-specific transcription (myogenin and MyoD) and cell cycle withdrawal (p21), bearing AU-rich regions, were found to be targets of HuR in a differentiation-dependent manner. Accordingly, mRNA half-lives were highest during differentiation, declining when differentiation was completed. Importantly, HuR-overexpressing C2C12 cells displayed increased target mRNA expression and half-life and underwent precocious differentiation. Our findings underscore a critical function for HuR during skeletal myogenesis linked to HuR's coordinate regulation of muscle differentiation genes. C1 NIA, Cellular & Mol Biol Lab, IRP, NIH, Baltimore, MD 21224 USA. Univ Autonoma Madrid, CSIC, Inst Invest Biomed Alberto Sols, Madrid 28029, Spain. Ctr Regulac Genom, Barcelona 08003, Spain. Duke Univ, Sch Med, Durham, NC 27710 USA. Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4072, Australia. RP Gorospe, M (reprint author), NIA, Cellular & Mol Biol Lab, IRP, NIH, Box 12,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Munoz-Canoves, Pura/B-3889-2015 OI Munoz-Canoves, Pura/0000-0002-7533-9047 FU NIAID NIH HHS [R01-AI46451, R01 AI046451] NR 43 TC 115 Z9 116 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2003 VL 23 IS 14 BP 4991 EP 5004 DI 10.1128/MCB.23.14.4991-5004.2003 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 697RY UT WOS:000183958100023 PM 12832484 ER PT J AU Sahlgren, CM Mikhailov, A Vaittinen, S Pallari, HM Kalimo, H Pant, HC Eriksson, JE AF Sahlgren, CM Mikhailov, A Vaittinen, S Pallari, HM Kalimo, H Pant, HC Eriksson, JE TI Cdk5 regulates the organization of nestin and its association with p35 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CYCLIN-DEPENDENT KINASE-5; INTERMEDIATE-FILAMENT PROTEIN; NEURONAL-SPECIFIC ACTIVATOR; SKELETAL-MUSCLE; NEURITE OUTGROWTH; TAIL DOMAIN; KDA SUBUNIT; IN-VITRO; NEUROFILAMENT; CELLS AB The intermediate filament protein nestin is characterized by its specific expression during the development of neuronal and myogenic tissues. We identify nestin as a novel in vivo target for cdk5 and p35 kinase, a critical signaling determinant in development. Two cdk5-specific phosphorylation sites on nestin, Thr-1495 and Thr316, were established, the latter of which was used as a marker for cdk5-specific phosphorylation in vivo. Ectopic expression of cdk5 and p35 in central nervous system progenitor cells and in myogenic precursor cells induced elevated phosphorylation and reorganization of nestin. The kinetics of nestin expression corresponded to elevated expression and activation of cdk5 during differentiation of myoblast cell cultures and during regeneration of skeletal muscle. In the myoblasts, a disassembly-linked phosphorylation of Thr-316 indicated active phosphorylation of nestin by cdk5. Moreover, cdk5 occurred in physical association with nestin. Inhibition of cdk5 activity-either by transfection with dominant-negative cdk5 or by using a specific cdk5 inhibitor-blocked myoblast differentiation and phosphorylation of nestin at Thr-316, and this inhibition markedly disturbed the organization of nestin. Interestingly, the interaction between p35, the cdk5 activator, and nestin appeared to be regulated by cdk5. In differentiating myoblasts, p35 was not complexed with nestin phosphorylated at Thr-316, and inhibition of cdk5 activity during differentiation induced a marked association of p35 with nestin. These results demonstrate that there is a continuous turnover of cdk5 and p35 activity on a scaffold formed by nestin. This association is likely to affect the organization and operation of both cdk5 and nestin during development. C1 Univ Turku, Physiol Anim Lab, Dept Biol, FIN-20014 Turku, Finland. Abo Akad Univ, Dept Biol, FIN-20520 Turku, Finland. Turku Univ Hosp, Dept Pathol, FIN-20520 Turku, Finland. Turku Univ, Turku Ctr Biotechnol, FIN-20521 Turku, Finland. Abo Akad Univ, FIN-20521 Turku, Finland. Canc Res Ctr, Moscow 115478, Russia. NINDS, NIH, Neurochem Lab, Bethesda, MD 20892 USA. RP Eriksson, JE (reprint author), Univ Turku, Physiol Anim Lab, Dept Biol, FIN-20014 Turku, Finland. OI , cecilia/0000-0001-6365-6275 NR 43 TC 88 Z9 92 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2003 VL 23 IS 14 BP 5090 EP 5106 DI 10.1128/MCB.23.14.5090-5106.2003 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 697RY UT WOS:000183958100031 PM 12832492 ER PT J AU Yacoub, A Mitchell, C Brannon, J Rosenberg, E Qiao, L McKinstry, R Linehan, WM Su, ZS Sarkar, D Lebedeva, IV Valerie, K Gopalkrishnan, RV Grant, S Fisher, PB Dent, P AF Yacoub, A Mitchell, C Brannon, J Rosenberg, E Qiao, L McKinstry, R Linehan, WM Su, ZS Sarkar, D Lebedeva, IV Valerie, K Gopalkrishnan, RV Grant, S Fisher, PB Dent, P TI MDA-7 (interieukin-24) inhibits the proliferation of renal carcinoma cells and interacts with free radicals to promote cell death and loss of reproductive capacity SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID DIFFERENTIATION-ASSOCIATED GENE; HUMAN-MELANOMA CELLS; ARSENIC TRIOXIDE; INDUCED APOPTOSIS; ADENOVIRUS RECEPTOR; PROSTATE CARCINOMA; MYELOMA CELLS; CANCER CELLS; GROWTH; THERAPY AB The median survival of metastatic renal cell carcinoma (RCC) is 12 months, and the majority of treatment options are palliative. MDA-7 (interieukin-24), when expressed via a recombinant replication defective adenovirus, Ad.mda-7, has profound antiproliferative and cytotoxic effects in a wide variety of tumor cells but not in nontransformed cells. The studies in this study examined the impact of MDA-7 on RCC proliferation and survival. RCC lines (A498 and UOK121N), but not primary renal epithelial cells, were resistant to adenoviral infection that correlated with a lack of coxsackievirus and adenovirus receptor expression. Additional studies were performed using purified preparations of bacterially synthesized glutathione S-transferase (GST)-MDA-7 protein. GST-MDA-7, but not GST, caused a dose-dependent inhibition of RCC proliferation but not of primary renal epithelial cells. Clinically achievable concentrations of the novel therapeutic agent arsenic trioxide (0.5-1 muM) were found to have little effect on RCC growth. However, the combination of GST-MDA-7 and arsenic trioxide resulted in a greater than additive reduction in cell growth that correlated with a large increase in tumor cell death. The free radical scavenger N-acetyl cysteine abolished the potentiating effect of arsenic trioxide. Although pro-caspase 3, poly(ADP-ribose) polymerase, and Bcl-(XL) levels, as well as nucleosomal DNA integrity, were reduced by combined treatment, cell killing was predominantly nonapoptotic. Combined treatment of RCC lines with GST-MDA-7 and arsenic trioxide also resulted in a substantial reduction in clonogenic survival compared with either treatment individually. Collectively, these findings demonstrate that MDA-7 protein, in combination with agents that generate free radicals, may have potential in the treatment of RCC. C1 Virginia Commonwealth Univ, Med Coll Virginia, Dept Radiat Oncol, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Hematol Oncol, Richmond, VA 23298 USA. NCI, Urol Oncol Branch, Rockville, MD 20852 USA. Columbia Univ, Dept Pathol, New York, NY 10032 USA. Columbia Univ, Dept Neurosurg, New York, NY 10032 USA. Columbia Univ, Dept Urol, New York, NY 10032 USA. RP Dent, P (reprint author), Virginia Commonwealth Univ, Med Coll Virginia, Dept Radiat Oncol, 401 Coll St, Richmond, VA 23298 USA. FU NCI NIH HHS [CA97318] NR 46 TC 59 Z9 67 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2003 VL 2 IS 7 BP 623 EP 632 PG 10 WC Oncology SC Oncology GA 704DZ UT WOS:000184324300005 PM 12883035 ER PT J AU Fishel, ML Delaney, SM Friesen, LD Hansen, RJ Zuhowski, EG Moschel, RC Egorin, MJ Dolan, ME AF Fishel, ML Delaney, SM Friesen, LD Hansen, RJ Zuhowski, EG Moschel, RC Egorin, MJ Dolan, ME TI Enhancement of platinum-induced cytotoxicity by O-6-Benzylguanine SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID HAMSTER OVARY CELLS; CISPLATIN-INDUCED APOPTOSIS; NUCLEOTIDE EXCISION-REPAIR; INDUCED DNA-DAMAGE; PHASE-I TRIAL; ANTICANCER DRUGS; CROSS-LINKING; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; CELLULAR-RESPONSES; TESTICULAR CANCER AB O-6-Benzylguanine (O-6-BG), a potent inactivator of the DNA repair protein O-6-alkylguanine-DNA alkyltransferase (AGT), is presently in clinical trials combined with alkylating agents that modify the O-6 position of DNA guanine residues, i.e., 1,3-bis(2-chloroethyl)-1-nitrosourea and temozolomide. Previous work demonstrated that O-6-BG also enhances the cytotoxicity of cyclophosphamide, ifosfamide, and nitrogen mustards in Chinese hamster ovary cells. We have extended this study to include other clinically relevant agents that form interstrand and intrastrand cross-links including cisplatin and carboplatin. Pretreatment of a series of head and neck tumor cell lines (i.e., SQ20b, JSQ3, SCC25, SCC35, and SCC61), Chinese hamster ovary cells, and HT29 human colon tumor cells with O-6-BG (100 muM for 2 h before treatment and 2 h during treatment) resulted in a 2-fold decrease in the ED50 of cisplatin and a concomitant increase in the percentage of cells undergoing apoptosis. The enhancement was independent of AGT activity. Similar enhancement was observed with carboplatin, but no enhancement was seen in AGT-deficient cell lines with radiation or temozolomide, demonstrating the dependence of the effect on bifunctional, cross-linking agents. Furthermore, levels of platinum on DNA after treatment with cisplatin increased 1.4-fold in SQ20b cells and 4.5-fold in JSQ3 cells immediately after treatment with Q(6)-BG plus cisplatin and remained elevated for 48 h. Consistent with greater cytotoxicity and apoptosis is the similar to2-fold higher amount of DNA damage when cells are treated with O-6-BG plus cisplatin compared with cisplatin alone. Modulation of cisplatin therapy with O-6-BG might improve the prognosis of patients with head and neck, ovarian, testicular, or lung cancer who are treated with this drug. C1 Univ Chicago, Dept Med, Committee Canc Biol, Chicago, IL 60637 USA. Univ Chicago, Dept Med, Ctr Canc Res, Chicago, IL 60637 USA. NCI, Comparat Carcinogenesis Lab, Ft Detrick, MD 21702 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. RP Dolan, ME (reprint author), Univ Chicago, Dept Med, Committee Canc Biol, 5841 S Maryland Ave,Box MC2115, Chicago, IL 60637 USA. FU NCI NIH HHS [CA81485] NR 55 TC 31 Z9 31 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2003 VL 2 IS 7 BP 633 EP 640 PG 8 WC Oncology SC Oncology GA 704DZ UT WOS:000184324300006 PM 12883036 ER PT J AU Kees, UR Ford, J Watson, M Murch, A Ringner, M Walker, RL Meltzer, P AF Kees, UR Ford, J Watson, M Murch, A Ringner, M Walker, RL Meltzer, P TI Gene expression profiles in a panel of childhood leukemia cell lines mirror critical features of the disease SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; HIGH-DOSE TREATMENT; FUSION TRANSCRIPTS; PRE-B; REARRANGEMENT; CANCER; 1-BETA-D-ARABINOFURANOSYLCYTOSINE; T(1-19)(Q23-P13); CLASSIFICATION; ESTABLISHMENT AB The development of new drugs against cancer requires established cell lines. They are needed for in vitro studies to identify candidate drugs and in xenograft models to measure drug efficacy in vivo. Specific criteria need to be fulfilled by cell lines used in the evaluation of potential novel therapeutic agents. It is imperative that they display the features of the particular cancer under investigation. Given the documented heterogeneity of cancers, relevant subtypes need to be represented. In this study, we have examined these aspects for pediatric acute lymphoblastic leukemia. A panel of 13 leukemia cell lines recently established in our laboratory was analyzed. We used cDNA microarrays to define the gene expression profiles and compared the data with immunophenotyping and cytogenetic analyses. The expression profiles obtained showed excellent concordance with corresponding protein levels. Importantly, the panel of lines displayed the critical genetic features identified in clinically important acute lymphoblastic leukemia subtypes in childhood leukemia patients. C1 Univ Western Australia, Telethon Inst Child Hlth Res, Div Childrens Leukemia & Canc Res, Perth, WA 6872, Australia. Univ Western Australia, Ctr Child Hlth Res, Perth, WA 6009, Australia. King Edward Mem Hosp Women, Perth, WA, Australia. Princess Margaret Hosp, Perth, WA, Australia. NIH, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. RP Kees, UR (reprint author), Univ Western Australia, Telethon Inst Child Hlth Res, Div Childrens Leukemia & Canc Res, POB 855, Perth, WA 6872, Australia. RI Ringner, Markus/G-3641-2011 OI Ringner, Markus/0000-0001-5469-8940 NR 35 TC 22 Z9 24 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2003 VL 2 IS 7 BP 671 EP 677 PG 7 WC Oncology SC Oncology GA 704DZ UT WOS:000184324300010 PM 12883040 ER PT J AU Fulco, M Schiltz, RL Iezzi, S King, MT Zhao, P Kashiwaya, Y Hoffman, E Veech, RL Sartorelli, V AF Fulco, M Schiltz, RL Iezzi, S King, MT Zhao, P Kashiwaya, Y Hoffman, E Veech, RL Sartorelli, V TI Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state SO MOLECULAR CELL LA English DT Article ID NICOTINAMIDE-ADENINE-DINUCLEOTIDE; SMALL-MOLECULE INHIBITORS; SILENCING PROTEIN SIR2; SACCHAROMYCES-CEREVISIAE; HISTONE DEACETYLASES; BHLH REPRESSORS; LIFE-SPAN; MYOD; CHROMATIN; ACETYLATION AB Sir2 is a NAD(+)-dependent histone deacetylase that controls gene silencing, cell cycle, DNA damage repair, and life span. Prompted by the observation that the [NAD(+)]/[NADH] ratio is subjected to dynamic fluctuations in skeletal muscle, we have tested whether Sir2 regulates muscle gene expression and differentiation. Sir2 forms a complex with the acetyltransferase PCAF and MyoD and, when overexpressed, retards muscle differentiation. Conversely, cells with decreased Sir2 differentiate prematurely. To inhibit myogenesis, Sir2 requires its NAD(+)-dependent deacetylase activity. The [NAD(+)]/[NADH] ratio decreases as muscle cells differentiate, while an increased [NAD(+)]/ [NADH] ratio inhibits muscle gene expression. Cells with reduced Sir2 levels are less sensitive to the inhibition imposed by an elevated [NAD(+)]/[NADH] ratio. These results indicate that Sir2 regulates muscle gene expression and differentiation by possibly functioning as a redox sensor. In response to exercise, food intake, and starvation, Sir2 may sense modifications of the redox state and promptly modulate gene expression. C1 NIAMS, Muscle Gene Express Grp, Muscle Biol Lab, NIH, Bethesda, MD 20892 USA. NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. RP Sartorelli, V (reprint author), NIAMS, Muscle Gene Express Grp, Muscle Biol Lab, NIH, Bethesda, MD 20892 USA. NR 44 TC 402 Z9 425 U1 2 U2 15 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUL PY 2003 VL 12 IS 1 BP 51 EP 62 DI 10.1016/S1097-2765(03)00226-0 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 707UK UT WOS:000184528100007 PM 12887892 ER PT J AU Shen, XT Ranallo, R Choi, E Wu, C AF Shen, XT Ranallo, R Choi, E Wu, C TI Involvement of actin-related proteins in ATP-dependent chromatin remodeling SO MOLECULAR CELL LA English DT Article ID YEAST SWI/SNF COMPLEX; SACCHAROMYCES-CEREVISIAE; NUCLEAR ACTIN; HISTONE OCTAMER; NUCLEOSOME; TRANSCRIPTION; BINDING; ACT3P/ARP4; DISRUPTION; SUBUNITS AB Actin-related proteins (Arps) and conventional actin are enigmatic components of many chromatin-remodeling enzyme complexes. The yeast INO80 ATP-dependent chromatin-remodeling complex contains stoichiometric amounts of Arp4, Arp5, Arp8, and actin. Here we have revealed functions of Arp5 and Arp8 by analysis of mutants. arp5Delta and arp8Delta mutants display an ino80Delta phenotype. Purification of INO80 complexes from arp5Delta and arp8Delta cells shows that protein complexes remain intact but are compromised for INO80 ATPase activity, DNA binding, and nucleosome mobilization. The INO80 (arp8Delta) complex is strikingly deficient, not only for the Arp8 subunit, but also for Arp4 and actin, suggesting an ordered assembly of Arps. Binding of Arp8 to the INO80 complex requires an N-terminal region of Ino80 adjacent to the conserved ATPase domain. GST-Arp8 binds preferentially to histones H3 and H4 in vitro, suggesting a histone chaperone function. These findings show direct involvement of Arps in the chromatin-remodeling process. C1 NCI, Mol Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Wu, C (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Carcinogenesis, Div Sci Pk Res, Smithville, TX 78957 USA. NR 37 TC 221 Z9 236 U1 2 U2 9 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUL PY 2003 VL 12 IS 1 BP 147 EP 155 DI 10.1016/S1097-2765(03)00264-8 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 707UK UT WOS:000184528100015 PM 12887900 ER PT J AU O'Shea, PJ Harvey, CB Suzuki, H Kaneshige, M Kaneshige, K Cheng, SY Williams, GR AF O'Shea, PJ Harvey, CB Suzuki, H Kaneshige, M Kaneshige, K Cheng, SY Williams, GR TI A thyrotoxic skeletal phenotype of advanced bone formation in mice with resistance to thyroid hormone SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID OSTEOBLAST-LIKE CELLS; RECEPTOR-BETA GENE; INDIAN HEDGEHOG; CHONDROCYTE DIFFERENTIATION; ALPHA LOCUS; GROWTH; EXPRESSION; ISOFORMS; STIMULATION; PROTEIN AB Thyroid hormone (T-3) regulates bone turnover and mineralization in adults and is essential for skeletal development during childhood. Hyperthyroidism is an established risk factor for osteoporosis. Nevertheless, T-3 actions in bone remain poorly understood. Patients with resistance to thyroid hormone, due to mutations of the T-3-receptor beta (TRbeta) gene, display variable phenotypic abnormalities, particularly in the skeleton. To investigate the actions of T-3 during bone development, we characterized the skeleton in TRbetaPV mutant mice. TRbetaPV mice harbor a targeted resistance to thyroid hormone mutation in TRbeta and recapitulate the human condition. A severe phenotype, which includes shortened body length, was evident in homozygous TRbeta(PV/PV) animals. Accelerated growth in utero was associated with advanced endochondral and intramembranous ossification. Advanced bone formation resulted in postnatal growth retardation, premature quiescence of the growth plates, and shortened bone length, together with increased bone mineralization and craniosynostosis. In situ hybridization demonstrated increased expression of fibroblast growth factor receptor-1, a T-3-regulated gene in bone, in TRbeta(PV/PV) perichondrium, growth plate chondrocytes, and osteoblasts. Thus, the skeleton in TRbeta(PV/PV) mice is thyrotoxic and displays phenotypic features typical of juvenile hyperthyroidism. C1 Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp,Fac Med, Mol Endocrinol Grp, MRC,Clin Sci Ctr, London W12 0NN, England. Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp,Fac Med, Mol Endocrinol Grp, Div Med, London W12 0NN, England. NCI, Gene Regulat Sect, Mol Biol Lab, Bethesda, MD 20892 USA. RP Williams, GR (reprint author), Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp,Fac Med, Mol Endocrinol Grp, MRC,Clin Sci Ctr, Clin Res Bldg,5th Floor,Du Cane Rd, London W12 0NN, England. NR 43 TC 68 Z9 71 U1 0 U2 3 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUL PY 2003 VL 17 IS 7 BP 1410 EP 1424 DI 10.1210/me.2002-0296 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 696KF UT WOS:000183885500018 PM 12677005 ER PT J AU Hellerud, C Adamowicz, M Jurkiewicz, D Taybert, J Kubalska, J Ciara, E Popowska, E Ellis, JR Lindstedt, S Pronicka, E AF Hellerud, C Adamowicz, M Jurkiewicz, D Taybert, J Kubalska, J Ciara, E Popowska, E Ellis, JR Lindstedt, S Pronicka, E TI Clinical heterogeneity and molecular findings in five Polish patients with glycerol kinase deficiency: investigation of two splice site mutations with computerized splice junction analysis and Xp21 gene-specific mRNA analysis SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE adrenal hypoplasia; Duchenne muscular dystrophy; glycerol kinase deficiency; heterozygote; insertion; mutation; RT-PCR; splice junction analysis; splice site; xp21 ID CONGENITAL ADRENAL HYPOPLASIA; FRUCTOSE-1,6-DIPHOSPHATASE DEFICIENCY; HYPOGONADOTROPIC HYPOGONADISM; INFORMATION-CONTENT; DELETION; DNA; COMPLEXITY; SEQUENCES; PHENOTYPE; FAMILIES AB Five cases of glycerol kinase deficiency are presented with clinical, biochemical, and genetic results. Two had the glycerol kinase deficiency as part of an Xp21 contiguous gene deletion syndrome-complex form-and three had an isolated form of the enzyme deficiency. In these we found two splice site mutations (IVS1 + 4A > G, IVS9-1G > T) and one insertion (1393_1394insG). In patients with the complex form, a deletion of the DAX1, GK genes and the distal part of the DMD gene was found. A computerized study was performed to predict the effects of the splice site mutations. It showed that the IVS9-1G > T mutation substantially altered and removed the wild-type site and enhanced a cryptic site seven nucleotides downstream, and that the IVS1 + 4A > G diminished the strength of the wild-type donor site from strong to leaky. To verify these predictions, we developed an RT-PCR system with gene-specific primers that exclusively amplifies the Xp21 glycerol kinase gene transcript. Identification of individuals at risk is motivated by a need to avoid delay in a correct diagnosis. For reliable identification of heterozygotes for isolated glycerol kinase deficiency, knowledge of the specific mutation in the proband is required. This is easily obtained with the RT-PCR analyses developed in this study. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Univ Gothenburg, Sahlgrens Univ Hosp, Dept Clin Chem & Transfus Med, S-413415 Gothenburg, Sweden. Childrens Mem Hlth Inst, Lab Diagnost Dept, Warsaw, Poland. Childrens Mem Hlth Inst, Dept Med Genet, Warsaw, Poland. Childrens Mem Hlth Inst, Dept Metab Dis, Warsaw, Poland. NIH, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. RP Hellerud, C (reprint author), Univ Gothenburg, Sahlgrens Univ Hosp, Dept Clin Chem & Transfus Med, Bruna Straket 16, S-413415 Gothenburg, Sweden. NR 36 TC 11 Z9 12 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUL PY 2003 VL 79 IS 3 BP 149 EP 159 DI 10.1016/S1096-7192(03)00094-5 PG 11 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 703WF UT WOS:000184304300001 PM 12855219 ER PT J AU Rawat, SS Viard, M Gallo, SA Rein, A Blumenthal, R Puri, A AF Rawat, SS Viard, M Gallo, SA Rein, A Blumenthal, R Puri, A TI Modulation of entry of enveloped viruses by cholesterol and sphingolipids (Review) SO MOLECULAR MEMBRANE BIOLOGY LA English DT Review DE viral entry; lipid rafts; cholesterol; sphingolipids; membrane fusion ID HUMAN-IMMUNODEFICIENCY-VIRUS; SEMLIKI-FOREST-VIRUS; VESICULAR STOMATITIS-VIRUS; TRANSBILAYER PHOSPHOLIPID DISTRIBUTION; BORNE ENCEPHALITIS-VIRUS; MEDIATED MEMBRANE-FUSION; MURINE LEUKEMIA-VIRUS; INFLUENZA-VIRUS; LIPID RAFTS; SENDAI-VIRUS AB Enveloped animal viruses infect host cells by fusion of viral and target membranes. This crucial fusion event occurs either with the plasma membrane of the host cells at the physiological pH or with the endosomal membranes at low pH and is triggered by specific glycoproteins in the virus envelope. Both lipids and proteins play critical and co-operative roles in the fusion process. Interactions of viral proteins with their receptors direct which membranes fuse and viral fusion proteins then drive the process. These fusion proteins operate on lipid assemblies, whose physical and mechanical properties are equally important to the proper functioning of the process. Lipids contribute to the viral fusion process by virtue of their distinct chemical structure, composition and/or their preferred partitioning into specific microdomains in the plasma membrane called 'rafts'. An involvement of lipid rafts in viral entry and membrane fusion has been examined recently. However, the mechanism(s) by which lipids as dynamic raft components control viral envelope-g lycoprotein-triggered fusion is not clear. This paper will review literature findings on the contribution of the two raft-associated lipids, cholesterol and sphingolipids in viral entry. C1 NCI, Lab Expt & Computat Biol, Canc Res Ctr, NIH, Ft Detrick, MD 21702 USA. RP Puri, A (reprint author), NCI, Lab Expt & Computat Biol, Canc Res Ctr, NIH, POB B,Bldg 469,Rm 211,Miller Dr Frederick, Ft Detrick, MD 21702 USA. NR 119 TC 66 Z9 68 U1 2 U2 11 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0968-7688 J9 MOL MEMBR BIOL JI Mol. Membr. Biol. PD JUL-SEP PY 2003 VL 20 IS 3 BP 243 EP 254 DI 10.1080/0968768031000104944 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 714WG UT WOS:000184936000005 PM 12893532 ER PT J AU Daniell, SJ Kocsis, E Morris, E Knutton, S Booy, FR Frankel, G AF Daniell, SJ Kocsis, E Morris, E Knutton, S Booy, FR Frankel, G TI 3D structure of EspA filaments from enteropathogenic Escherichia coli SO MOLECULAR MICROBIOLOGY LA English DT Article ID III SECRETION SYSTEM; TISSUE-CULTURE CELLS; COILED-COIL DOMAIN; SALMONELLA-TYPHIMURIUM; NEEDLE COMPLEX; ELECTRON CRYOMICROSCOPY; MOLECULAR CHARACTERIZATION; SUPRAMOLECULAR STRUCTURE; PROTEIN TRANSLOCATION; ANGSTROM RESOLUTION AB The type III secretion system (TTSS) is a modular apparatus assembled by many pathogenic Gram-negative bacteria and is designed to translocate proteins through the bacterial cell wall into the eukaryotic host cell. The conserved components of the TTSS comprise stacks of rings spanning the inner and outer bacterial membrane and a narrow, needle-like structure projecting outwards. The TTSS of enteropathogenic E. coli is unique in that one of the translocator proteins, EspA, polymerizes to form an extension to the needle complex which interacts with the host cell. In this study we present the 3D structure of EspA filaments to c. 26 Angstrom resolution determined from electron micrographs of negatively stained preparations by image processing. The structure comprises a helical tube with a diameter of 120 Angstrom enclosing a central channel of 25 Angstrom diameter through which effector proteins may be transported. The subunit arrangement corresponds to a one-start helix with 28 subunits present in five turns of the helix and an axial rise of 4.6 Angstrom per subunit. This is the first report of a 3D structure of a filamentous extension to the TTSS. C1 Univ London Imperial Coll Sci Technol & Med, Dept Biol Sci, Ctr Mol Microbiol & Infect, London SW7 2AZ, England. NIH, DBEPS, ORS, Bethesda, MD 20892 USA. Inst Child Hlth, Birmingham B4 6NH, W Midlands, England. RP Frankel, G (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Biol Sci, Ctr Mol Microbiol & Infect, London SW7 2AZ, England. NR 47 TC 63 Z9 67 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUL PY 2003 VL 49 IS 2 BP 301 EP 308 DI 10.1046/j.1365-2958.2003.03555.x PG 8 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 702LE UT WOS:000184224700002 PM 12828630 ER PT J AU Zhang, ZX Anderson, DW Huang, JB Li, H Hong, X Wei, J Yang, EL Maraganore, DM AF Zhang, ZX Anderson, DW Huang, JB Li, H Hong, X Wei, J Yang, EL Maraganore, DM TI Prevalence of Parkinson's disease and related disorders in the elderly population of greater Beijing, China SO MOVEMENT DISORDERS LA English DT Review DE epidemiology; Parkinson's disease; prevalence ID TO-DOOR SURVEY; ENVIRONMENTAL RISK-FACTORS; REPUBLIC-OF-CHINA; HEALTH-CARE; MORTALITY; DIAGNOSIS; CRITERIA; SYSTEM AB A lower prevalence of Parkinson's disease (PD) has been reported for Chinese populations, but it is unclear whether this observation reflects a lower disease risk or is an artifact of case finding. We ascertained the prevalence of PD in elderly residents of an area that was a composite of 27 urban and rural communities of Greater Beijing, China. A team of university neurologists went door-to-door throughout the study area, examining 5,743 residents (at age 55 years or older) and made preliminary determinations of which residents had PD or other types of parkinsonism. Final determinations were made after follow-up and reevaluation of those persons who were either deemed to have parkinsonism or were suspected of having the condition (n = 144; median follow-up = 40 months). Based on stringent diagnostic criteria, 110 persons were identified to have parkinsonism, of whom 64 (58%) had PD. The prevalence of PD increased with advancing age and was about 1% overall and for each gender. In rural communities, 22 persons had PD, but 20 persons (91%) were first diagnosed for this condition by the study neurologists. The prevalence figures obtained in this study are similar to some of the highest prevalence figures reported in the West. (C) 2003 Movement Disorder Society. C1 Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Neurol, Beijing 100037, Peoples R China. Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Clin Epidemiol, Beijing 100037, Peoples R China. NINDS, Populat Studies Unit, Biostat Branch, Bethesda, MD USA. Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Epidemiol, Beijing 100037, Peoples R China. Sixth Hosp, Dept Neurol, Beijing, Peoples R China. Mayo Clin & Mayo Fdn, Dept Neurol, Rochester, MN 55905 USA. RP Anderson, DW (reprint author), NINDS, Ctr Neurosci, NIH, Room 2156,6001 Execut Blvd,MSC 9531, Bethesda, MD 20892 USA. FU NIEHS NIH HHS [ES10751]; NINDS NIH HHS [NS33978] NR 37 TC 26 Z9 30 U1 0 U2 6 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUL PY 2003 VL 18 IS 7 BP 764 EP 772 DI 10.1002/mds.10445 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 701CA UT WOS:000184148300005 PM 12815655 ER PT J AU Wenk, MR Lucast, L Di Paolo, G Romanelli, AJ Suchy, SF Nussbaum, RL Cline, GW Shulman, GI McMurray, W De Camilli, P AF Wenk, MR Lucast, L Di Paolo, G Romanelli, AJ Suchy, SF Nussbaum, RL Cline, GW Shulman, GI McMurray, W De Camilli, P TI Phosphoinositide profiling in complex lipid mixtures using electrospray ionization mass spectrometry SO NATURE BIOTECHNOLOGY LA English DT Article ID YEAST; MEMBRANE; PHOSPHATIDYLINOSITOL; 3-KINASE; KINASE; SECRETION; SAC1 AB Phosphoinositides (phosphorylated derivatives of phosphatidylinositol, PI) are versatile intracellular signaling lipids whose occurrence in low concentrations complicates direct mass measurements(1-3). Here we present a sensitive method to detect, identify and quantify phosphatidylinositol phosphate (PIP) and phosphatidylinositol bisphosphate (PIP 2) with different fatty acid compositions (phosphoinositide profiles) in total lipid extracts by electrospray ionization mass spectrometry (ESI-MS). Using this method, we detected elevated concentrations of PIP2 in human fibroblasts from patients with Lowe syndrome, a genetic disorder that affects lphosphoinositide metabolism(4). Saccharomyces cerevisiae cells deficient in enzymes involved in PIP metabolism-Sac1p, a phosphoinositide phosphatase(5), and Vps34p and Pik1p, a PI 3-kinase(6) and PI 4-kinase(7), respectively-showed not only different PIP concentrations but also differential changes in PIP profiles indicating metabolic and/or subcellular pooling. Mass spectrometric analysis of phosphoinositides offers unique advantages over existing approaches and may represent a powerful diagnostic tool for human diseases that involve defective phosphoinositide metabolism. C1 Yale Univ, Sch Med, Boyer Ctr Mol Med, Howard Hughes Med Inst,Dept Cell Biol, New Haven, CT 06511 USA. Yale Univ, Sch Med, Dept Internal Med, Howard Hughes Med Inst, New Haven, CT 06511 USA. Yale Univ, Sch Med, Boyer Ctr Mol Med, WM Keck Mass Spectrometry Resource, New Haven, CT 06511 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Wenk, MR (reprint author), Yale Univ, Sch Med, Boyer Ctr Mol Med, Howard Hughes Med Inst,Dept Cell Biol, 295 Congress Ave, New Haven, CT 06511 USA. RI Wenk, Markus/D-1441-2014 FU NCI NIH HHS [CA46128]; NIDDK NIH HHS [DK49230, DK 54913, DK59635, R01 DK040936]; NINDS NIH HHS [NS36251] NR 20 TC 143 Z9 150 U1 6 U2 31 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUL PY 2003 VL 21 IS 7 BP 813 EP 817 DI 10.1038/nbt837 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 696KL UT WOS:000183886000036 PM 12808461 ER PT J AU Celeste, A Fernandez-Capetillo, O Kruhlak, MJ Pilch, DR Staudt, DW Lee, A Bonner, RF Bonner, WM Nussenzweig, A AF Celeste, A Fernandez-Capetillo, O Kruhlak, MJ Pilch, DR Staudt, DW Lee, A Bonner, RF Bonner, WM Nussenzweig, A TI Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks SO NATURE CELL BIOLOGY LA English DT Article ID DOUBLE-STRAND BREAKS; DEPENDENT NUCLEAR-DYNAMICS; MRE11 COMPLEX; GENOMIC INSTABILITY; CELLULAR-RESPONSE; REPAIR; DAMAGE; 53BP1; FOCI; REPLICATION AB Histone H2AX is rapidly phosphorylated in the chromatin micro-environment surrounding a DNA double-strand break (DSB). Although H2AX deficiency is not detrimental to life, H2AX is required for the accumulation of numerous essential proteins into irradiation induced foci (IRIF). However, the relationship between IRIF formation, H2AX phosphorylation (gamma-H2AX) and the detection of DNA damage is unclear. Here, we show that the migration of repair and signalling proteins to DSBs is not abrogated in H2AX(-/-) cells, or in H2AX-deficient cells that have been reconstituted with H2AX mutants that eliminate phosphorylation. Despite their initial recruitment to DSBs, numerous factors, including Nbs1, 53BP1 and Brca1, subsequently fail to form IRIF. We propose that gamma-H2AX does not constitute the primary signal required for the redistribution of repair complexes to damaged chromatin, but may function to concentrate proteins in the vicinity of DNA lesions. The differential requirements for factor recruitment to DSBs and sequestration into IRIF may explain why essential regulatory pathways controlling the ability of cells to respond to DNA damage are not abolished in the absence of H2AX. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NIH, Sect Med Biophys, Lab Integrat & Med Biophys, Bethesda, MD 20892 USA. RP Nussenzweig, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Bonner, Robert/C-6783-2015; Fernandez-Capetillo, Oscar/H-3508-2015 OI Fernandez-Capetillo, Oscar/0000-0002-2690-6885 NR 27 TC 642 Z9 675 U1 5 U2 42 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JUL PY 2003 VL 5 IS 7 BP 675 EP U51 DI 10.1038/ncb1004 PG 7 WC Cell Biology SC Cell Biology GA 696WY UT WOS:000183911600019 PM 12792649 ER PT J AU Roix, JJ McQueen, PG Munson, PJ Parada, LA Misteli, T AF Roix, JJ McQueen, PG Munson, PJ Parada, LA Misteli, T TI Spatial proximity of translocation-prone gene loci in human lymphomas SO NATURE GENETICS LA English DT Article ID HUMAN LEUKEMIC-CELLS; C-MYC; CHROMOSOME-ABERRATIONS; NUCLEAR TOPOGRAPHY; CANCER; INTERPHASE; LOCATION; ABL; BCR; DIFFERENTIATION AB Cancer cells frequently have disease-specific chromosome rearrangements(1-4). It is poorly understood why translocations between chromosomes recur at specific breakpoints in the genome. Here we provide evidence that higher-order spatial genome organization is a contributing factor in the formation of recurrent translocations. We show that MYC, BCL and immunoglobulin loci, which are recurrently translocated in various B-cell lymphomas, are preferentially positioned in close spatial proximity relative to each other in normal B cells. Loci in spatial proximity are non-randomly positioned towards the nuclear interior in normal B cells. This locus proximity is the consequence of higher-order genome structure rather than a property of individual genes. Our results suggest that the formation of specific translocations in human lymphomas, and perhaps other tissues, is determined in part by higher-order spatial organization of the genome. C1 NCI, NIH, Bethesda, MD 20892 USA. NIH, Math & Stat Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 29 TC 253 Z9 259 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUL PY 2003 VL 34 IS 3 BP 287 EP 291 DI 10.1038/ng1177 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 695DF UT WOS:000183815300015 PM 12808455 ER PT J AU Jin, YH Clark, AB Slebos, RJC Al-Refai, H Taylor, JA Kunkel, TA Resnick, MA Gordenin, DA AF Jin, YH Clark, AB Slebos, RJC Al-Refai, H Taylor, JA Kunkel, TA Resnick, MA Gordenin, DA TI Cadmium is a mutagen that acts by inhibiting mismatch repair SO NATURE GENETICS LA English DT Article ID DNA-POLYMERASE-DELTA; SACCHAROMYCES-CEREVISIAE; GENOME INSTABILITY; REPLICATION; EPSILON; CANCER; ERRORS; RISK; RUNS; PCNA AB Most errors that arise during DNA replication can be corrected by DNA polymerase proofreading or by post-replication mismatch repair (MMR). Inactivation of both mutation-avoidance systems results in extremely high mutability that can lead to error catastrophe(1,2). High mutability and the likelihood of cancer can be caused by mutations and epigenetic changes that reduce MMR3,4. Hypermutability can also be caused by external factors that directly inhibit MMR. Identifying such factors has important implications for understanding the role of the environment in genome stability. We found that chronic exposure of yeast to environmentally relevant concentrations of cadmium, a known human carcinogen(5), can result in extreme hypermutability. The mutation specificity along with responses in proofreading-deficient and MMR-deficient mutants indicate that cadmium reduces the capacity for MMR of small misalignments and base-base mismatches. In extracts of human cells, cadmium inhibited at least one step leading to mismatch removal. Together, our data show that a high level of genetic instability can result from environmental impediment of a mutation-avoidance system. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Gordenin, DA (reprint author), NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. OI Gordenin, Dmitry/0000-0002-8399-1836; taylor, jack/0000-0001-5303-6398 FU Intramural NIH HHS [Z99 ES999999] NR 29 TC 268 Z9 287 U1 2 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUL PY 2003 VL 34 IS 3 BP 326 EP 329 DI 10.1038/ng1172 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 695DF UT WOS:000183815300022 PM 12796780 ER PT J AU Caughey, B AF Caughey, B TI Probing for prions: recognizing misfolded PrP SO NATURE MEDICINE LA English DT Editorial Material ID ANTIBODIES; PROTEIN AB New antibodies specific for the misfolded, and presumably pathogenic, form of the PrP protein have now made their long-awaited debut. These antibodies could provide tools for diagnostics, research and therapy (pages 893-899). C1 NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Caughey, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. NR 8 TC 6 Z9 6 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2003 VL 9 IS 7 BP 819 EP 820 DI 10.1038/nm0703-819 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 698CD UT WOS:000183979300013 PM 12835691 ER PT J AU Steeg, PS AF Steeg, PS TI Angiogenesis inhibitors: motivators of metastasis? SO NATURE MEDICINE LA English DT Editorial Material ID HUMAN-MELANOMA XENOGRAFTS; INVASIVE GROWTH; HYPOXIA; RECEPTORS; TUMORS AB Angiogenesis inhibitors have shown promise in hindering blood supply and holding tumors in check. But it now seems that such inhibitors, by depriving tumors of oxygen, could have an unintended effect: promotion of metastasis. C1 NCI, Womens Canc Sect, Pathol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. RP Steeg, PS (reprint author), NCI, Womens Canc Sect, Pathol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. NR 9 TC 69 Z9 73 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2003 VL 9 IS 7 BP 822 EP 823 DI 10.1038/nm0703-822 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 698CD UT WOS:000183979300015 PM 12835693 ER PT J AU Fauci, AS AF Fauci, AS TI HIV and AIDS: 20 years of science SO NATURE MEDICINE LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; PNEUMOCYSTIS-CARINII PNEUMONIA; IMMUNE-DEFICIENCY SYNDROME; HISTORICAL ESSAY; HUMAN RETROVIRUS; T-LYMPHOCYTES; INFECTION; PATHOGENESIS; CHEMOKINES; DISEASE AB From the identification of HIV as the agent that causes AIDS, to the development of effective antiretroviral drugs, the scientific achievements in HIV research in the past 20 years have been formidable. Some of the other important areas of accomplishment include the development of blood tests for HIV and increased knowledge of the molecular virology, epidemiology and pathogenesis of this virus. C1 NIAID, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, Dept Hlth & Human Serv, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 48 TC 103 Z9 119 U1 2 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2003 VL 9 IS 7 BP 839 EP 843 DI 10.1038/nm0703-839 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 698CD UT WOS:000183979300021 PM 12835701 ER PT J AU Kirvan, CA Swedo, SE Heuser, JS Cunningham, MW AF Kirvan, CA Swedo, SE Heuser, JS Cunningham, MW TI Mimicry and auto antibody-mediated neuronal cell signaling in Sydenham chorea SO NATURE MEDICINE LA English DT Article ID GUILLAIN-BARRE-SYNDROME; BETA-D-GLUCOSAMINE; PROTEIN-KINASE-II; STREPTOCOCCAL-M-PROTEINS; MILLER-FISHER-SYNDROME; ACUTE RHEUMATIC-FEVER; MONOCLONAL-ANTIBODIES; BASAL GANGLIA; MUTANT MICE; GANGLIOSIDES AB Streptococcus pyogenes-induced acute rheumatic fever (ARF) is one of the best examples of postinfectious autoimmunity due to molecular mimicry between host and pathogen. Sydenham chorea is the major neurological manifestation of ARF but its pathogenesis has remained elusive, with no candidate autoantigen or mechanism of pathogenesis described. Chorea monoclonal antibodies showed specificity for mammalian lysoganglioside and N-acetyl-beta-D-glucosamine (GlcNAc), the dominant epitope of the group A streptococcal (GAS) carbohydrate. Chorea antibodies targeted the surface of human neuronal cells, with specific induction of calcium/calmodulin-dependent protein (CaM) kinase II activity by monoclonal antibody 24.3.1 and sera from active chorea. Convalescent sera and sera from other streptococcal diseases in the absence of chorea did not activate the kinase. The new evidence implicates anti body-mediated neuronal cell signaling in the immunopathogenesis of Sydenham chorea and will lead to a better understanding of other antibody-mediated neurological disorders. C1 Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. NIMH, Pediat & Dev Neuropsychiat Branch, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Cunningham, MW (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. FU NHLBI NIH HHS [HL35280]; NIAID NIH HHS [1T32-AI07633-01A1] NR 44 TC 201 Z9 208 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2003 VL 9 IS 7 BP 914 EP 920 DI 10.1038/nm892 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 698CD UT WOS:000183979300033 PM 12819778 ER PT J AU Bouma, G Strober, W AF Bouma, G Strober, W TI The immunological and genetic basis of inflammatory bowel disease SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID REGULATORY T-CELLS; INTESTINAL EPITHELIAL-CELLS; GROWTH-FACTOR-BETA; NF-KAPPA-B; HELPER CELL-TYPE-1 RESPONSE; PROPRIA MONONUCLEAR-CELLS; NECROSIS-FACTOR-ALPHA; CROHNS-DISEASE; ULCERATIVE-COLITIS; CUTTING EDGE AB The inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract. Enormous progress has been made recently in understanding the pathogenesis of these diseases. Through the study of patients and mouse models, it has emerged that Crohn's disease is driven by the production of interleukin-12 (IL-12) and interferon-gamma (IFN-gamma), whereas ulcerative colitis is probably driven by the production of IL-13. A second area of progress is in the identification of specific genetic abnormalities that are responsible for disease. The most important finding is the identification of mutations in the gene that encodes NOD2 (nucleotide-binding oligomerization domain 2) protein in a subgroup of patients with Crohn's disease. Here, we discuss these recent findings and the implications for therapy. C1 NIAID, Mucosal Immun Sect, NIH, Clin Invest Lab, Bethesda, MD 20892 USA. Vrije Univ Amsterdam, Med Ctr, Immunogenet Lab, Amsterdam, Netherlands. RP Strober, W (reprint author), NIAID, Mucosal Immun Sect, NIH, Clin Invest Lab, 10 Ctr Dr,Room 11N238, Bethesda, MD 20892 USA. RI bouma, gerd/E-2520-2013; Ain, Kenneth/A-5179-2012 OI Ain, Kenneth/0000-0002-2668-934X NR 138 TC 1043 Z9 1079 U1 5 U2 122 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 JUL PY 2003 VL 3 IS 7 BP 521 EP 533 DI 10.1038/nri1132 PG 13 WC Immunology SC Immunology GA 699RN UT WOS:000184069900017 PM 12876555 ER PT J AU Trievel, RC Flynn, EM Houtz, RL Hurley, JH AF Trievel, RC Flynn, EM Houtz, RL Hurley, JH TI Mechanism of multiple lysine methylation by the SET domain enzyme Rubisco LSMT SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID RIBULOSE-1,5-BISPHOSPHATE CARBOXYLASE OXYGENASE; HISTONE METHYLTRANSFERASE SET7/9; ELECTRON-DENSITY MAPS; O HYDROGEN-BONDS; LARGE SUBUNIT; N-METHYLTRANSFERASE; CATALYTIC MECHANISM; ACTIVE GENES; H3; PROTEINS AB SET domain protein methyltransferases catalyze the transfer of methyl groups from the cofactor S-adenosylmethionine (AdoMet) to specific lysine residues of protein substrates, such as the N-terminal tails of histones H3 and H4 and the large subunit of the Rubisco holoenzyme complex. The crystal structures of pea Rubisco large subunit methyltransferase ( LSMT) in ternary complexes with either lysine or epsilon-N-methyllysine (MeLys) and the product S-adenosylhomocysteine (AdoHcy) were determined to resolutions of 2.65 and 2.55 Angstrom, respectively. The zeta-methyl group of MeLys is bound to the enzyme via carbon-oxygen hydrogen bonds that play a key role in catalysis. The methyl donor and acceptor are aligned in a linear geometry for S(N)2 nucleophilic transfer of the methyl group during catalysis. Differences in hydrogen bonding between the MeLys epsilon-amino group and Rubisco LSMT and SET7/9 explain why Rubisco LSMT generates multiply methylated Lys, wheras SET7/9 generates only MeLys. C1 NIDDKD, Mol Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Kentucky, Dept Hort, Plant Physiol Biochem Mol Biol Program, Lexington, KY 40546 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NR 48 TC 71 Z9 73 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD JUL PY 2003 VL 10 IS 7 BP 545 EP 552 DI 10.1038/nsb946 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 694GZ UT WOS:000183767400014 PM 12819771 ER PT J AU Frank, RA Galasko, D Hampel, H Hardy, J de Leon, MJ Mehta, PD Rogers, J Siemers, E Trojanowski, JQ AF Frank, RA Galasko, D Hampel, H Hardy, J de Leon, MJ Mehta, PD Rogers, J Siemers, E Trojanowski, JQ TI Biological markers for therapeutic trials in Alzheimer's disease - Proceedings of the biological markers working group; NIA initiative on neuroimaging in Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Review DE Alzheimer's disease; mild cognitive impairment (MCI); biomarkers; surrogate endpoints; disease modification; drug development; dementia; screening; diagnostics; prognostics; enrichment strategy; bioassay; progression; CSF; blood ID AMYLOID PRECURSOR PROTEIN; CEREBROSPINAL-FLUID TAU; MILD COGNITIVE IMPAIRMENT; FIBRILLARY ACIDIC PROTEIN; NEURONAL THREAD PROTEIN; AMYOTROPHIC-LATERAL-SCLEROSIS; INCREASED OXIDATIVE DAMAGE; APOLIPOPROTEIN-E; BETA-PEPTIDE; NEURODEGENERATIVE DISEASES C1 Pharmacia Corp, Peapack, NJ 07977 USA. UCSD, Dept Neurosci, VA Med Ctr, San Diego, CA 92161 USA. Univ Munich, Dept Psychiat, Alzheimer Mem Ctr, D-80336 Munich, Germany. Univ Munich, Geriatr Psychiat Branch, D-80336 Munich, Germany. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. NYU, Sch Med, Ctr Brain Hlth, Dept Psychiat, New York, NY 10016 USA. Inst Basic Res Dev Disabil, Div Immunol, Dept Dev Neurobiol, Staten Isl, NY 10314 USA. Sun Hlth Res Inst, Sun City, AZ 85351 USA. Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA. Univ Penn, Sch Med, Dept Pathol & Lab Med, Inst Aging,Alzheimers Dis Ctr,Ctr Neurodegeneret, Philadelphia, PA 19104 USA. RP Frank, RA (reprint author), Pharmacia Corp, Mailstop 134, Peapack, NJ 07977 USA. RI Hardy, John/C-2451-2009 NR 165 TC 165 Z9 171 U1 1 U2 4 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 JUL-AUG PY 2003 VL 24 IS 4 BP 521 EP 536 DI 10.1016/S0197-4580(03)00002-2 PG 16 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 677HB UT WOS:000182799900001 PM 12714109 ER PT J AU Tyas, SL White, LR Petrovitch, H Ross, GW Foley, DJ Heimovitz, HK Launer, LJ AF Tyas, SL White, LR Petrovitch, H Ross, GW Foley, DJ Heimovitz, HK Launer, LJ TI Mid-life smoking and late-life dementia: the Honolulu-Asia Aging Study SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer's disease; dementia; epidemiology; longitudinal study; elderly; vascular dementia; smoking; risk factors; neuropathology ID JAPANESE-AMERICAN MEN; ALZHEIMERS-DISEASE; RISK; CRITERIA; CALIFORNIA; DIAGNOSIS; NICOTINE; TOBACCO; COHORT; HAWAII AB We studied the association between mid-life smoking and late-life dementia in the Honolulu Heart Program (1965-1971) and follow-up assessment for dementia (1991-1996) of 3734 Japanese-American men (80% of survivors). Neuropathologic data were available for 218 men. Adjusting for age, education and apolipoprotein E (APOE) genotype, the risk of Alzheimer's disease (AD) in smokers increased with pack-years of smoking at medium (odds ratio (OR) = 2.18, 95% confidence interval (CI) = 1.07-4.69) and heavy (OR = 2.40; 95% CI = 1.16-5.17) smoking levels. Very heavy smoking was not associated with AD (OR = 1.08; 95% CI = 0.43-2.63). Findings were similar when AD cases included those with cerebrovascular disease and for all dementias combined. Adjustment for cardiovascular and respiratory factors or stratification by apolipoprotein E genotype did not change these associations. In an autopsied subsample, the number of neuritic plaques increased with amount smoked. This study suggests that amount smoked is associated with an increasing risk of AD and Alzheimer-type neuropathology up to heavy smoking levels. The lack of association in very heavy smokers may be due to a hardy survivor effect. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Univ Kentucky, Kentucky Sch Publ Hlth, Sanders Brown Ctr Aging, Lexington, KY 40506 USA. Pacific Hlth Res Inst, Honolulu, HI USA. Dept Vet Affairs, Honolulu, HI USA. NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD USA. US Bur Census, Planning Res & Evaluat Div, Washington, DC USA. RP Tyas, SL (reprint author), Univ Kentucky, Kentucky Sch Publ Hlth, Sanders Brown Ctr Aging, 203B Sanders Brown Bldg, Lexington, KY 40506 USA. FU NHLBI NIH HHS [N01-HC-05102]; NIA NIH HHS [5-P50-AG05144, 1-P01-AG05119, N01-AG-4-2149] NR 32 TC 109 Z9 115 U1 5 U2 7 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 JUL-AUG PY 2003 VL 24 IS 4 BP 589 EP 596 AR PII S0197-4580(02)00156-2 DI 10.1016/S0197-4580(02)00156-2 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 677HB UT WOS:000182799900008 PM 12714116 ER PT J AU Kinney, JW Starosta, G Crawley, JN AF Kinney, JW Starosta, G Crawley, JN TI Central galanin administration blocks consolidation of spatial learning SO NEUROBIOLOGY OF LEARNING AND MEMORY LA English DT Article DE galanin; long-term memory; consolidation; adenylate cyclase; forskolin; Alzheimer's disease ID LONG-TERM-MEMORY; DEPENDENT PROTEIN-KINASE; SPONTANEOUS-ALTERNATION PERFORMANCE; RECEPTOR-MEDIATED INHIBITION; RAT VENTRAL HIPPOCAMPUS; NONMATCHING-TO-SAMPLE; ADENYLATE-CYCLASE; ALZHEIMERS-DISEASE; TRANSGENIC MICE; ACETYLCHOLINE-RELEASE AB Galanin is a neuropeptide that inhibits the evoked release of several neurotransmitters, inhibits the activation of intracellular second messengers, and produces deficits in a variety of rodent learning and memory tasks. To evaluate the actions of galanin on encoding, consolidation, and storage/retrieval, galanin was acutely administered to Sprague-Dawley rats at time points before and after training trials in the Morris water maze. Intraventricular administration of galanin up to 3 h after subjects had completed daily training trials in the Morris water task impaired performance on the probe trial, indicating that galanin-blocked consolidation. Pretreatment with an adenylate cyclase activator, forskolin, prevented the deficits in distal cue learning produced by galanin. Dideoxyforskolin, an inactive analog of forskolin, had no effect. These results provide the first evidence that galanin interferes with long-term memory consolidation processes. A potential mechanism by which galanin produces this impairment may involve the inhibition of adenylate cyclase activity, leading to inhibition of downstream molecular events that are necessary for consolidation of long-term memory. Published by Elsevier Science (USA). C1 NIMH, Sect Behav Genom, Galanin Inhibits Consolidat, Bethesda, MD 20892 USA. RP Kinney, JW (reprint author), Scripps Res Inst, 10550 N Torrey Pines Rd,SR307, La Jolla, CA 92037 USA. NR 81 TC 28 Z9 28 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 1074-7427 J9 NEUROBIOL LEARN MEM JI Neurobiol. Learn. Mem. PD JUL PY 2003 VL 80 IS 1 BP 42 EP 54 DI 10.1016/S1074-7427(03)00023-6 PG 13 WC Behavioral Sciences; Neurosciences; Psychology; Psychology, Multidisciplinary SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 686UN UT WOS:000183339500005 PM 12737933 ER PT J AU Bolla, KI Eldreth, DA London, ED Kiehl, KA Mouratidis, M Contoreggi, C Matochik, JA Kurian, V Cadet, JL Kimes, AS Funderburk, FR Ernst, M AF Bolla, KI Eldreth, DA London, ED Kiehl, KA Mouratidis, M Contoreggi, C Matochik, JA Kurian, V Cadet, JL Kimes, AS Funderburk, FR Ernst, M TI Orbitofrontal cortex dysfunction in abstinent cocaine abusers performing a decision-making task SO NEUROIMAGE LA English DT Article ID VENTROMEDIAL PREFRONTAL CORTEX; ACTIVATION; ADDICTION; RESPONSES; DEFICITS; SCHIZOPHRENIA; CONSEQUENCES; INVOLVEMENT; CINGULATE; CORTICES AB Cocaine abusers demonstrate faulty decision-making as manifested by their inability to discontinue self-destructive drug-seeking behaviors. The orbitofrontal cortex (OFC) plays an important role in decision-making. In this preliminary study we tested whether 25-day-abstinent cocaine abusers show alterations in normalized cerebral blood flow (rCBF) in the OFC using PET with 15 0 during the Iowa Gambling Task (a decision-making task). This task measures the ability to weigh short-term rewards against long-term losses. A control task matched the sensorimotor aspects of the task but did not require decision-making. Cocaine abusers (N = 13) showed greater activation during performance of the Iowa Gambling Task in the right OFC and less activation in the right dorsolateral prefrontal cortex (DLPFC) and left medial prefrontal cortex (MPFC) compared to a control group (N = 13). Better Iowa Gambling Task performance was associated with greater activation in the right OFC in both groups. Also, the amount of cocaine used (grams/week) prior to the 25 days of enforced abstinence was negatively correlated with activation in the left OFC. Greater activation in the OFC in cocaine abusers compared to a control group may reflect differences in the anticipation of reward while less activation in the DLPFC and MPFC may reflect differences in planning and working memory. These findings suggest that cocaine abusers show persistent functional abnormalities in prefrontal neural networks involved in decision-making and these effects are related to cocaine abuse. Compromised decision-making could contribute to the development of addiction and undermine attempts at abstinence. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat, Los Angeles, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Biobehav Sci, Los Angeles, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA USA. Hartford Hosp, Inst Living, Hartford, CT 06115 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. NIDA, Neuroimaging Res Branch, DHSS, NIH,Intramural Res Program, Baltimore, MD USA. NIDA, Mol Neuropsychiat Branch, DHSS, NIH,Intramural Res Program, Baltimore, MD USA. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Bolla, KI (reprint author), Johns Hopkins Bayview Med Ctr, Dept Neurol, 4940 Eastern Ave, Baltimore, MD 21224 USA. FU NCRR NIH HHS [M01 RR002719, M01 RR02719]; NIDA NIH HHS [DA 11426, R01 DA011426-02]; NIMH NIH HHS [R01 MH085010] NR 46 TC 314 Z9 330 U1 5 U2 23 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL PY 2003 VL 19 IS 3 BP 1085 EP 1094 DI 10.1016/S1053-8119(03)00113-7 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 706ZR UT WOS:000184485400054 PM 12880834 ER EF